Case-Based Review

CASE Paranoid and hallucinating
Ms. S, age 30, is an unmarried graduate stu­dent who has been given a diagnosis of schizophrenia, paranoid type, during inpatient hospitalization that was prompted by impair­ment in school functioning (difficulty turning in assignments, poor concentration, making careless mistakes on tests), paranoid delu­sions, and multisensory hallucinations. She says that her roommate and classmates are working together to make her leave school, and recalls seeing them “snare and smirk” as she passes by. Ms. S says that she feels her classmates are calling her names and talking badly about her as soon as she is out of sight.

Ms. S is antipsychotic-naïve and has a base­line body mass index of 17.8 kg/m², indicat­ing that she is underweight. We believe that olanzapine, 20 mg/d, is a good initial treat­ment because of its propensity for weight gain; however, she experiences only marginal improvement. Ms. S does not have health insurance, and cannot afford a brand name medication; therefore, she is cross-tapered to perphenazine, 8 mg, and benzatropine, 0.5 mg, both taken twice daily (olanzapine was not available as a generic at the time).

At discharge, Ms. S does not report any hallucinatory experiences, but is guarded, voices suspicions about the treatment team, and asks “What are they doing with all my blood?”—referring to blood draws for labora­tory testing during hospitalization.

As an outpatient, Ms. S is continued on the same medications until she has to be switched because she cannot afford the out-of-pocket cost of the antipsychotic, perphenazine ($80 a month). Clozapine is recommended, but Ms. S refuses because of the mandatory weekly blood monitoring. She briefly tries fluphen­azine, 2.5 mg/d, but it is discontinued because of malaise and lightheadedness without extrapyramidal symptoms.

Clozapine is again recommended, but Ms. S remains suspicious of the necessary blood draws and refuses. After several trials of antipsychotics, Ms. S starts paliperidone using samples from the clinic, titrated to 6 mg at bedtime. Once tolerance and therapeutic improvement are observed, she is continued on this medication through the manufactur­er’s patient assistance program.

Within 3 months, Ms. S and her fam­ily find that she has improved signifi­cantly. She no longer reports hallucinatory experiences, is less guarded during ses­sions, and has followed through with paid and volunteer job applications and inter­views. She soon finds a job teaching entry-level classes at a community college and is looking forward to a summer trip abroad.

During a follow-up appointment, Ms. S reports that she had missed 2 consecutive menstrual cycles without galactorrhea or fractures. A urine pregnancy test is negative; the prolactin level is 72 μg/L.

Hyperprolactinemia in women is defined as a plasma prolactin level of 

a)>2.5 µg/L
b) >5 µg/L
c) >10 µg/L
d) >20 µg/L
e) >25 µg/L


The authors’ observations
A prolactin level >25 μg/L is considered abnormal.¹ A level of >250 μg/L may identify a prolactinoma; however, levels >200 μg/L have been observed in patients taking an antipsychotic.¹ Given Ms. S’s clinically significant elevation of prolactin, she is referred to her primary care physi­cian. We decide to augment her regimen with aripiprazole, 10 mg/d, because this drug has been noted to help in cases of hyperprolactinemia associated with other antipsychotics.^2,3

Prolactin serves several roles in the body, including but not limited to lacta­tion, sexual gratification, proliferation of oligodendrocyte precursor cells, surfac­tant synthesis of fetal lungs at the end of pregnancy, and neurogenesis in maternal and fetal brains (Figure 1 and Figure 2). A 2004 review reported secondary amenor­rhea, galactorrhea, and osteopenia as com­mon symptoms of hyperprolactinemia.⁵ Hyperprolactinemia has been seen with most antipsychotics, both typical and atypical. Although several studies docu­ment prolactin elevation with risperidone, fewer have examined the active metabolite (9-hydroxyrisperidone) paliperidone.^5-7

a) menstrual disturbance
b) galactorrhea
c) breast engorgement
d) sexual dysfunction
e) all of the above


The authors’ observations
Acutely, hyperprolactinemia can cause menstrual abnormalities, decreased libido, breast engorgement, galactorrhea, and sexual dysfunction in women.⁸ In men, the most common symptoms of hyperprolac­tinemia are loss of interest in sex, erectile dysfunction, infertility, and gynecomas­tia. Osteoporosis has been associated with chronic elevation of the prolactin level⁸ (Table).

TREATMENT Adjunctive aripiprazole
After 8 weeks of adjunctive aripiprazole, Ms. S’s prolactin level decreases to 42 μg/L, but menses do not return. Because her family and primary care providers are eager to have the prolactin level return to nor­mal, reducing her risk of complications, we decide to decrease paliperidone to 3 mg at bedtime.
Eight weeks later, Ms. S shows functional improvement. A repeat test of prolactin is 24 μg/L; she reports a 4-day period of spotting 1 week ago. One month later, the prolactin level is 21 μg/L, and she reports having a normal menstrual period. She continues treatment with paliperidone, 3 mg/d, and aripiprazole, 10 mg/d, experiences regular menses, and continues teaching.


Pharmacotherapy of hyperprolactinemia includes

a) haloperidol
b) perphenazine
c) bromocriptine
d) olanzapine
e) risperidone

The authors' observations
Our goal in treating Ms. S was to address her schizophrenia symptoms and improve her overall functioning. Often, finding an effective treatment can be challeng­ing, and there is little evidence to support the efficacy of one antipsychotic over another.⁴ In Ms. S’s case, our care was stymied by the cost of medication, chal­lenges related to delusions intrinsic to the illness (she refused clozapine because of required blood draws), and adverse effects. When Ms. S developed amenorrhea while taking paliperidone— the only medication that showed sig­nificant improvement in her psychotic symptoms—our goal was to maintain her functional level without significant long-term adverse effects.

Managing hyperprolactinemia
Management of iatrogenic hyperprolac­tinemia includes decreasing the dosage of the offending agent, using a prolactin-sparing antipsychotic, or initiating a dopa­mine agonist, such as bromocriptine or cabergoline, in addition to an antipsy­chotic.^1,4 Aripiprazole is considered to be a prolactin-sparing agent because of its pro­pensity to increase the prolactin level to less of a degree than what is seen with other antipsychotics; in fact, it has been shown to reduce an elevated prolactin level.^9-11

Most typical and atypical antipsychotics are dopamine—specifically D2—receptor antagonists. These antipsychotics prevent dopamine from binding to the D2 recep­tor and from inhibiting prolactin release, therefore causing hyperprolactinemia. Aripiprazole differs from other antipsychot­ics: It is a partial D2 receptor agonist with high affinity, and therefore suppresses pro­lactin release.⁸ In a randomized controlled trial, aripiprazole had a lower rate of prolac­tin elevation compared with placebo.¹²

Aripiprazole’s ability to reduce an elevated prolactin level caused by other antipsychotics has been demonstrated in several studies with haloperidol,¹³ olan­zapine,^14,15 and risperidone.^15-17 There has been 1 case report,18 but no controlled stud­ies, of aripiprazole being used to decrease the prolactin level in patients treated with paliperidone.

In Ms. S’s case, adding aripiprazole, 10 mg/d, reduced her prolactin level by approximately 50%. Because several stud­ies have shown that adjunctive aripipra­zole with a D2 antagonist normalizes the prolactin level,¹⁹ it is reasonable to con­clude that adding aripiprazole facilitated reduction of her prolactin level and might have continued to do so if given more time. Regrettably, because of patient and fam­ily concerns, paliperidone was reduced before this could be determined. It is unclear whether normalization of Ms. S’s prolactin level and return of her menstrual cycle was caused by adding aripiprazole or by reducing the dosage of paliperidone.

Although additional randomized con­trolled trials should be conducted on the utility of this approach, it is reasonable to consider augmentation with aripiprazole when treating a patient who is stable on an antipsychotic, including paliperidone, but has developed hyperprolactinemia secondary to treatment.

BOTTOM LINE
Hyperprolactinemia is a relatively common, underreported side effect of both typical and atypical antipsychotics. Paliperidone and risperidone have been shown to have the highest risk among the atypical antipsychotics; aripiprazole has the lowest risk. Treatment of an elevated prolactin level should include reduction or discontinuation of the offending agent and augmentation with aripiprazole.

Related Resources
• Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review [published online March 28, 2014]. CNS Drugs. doi: 10.1007/s40263-014-0157-3.
• Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One. 2013;8(8):e70179. doi: 10.1371/journal.pone.0070179.

Drug Brand Names
Aripiprazole • Abilify               Haloperidol • Haldol
Benzatropine • Cogentin         Olanzapine • Zyprexa
Bromocriptine • Parlodel         Paliperidone • Invega
Cabergoline • Dostinex           Perphenazine • Trilafon
Clozapine • Clozaril                Risperidone • Risperdal
Fluphenazine • Prolixin

DisclosureThe authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Paranoid and hallucinating
Ms. S, age 30, is an unmarried graduate stu­dent who has been given a diagnosis of schizophrenia, paranoid type, during inpatient hospitalization that was prompted by impair­ment in school functioning (difficulty turning in assignments, poor concentration, making careless mistakes on tests), paranoid delu­sions, and multisensory hallucinations. She says that her roommate and classmates are working together to make her leave school, and recalls seeing them “snare and smirk” as she passes by. Ms. S says that she feels her classmates are calling her names and talking badly about her as soon as she is out of sight.

Ms. S is antipsychotic-naïve and has a base­line body mass index of 17.8 kg/m², indicat­ing that she is underweight. We believe that olanzapine, 20 mg/d, is a good initial treat­ment because of its propensity for weight gain; however, she experiences only marginal improvement. Ms. S does not have health insurance, and cannot afford a brand name medication; therefore, she is cross-tapered to perphenazine, 8 mg, and benzatropine, 0.5 mg, both taken twice daily (olanzapine was not available as a generic at the time).

At discharge, Ms. S does not report any hallucinatory experiences, but is guarded, voices suspicions about the treatment team, and asks “What are they doing with all my blood?”—referring to blood draws for labora­tory testing during hospitalization.

As an outpatient, Ms. S is continued on the same medications until she has to be switched because she cannot afford the out-of-pocket cost of the antipsychotic, perphenazine ($80 a month). Clozapine is recommended, but Ms. S refuses because of the mandatory weekly blood monitoring. She briefly tries fluphen­azine, 2.5 mg/d, but it is discontinued because of malaise and lightheadedness without extrapyramidal symptoms.

Clozapine is again recommended, but Ms. S remains suspicious of the necessary blood draws and refuses. After several trials of antipsychotics, Ms. S starts paliperidone using samples from the clinic, titrated to 6 mg at bedtime. Once tolerance and therapeutic improvement are observed, she is continued on this medication through the manufactur­er’s patient assistance program.

Within 3 months, Ms. S and her fam­ily find that she has improved signifi­cantly. She no longer reports hallucinatory experiences, is less guarded during ses­sions, and has followed through with paid and volunteer job applications and inter­views. She soon finds a job teaching entry-level classes at a community college and is looking forward to a summer trip abroad.

During a follow-up appointment, Ms. S reports that she had missed 2 consecutive menstrual cycles without galactorrhea or fractures. A urine pregnancy test is negative; the prolactin level is 72 μg/L.

Hyperprolactinemia in women is defined as a plasma prolactin level of 

a)>2.5 µg/L
b) >5 µg/L
c) >10 µg/L
d) >20 µg/L
e) >25 µg/L


The authors’ observations
A prolactin level >25 μg/L is considered abnormal.¹ A level of >250 μg/L may identify a prolactinoma; however, levels >200 μg/L have been observed in patients taking an antipsychotic.¹ Given Ms. S’s clinically significant elevation of prolactin, she is referred to her primary care physi­cian. We decide to augment her regimen with aripiprazole, 10 mg/d, because this drug has been noted to help in cases of hyperprolactinemia associated with other antipsychotics.^2,3

Prolactin serves several roles in the body, including but not limited to lacta­tion, sexual gratification, proliferation of oligodendrocyte precursor cells, surfac­tant synthesis of fetal lungs at the end of pregnancy, and neurogenesis in maternal and fetal brains (Figure 1 and Figure 2). A 2004 review reported secondary amenor­rhea, galactorrhea, and osteopenia as com­mon symptoms of hyperprolactinemia.⁵ Hyperprolactinemia has been seen with most antipsychotics, both typical and atypical. Although several studies docu­ment prolactin elevation with risperidone, fewer have examined the active metabolite (9-hydroxyrisperidone) paliperidone.^5-7

a) menstrual disturbance
b) galactorrhea
c) breast engorgement
d) sexual dysfunction
e) all of the above


The authors’ observations
Acutely, hyperprolactinemia can cause menstrual abnormalities, decreased libido, breast engorgement, galactorrhea, and sexual dysfunction in women.⁸ In men, the most common symptoms of hyperprolac­tinemia are loss of interest in sex, erectile dysfunction, infertility, and gynecomas­tia. Osteoporosis has been associated with chronic elevation of the prolactin level⁸ (Table).

TREATMENT Adjunctive aripiprazole
After 8 weeks of adjunctive aripiprazole, Ms. S’s prolactin level decreases to 42 μg/L, but menses do not return. Because her family and primary care providers are eager to have the prolactin level return to nor­mal, reducing her risk of complications, we decide to decrease paliperidone to 3 mg at bedtime.
Eight weeks later, Ms. S shows functional improvement. A repeat test of prolactin is 24 μg/L; she reports a 4-day period of spotting 1 week ago. One month later, the prolactin level is 21 μg/L, and she reports having a normal menstrual period. She continues treatment with paliperidone, 3 mg/d, and aripiprazole, 10 mg/d, experiences regular menses, and continues teaching.


Pharmacotherapy of hyperprolactinemia includes

a) haloperidol
b) perphenazine
c) bromocriptine
d) olanzapine
e) risperidone

The authors' observations
Our goal in treating Ms. S was to address her schizophrenia symptoms and improve her overall functioning. Often, finding an effective treatment can be challeng­ing, and there is little evidence to support the efficacy of one antipsychotic over another.⁴ In Ms. S’s case, our care was stymied by the cost of medication, chal­lenges related to delusions intrinsic to the illness (she refused clozapine because of required blood draws), and adverse effects. When Ms. S developed amenorrhea while taking paliperidone— the only medication that showed sig­nificant improvement in her psychotic symptoms—our goal was to maintain her functional level without significant long-term adverse effects.

Managing hyperprolactinemia
Management of iatrogenic hyperprolac­tinemia includes decreasing the dosage of the offending agent, using a prolactin-sparing antipsychotic, or initiating a dopa­mine agonist, such as bromocriptine or cabergoline, in addition to an antipsy­chotic.^1,4 Aripiprazole is considered to be a prolactin-sparing agent because of its pro­pensity to increase the prolactin level to less of a degree than what is seen with other antipsychotics; in fact, it has been shown to reduce an elevated prolactin level.^9-11

Most typical and atypical antipsychotics are dopamine—specifically D2—receptor antagonists. These antipsychotics prevent dopamine from binding to the D2 recep­tor and from inhibiting prolactin release, therefore causing hyperprolactinemia. Aripiprazole differs from other antipsychot­ics: It is a partial D2 receptor agonist with high affinity, and therefore suppresses pro­lactin release.⁸ In a randomized controlled trial, aripiprazole had a lower rate of prolac­tin elevation compared with placebo.¹²

Aripiprazole’s ability to reduce an elevated prolactin level caused by other antipsychotics has been demonstrated in several studies with haloperidol,¹³ olan­zapine,^14,15 and risperidone.^15-17 There has been 1 case report,18 but no controlled stud­ies, of aripiprazole being used to decrease the prolactin level in patients treated with paliperidone.

In Ms. S’s case, adding aripiprazole, 10 mg/d, reduced her prolactin level by approximately 50%. Because several stud­ies have shown that adjunctive aripipra­zole with a D2 antagonist normalizes the prolactin level,¹⁹ it is reasonable to con­clude that adding aripiprazole facilitated reduction of her prolactin level and might have continued to do so if given more time. Regrettably, because of patient and fam­ily concerns, paliperidone was reduced before this could be determined. It is unclear whether normalization of Ms. S’s prolactin level and return of her menstrual cycle was caused by adding aripiprazole or by reducing the dosage of paliperidone.

Although additional randomized con­trolled trials should be conducted on the utility of this approach, it is reasonable to consider augmentation with aripiprazole when treating a patient who is stable on an antipsychotic, including paliperidone, but has developed hyperprolactinemia secondary to treatment.

BOTTOM LINE
Hyperprolactinemia is a relatively common, underreported side effect of both typical and atypical antipsychotics. Paliperidone and risperidone have been shown to have the highest risk among the atypical antipsychotics; aripiprazole has the lowest risk. Treatment of an elevated prolactin level should include reduction or discontinuation of the offending agent and augmentation with aripiprazole.

Related Resources
• Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review [published online March 28, 2014]. CNS Drugs. doi: 10.1007/s40263-014-0157-3.
• Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One. 2013;8(8):e70179. doi: 10.1371/journal.pone.0070179.

Drug Brand Names
Aripiprazole • Abilify               Haloperidol • Haldol
Benzatropine • Cogentin         Olanzapine • Zyprexa
Bromocriptine • Parlodel         Paliperidone • Invega
Cabergoline • Dostinex           Perphenazine • Trilafon
Clozapine • Clozaril                Risperidone • Risperdal
Fluphenazine • Prolixin

DisclosureThe authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Paranoid and hallucinating
Ms. S, age 30, is an unmarried graduate stu­dent who has been given a diagnosis of schizophrenia, paranoid type, during inpatient hospitalization that was prompted by impair­ment in school functioning (difficulty turning in assignments, poor concentration, making careless mistakes on tests), paranoid delu­sions, and multisensory hallucinations. She says that her roommate and classmates are working together to make her leave school, and recalls seeing them “snare and smirk” as she passes by. Ms. S says that she feels her classmates are calling her names and talking badly about her as soon as she is out of sight.

Ms. S is antipsychotic-naïve and has a base­line body mass index of 17.8 kg/m², indicat­ing that she is underweight. We believe that olanzapine, 20 mg/d, is a good initial treat­ment because of its propensity for weight gain; however, she experiences only marginal improvement. Ms. S does not have health insurance, and cannot afford a brand name medication; therefore, she is cross-tapered to perphenazine, 8 mg, and benzatropine, 0.5 mg, both taken twice daily (olanzapine was not available as a generic at the time).

At discharge, Ms. S does not report any hallucinatory experiences, but is guarded, voices suspicions about the treatment team, and asks “What are they doing with all my blood?”—referring to blood draws for labora­tory testing during hospitalization.

As an outpatient, Ms. S is continued on the same medications until she has to be switched because she cannot afford the out-of-pocket cost of the antipsychotic, perphenazine ($80 a month). Clozapine is recommended, but Ms. S refuses because of the mandatory weekly blood monitoring. She briefly tries fluphen­azine, 2.5 mg/d, but it is discontinued because of malaise and lightheadedness without extrapyramidal symptoms.

Clozapine is again recommended, but Ms. S remains suspicious of the necessary blood draws and refuses. After several trials of antipsychotics, Ms. S starts paliperidone using samples from the clinic, titrated to 6 mg at bedtime. Once tolerance and therapeutic improvement are observed, she is continued on this medication through the manufactur­er’s patient assistance program.

Within 3 months, Ms. S and her fam­ily find that she has improved signifi­cantly. She no longer reports hallucinatory experiences, is less guarded during ses­sions, and has followed through with paid and volunteer job applications and inter­views. She soon finds a job teaching entry-level classes at a community college and is looking forward to a summer trip abroad.

During a follow-up appointment, Ms. S reports that she had missed 2 consecutive menstrual cycles without galactorrhea or fractures. A urine pregnancy test is negative; the prolactin level is 72 μg/L.

Hyperprolactinemia in women is defined as a plasma prolactin level of 

a)>2.5 µg/L
b) >5 µg/L
c) >10 µg/L
d) >20 µg/L
e) >25 µg/L


The authors’ observations
A prolactin level >25 μg/L is considered abnormal.¹ A level of >250 μg/L may identify a prolactinoma; however, levels >200 μg/L have been observed in patients taking an antipsychotic.¹ Given Ms. S’s clinically significant elevation of prolactin, she is referred to her primary care physi­cian. We decide to augment her regimen with aripiprazole, 10 mg/d, because this drug has been noted to help in cases of hyperprolactinemia associated with other antipsychotics.^2,3

Prolactin serves several roles in the body, including but not limited to lacta­tion, sexual gratification, proliferation of oligodendrocyte precursor cells, surfac­tant synthesis of fetal lungs at the end of pregnancy, and neurogenesis in maternal and fetal brains (Figure 1 and Figure 2). A 2004 review reported secondary amenor­rhea, galactorrhea, and osteopenia as com­mon symptoms of hyperprolactinemia.⁵ Hyperprolactinemia has been seen with most antipsychotics, both typical and atypical. Although several studies docu­ment prolactin elevation with risperidone, fewer have examined the active metabolite (9-hydroxyrisperidone) paliperidone.^5-7

a) menstrual disturbance
b) galactorrhea
c) breast engorgement
d) sexual dysfunction
e) all of the above


The authors’ observations
Acutely, hyperprolactinemia can cause menstrual abnormalities, decreased libido, breast engorgement, galactorrhea, and sexual dysfunction in women.⁸ In men, the most common symptoms of hyperprolac­tinemia are loss of interest in sex, erectile dysfunction, infertility, and gynecomas­tia. Osteoporosis has been associated with chronic elevation of the prolactin level⁸ (Table).

TREATMENT Adjunctive aripiprazole
After 8 weeks of adjunctive aripiprazole, Ms. S’s prolactin level decreases to 42 μg/L, but menses do not return. Because her family and primary care providers are eager to have the prolactin level return to nor­mal, reducing her risk of complications, we decide to decrease paliperidone to 3 mg at bedtime.
Eight weeks later, Ms. S shows functional improvement. A repeat test of prolactin is 24 μg/L; she reports a 4-day period of spotting 1 week ago. One month later, the prolactin level is 21 μg/L, and she reports having a normal menstrual period. She continues treatment with paliperidone, 3 mg/d, and aripiprazole, 10 mg/d, experiences regular menses, and continues teaching.


Pharmacotherapy of hyperprolactinemia includes

a) haloperidol
b) perphenazine
c) bromocriptine
d) olanzapine
e) risperidone

The authors' observations
Our goal in treating Ms. S was to address her schizophrenia symptoms and improve her overall functioning. Often, finding an effective treatment can be challeng­ing, and there is little evidence to support the efficacy of one antipsychotic over another.⁴ In Ms. S’s case, our care was stymied by the cost of medication, chal­lenges related to delusions intrinsic to the illness (she refused clozapine because of required blood draws), and adverse effects. When Ms. S developed amenorrhea while taking paliperidone— the only medication that showed sig­nificant improvement in her psychotic symptoms—our goal was to maintain her functional level without significant long-term adverse effects.

Managing hyperprolactinemia
Management of iatrogenic hyperprolac­tinemia includes decreasing the dosage of the offending agent, using a prolactin-sparing antipsychotic, or initiating a dopa­mine agonist, such as bromocriptine or cabergoline, in addition to an antipsy­chotic.^1,4 Aripiprazole is considered to be a prolactin-sparing agent because of its pro­pensity to increase the prolactin level to less of a degree than what is seen with other antipsychotics; in fact, it has been shown to reduce an elevated prolactin level.^9-11

Most typical and atypical antipsychotics are dopamine—specifically D2—receptor antagonists. These antipsychotics prevent dopamine from binding to the D2 recep­tor and from inhibiting prolactin release, therefore causing hyperprolactinemia. Aripiprazole differs from other antipsychot­ics: It is a partial D2 receptor agonist with high affinity, and therefore suppresses pro­lactin release.⁸ In a randomized controlled trial, aripiprazole had a lower rate of prolac­tin elevation compared with placebo.¹²

Aripiprazole’s ability to reduce an elevated prolactin level caused by other antipsychotics has been demonstrated in several studies with haloperidol,¹³ olan­zapine,^14,15 and risperidone.^15-17 There has been 1 case report,18 but no controlled stud­ies, of aripiprazole being used to decrease the prolactin level in patients treated with paliperidone.

In Ms. S’s case, adding aripiprazole, 10 mg/d, reduced her prolactin level by approximately 50%. Because several stud­ies have shown that adjunctive aripipra­zole with a D2 antagonist normalizes the prolactin level,¹⁹ it is reasonable to con­clude that adding aripiprazole facilitated reduction of her prolactin level and might have continued to do so if given more time. Regrettably, because of patient and fam­ily concerns, paliperidone was reduced before this could be determined. It is unclear whether normalization of Ms. S’s prolactin level and return of her menstrual cycle was caused by adding aripiprazole or by reducing the dosage of paliperidone.

Although additional randomized con­trolled trials should be conducted on the utility of this approach, it is reasonable to consider augmentation with aripiprazole when treating a patient who is stable on an antipsychotic, including paliperidone, but has developed hyperprolactinemia secondary to treatment.

BOTTOM LINE
Hyperprolactinemia is a relatively common, underreported side effect of both typical and atypical antipsychotics. Paliperidone and risperidone have been shown to have the highest risk among the atypical antipsychotics; aripiprazole has the lowest risk. Treatment of an elevated prolactin level should include reduction or discontinuation of the offending agent and augmentation with aripiprazole.

Related Resources
• Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review [published online March 28, 2014]. CNS Drugs. doi: 10.1007/s40263-014-0157-3.
• Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One. 2013;8(8):e70179. doi: 10.1371/journal.pone.0070179.

Drug Brand Names
Aripiprazole • Abilify               Haloperidol • Haldol
Benzatropine • Cogentin         Olanzapine • Zyprexa
Bromocriptine • Parlodel         Paliperidone • Invega
Cabergoline • Dostinex           Perphenazine • Trilafon
Clozapine • Clozaril                Risperidone • Risperdal
Fluphenazine • Prolixin

DisclosureThe authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Self Signing
Mrs. H, a 47-year-old, deaf, African American woman, is brought into the emergency room because she is becoming increasingly withdrawn and is signing to herself. She was hospitalized more than 10 years ago after de­veloping psychotic symptoms and received a diagnosis of psychotic disorder, not otherwise specified. She was treated with olanzapine, 10 mg/d, and valproic acid, 1,000 mg/d, but she has not seen a psychiatrist or taken any psy­chotropics in 8 years. Upon admission to the inpatient psychiatric unit, Mrs. H reports, through an American Sign Language (ASL) interpreter, that she has had “problems with her parents” and with “being fair” and that she is 18 months pregnant. Urine pregnancy test is negative. Mrs. H also reports that her mother is pregnant. She indicates that it is difficult for her to describe what she is try­ing to say and that it is difficult to be deaf. 

She endorses “very strong” racing thoughts, which she first states have been present for 15 years, then reports it has been 20 months. She endorses high-energy levels, feeling like there is “work to do,” and poor sleep. However, when asked, she indicates that she sleeps for 15 hours a day.

Which is critical when conducting a psychiatric assessment for a deaf patient?

   a) rely only on the ASL interpreter
   b) inquire about the patient’s communica­tion preferences
   c) use written language to communicate instead of speech
   d) use a family member as interpreter

The authors’ observations
Mental health assessment of a deaf a patient involves a unique set of challenges and requires a specialized skill set for mental health practitioners—a skill set that is not routinely covered in psychiatric training programs.

a We use the term “deaf” to describe patients who have severe hearing loss. Other terms, such as “hearing impaired,” might be considered pejorative in the Deaf community. The term “Deaf” (capitalized) refers to Deaf culture and community, which deaf patients may or may not identify with.

Deafness history
It is important to assess the cause of deafness,^1,2 if known, and its age of onset (Table 1). A person is considered to be pre­lingually deaf if hearing loss was diagnosed before age 3.² Clinicians should establish the patient’s communication preferences (use of assistive devices or interpreters or preference for lip reading), home commu­nication dynamic,² and language fluency level.^1-3 Ask the patient if she attended a specialized school for the deaf and, if so, if there was an emphasis on oral communica­tion or signing.²

HISTORY Conflicting reports
Mrs. H reports that she has been deaf since age 9, and that she learned sign language in India, where she became the “star king.” Mrs. H states that she then moved to the United States where she went to a school for the deaf. When asked if her family is able to communicate with her in sign language, she nods and indicates that they speak to her in “African and Indian.”

Mrs. H’s husband, who is hearing, says that Mrs. H is congenitally deaf, and was raised in the Midwestern United States where she at­tended a specialized school for the deaf. Mr. H and his 2 adult sons are hearing but commu­nicate with Mrs. H in basic ASL. He states that Mrs. H sometimes uses signs that he and his sons cannot interpret. In addition to increased self-preoccupation and self-signing, Mrs. H has become more impulsive.

What are limitations of the mental status examination when evaluating a deaf patient?

   a) facial expressions have a specific linguis­tic function in ASL
   b) there is no differentiation in the mental status exam of deaf patients from that of hearing patients
   c) the Mini-Mental State Examination (MMSE) is a validated tool to assess cogni­tion in deaf patients
   d) the clinician should not rely on the in­terpreter to assist with the mental status examination

The authors’ observation
Performing a mental status examination of a deaf patient without recognizing some of the challenges inherent to this task can lead to misleading findings. For example, sign­ing and gesturing can give the clinician an impression of psychomotor agitation.² What appears to be socially withdrawn behavior might be a reaction to the patient’s inability to communicate with others.^2,3 Social skills may be affected by language deprivation, if present.³ In ASL, facial expressions have specific linguistic functions in addition to representing emotions,² and can affect the meaning of the sign used. An exaggerated or intense facial expression with the sign “quiet,” for example, usually means “very quiet.”⁴ In assessing cognition, the MMSE is not available in ASL and has not been vali­dated in deaf patients.⁵ Also, deaf people have reduced access to information, and a lack of knowledge does not necessarily cor­relate with low IQ.²

The interpreter’s role
An ASL interpreter can aid in assessing a deaf patient’s communication skills. The interpreter can help with a thorough lan­guage evaluation^1,6 and provide information about socio-cultural norms in the Deaf community.⁷ Using an ASL interpreter with special training in mental health^1,3,6,7 is im­portant to accurately diagnose thought dis­orders in deaf patients.¹

EVALUATION Mental status exam
Mrs. H is poorly groomed and is wearing a pink housecoat, with her hair in disarray. She seems to be distracted by something next to the in­terpreter, because her eyes keep roving in this direction. She has moderate psychomotor agi­tation, based on the rapidity of her signing and gesturing. Mrs. H makes indecipherable vocal­izations while signing, often loud and with an urgent quality. Her affect is elevated and ex­pansive. She is not oriented to place or time and when asked where she is, signs, “many times, every day, 6-9-9, 2-5, more trouble…”

The ASL interpreter notes that Mrs. H signs so quickly that only about one-half of her signs are interpretable. Mrs. H’s grammar is not always correct and that her syntax is, at times, inappro­priate. Mrs. H’s letters are difficult to interpret because she often starts and concludes a word with a clear sign, but the intervening letters are rapid and uninterpretable. She also uses several non-alphabet signs that cannot be in­terpreted (approximately 10% to 15% of signs) and repeats signs without clear context, such as “nothing off.” Mrs. H can pause to clarify for the interpreter at the beginning of the interview but is not able to do so by the end of the interview.

How does assessment of psychosis differ when evaluating deaf patients?

   a) language dysfluency must be carefully differentiated from a thought disorder
   b) signing to oneself does not necessarily indicate a response to internal stimuli
   c) norms in Deaf culture might be miscon­strued as delusions
   d) all of the above

The authors’ observations
The prevalence of psychotic disorders among deaf patients is unknown.⁸ Although older studies have reported an increased prevalence of psychotic disorders among deaf patients, these studies suffer from methodological problems.¹ Other studies are at odds with each other, variably reporting a greater,⁹ equivalent,¹⁰ and lesser incidence of psychotic disorders in deaf psychiatric in­patients.¹¹ Deaf patients with psychotic dis­orders experience delusions, hallucinations, and thought disorders,^1,3 and assessing for these symptoms in deaf patients can present a diagnostic challenge (Table 2).

Delusions are thought to present simi­larly in deaf patients with psychotic dis­orders compared with hearing patients.^1,3 Paranoia may be increased in patients who are postlingually deaf, but has not been as­sociated with prelingual deafness. Deficits in theory of mind related to hearing im­pairment have been thought to contribute to delusions in deaf patients.^1,12

Many deaf patients distrust health care systems and providers,^2,3,13 which may be misinterpreted as paranoia. Poor commu­nication between deaf patients and clini­cians and poor health literacy among deaf patients contribute to feelings of mistrust. Deaf patients often report experiencing prejudice within the health care system, and think that providers lack sufficient knowledge of deafness.¹³ Care must be taken to ensure that Deaf cultural norms are not misinterpreted as delusions.

Hallucinations. How deaf patients expe­rience hallucinations, especially in prelingual deafness, likely is different from hallucinatory experiences of hearing patients.^1,14 Deaf people with psychosis have described ”ideas coming into one’s head” and an almost “telepathic” process of “knowing.”¹⁴ Deaf patients with schizo­phrenia are more likely to report visual elements to their hallucinations; however, these may be subvisual precepts rather than true visual hallucinations.^1,15 For ex­ample, hallucination might include the perception of being signed to.¹

Deaf patients’ experience of auditory hallucinations is thought to be closely re­lated to past auditory experiences. It is unlikely that prelingually deaf patients experience true auditory hallucinations.^1,14 An endorsement of hearing a “voice” in ASL does not necessarily translate to an audiological experience.¹⁵ If profoundly prelingually deaf patients endorse hearing voices, generally they cannot assign acous­tic properties (pitch, tone, volume, accent, etc.).^1,14,15 It may not be necessary to fully comprehend the precise modality of how hallucinations are experienced by deaf pa­tients to provide therapy.¹⁴

Self-signing, or signing to oneself, does not necessarily indicate that a deaf person is responding to a hallucinatory experience. Non-verbal patients may gesture to them­selves without clear evidence of psychosis. When considering whether a patient is ex­periencing hallucinations, it is important to look for other evidence of psychosis.³

Possible approaches to evaluating hal­lucinations in deaf patients include ask­ing,, “is someone signing in your head?” or “Is someone who is not in the room trying to communicate with you?”

Thought disorders in deaf psychiatric in­patients are difficult to diagnose, in part because of a high rate of language dysflu­ency in deaf patients; in samples of psychi­atric inpatients, 75% are not fluent in ASL, 66% are not fluent in any language).^1,3,11 Commonly, language dysfluency is related to language deprivation because of late or inadequate exposure to ASL, although it may be related to neurologic damage or aphasia.^1,3,6,16 Deaf patients can have addi­tional disabilities, including learning dis­abilities, that might contribute to language dysfluency.² Language dysfluency can be misattributed to a psychotic process^1-3,7 (Table 3).¹

Language dysfluency and thought dis­orders can be difficult to differentiate and may be comorbid. Loose associations and flight of ideas can be hard to assess in pa­tients with language dysfluency. In general, increasing looseness of association between concepts corresponds to an increasing like­lihood that a patient has true loose asso­ciations rather than language dysfluency alone.³ Deaf patients with schizophrenia can be identified by the presence of associ­ated symptoms of psychosis, especially if delusions are present.^1,3

EVALUATION Psychotic symptoms
Mrs. H’s thought process appears disorganized and illogical, with flight of ideas. She might have an underlying language dysfluency. It is likely that Mrs. H is using neologisms to communi­cate because of her family’s lack of familiarity with some of her signs. She also demonstrates perseveration, with use of certain signs repeat­edly without clear context (ie, “nothing off”).

Her thought content includes racial themes—she mentions Russia, Germany, and Vietnam without clear context—and delusions of being the “star king” and of being pregnant. She endorses paranoid feelings that people on the inpatient unit are trying to hurt her, al­though it isn’t clear whether this represents a true paranoid delusion because of the hectic climate of the unit, and she did not show unnecessarily defensive or guarded behaviors.

She is seen signing to herself in the dayroom and endorses feeling as though someone who is not in the room—described as an Indian teacher (and sometimes as a boss or principal) known as “Mr. Smith” or “Mr. Donald”—is trying to communicate with her. She describes this person as being male and female. She men­tions that sometimes she sees an Indian man and another man fighting. It is likely that Mrs. H is experiencing hallucinations from decompen­sated psychosis, because of the constellation and trajectory of her symptoms. Her nonverbal behavior—her eyes rove around the room dur­ing interviews—also supports this conclusion.

Because of evidence of mood and psychotic symptoms, and with a collateral history that suggests significant baseline disorganization, Mrs. H receives a diagnosis of schizoaffective disorder, bipolar type. She is restarted on olan­zapine, 10 mg/d, and valproic acid, 1,000 mg/d.

Mrs. H’s psychomotor acceleration and af­fective elevation gradually improve with phar­macotherapy. After a 2-week hospitalization, despite ongoing disorganization and self-sign­ing, Mrs. H’s husband says that he feels she is improved enough to return home, with plans to continue to take her medications and to re­establish outpatient follow-up.

Bottom Line

Psychiatric assessment of deaf patients presents distinctive challenges related to cultural and language barriers—making it important to engage an ASL interpreter with training in mental health during assessment of a deaf patient. Clinicians must become familiar with these challenges to provide effective care for mentally ill deaf patients.

Related Resources
• Landsberger SA, Diaz DR. Communicating with deaf pa­tients: 10 tips to deliver appropriate care. Current Psychiatry. 2010;9(6):36-37.
• Deaf Wellness Center. University of Rochester School of Medicine. www.urmc.rochester.edu/deaf-wellness-center.
• Gallaudet University Mental Health Center. www.gallaudet.edu/
mental_health_center.html.

Drug Brand Names
Olanzapine • Zyprexa
Valproic acid • Depakote

Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Self Signing
Mrs. H, a 47-year-old, deaf, African American woman, is brought into the emergency room because she is becoming increasingly withdrawn and is signing to herself. She was hospitalized more than 10 years ago after de­veloping psychotic symptoms and received a diagnosis of psychotic disorder, not otherwise specified. She was treated with olanzapine, 10 mg/d, and valproic acid, 1,000 mg/d, but she has not seen a psychiatrist or taken any psy­chotropics in 8 years. Upon admission to the inpatient psychiatric unit, Mrs. H reports, through an American Sign Language (ASL) interpreter, that she has had “problems with her parents” and with “being fair” and that she is 18 months pregnant. Urine pregnancy test is negative. Mrs. H also reports that her mother is pregnant. She indicates that it is difficult for her to describe what she is try­ing to say and that it is difficult to be deaf. 

She endorses “very strong” racing thoughts, which she first states have been present for 15 years, then reports it has been 20 months. She endorses high-energy levels, feeling like there is “work to do,” and poor sleep. However, when asked, she indicates that she sleeps for 15 hours a day.

Which is critical when conducting a psychiatric assessment for a deaf patient?

   a) rely only on the ASL interpreter
   b) inquire about the patient’s communica­tion preferences
   c) use written language to communicate instead of speech
   d) use a family member as interpreter

The authors’ observations
Mental health assessment of a deaf a patient involves a unique set of challenges and requires a specialized skill set for mental health practitioners—a skill set that is not routinely covered in psychiatric training programs.

a We use the term “deaf” to describe patients who have severe hearing loss. Other terms, such as “hearing impaired,” might be considered pejorative in the Deaf community. The term “Deaf” (capitalized) refers to Deaf culture and community, which deaf patients may or may not identify with.

Deafness history
It is important to assess the cause of deafness,^1,2 if known, and its age of onset (Table 1). A person is considered to be pre­lingually deaf if hearing loss was diagnosed before age 3.² Clinicians should establish the patient’s communication preferences (use of assistive devices or interpreters or preference for lip reading), home commu­nication dynamic,² and language fluency level.^1-3 Ask the patient if she attended a specialized school for the deaf and, if so, if there was an emphasis on oral communica­tion or signing.²

HISTORY Conflicting reports
Mrs. H reports that she has been deaf since age 9, and that she learned sign language in India, where she became the “star king.” Mrs. H states that she then moved to the United States where she went to a school for the deaf. When asked if her family is able to communicate with her in sign language, she nods and indicates that they speak to her in “African and Indian.”

Mrs. H’s husband, who is hearing, says that Mrs. H is congenitally deaf, and was raised in the Midwestern United States where she at­tended a specialized school for the deaf. Mr. H and his 2 adult sons are hearing but commu­nicate with Mrs. H in basic ASL. He states that Mrs. H sometimes uses signs that he and his sons cannot interpret. In addition to increased self-preoccupation and self-signing, Mrs. H has become more impulsive.

What are limitations of the mental status examination when evaluating a deaf patient?

   a) facial expressions have a specific linguis­tic function in ASL
   b) there is no differentiation in the mental status exam of deaf patients from that of hearing patients
   c) the Mini-Mental State Examination (MMSE) is a validated tool to assess cogni­tion in deaf patients
   d) the clinician should not rely on the in­terpreter to assist with the mental status examination

The authors’ observation
Performing a mental status examination of a deaf patient without recognizing some of the challenges inherent to this task can lead to misleading findings. For example, sign­ing and gesturing can give the clinician an impression of psychomotor agitation.² What appears to be socially withdrawn behavior might be a reaction to the patient’s inability to communicate with others.^2,3 Social skills may be affected by language deprivation, if present.³ In ASL, facial expressions have specific linguistic functions in addition to representing emotions,² and can affect the meaning of the sign used. An exaggerated or intense facial expression with the sign “quiet,” for example, usually means “very quiet.”⁴ In assessing cognition, the MMSE is not available in ASL and has not been vali­dated in deaf patients.⁵ Also, deaf people have reduced access to information, and a lack of knowledge does not necessarily cor­relate with low IQ.²

The interpreter’s role
An ASL interpreter can aid in assessing a deaf patient’s communication skills. The interpreter can help with a thorough lan­guage evaluation^1,6 and provide information about socio-cultural norms in the Deaf community.⁷ Using an ASL interpreter with special training in mental health^1,3,6,7 is im­portant to accurately diagnose thought dis­orders in deaf patients.¹

EVALUATION Mental status exam
Mrs. H is poorly groomed and is wearing a pink housecoat, with her hair in disarray. She seems to be distracted by something next to the in­terpreter, because her eyes keep roving in this direction. She has moderate psychomotor agi­tation, based on the rapidity of her signing and gesturing. Mrs. H makes indecipherable vocal­izations while signing, often loud and with an urgent quality. Her affect is elevated and ex­pansive. She is not oriented to place or time and when asked where she is, signs, “many times, every day, 6-9-9, 2-5, more trouble…”

The ASL interpreter notes that Mrs. H signs so quickly that only about one-half of her signs are interpretable. Mrs. H’s grammar is not always correct and that her syntax is, at times, inappro­priate. Mrs. H’s letters are difficult to interpret because she often starts and concludes a word with a clear sign, but the intervening letters are rapid and uninterpretable. She also uses several non-alphabet signs that cannot be in­terpreted (approximately 10% to 15% of signs) and repeats signs without clear context, such as “nothing off.” Mrs. H can pause to clarify for the interpreter at the beginning of the interview but is not able to do so by the end of the interview.

How does assessment of psychosis differ when evaluating deaf patients?

   a) language dysfluency must be carefully differentiated from a thought disorder
   b) signing to oneself does not necessarily indicate a response to internal stimuli
   c) norms in Deaf culture might be miscon­strued as delusions
   d) all of the above

The authors’ observations
The prevalence of psychotic disorders among deaf patients is unknown.⁸ Although older studies have reported an increased prevalence of psychotic disorders among deaf patients, these studies suffer from methodological problems.¹ Other studies are at odds with each other, variably reporting a greater,⁹ equivalent,¹⁰ and lesser incidence of psychotic disorders in deaf psychiatric in­patients.¹¹ Deaf patients with psychotic dis­orders experience delusions, hallucinations, and thought disorders,^1,3 and assessing for these symptoms in deaf patients can present a diagnostic challenge (Table 2).

Delusions are thought to present simi­larly in deaf patients with psychotic dis­orders compared with hearing patients.^1,3 Paranoia may be increased in patients who are postlingually deaf, but has not been as­sociated with prelingual deafness. Deficits in theory of mind related to hearing im­pairment have been thought to contribute to delusions in deaf patients.^1,12

Many deaf patients distrust health care systems and providers,^2,3,13 which may be misinterpreted as paranoia. Poor commu­nication between deaf patients and clini­cians and poor health literacy among deaf patients contribute to feelings of mistrust. Deaf patients often report experiencing prejudice within the health care system, and think that providers lack sufficient knowledge of deafness.¹³ Care must be taken to ensure that Deaf cultural norms are not misinterpreted as delusions.

Hallucinations. How deaf patients expe­rience hallucinations, especially in prelingual deafness, likely is different from hallucinatory experiences of hearing patients.^1,14 Deaf people with psychosis have described ”ideas coming into one’s head” and an almost “telepathic” process of “knowing.”¹⁴ Deaf patients with schizo­phrenia are more likely to report visual elements to their hallucinations; however, these may be subvisual precepts rather than true visual hallucinations.^1,15 For ex­ample, hallucination might include the perception of being signed to.¹

Deaf patients’ experience of auditory hallucinations is thought to be closely re­lated to past auditory experiences. It is unlikely that prelingually deaf patients experience true auditory hallucinations.^1,14 An endorsement of hearing a “voice” in ASL does not necessarily translate to an audiological experience.¹⁵ If profoundly prelingually deaf patients endorse hearing voices, generally they cannot assign acous­tic properties (pitch, tone, volume, accent, etc.).^1,14,15 It may not be necessary to fully comprehend the precise modality of how hallucinations are experienced by deaf pa­tients to provide therapy.¹⁴

Self-signing, or signing to oneself, does not necessarily indicate that a deaf person is responding to a hallucinatory experience. Non-verbal patients may gesture to them­selves without clear evidence of psychosis. When considering whether a patient is ex­periencing hallucinations, it is important to look for other evidence of psychosis.³

Possible approaches to evaluating hal­lucinations in deaf patients include ask­ing,, “is someone signing in your head?” or “Is someone who is not in the room trying to communicate with you?”

Thought disorders in deaf psychiatric in­patients are difficult to diagnose, in part because of a high rate of language dysflu­ency in deaf patients; in samples of psychi­atric inpatients, 75% are not fluent in ASL, 66% are not fluent in any language).^1,3,11 Commonly, language dysfluency is related to language deprivation because of late or inadequate exposure to ASL, although it may be related to neurologic damage or aphasia.^1,3,6,16 Deaf patients can have addi­tional disabilities, including learning dis­abilities, that might contribute to language dysfluency.² Language dysfluency can be misattributed to a psychotic process^1-3,7 (Table 3).¹

Language dysfluency and thought dis­orders can be difficult to differentiate and may be comorbid. Loose associations and flight of ideas can be hard to assess in pa­tients with language dysfluency. In general, increasing looseness of association between concepts corresponds to an increasing like­lihood that a patient has true loose asso­ciations rather than language dysfluency alone.³ Deaf patients with schizophrenia can be identified by the presence of associ­ated symptoms of psychosis, especially if delusions are present.^1,3

EVALUATION Psychotic symptoms
Mrs. H’s thought process appears disorganized and illogical, with flight of ideas. She might have an underlying language dysfluency. It is likely that Mrs. H is using neologisms to communi­cate because of her family’s lack of familiarity with some of her signs. She also demonstrates perseveration, with use of certain signs repeat­edly without clear context (ie, “nothing off”).

Her thought content includes racial themes—she mentions Russia, Germany, and Vietnam without clear context—and delusions of being the “star king” and of being pregnant. She endorses paranoid feelings that people on the inpatient unit are trying to hurt her, al­though it isn’t clear whether this represents a true paranoid delusion because of the hectic climate of the unit, and she did not show unnecessarily defensive or guarded behaviors.

She is seen signing to herself in the dayroom and endorses feeling as though someone who is not in the room—described as an Indian teacher (and sometimes as a boss or principal) known as “Mr. Smith” or “Mr. Donald”—is trying to communicate with her. She describes this person as being male and female. She men­tions that sometimes she sees an Indian man and another man fighting. It is likely that Mrs. H is experiencing hallucinations from decompen­sated psychosis, because of the constellation and trajectory of her symptoms. Her nonverbal behavior—her eyes rove around the room dur­ing interviews—also supports this conclusion.

Because of evidence of mood and psychotic symptoms, and with a collateral history that suggests significant baseline disorganization, Mrs. H receives a diagnosis of schizoaffective disorder, bipolar type. She is restarted on olan­zapine, 10 mg/d, and valproic acid, 1,000 mg/d.

Mrs. H’s psychomotor acceleration and af­fective elevation gradually improve with phar­macotherapy. After a 2-week hospitalization, despite ongoing disorganization and self-sign­ing, Mrs. H’s husband says that he feels she is improved enough to return home, with plans to continue to take her medications and to re­establish outpatient follow-up.

Bottom Line

Psychiatric assessment of deaf patients presents distinctive challenges related to cultural and language barriers—making it important to engage an ASL interpreter with training in mental health during assessment of a deaf patient. Clinicians must become familiar with these challenges to provide effective care for mentally ill deaf patients.

Related Resources
• Landsberger SA, Diaz DR. Communicating with deaf pa­tients: 10 tips to deliver appropriate care. Current Psychiatry. 2010;9(6):36-37.
• Deaf Wellness Center. University of Rochester School of Medicine. www.urmc.rochester.edu/deaf-wellness-center.
• Gallaudet University Mental Health Center. www.gallaudet.edu/
mental_health_center.html.

Drug Brand Names
Olanzapine • Zyprexa
Valproic acid • Depakote

Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Self Signing
Mrs. H, a 47-year-old, deaf, African American woman, is brought into the emergency room because she is becoming increasingly withdrawn and is signing to herself. She was hospitalized more than 10 years ago after de­veloping psychotic symptoms and received a diagnosis of psychotic disorder, not otherwise specified. She was treated with olanzapine, 10 mg/d, and valproic acid, 1,000 mg/d, but she has not seen a psychiatrist or taken any psy­chotropics in 8 years. Upon admission to the inpatient psychiatric unit, Mrs. H reports, through an American Sign Language (ASL) interpreter, that she has had “problems with her parents” and with “being fair” and that she is 18 months pregnant. Urine pregnancy test is negative. Mrs. H also reports that her mother is pregnant. She indicates that it is difficult for her to describe what she is try­ing to say and that it is difficult to be deaf. 

She endorses “very strong” racing thoughts, which she first states have been present for 15 years, then reports it has been 20 months. She endorses high-energy levels, feeling like there is “work to do,” and poor sleep. However, when asked, she indicates that she sleeps for 15 hours a day.

Which is critical when conducting a psychiatric assessment for a deaf patient?

   a) rely only on the ASL interpreter
   b) inquire about the patient’s communica­tion preferences
   c) use written language to communicate instead of speech
   d) use a family member as interpreter

The authors’ observations
Mental health assessment of a deaf a patient involves a unique set of challenges and requires a specialized skill set for mental health practitioners—a skill set that is not routinely covered in psychiatric training programs.

a We use the term “deaf” to describe patients who have severe hearing loss. Other terms, such as “hearing impaired,” might be considered pejorative in the Deaf community. The term “Deaf” (capitalized) refers to Deaf culture and community, which deaf patients may or may not identify with.

Deafness history
It is important to assess the cause of deafness,^1,2 if known, and its age of onset (Table 1). A person is considered to be pre­lingually deaf if hearing loss was diagnosed before age 3.² Clinicians should establish the patient’s communication preferences (use of assistive devices or interpreters or preference for lip reading), home commu­nication dynamic,² and language fluency level.^1-3 Ask the patient if she attended a specialized school for the deaf and, if so, if there was an emphasis on oral communica­tion or signing.²

HISTORY Conflicting reports
Mrs. H reports that she has been deaf since age 9, and that she learned sign language in India, where she became the “star king.” Mrs. H states that she then moved to the United States where she went to a school for the deaf. When asked if her family is able to communicate with her in sign language, she nods and indicates that they speak to her in “African and Indian.”

Mrs. H’s husband, who is hearing, says that Mrs. H is congenitally deaf, and was raised in the Midwestern United States where she at­tended a specialized school for the deaf. Mr. H and his 2 adult sons are hearing but commu­nicate with Mrs. H in basic ASL. He states that Mrs. H sometimes uses signs that he and his sons cannot interpret. In addition to increased self-preoccupation and self-signing, Mrs. H has become more impulsive.

What are limitations of the mental status examination when evaluating a deaf patient?

   a) facial expressions have a specific linguis­tic function in ASL
   b) there is no differentiation in the mental status exam of deaf patients from that of hearing patients
   c) the Mini-Mental State Examination (MMSE) is a validated tool to assess cogni­tion in deaf patients
   d) the clinician should not rely on the in­terpreter to assist with the mental status examination

The authors’ observation
Performing a mental status examination of a deaf patient without recognizing some of the challenges inherent to this task can lead to misleading findings. For example, sign­ing and gesturing can give the clinician an impression of psychomotor agitation.² What appears to be socially withdrawn behavior might be a reaction to the patient’s inability to communicate with others.^2,3 Social skills may be affected by language deprivation, if present.³ In ASL, facial expressions have specific linguistic functions in addition to representing emotions,² and can affect the meaning of the sign used. An exaggerated or intense facial expression with the sign “quiet,” for example, usually means “very quiet.”⁴ In assessing cognition, the MMSE is not available in ASL and has not been vali­dated in deaf patients.⁵ Also, deaf people have reduced access to information, and a lack of knowledge does not necessarily cor­relate with low IQ.²

The interpreter’s role
An ASL interpreter can aid in assessing a deaf patient’s communication skills. The interpreter can help with a thorough lan­guage evaluation^1,6 and provide information about socio-cultural norms in the Deaf community.⁷ Using an ASL interpreter with special training in mental health^1,3,6,7 is im­portant to accurately diagnose thought dis­orders in deaf patients.¹

EVALUATION Mental status exam
Mrs. H is poorly groomed and is wearing a pink housecoat, with her hair in disarray. She seems to be distracted by something next to the in­terpreter, because her eyes keep roving in this direction. She has moderate psychomotor agi­tation, based on the rapidity of her signing and gesturing. Mrs. H makes indecipherable vocal­izations while signing, often loud and with an urgent quality. Her affect is elevated and ex­pansive. She is not oriented to place or time and when asked where she is, signs, “many times, every day, 6-9-9, 2-5, more trouble…”

The ASL interpreter notes that Mrs. H signs so quickly that only about one-half of her signs are interpretable. Mrs. H’s grammar is not always correct and that her syntax is, at times, inappro­priate. Mrs. H’s letters are difficult to interpret because she often starts and concludes a word with a clear sign, but the intervening letters are rapid and uninterpretable. She also uses several non-alphabet signs that cannot be in­terpreted (approximately 10% to 15% of signs) and repeats signs without clear context, such as “nothing off.” Mrs. H can pause to clarify for the interpreter at the beginning of the interview but is not able to do so by the end of the interview.

How does assessment of psychosis differ when evaluating deaf patients?

   a) language dysfluency must be carefully differentiated from a thought disorder
   b) signing to oneself does not necessarily indicate a response to internal stimuli
   c) norms in Deaf culture might be miscon­strued as delusions
   d) all of the above

The authors’ observations
The prevalence of psychotic disorders among deaf patients is unknown.⁸ Although older studies have reported an increased prevalence of psychotic disorders among deaf patients, these studies suffer from methodological problems.¹ Other studies are at odds with each other, variably reporting a greater,⁹ equivalent,¹⁰ and lesser incidence of psychotic disorders in deaf psychiatric in­patients.¹¹ Deaf patients with psychotic dis­orders experience delusions, hallucinations, and thought disorders,^1,3 and assessing for these symptoms in deaf patients can present a diagnostic challenge (Table 2).

Delusions are thought to present simi­larly in deaf patients with psychotic dis­orders compared with hearing patients.^1,3 Paranoia may be increased in patients who are postlingually deaf, but has not been as­sociated with prelingual deafness. Deficits in theory of mind related to hearing im­pairment have been thought to contribute to delusions in deaf patients.^1,12

Many deaf patients distrust health care systems and providers,^2,3,13 which may be misinterpreted as paranoia. Poor commu­nication between deaf patients and clini­cians and poor health literacy among deaf patients contribute to feelings of mistrust. Deaf patients often report experiencing prejudice within the health care system, and think that providers lack sufficient knowledge of deafness.¹³ Care must be taken to ensure that Deaf cultural norms are not misinterpreted as delusions.

Hallucinations. How deaf patients expe­rience hallucinations, especially in prelingual deafness, likely is different from hallucinatory experiences of hearing patients.^1,14 Deaf people with psychosis have described ”ideas coming into one’s head” and an almost “telepathic” process of “knowing.”¹⁴ Deaf patients with schizo­phrenia are more likely to report visual elements to their hallucinations; however, these may be subvisual precepts rather than true visual hallucinations.^1,15 For ex­ample, hallucination might include the perception of being signed to.¹

Deaf patients’ experience of auditory hallucinations is thought to be closely re­lated to past auditory experiences. It is unlikely that prelingually deaf patients experience true auditory hallucinations.^1,14 An endorsement of hearing a “voice” in ASL does not necessarily translate to an audiological experience.¹⁵ If profoundly prelingually deaf patients endorse hearing voices, generally they cannot assign acous­tic properties (pitch, tone, volume, accent, etc.).^1,14,15 It may not be necessary to fully comprehend the precise modality of how hallucinations are experienced by deaf pa­tients to provide therapy.¹⁴

Self-signing, or signing to oneself, does not necessarily indicate that a deaf person is responding to a hallucinatory experience. Non-verbal patients may gesture to them­selves without clear evidence of psychosis. When considering whether a patient is ex­periencing hallucinations, it is important to look for other evidence of psychosis.³

Possible approaches to evaluating hal­lucinations in deaf patients include ask­ing,, “is someone signing in your head?” or “Is someone who is not in the room trying to communicate with you?”

Thought disorders in deaf psychiatric in­patients are difficult to diagnose, in part because of a high rate of language dysflu­ency in deaf patients; in samples of psychi­atric inpatients, 75% are not fluent in ASL, 66% are not fluent in any language).^1,3,11 Commonly, language dysfluency is related to language deprivation because of late or inadequate exposure to ASL, although it may be related to neurologic damage or aphasia.^1,3,6,16 Deaf patients can have addi­tional disabilities, including learning dis­abilities, that might contribute to language dysfluency.² Language dysfluency can be misattributed to a psychotic process^1-3,7 (Table 3).¹

Language dysfluency and thought dis­orders can be difficult to differentiate and may be comorbid. Loose associations and flight of ideas can be hard to assess in pa­tients with language dysfluency. In general, increasing looseness of association between concepts corresponds to an increasing like­lihood that a patient has true loose asso­ciations rather than language dysfluency alone.³ Deaf patients with schizophrenia can be identified by the presence of associ­ated symptoms of psychosis, especially if delusions are present.^1,3

EVALUATION Psychotic symptoms
Mrs. H’s thought process appears disorganized and illogical, with flight of ideas. She might have an underlying language dysfluency. It is likely that Mrs. H is using neologisms to communi­cate because of her family’s lack of familiarity with some of her signs. She also demonstrates perseveration, with use of certain signs repeat­edly without clear context (ie, “nothing off”).

Her thought content includes racial themes—she mentions Russia, Germany, and Vietnam without clear context—and delusions of being the “star king” and of being pregnant. She endorses paranoid feelings that people on the inpatient unit are trying to hurt her, al­though it isn’t clear whether this represents a true paranoid delusion because of the hectic climate of the unit, and she did not show unnecessarily defensive or guarded behaviors.

She is seen signing to herself in the dayroom and endorses feeling as though someone who is not in the room—described as an Indian teacher (and sometimes as a boss or principal) known as “Mr. Smith” or “Mr. Donald”—is trying to communicate with her. She describes this person as being male and female. She men­tions that sometimes she sees an Indian man and another man fighting. It is likely that Mrs. H is experiencing hallucinations from decompen­sated psychosis, because of the constellation and trajectory of her symptoms. Her nonverbal behavior—her eyes rove around the room dur­ing interviews—also supports this conclusion.

Because of evidence of mood and psychotic symptoms, and with a collateral history that suggests significant baseline disorganization, Mrs. H receives a diagnosis of schizoaffective disorder, bipolar type. She is restarted on olan­zapine, 10 mg/d, and valproic acid, 1,000 mg/d.

Mrs. H’s psychomotor acceleration and af­fective elevation gradually improve with phar­macotherapy. After a 2-week hospitalization, despite ongoing disorganization and self-sign­ing, Mrs. H’s husband says that he feels she is improved enough to return home, with plans to continue to take her medications and to re­establish outpatient follow-up.

Bottom Line

Psychiatric assessment of deaf patients presents distinctive challenges related to cultural and language barriers—making it important to engage an ASL interpreter with training in mental health during assessment of a deaf patient. Clinicians must become familiar with these challenges to provide effective care for mentally ill deaf patients.

Related Resources
• Landsberger SA, Diaz DR. Communicating with deaf pa­tients: 10 tips to deliver appropriate care. Current Psychiatry. 2010;9(6):36-37.
• Deaf Wellness Center. University of Rochester School of Medicine. www.urmc.rochester.edu/deaf-wellness-center.
• Gallaudet University Mental Health Center. www.gallaudet.edu/
mental_health_center.html.

Drug Brand Names
Olanzapine • Zyprexa
Valproic acid • Depakote

Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. V, age 29, is a US Army veteran who presents to the psychiatric emergen­cy department because of increasing aggression. He recently returned from deployment overseas and lives with his parents. Mr. V’s mother reports that he has been in­creasingly “unstable” and describes an inci­dent during which he punched a hole in his bedroom window after a temporary slow-down in the home’s Internet connection.

The workup and review of the history rules out substance abuse, posttraumatic stress dis­order, bipolar disorder, seizure disorder, and personality disorders. He is currently taking only omeprazole, 40 mg/d, for acid reflux. The psychiatrist considers prescribing an antiepi­leptic medication to treat the agitation. Why this choice of agent?

According to DSM-5, patients who have re­peated episodes of aggression can be given a diagnosis of intermittent explosive disor­der, but such behavior can occur secondary to other psychiatric diagnoses (Table 1). No medications are FDA approved for aggression.¹

Aggression and associated verbal and physical acts fall into 2 subtypes: impulsive type and premeditated (predatory) type. Impulsive aggression generally is described as an emotionally charged aggressive response characterized by a loss of behavioral control.

Premeditated aggression

Pharmacotherapy is directed primarily at treating impulsive aggression because this subtype is thought to be caused by neurologic deficits that can affect a person’s ability to process, and react appropriately to, external stimuli. Agitation can result from neuronal hyperactivity.² Agents such as antiepileptic drugs (AEDs) have the potential to reduce the intensity and frequency of such behaviors.²

In this article, we focus on the use of AEDs for treating impulsive aggression in adults.

Reviewing the evidence for AEDs
The neurobiology of aggression involves multiple neurotransmitters, intracellular pathways, and ion channels.³ AEDs have several mechanisms of action, however; pri­mary mechanisms include action on sodium and calcium channels and modulation of γ-aminobutyric acid (GABA), glutamate, and carbonic anhydrase.^2,3 Agent-specific mecha­nisms of actions are listed in Table 2.

Phenytoin. Several double-blind, placebo-controlled trials have found a statistically significant difference between phenytoin and placebo for treating impulsive aggres­sion, as measured by the Overt Aggression Scale (OAS)a or a modified version (MOAS/ OAS-M).^1,2,4 Researchers found that phenyt­oin, 300 mg/d, but not 100 mg/d, decreased impulsive aggression.<sup>4

a</sup> Studies generally used the OAS, or one of its modifications, to evaluate aggressive behavior.^2,4

Valproate. Trials of valproate for decreasing aggressive behaviors have produced mixed results with regard to primary outcome when used at standard dosages and within the ther­apeutic range measured by serum concentra­tion.^2,3 In a pooled analysis of studies that met stringent criteria (randomized, controlled tri­al, aggressive behavior as primary outcome, patients free of organic illness or neurologic illness), Jones and colleagues¹ reported that valproate/divalproex did not produce statis­tically significant results compared with pla­cebo for treating impulsive aggression. 

Carbamazepine and oxcarbazepine. Double-blind, placebo-controlled trials and case studies of carbamazepine have shown mixed results. In contrast, oxcarbazepine has been found to significantly decrease aggres­sive behavior, measured by OAS/MOAS/ OAS-M scores.^2,3 Total daily dosages of ox­carbazepine ranged from 1,500 to 2,400 mg.^2-4 It has been speculated that oxcarbazepine might be a useful option for treating impul­sive aggression because of its therapeutic val­ue in temporal lobe seizures—a subtype of seizure disorder that involves the limbic sys­tem, which also modulates aggressiveness.⁵

Additionally, when compared with carba­mazepine, oxcarbazepine has a lower risk of cardiotoxicity, neurotoxicity, and blood dys­crasia. Oxcarbazepine has fewer drug-drug interactions because of a lower degree of he­patic enzyme induction.

Topiramate. Several studies have confirmed the efficacy of topiramate for aggressive be­havior.^2,3 However, there have been reports that topiramate can induce or exacerbate aggression in some patients, an effect that might be dose-related. Aggression might respond better to a higher, short-term dos­age (eg, 400 mg/d) than to lower (100 to 300 mg/d) dosages, which might exacerbate aggression.³

Gabapentin. Research on using gabapen­tin for aggression is limited. Speculation is that the combined activity of gabapentin on GABA and glutamate give the drug its anti­aggressive effect.³ No randomized, double-blind, placebo-controlled trials are underway comparing gabapentin and placebo or other active medication for impulsive aggression.

Some case reports and small-scale, open-label studies report a decrease in aggression with gabapentin. As is the case with topira­mate, a lower dosage (200 mg to 400 mg) has been reported to result in increased aggres­sion—whereas a higher dosages (800 mg) decreases aggressive behavior.^2,3

Lamotrigine. The results of several studies, including double-blind, placebo-controlled trials, support the use of lamotrigine for ag­gressive behavior. A number of these studies, however, used scales other than OAS (or its modifications) to determine this outcome. One trial showed increased aggression in several patients on lower-dosage lamotrigine (100 mg/d) that resolved when the dosage was increased.^2,3

Treatment recommendations
Although all AEDs have some documented efficacy against aggression, choosing the ap­propriate agent depends on patient-specific variables. Avoiding divalproex in patients with liver dysfunction, for example, or car­bamazepine in those with a preexisting car­diac conduction abnormality will improve outcomes by avoiding complications.

It is important to rule out all other causes of aggression before selecting a treatment. The presence of one or more of the diagnoses listed in Table 1 could lead to selection of an alternate class of medication. Nondrug ther­apies, such as cognitive-behavioral therapy, also should be considered.
 

Related Resources
• Coccaro EF. Aggression. Psychiatric assessment and treat­ment. Chicago, IL: Marcel Dekker, Inc.; 2003.
• Citrome LL. Aggression. http://emedicine.medscape.com/article/288689-overview. Updated June 18, 2012. Accessed February 28, 2014.
 

Drug Brand Names
Carbamazepine • Tegretol                 Phenytoin • Dilantin
Gabapentin • Neurontin                    Topiramate • Topamax
Lamotrigine • Lamictal                      Valproate/Divalproex
Omeprazole • Prilosec                          • Depakote           
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. V, age 29, is a US Army veteran who presents to the psychiatric emergen­cy department because of increasing aggression. He recently returned from deployment overseas and lives with his parents. Mr. V’s mother reports that he has been in­creasingly “unstable” and describes an inci­dent during which he punched a hole in his bedroom window after a temporary slow-down in the home’s Internet connection.

The workup and review of the history rules out substance abuse, posttraumatic stress dis­order, bipolar disorder, seizure disorder, and personality disorders. He is currently taking only omeprazole, 40 mg/d, for acid reflux. The psychiatrist considers prescribing an antiepi­leptic medication to treat the agitation. Why this choice of agent?

According to DSM-5, patients who have re­peated episodes of aggression can be given a diagnosis of intermittent explosive disor­der, but such behavior can occur secondary to other psychiatric diagnoses (Table 1). No medications are FDA approved for aggression.¹

Aggression and associated verbal and physical acts fall into 2 subtypes: impulsive type and premeditated (predatory) type. Impulsive aggression generally is described as an emotionally charged aggressive response characterized by a loss of behavioral control.

Premeditated aggression

Pharmacotherapy is directed primarily at treating impulsive aggression because this subtype is thought to be caused by neurologic deficits that can affect a person’s ability to process, and react appropriately to, external stimuli. Agitation can result from neuronal hyperactivity.² Agents such as antiepileptic drugs (AEDs) have the potential to reduce the intensity and frequency of such behaviors.²

In this article, we focus on the use of AEDs for treating impulsive aggression in adults.

Reviewing the evidence for AEDs
The neurobiology of aggression involves multiple neurotransmitters, intracellular pathways, and ion channels.³ AEDs have several mechanisms of action, however; pri­mary mechanisms include action on sodium and calcium channels and modulation of γ-aminobutyric acid (GABA), glutamate, and carbonic anhydrase.^2,3 Agent-specific mecha­nisms of actions are listed in Table 2.

Phenytoin. Several double-blind, placebo-controlled trials have found a statistically significant difference between phenytoin and placebo for treating impulsive aggres­sion, as measured by the Overt Aggression Scale (OAS)a or a modified version (MOAS/ OAS-M).^1,2,4 Researchers found that phenyt­oin, 300 mg/d, but not 100 mg/d, decreased impulsive aggression.<sup>4

a</sup> Studies generally used the OAS, or one of its modifications, to evaluate aggressive behavior.^2,4

Valproate. Trials of valproate for decreasing aggressive behaviors have produced mixed results with regard to primary outcome when used at standard dosages and within the ther­apeutic range measured by serum concentra­tion.^2,3 In a pooled analysis of studies that met stringent criteria (randomized, controlled tri­al, aggressive behavior as primary outcome, patients free of organic illness or neurologic illness), Jones and colleagues¹ reported that valproate/divalproex did not produce statis­tically significant results compared with pla­cebo for treating impulsive aggression. 

Carbamazepine and oxcarbazepine. Double-blind, placebo-controlled trials and case studies of carbamazepine have shown mixed results. In contrast, oxcarbazepine has been found to significantly decrease aggres­sive behavior, measured by OAS/MOAS/ OAS-M scores.^2,3 Total daily dosages of ox­carbazepine ranged from 1,500 to 2,400 mg.^2-4 It has been speculated that oxcarbazepine might be a useful option for treating impul­sive aggression because of its therapeutic val­ue in temporal lobe seizures—a subtype of seizure disorder that involves the limbic sys­tem, which also modulates aggressiveness.⁵

Additionally, when compared with carba­mazepine, oxcarbazepine has a lower risk of cardiotoxicity, neurotoxicity, and blood dys­crasia. Oxcarbazepine has fewer drug-drug interactions because of a lower degree of he­patic enzyme induction.

Topiramate. Several studies have confirmed the efficacy of topiramate for aggressive be­havior.^2,3 However, there have been reports that topiramate can induce or exacerbate aggression in some patients, an effect that might be dose-related. Aggression might respond better to a higher, short-term dos­age (eg, 400 mg/d) than to lower (100 to 300 mg/d) dosages, which might exacerbate aggression.³

Gabapentin. Research on using gabapen­tin for aggression is limited. Speculation is that the combined activity of gabapentin on GABA and glutamate give the drug its anti­aggressive effect.³ No randomized, double-blind, placebo-controlled trials are underway comparing gabapentin and placebo or other active medication for impulsive aggression.

Some case reports and small-scale, open-label studies report a decrease in aggression with gabapentin. As is the case with topira­mate, a lower dosage (200 mg to 400 mg) has been reported to result in increased aggres­sion—whereas a higher dosages (800 mg) decreases aggressive behavior.^2,3

Lamotrigine. The results of several studies, including double-blind, placebo-controlled trials, support the use of lamotrigine for ag­gressive behavior. A number of these studies, however, used scales other than OAS (or its modifications) to determine this outcome. One trial showed increased aggression in several patients on lower-dosage lamotrigine (100 mg/d) that resolved when the dosage was increased.^2,3

Treatment recommendations
Although all AEDs have some documented efficacy against aggression, choosing the ap­propriate agent depends on patient-specific variables. Avoiding divalproex in patients with liver dysfunction, for example, or car­bamazepine in those with a preexisting car­diac conduction abnormality will improve outcomes by avoiding complications.

It is important to rule out all other causes of aggression before selecting a treatment. The presence of one or more of the diagnoses listed in Table 1 could lead to selection of an alternate class of medication. Nondrug ther­apies, such as cognitive-behavioral therapy, also should be considered.
 

Related Resources
• Coccaro EF. Aggression. Psychiatric assessment and treat­ment. Chicago, IL: Marcel Dekker, Inc.; 2003.
• Citrome LL. Aggression. http://emedicine.medscape.com/article/288689-overview. Updated June 18, 2012. Accessed February 28, 2014.
 

Drug Brand Names
Carbamazepine • Tegretol                 Phenytoin • Dilantin
Gabapentin • Neurontin                    Topiramate • Topamax
Lamotrigine • Lamictal                      Valproate/Divalproex
Omeprazole • Prilosec                          • Depakote           
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. V, age 29, is a US Army veteran who presents to the psychiatric emergen­cy department because of increasing aggression. He recently returned from deployment overseas and lives with his parents. Mr. V’s mother reports that he has been in­creasingly “unstable” and describes an inci­dent during which he punched a hole in his bedroom window after a temporary slow-down in the home’s Internet connection.

The workup and review of the history rules out substance abuse, posttraumatic stress dis­order, bipolar disorder, seizure disorder, and personality disorders. He is currently taking only omeprazole, 40 mg/d, for acid reflux. The psychiatrist considers prescribing an antiepi­leptic medication to treat the agitation. Why this choice of agent?

According to DSM-5, patients who have re­peated episodes of aggression can be given a diagnosis of intermittent explosive disor­der, but such behavior can occur secondary to other psychiatric diagnoses (Table 1). No medications are FDA approved for aggression.¹

Aggression and associated verbal and physical acts fall into 2 subtypes: impulsive type and premeditated (predatory) type. Impulsive aggression generally is described as an emotionally charged aggressive response characterized by a loss of behavioral control.

Premeditated aggression

Pharmacotherapy is directed primarily at treating impulsive aggression because this subtype is thought to be caused by neurologic deficits that can affect a person’s ability to process, and react appropriately to, external stimuli. Agitation can result from neuronal hyperactivity.² Agents such as antiepileptic drugs (AEDs) have the potential to reduce the intensity and frequency of such behaviors.²

In this article, we focus on the use of AEDs for treating impulsive aggression in adults.

Reviewing the evidence for AEDs
The neurobiology of aggression involves multiple neurotransmitters, intracellular pathways, and ion channels.³ AEDs have several mechanisms of action, however; pri­mary mechanisms include action on sodium and calcium channels and modulation of γ-aminobutyric acid (GABA), glutamate, and carbonic anhydrase.^2,3 Agent-specific mecha­nisms of actions are listed in Table 2.

Phenytoin. Several double-blind, placebo-controlled trials have found a statistically significant difference between phenytoin and placebo for treating impulsive aggres­sion, as measured by the Overt Aggression Scale (OAS)a or a modified version (MOAS/ OAS-M).^1,2,4 Researchers found that phenyt­oin, 300 mg/d, but not 100 mg/d, decreased impulsive aggression.<sup>4

a</sup> Studies generally used the OAS, or one of its modifications, to evaluate aggressive behavior.^2,4

Valproate. Trials of valproate for decreasing aggressive behaviors have produced mixed results with regard to primary outcome when used at standard dosages and within the ther­apeutic range measured by serum concentra­tion.^2,3 In a pooled analysis of studies that met stringent criteria (randomized, controlled tri­al, aggressive behavior as primary outcome, patients free of organic illness or neurologic illness), Jones and colleagues¹ reported that valproate/divalproex did not produce statis­tically significant results compared with pla­cebo for treating impulsive aggression. 

Carbamazepine and oxcarbazepine. Double-blind, placebo-controlled trials and case studies of carbamazepine have shown mixed results. In contrast, oxcarbazepine has been found to significantly decrease aggres­sive behavior, measured by OAS/MOAS/ OAS-M scores.^2,3 Total daily dosages of ox­carbazepine ranged from 1,500 to 2,400 mg.^2-4 It has been speculated that oxcarbazepine might be a useful option for treating impul­sive aggression because of its therapeutic val­ue in temporal lobe seizures—a subtype of seizure disorder that involves the limbic sys­tem, which also modulates aggressiveness.⁵

Additionally, when compared with carba­mazepine, oxcarbazepine has a lower risk of cardiotoxicity, neurotoxicity, and blood dys­crasia. Oxcarbazepine has fewer drug-drug interactions because of a lower degree of he­patic enzyme induction.

Topiramate. Several studies have confirmed the efficacy of topiramate for aggressive be­havior.^2,3 However, there have been reports that topiramate can induce or exacerbate aggression in some patients, an effect that might be dose-related. Aggression might respond better to a higher, short-term dos­age (eg, 400 mg/d) than to lower (100 to 300 mg/d) dosages, which might exacerbate aggression.³

Gabapentin. Research on using gabapen­tin for aggression is limited. Speculation is that the combined activity of gabapentin on GABA and glutamate give the drug its anti­aggressive effect.³ No randomized, double-blind, placebo-controlled trials are underway comparing gabapentin and placebo or other active medication for impulsive aggression.

Some case reports and small-scale, open-label studies report a decrease in aggression with gabapentin. As is the case with topira­mate, a lower dosage (200 mg to 400 mg) has been reported to result in increased aggres­sion—whereas a higher dosages (800 mg) decreases aggressive behavior.^2,3

Lamotrigine. The results of several studies, including double-blind, placebo-controlled trials, support the use of lamotrigine for ag­gressive behavior. A number of these studies, however, used scales other than OAS (or its modifications) to determine this outcome. One trial showed increased aggression in several patients on lower-dosage lamotrigine (100 mg/d) that resolved when the dosage was increased.^2,3

Treatment recommendations
Although all AEDs have some documented efficacy against aggression, choosing the ap­propriate agent depends on patient-specific variables. Avoiding divalproex in patients with liver dysfunction, for example, or car­bamazepine in those with a preexisting car­diac conduction abnormality will improve outcomes by avoiding complications.

It is important to rule out all other causes of aggression before selecting a treatment. The presence of one or more of the diagnoses listed in Table 1 could lead to selection of an alternate class of medication. Nondrug ther­apies, such as cognitive-behavioral therapy, also should be considered.
 

Related Resources
• Coccaro EF. Aggression. Psychiatric assessment and treat­ment. Chicago, IL: Marcel Dekker, Inc.; 2003.
• Citrome LL. Aggression. http://emedicine.medscape.com/article/288689-overview. Updated June 18, 2012. Accessed February 28, 2014.
 

Drug Brand Names
Carbamazepine • Tegretol                 Phenytoin • Dilantin
Gabapentin • Neurontin                    Topiramate • Topamax
Lamotrigine • Lamictal                      Valproate/Divalproex
Omeprazole • Prilosec                          • Depakote           
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Abstract

• Objective: To describe Acceptance and Commitment Therapy (ACT) and its application in the treatment of chronic pain.
• Methods: Review of the theoretical and clinical literature and presentation of a case example.
• Results: General cognitive behavioral approaches for chronic pain have a consistent and large evidence base supporting their benefits. Even so, these treatments continue to develop with the aim to improve. One example of a relatively new development within the cognitive behavioral approaches is ACT, a treatment that focuses on increasing psychological flexibility. Here we describe ACT and the therapeutic model on which it is based, present its distinguishing features, and summarize the evidence for it as a treatment for chronic pain. We also discuss such issues as dissemination, implementation, and training.
• Conclusion: There are now 7 randomized controlled trials, a number of innovative uncontrolled trials, and at least 1 systematic review that support the clinical efficacy and effectiveness of ACT for chronic pain. Further research and development of this approach is underway.

The introduction of the gate control theory of pain [1] in 1965, among other events, signaled a shift in our understanding of pain, particularly chronic pain. This shift, which continues today, is a shift from a predominantly biomedical model of chronic pain to a biospsychosocial model. This model, as the name suggests, includes psycho-social influences in a key role in relation to the experience of pain and the impact of this experience. During this same period of time, psychosocial models and treatment methods have also shifted and evolved. This evolution has included the operant approach [2], the cognitive behavioral approach [3], and the latest developments, contextual cognitive behavioral approaches [4,5], among which Acceptance and Commitment Therapy (ACT) and mindfulness-based therapies are key examples.

Until about 10 years ago, the mainstream of psycho-logical treatments for chronic pain and other physical health problems was dominated almost exclusively by concepts and methods of what we will refer to as “traditional” cognitive behavioral therapy (CBT). Specific constructs within what is called the “common sense model” [6], such as illness perceptions, beliefs about control over one’s illness, amongst other constructs such as self-efficacy, catastrophising, fear avoidance, and pain-related anxiety, captured a substantial focus of research and treatment development during most of the past 3 decades [7]. The treatment methods that have emerged and persisted from this work have included relaxation, attention-based and cognitive coping strategies, cognitive restructuring, the use of imagery, and certain activity management strategies [8]. However, despite consistent supportive evidence for CBT interventions for chronic pain [9], there remain gaps and areas of relative weakness, both in the conceptual models underlying this work and in the base of evidence. Research clearly shows that not all patients benefit from traditional CBT interventions, and recent reviews of CBT for chronic pain generally show effect sizes that are usually small or mediumat best [9–11].

The Problem with Pain

Pain hurts and is often viewed as harmful, and this leads to fear or anxiety, avoidance, or attempts to control the pain. Seeking to control pain is entirely natural and even seems necessary to reduce the undesirable effects of pain in one’s life.

Dependent on the situation, pain avoidance, sometimes also referred to as “fear avoidance,” in studies of chronic pain can present itself in many forms. Avoidance behavior can include refusal to engage in any activity believed to cause an increase in pain. It may also include “guarding” or bracing around an area of pain, information seeking, treatment seeking, taking medications, overdosing on medications, using aids like heat or ice, withdrawing from social activity, as well as being unwilling to talk about emotional experiences, amongst others [5]. Today, avoidance is recognized as a key foundation element in pain-related suffering and disability [12], and addressing it effectively has become a prime focus in many or most current treatments.

Acceptance and Psychological Flexibility

In recent years, the concept of “acceptance” has gained prominence as a potentially important process for addressing a broad array of psychological problems, including those associated with chronic pain. From this new interest, a fundamentally different treatment emphasis has emerged. This includes a shift away from a predominant focus on changing thoughts and feelings, a focus sometimes adopted within some traditional CBT methods, towards a focus on reducing the influence of thoughts and feelings on our actions instead. This can be a rather confusing distinction. This is because the influence of our thoughts and feelings is often automatic and even invisible to us as it occurs. As such, the influences of our thoughts and feelings appear directly tied to the content of thoughts and feelings, but the matter is not that simple. Clearly there are occasions when our actions contradict our thoughts and feelings, such as when we have perfectly confident beliefs and fail, or significant anxiety and perform successfully. Such instances illustrate what we might call a “2-dimensional” quality of experience; it is the content of experience and the context of experience that determine the influence exerted. Suffice it to say acceptance-based methods are designed to address the difference between experiences that are difficult to control, such as thoughts and feelings, and things that are easier to control: the actions we take in relation to our thoughts and feelings. They do this by taking a focus on creating changes in context and ultimately in behavior. Acceptance includes especially a focus on allowing or opening up to feelings rather than struggling with them or retreating from them. Here, the capacity for openness is a contextual process.

Acceptance methods are not used in isolation. They are usually used in combination with other traditional behavior change strategies, with methods to facilitate values clarification, committed action, and other methods from ACT. Notions of acceptance have even been incorporated into many behavioral and cognitive therapies before, including dialectical behavior therapy [13] and mindfulness-based treatment [14,15], and so this process is not the exclusive domain of ACT. In implementing acceptance-based methods, patients are taught skills, such as to (a) notice feelings specifically in detail, (b) notice that thoughts about pain are products of thinking and not the same as direct experience, (c) notice urges to struggle with thoughts and feelings, (d) to practice refraining from struggling and adopt an observing, allowing, and “making room”–type posture, and (e) take action in line with their goals [4,5].

The wider processes around acceptance in combination are referred to as psychological flexibility [16]. Psychological flexibility relates to one’s ability to directly contact the present moment; to be aware of the thoughts, feelings and potentially unwanted internal experiences it brings; and to follow through with a behavior change or persist with a chosen behavior in the direction of chosen values. Psychological flexibility is the model for psychological health from an ACT perspective [17].

Psychological Flexibility and the 6 Core ACT Processes

Acceptance

Acceptance involves the patients’ willingness to have pain while remaining able to actively choose to continue participating in their life as they want it to be. ACT encour-ages patients to act in ways that are consistent with direct experiences rather than what the mind interprets these events to mean.

Cognitive Defusion

Cognitive defusion is the process of modifying one’s reaction to thoughts by constructing contexts where the influences of these thoughts on behavior are lessened [18]. Unlike traditional cognitive behavior approaches, in ACT it is not the content and actual validity of these thoughts that is challenged but the functions, or influences, of thoughts [19].

Present Moment Awareness

Contact with the present moment reflects the process wherein the person is aware of the situation in “the now” as opposed to focusing on events that happened in the past or might happen in the future [18]. To be “present” requires the individual to flexibly focus attention on experiences as they are happening in the environment, in real time, and to be fully open to what is taking place [20]. It is important the individual is able to notice when he or she is not acting in relation to the present moment and has the ability to shift attention to the present if this shift benefits them.

Self as Context

The sense of self-as-context or self-as-observer is considered the ability to adopt a perspective or point of view that is separate from and not defined by thoughts and feelings or even the physical body. This contrasts a sense of self as made up of personality characteristics, self-evaluations, or a narrative about who we are [5,16]. In ACT, perspective taking can be trained to help people connect with the experience of a distinction between self and psychological experiences. From this, one can choose to follow one’s inner verbal constructions of what defines us, our “stories” of who we are, in certain situations when it works to do so, and not in situations where it leads to unhealthy responses and behavioral restriction.

Values

Values are defined as guiding principles in one’s life. Values are often contrasted with goals, where the difference is that goals can be achieved while values are part of an ongoing process of action and cannot be completed once and for all. In a sense, goals represent set plans of action to be achieved while values are general life directions. If life is like a journey, then goals would be the chosen destination and values would simply be represented by a general direction of travel. Values are helpful when patients struggle with unwanted internal experiences like pain, as they not only serve as a guide for the client to persist in behavior change but also function as a motivating element. Values clarification exercise in therapy encourages the patient to define their values in specific domains of “career, family, intimate relationships, friendships, health, education and spirituality” [4,21] regardless of the primary problem. Personally chosen and clarified values can function as guides when people have difficulty initiating and maintaining behavior change in the presence of unwanted internal experiences.

Committed Action

Committed action is an ongoing process of redirecting behavior in order to create patterns of flexible and effective action in line with a defined value [22]. Patients are encouraged to follow through with their chosen actions that are in line with their values, and to persist or alter their course flexibly. Without the capacity for committed action, behavior change is less likely to persist and integrate into patterns of behavior more generally.

Case Study

Initial Presentation and History

Ms X, a 45-year-old woman, presents with the chief complaint of low back pain, which she has experienced for 3 years. She works part-time due to her pain problem. When she is not at work, she busies herself with seeking both conventional and alternative treatments for her pain condition. In the past, during periods where she experienced pain relief, she attempted to engage in her hobby of photography. However, this often led to a pain flare the next day and required 2 to 3 days of medical leave with increased medication from her PCP before she is able to return to work. As a result, Ms X chose to give up her hobby and focus on treating her pain instead. Ms X in in a constant struggle with her pain condition and believes that she can only return to photography, and live a more normal life, after her pain is cured.

• What are considerations for applying ACT in this scenario?

From an ACT conceptualization this case shows patterns of avoidance that are apparently not helping the person to reach her goals but are causing her distress and restrictions in functioning. An ACT therapist would approach this scenario by first reflecting how normal it is to struggle with pain and stop activities when in pain. From there they might (a) identify what the patient wants from treatment, (b) look at what has been done so far to attain this, (c) examine how well those things have been working, (d) consider the costs of the approach being taken, and (e) if the approach is not working and the cost is high, see if the patient is willing to stop this approach [23].

Therapist’s Initial Approach

Therapist: By what you have told me, your pain has become a big problem for you and it has been going on a long time—3 years. I can see some of the impacts it has had in your life, such as on your work, your photography, and time spent seeking treatment.

Ms X: Yes, it seems like pain has taken over …

Therapist: Exactly, it seems that is a good way to say it. So, understanding that pain has taken over, can I ask you another question?

Ms X: If your question will help me get over this problem, of course.

Therapist: Ok. What is it you want from coming here to participate in this treatment?

Ms X: Well, I want to get rid of this pain, obviously. It’s ruining my life.

Therapist: Ah, that makes sense. You want to eliminate your pain because it has, as you say, ruined your life, and then I guess your life will be better again.

Ms X: Correct.

Therapist: So, can I check in with the things you have been doing so far to reach this goal to eliminate pain?

 Ms X: You name it, I’ve tried it: acupuncture, medication, herbs, rest, exercise, magnets, yoga, and more.

 Therapist: Ok, you have tried many treatments focused on trying to get rid of the pain. I think that’s a very natural thing to do. In your experience have these methods been successful?

 Ms X: Well, some of them seem to work at the time but it all becomes very confusing, because here I am looking for another treatment. It can feel good to get away from the pain for a little while, but soon I will experience a pain flare bringing me back to square one.

 Therapist: I see what you are saying. Let me ask my earlier question in a different way. What would your life look like, and what would you be doing, if your pain were not the problem it is today?

 Ms X: I would be taking pictures again, be more consistent at work, and spend less time seeking treatments.

Therapist: So, is it your experience that the methods you have been using have helped you to live life this way?

Ms X: … I never thought about it that way ...

• What exercises or techniques are used in ACT?

In practice, ACT is somewhat unique in that it often relies on the use of metaphors and experiential exercises in treatment delivery. Metaphors and stories are used in treatment and communicated in terms that fit with the experience and background of the person seeking treatment. Although therapists can select from among many widely used and often appropriate metaphors and stories, an experienced therapist is likely to create patient specific metaphors “live,” within the context of a particular session. This is consistent with the philosophical underpinning of ACT in its aims for individual tailoring of methods. Unlike other current psychotherapeutic approaches that place a higher value on sticking to a specified protocol, the theory and philosophy behind ACT allow for flexibility and are open to creativity, individual style, and situational sensitivity of the therapist. This is expected to allow the patient to also adopt a similar sensitivity to changing environmental contingencies [19]. In ACT, the techniques typically do not follow a cookbook style of treatment delivery.

Case Continued

Therapist: What if trying to control your thoughts and feelings were not the answer?

Ms X: I have no idea what you mean.

Therapist: Well, you certainly have focused a lot of your effort on trying not to have the thoughts and feelings that seem to block you.

Ms X: What else is there to do, really?

Therapist: If you are willing to experiment with something, try this. Don’t think of a pineapple. (pause for 30 to 60 seconds). Ok, what happens.

Ms X: It didn’t work—I kept thinking about a pineapple.

Therapist: Weird, huh? Notice what is happening here. I wonder if some of your struggles with your experiences are just like this. It’s like by trying to get rid of something, there it is! I wonder if there were another way to do this, do you think you might be willing to test it out?

Ms X: Yes, I can try.

Further ACT Methods

ACT includes numerous experience-based methods and also direct rehearsal of targeted skills. In the previous scen-ario, the therapist might then proceed to instruction and practice of one or another type of acceptance-based skill, something like an “exposure” session or a mindfulness type of exercise that includes having the participant sit with the experience without doing anything else but observe it. The other type of method used includes metaphors that reveal how circumstances and behavior often work in life [4,16].

An Acceptance-Based Metaphor

Therapist: Imagine that you are new to the neighborhood and you invited all your neighbors over to a housewarming party. Everyone in the neighborhood is invited. On that day, the party’s going great, and here comes Joe, who smells and looks like he has not bathed in days. You are embarrassed by the way he looks and smells and try to close the door on him. However, he shows you a flyer that you put up stating that everyone in the neighborhood is invited. So you let him in and quickly shove him to the kitchen so that he will not embarrass you and disrupt your party. However, to stop him from leaving the kitchen, you end up having to stand guard at the doorway. Meanwhile the party is going on and your guests are enjoying themselves, but do you notice what else is happening here?

Ms X: I’ve stopped myself from enjoying my party in order to keep Joe away.

Therapist: What if your pain was like Joe?

Ms X: Huh? … Ah, I think I see what you are saying…

Therapist: It’s like if you allow Joe to simply be another guest, you can do whatever you like at your party. On the other hand, if you say “no” to Joe you also say “no” to the party.

Ms X: Are you saying that it is for me to choose?

• What is the role of therapist in modeling behavior change in ACT?

An important distinction can be made between talking about behavior change and doing behavior change. Within the psychological flexibility model the emphasis is placed on the latter. Here, especially through the use of experiential exercises, clients are put into contact with the experiences that have coordinated unhealthy behavior patterns in the past so that more effective behavior patterns can be acquired. Treatment delivery is guided by the underlying behavioral philosophy and theory. Patients learn to reduce the dominant influence of the literal meaning of language as the only tool for behavior change. Direct experience is moved to the front of awareness and literal meaning, mental and verbal analysis, and so forth, are moved to the back [20]. In treatment, the therapist models for the patient the behavior change processes that are being targeted and also may use examples from his or her life as well as that of the patient’s to develop psychological flexibility [22]. An example might include a therapist’s response to a person who shows an experience of emotional distress and struggling to manage this distress. Here the therapist, in line with ACT, instead of acting in some way to attempt to lessen the distress, would consciously show openness to the experiences and to their own reactions to helplessness around these experiences.

The therapist might say:

 “I would feel tired and probably in pain too if I did what you just did. Could we do a little closed-eyes exercise? Shall we put the distressing thought you are having on the table, and focus on it, and we can “observe” what your mind does, and what happens in your body and your emotions when that thought shows up? Are you willing?”

 “I’m feeling confused about this issue myself - how about both of us sitting quietly for a moment or two and observe what our minds do in response to this, just slowing things down, and watching?”

 “I feel anxious when I believe that my thoughts about pain are true - like I have to do something to make it go away but I don’t know how. What shows up for you when you believe such thoughts about pain?”

• How and when should ACT be used?

Based on current evidence how and when ACT ought to be used, as opposed to other treatment options, will be largely up to the individual professional and their level of competence. ACT is a form of CBT and many of the same guides pertain. In line with the pragmatic approach of ACT, an approach that makes ACT broadly applicable, there is no one particular manualised or scripted treatment protocol that must be adhered to in treatment for one specific condition or another. As mentioned earlier, the ACT approach does not usually follow a cookbook style of delivery, nor is it rigidly guided by strict protocols. There are protocols shared by researchers to support further development but there is no process by which these are deemed “official” or “recognized” or approved by anyone in particular.

A wide range of metaphors and exercises based on a set of behavioral principles that target a particular function has been proposed in ACT and this is part of its uniqueness as a therapeutic model.

Those developing ACT also have not required a standardised certification process to delivering ACT. Instead, they have chosen to create an open community of contributing researchers and clinicians who are “members” by virtue of their commitment to the same approach to clinical development and the same clinical model. Practicing ACT requires that the clinician is aware of their own competencies and delivers treatment accordingly.

• How effective is ACT?

Numerous studies have supported a general role of psychological flexibility in improving the well-being and physical functioning of patients with chronic pain, including patients in specialty care [24,28] and primary care [26]. Many studies support the particular role of acceptance of pain in adjustment to chronic pain [27–30]. Pain acceptance is a better predictor of outcomes than pain severity itself [31,32].

There are now several relatively large-scale studies conducted in actual clinical practice settings that demonstrate the effectiveness of ACT for chronic pain [25,27,33,34]. A more recent study, also conducted in an actual clinical practice setting, provided support for the specific treatment processes proposed within this approach [35]. This study showed that changes in traditionally conceived methods of pain management were unrelated to treatment improvements of pain intensity, physical disability, anxiety and depression for those who participated in treatment, while changes in psychological flexibility were consistently and significantly related to these improvements, with the exception of the results for depression.

Randomised Controlled Trials (RCTs)

To date, there are a total of 7 RCTs related to ACT and chronic pain [36–42], each providing supportive evidence. For example, in one of the early studies, Dahl and colleagues [36] showed that in comparison to treatment as usual, a group of workers who were at risk of long-term absenteeism from work due to pain or stress had a significant reduction in sick leave and healthcare usage after attending four hours of ACT sessions.

Wicksell and colleagues [37,38] conducted 2 separate RCTs with participants who suffered whiplash-associated disorder (WAD) and fibromyalgia, respectively. Post-treatment results of both RCTs showed an improvement in physical functioning, depression and psychological flexibility in the treatment group with gains maintained at follow-up. In addition, participants in the treatment group with WAD showed an improvement in life satisfaction and fear of movement while those in the treatment group with fibromyalgia showed significant improvements in fibromyalgia impact, self-efficacy and anxiety. There was however no change in pain intensity in those who received the ACT-based treatments.

An ACT-based treatment including a self-help manual showed a significant increase in acceptance, satisfaction in life with a higher level of function and decreased pain intensity compared with a wait-list condition and with applied relaxation (AR) [40]. In comparison to the AR condition, participants in the ACT condition also reported a significantly higher level of engagement in meaningful activities and a willingness to experience pain. Follow-up data support the maintenance of these improvements at first follow-up but differences were not significant at the second follow-up. Both depression and anxiety scores improved in both treatment groups.

Wetherell and colleagues [39] compared the effectiveness of ACT and traditional CBT and found that they both produced positive results. Results from the study also showed higher satisfaction in participants who attended ACT treatment than those that attended CBT treatment, suggesting that ACT “is an effective and acceptable” intervention for patients with chronic pain. Overall acceptance of pain was shown to differentiate patients who could function well with chronic pain from those that continued to suffer with it after treatment.

More recently the first internet-based RCT for ACT with chronic pain was conducted [41]. The authors found a reduction in measures of pain-related distress, depressive symptoms, and anxiety, with these gains maintained at 6 months follow-up in the ACT treatment group compared with controls. The most recent RCT was a pilot trial of a group-based treatment of people with chronic pain recruited from general practices in the UK [42]. Participants were randomised to either an ACT-based treatment or treatment as usual. Participants in the ACT-based group underwent 4 sessions each lasting 4 hours with the first 3 sessions completed in 1 week and the last session completed a week later. At 3 months follow-up, participants in the ACT group had lower disability, depression, and higher pain acceptance.

In general, results from the ACT-based RCTs on chronic pain support the efficacy of the treatment and reflect a high degree of versatility, based on the wide variety of modes of delivery tested. However, RCTs for chronic pain are still relatively few with some studies limited to small sample sizes, thus making it difficult to reach definitive conclusions on the general efficacy of ACT in chronic pain treatment. What the studies do seem to show is that ACT is a good alternative treatment option to more traditionally conceived current CBT-based treatments for chronic pain. Larger sample sizes and higher quality studies are needed to strengthen and establish the effectiveness of ACT and to understand the potential impact of wider implementation in clinical practice.

Meta-Analyses

A total of 4 meta-analyses [43–46] have been conducted on acceptance- or ACT-based treatment studies. Although the earlier meta-analyses [43,44] did not separately report the effectiveness of ACT for chronic pain, they reported a moderate effect size for ACT in general, with no evidence that ACT is more effective than established treatments.

Ruiz [46] conducted a review focusing on outcome or mediation/moderation type studies that compared ACT and CBT treatments. His review was not specific to chronic pain, although one study [39] involving a sample of chronic pain patients was included. Moderate effect sizes were found that favored ACT, with ACT showing a greater impact on change processes (g = 0.38) compared to no impact found in CBT (g = 0.05).

Essentially, only one meta-analysis [45] specifically reviewed the efficacy in chronic pain studies. Pain inten-sity and depression were selected as primary outcome measures, with anxiety, physical well-being, and quality of life selected as secondary outcomes. Out of 22 studies that were included in the review, only 2 studies [36,37] were ACT-based RCTs, with the rest of the studies mindfulness-based interventions. The overall effect size of 0.37 was found for pain and 0.32 for depression. In general, results showed significant effect sizes for both primary and secondary outcome measures in favor of the “acceptance-based treatments.” The authors concluded that at present, mindfulness-based stress reduction programs and ACT-based programs may not be superior to CBT but could be good alternatives for people with chronic pain.

The appropriateness of using pain intensity as a primary outcome measure for ACT-based studies is questionable [45]. The focus of ACT is to increase function rather than to reduce pain symptoms; hence possibly including interference of pain in daily life might be a more appropriate outcome measure.

Other Studies

A particularly important question to answer about ACT concerns its cost-effectivness, and we still know relatively little about this. We do know that when people participate in ACT-based treatments they are able to reduce medication use and health care visits and return to work after extended periods away from work [27,28]. It remains to conduct full health economic analyses of this type of approach for chronic pain.

ACT is known to produce significant benefits widely, in other applications apart from chronic pain, such as in workplace stress [47], psychosis [48], obsessive-compulsive disorder [49], and depression [50], among other mental health conditions [51].

• What are implications for policy makers?

Results from studies of ACT in chronic pain and in other areas are disseminating rapidly. This dissemination is aided in part by a professional organization devoted to ACT and psychological flexibility (Association for Contextual Behavioral Science; www.contextualscience.org), which has a new journal, the Journal of Contextual Behavioral Science, started in 2012.

With the development of ACT a focus on implementation, training, and treatment integrity began early. There was an implementation study of ACT was published by Strosahl and colleagues in 1998. Their study showed that training clinicians in ACT produced better outcomes and better treatment completion rates in an outpatient setting in comparison to clinicians not receiving this training.

Processes of training have also appeared during relatively early phases of research into ACT. Lappalainen and colleagues [52] compared the impact of treatment provided by trainee therapists trained in both a traditional CBT model and ACT. Here each trainee therapist treated one patient with traditional CBT and one with ACT. Although the therapists reported higher confidence in delivering traditional CBT, patients treated within an ACT model showed better symptoms improvement. Also, improved acceptance during treatment significantly predicted improvements across both groups of patients. Essentially, therapists with only a limited amount of training in both models demonstrated better clinical results with ACT.

A group-based ACT intervention has also been shown to be effective in reducing stress and improving the professional performance of clinical psychology trainees [53]. Here the trainees found the intervention personally and professionally useful and a majority showed a significant increase in psychological flexibility. This supports the applicability of ACT not only as a model to guide therapy but also as a model to guide training and professional performance [54]. Other results in a pain management setting show that transitioning to ACT as a treatment model can have similar benefits and may increase job satisfaction and staff well-
being [55].

• What are criticisms of ACT?

Many strong supporters of cognitive therapy and more traditional versions of CBT in the field claim that ACT is not new nor better than other current versions of CBT [56]. The proponents of ACT openly acknowledge that many methods used within ACT are adopted or modified from other established therapies [4]. Criticisms are not specific to the application of ACT with chronic pain but are based on others’ perceptions of ACT as a treatment approach and treatment techniques used in ACT in general.

Ost [43] criticised ACT and the third-wave therapies on 2 main grounds. First, he concluded that ACT and the rest of the third-wave therapies were not meeting the criteria of empirically supported treatments. He further concluded that there is no strong evidence to show that ACT is more effective than cognitive therapy. The methods of the Ost review have been challenged [57], yet to a certain degree the points raised are correct. Most of the limitations noted reflect a difference in the maturity of the evidence base for ACT versus traditional CBT-based approaches. Indeed, in comparison to CBT, which is the most empirically established form of psychotherapy and an active area of research for more than 40 years, ACT can be considered to be in its infancy stage of empirically supported treatments, where treatment evidence and availability of high-quality RCTs in general are few at present. Specific research on ACT for chronic pain though supportive is still preliminary to a certain degree. Even so, ACT for pain is regarded as an empirically supported treatment by the body within the American Psychological Association authorized to make this determination [58].

Conclusion

ACT is essentially a form of CBT, considered broadly. ACT brings with it a different philosophy and approach to science compared with some other forms of CBT—this can lead to some distinctive strategies and methods in treatment for chronic pain. Like traditionally designed CBT, however, ACT similarly aims for behavior change as the end point.

ACT is grounded in specific philosophical assumptions and includes the model of psychological flexibility at its core. Preliminary findings in broad clinical and nonclinical populations support the efficacy, effectiveness, and processes in the psychological flexibility model as mediators of change, in ACT [46,59]. Research has shown that most of the 6 ACT processes, all of those so far investigated, correlate with improved daily functioning and emotional well-being in patients with chronic pain. The evidence base for ACT is still developing. Larger trials, more carefully designed trials, and a continued focus on processes of change will be needed to strengthen this base.

Corresponding author: Su-Yin Yang, Health Psychology Section, Psychology Department, Institute of Psychiatry, King’s College London, 5th Fl, Bermondsey Wing, Guy’s Campus, London SE1 9RT, [email protected].

Financial disclosures: None.

Author contributions: conception and design, SY, LMM; analysis and interpretation of data, SY; drafting of article, SY, LMM; critical revision of the article, LMM; administrative or technical support, LMM; collection and assembly of data, SY.

Abstract

• Objective: To describe Acceptance and Commitment Therapy (ACT) and its application in the treatment of chronic pain.
• Methods: Review of the theoretical and clinical literature and presentation of a case example.
• Results: General cognitive behavioral approaches for chronic pain have a consistent and large evidence base supporting their benefits. Even so, these treatments continue to develop with the aim to improve. One example of a relatively new development within the cognitive behavioral approaches is ACT, a treatment that focuses on increasing psychological flexibility. Here we describe ACT and the therapeutic model on which it is based, present its distinguishing features, and summarize the evidence for it as a treatment for chronic pain. We also discuss such issues as dissemination, implementation, and training.
• Conclusion: There are now 7 randomized controlled trials, a number of innovative uncontrolled trials, and at least 1 systematic review that support the clinical efficacy and effectiveness of ACT for chronic pain. Further research and development of this approach is underway.

The introduction of the gate control theory of pain [1] in 1965, among other events, signaled a shift in our understanding of pain, particularly chronic pain. This shift, which continues today, is a shift from a predominantly biomedical model of chronic pain to a biospsychosocial model. This model, as the name suggests, includes psycho-social influences in a key role in relation to the experience of pain and the impact of this experience. During this same period of time, psychosocial models and treatment methods have also shifted and evolved. This evolution has included the operant approach [2], the cognitive behavioral approach [3], and the latest developments, contextual cognitive behavioral approaches [4,5], among which Acceptance and Commitment Therapy (ACT) and mindfulness-based therapies are key examples.

Until about 10 years ago, the mainstream of psycho-logical treatments for chronic pain and other physical health problems was dominated almost exclusively by concepts and methods of what we will refer to as “traditional” cognitive behavioral therapy (CBT). Specific constructs within what is called the “common sense model” [6], such as illness perceptions, beliefs about control over one’s illness, amongst other constructs such as self-efficacy, catastrophising, fear avoidance, and pain-related anxiety, captured a substantial focus of research and treatment development during most of the past 3 decades [7]. The treatment methods that have emerged and persisted from this work have included relaxation, attention-based and cognitive coping strategies, cognitive restructuring, the use of imagery, and certain activity management strategies [8]. However, despite consistent supportive evidence for CBT interventions for chronic pain [9], there remain gaps and areas of relative weakness, both in the conceptual models underlying this work and in the base of evidence. Research clearly shows that not all patients benefit from traditional CBT interventions, and recent reviews of CBT for chronic pain generally show effect sizes that are usually small or mediumat best [9–11].

The Problem with Pain

Pain hurts and is often viewed as harmful, and this leads to fear or anxiety, avoidance, or attempts to control the pain. Seeking to control pain is entirely natural and even seems necessary to reduce the undesirable effects of pain in one’s life.

Dependent on the situation, pain avoidance, sometimes also referred to as “fear avoidance,” in studies of chronic pain can present itself in many forms. Avoidance behavior can include refusal to engage in any activity believed to cause an increase in pain. It may also include “guarding” or bracing around an area of pain, information seeking, treatment seeking, taking medications, overdosing on medications, using aids like heat or ice, withdrawing from social activity, as well as being unwilling to talk about emotional experiences, amongst others [5]. Today, avoidance is recognized as a key foundation element in pain-related suffering and disability [12], and addressing it effectively has become a prime focus in many or most current treatments.

Acceptance and Psychological Flexibility

In recent years, the concept of “acceptance” has gained prominence as a potentially important process for addressing a broad array of psychological problems, including those associated with chronic pain. From this new interest, a fundamentally different treatment emphasis has emerged. This includes a shift away from a predominant focus on changing thoughts and feelings, a focus sometimes adopted within some traditional CBT methods, towards a focus on reducing the influence of thoughts and feelings on our actions instead. This can be a rather confusing distinction. This is because the influence of our thoughts and feelings is often automatic and even invisible to us as it occurs. As such, the influences of our thoughts and feelings appear directly tied to the content of thoughts and feelings, but the matter is not that simple. Clearly there are occasions when our actions contradict our thoughts and feelings, such as when we have perfectly confident beliefs and fail, or significant anxiety and perform successfully. Such instances illustrate what we might call a “2-dimensional” quality of experience; it is the content of experience and the context of experience that determine the influence exerted. Suffice it to say acceptance-based methods are designed to address the difference between experiences that are difficult to control, such as thoughts and feelings, and things that are easier to control: the actions we take in relation to our thoughts and feelings. They do this by taking a focus on creating changes in context and ultimately in behavior. Acceptance includes especially a focus on allowing or opening up to feelings rather than struggling with them or retreating from them. Here, the capacity for openness is a contextual process.

Acceptance methods are not used in isolation. They are usually used in combination with other traditional behavior change strategies, with methods to facilitate values clarification, committed action, and other methods from ACT. Notions of acceptance have even been incorporated into many behavioral and cognitive therapies before, including dialectical behavior therapy [13] and mindfulness-based treatment [14,15], and so this process is not the exclusive domain of ACT. In implementing acceptance-based methods, patients are taught skills, such as to (a) notice feelings specifically in detail, (b) notice that thoughts about pain are products of thinking and not the same as direct experience, (c) notice urges to struggle with thoughts and feelings, (d) to practice refraining from struggling and adopt an observing, allowing, and “making room”–type posture, and (e) take action in line with their goals [4,5].

The wider processes around acceptance in combination are referred to as psychological flexibility [16]. Psychological flexibility relates to one’s ability to directly contact the present moment; to be aware of the thoughts, feelings and potentially unwanted internal experiences it brings; and to follow through with a behavior change or persist with a chosen behavior in the direction of chosen values. Psychological flexibility is the model for psychological health from an ACT perspective [17].

Psychological Flexibility and the 6 Core ACT Processes

Acceptance

Acceptance involves the patients’ willingness to have pain while remaining able to actively choose to continue participating in their life as they want it to be. ACT encour-ages patients to act in ways that are consistent with direct experiences rather than what the mind interprets these events to mean.

Cognitive Defusion

Cognitive defusion is the process of modifying one’s reaction to thoughts by constructing contexts where the influences of these thoughts on behavior are lessened [18]. Unlike traditional cognitive behavior approaches, in ACT it is not the content and actual validity of these thoughts that is challenged but the functions, or influences, of thoughts [19].

Present Moment Awareness

Contact with the present moment reflects the process wherein the person is aware of the situation in “the now” as opposed to focusing on events that happened in the past or might happen in the future [18]. To be “present” requires the individual to flexibly focus attention on experiences as they are happening in the environment, in real time, and to be fully open to what is taking place [20]. It is important the individual is able to notice when he or she is not acting in relation to the present moment and has the ability to shift attention to the present if this shift benefits them.

Self as Context

The sense of self-as-context or self-as-observer is considered the ability to adopt a perspective or point of view that is separate from and not defined by thoughts and feelings or even the physical body. This contrasts a sense of self as made up of personality characteristics, self-evaluations, or a narrative about who we are [5,16]. In ACT, perspective taking can be trained to help people connect with the experience of a distinction between self and psychological experiences. From this, one can choose to follow one’s inner verbal constructions of what defines us, our “stories” of who we are, in certain situations when it works to do so, and not in situations where it leads to unhealthy responses and behavioral restriction.

Values

Values are defined as guiding principles in one’s life. Values are often contrasted with goals, where the difference is that goals can be achieved while values are part of an ongoing process of action and cannot be completed once and for all. In a sense, goals represent set plans of action to be achieved while values are general life directions. If life is like a journey, then goals would be the chosen destination and values would simply be represented by a general direction of travel. Values are helpful when patients struggle with unwanted internal experiences like pain, as they not only serve as a guide for the client to persist in behavior change but also function as a motivating element. Values clarification exercise in therapy encourages the patient to define their values in specific domains of “career, family, intimate relationships, friendships, health, education and spirituality” [4,21] regardless of the primary problem. Personally chosen and clarified values can function as guides when people have difficulty initiating and maintaining behavior change in the presence of unwanted internal experiences.

Committed Action

Committed action is an ongoing process of redirecting behavior in order to create patterns of flexible and effective action in line with a defined value [22]. Patients are encouraged to follow through with their chosen actions that are in line with their values, and to persist or alter their course flexibly. Without the capacity for committed action, behavior change is less likely to persist and integrate into patterns of behavior more generally.

Case Study

Initial Presentation and History

Ms X, a 45-year-old woman, presents with the chief complaint of low back pain, which she has experienced for 3 years. She works part-time due to her pain problem. When she is not at work, she busies herself with seeking both conventional and alternative treatments for her pain condition. In the past, during periods where she experienced pain relief, she attempted to engage in her hobby of photography. However, this often led to a pain flare the next day and required 2 to 3 days of medical leave with increased medication from her PCP before she is able to return to work. As a result, Ms X chose to give up her hobby and focus on treating her pain instead. Ms X in in a constant struggle with her pain condition and believes that she can only return to photography, and live a more normal life, after her pain is cured.

• What are considerations for applying ACT in this scenario?

From an ACT conceptualization this case shows patterns of avoidance that are apparently not helping the person to reach her goals but are causing her distress and restrictions in functioning. An ACT therapist would approach this scenario by first reflecting how normal it is to struggle with pain and stop activities when in pain. From there they might (a) identify what the patient wants from treatment, (b) look at what has been done so far to attain this, (c) examine how well those things have been working, (d) consider the costs of the approach being taken, and (e) if the approach is not working and the cost is high, see if the patient is willing to stop this approach [23].

Therapist’s Initial Approach

Therapist: By what you have told me, your pain has become a big problem for you and it has been going on a long time—3 years. I can see some of the impacts it has had in your life, such as on your work, your photography, and time spent seeking treatment.

Ms X: Yes, it seems like pain has taken over …

Therapist: Exactly, it seems that is a good way to say it. So, understanding that pain has taken over, can I ask you another question?

Ms X: If your question will help me get over this problem, of course.

Therapist: Ok. What is it you want from coming here to participate in this treatment?

Ms X: Well, I want to get rid of this pain, obviously. It’s ruining my life.

Therapist: Ah, that makes sense. You want to eliminate your pain because it has, as you say, ruined your life, and then I guess your life will be better again.

Ms X: Correct.

Therapist: So, can I check in with the things you have been doing so far to reach this goal to eliminate pain?

 Ms X: You name it, I’ve tried it: acupuncture, medication, herbs, rest, exercise, magnets, yoga, and more.

 Therapist: Ok, you have tried many treatments focused on trying to get rid of the pain. I think that’s a very natural thing to do. In your experience have these methods been successful?

 Ms X: Well, some of them seem to work at the time but it all becomes very confusing, because here I am looking for another treatment. It can feel good to get away from the pain for a little while, but soon I will experience a pain flare bringing me back to square one.

 Therapist: I see what you are saying. Let me ask my earlier question in a different way. What would your life look like, and what would you be doing, if your pain were not the problem it is today?

 Ms X: I would be taking pictures again, be more consistent at work, and spend less time seeking treatments.

Therapist: So, is it your experience that the methods you have been using have helped you to live life this way?

Ms X: … I never thought about it that way ...

• What exercises or techniques are used in ACT?

In practice, ACT is somewhat unique in that it often relies on the use of metaphors and experiential exercises in treatment delivery. Metaphors and stories are used in treatment and communicated in terms that fit with the experience and background of the person seeking treatment. Although therapists can select from among many widely used and often appropriate metaphors and stories, an experienced therapist is likely to create patient specific metaphors “live,” within the context of a particular session. This is consistent with the philosophical underpinning of ACT in its aims for individual tailoring of methods. Unlike other current psychotherapeutic approaches that place a higher value on sticking to a specified protocol, the theory and philosophy behind ACT allow for flexibility and are open to creativity, individual style, and situational sensitivity of the therapist. This is expected to allow the patient to also adopt a similar sensitivity to changing environmental contingencies [19]. In ACT, the techniques typically do not follow a cookbook style of treatment delivery.

Case Continued

Therapist: What if trying to control your thoughts and feelings were not the answer?

Ms X: I have no idea what you mean.

Therapist: Well, you certainly have focused a lot of your effort on trying not to have the thoughts and feelings that seem to block you.

Ms X: What else is there to do, really?

Therapist: If you are willing to experiment with something, try this. Don’t think of a pineapple. (pause for 30 to 60 seconds). Ok, what happens.

Ms X: It didn’t work—I kept thinking about a pineapple.

Therapist: Weird, huh? Notice what is happening here. I wonder if some of your struggles with your experiences are just like this. It’s like by trying to get rid of something, there it is! I wonder if there were another way to do this, do you think you might be willing to test it out?

Ms X: Yes, I can try.

Further ACT Methods

ACT includes numerous experience-based methods and also direct rehearsal of targeted skills. In the previous scen-ario, the therapist might then proceed to instruction and practice of one or another type of acceptance-based skill, something like an “exposure” session or a mindfulness type of exercise that includes having the participant sit with the experience without doing anything else but observe it. The other type of method used includes metaphors that reveal how circumstances and behavior often work in life [4,16].

An Acceptance-Based Metaphor

Therapist: Imagine that you are new to the neighborhood and you invited all your neighbors over to a housewarming party. Everyone in the neighborhood is invited. On that day, the party’s going great, and here comes Joe, who smells and looks like he has not bathed in days. You are embarrassed by the way he looks and smells and try to close the door on him. However, he shows you a flyer that you put up stating that everyone in the neighborhood is invited. So you let him in and quickly shove him to the kitchen so that he will not embarrass you and disrupt your party. However, to stop him from leaving the kitchen, you end up having to stand guard at the doorway. Meanwhile the party is going on and your guests are enjoying themselves, but do you notice what else is happening here?

Ms X: I’ve stopped myself from enjoying my party in order to keep Joe away.

Therapist: What if your pain was like Joe?

Ms X: Huh? … Ah, I think I see what you are saying…

Therapist: It’s like if you allow Joe to simply be another guest, you can do whatever you like at your party. On the other hand, if you say “no” to Joe you also say “no” to the party.

Ms X: Are you saying that it is for me to choose?

• What is the role of therapist in modeling behavior change in ACT?

An important distinction can be made between talking about behavior change and doing behavior change. Within the psychological flexibility model the emphasis is placed on the latter. Here, especially through the use of experiential exercises, clients are put into contact with the experiences that have coordinated unhealthy behavior patterns in the past so that more effective behavior patterns can be acquired. Treatment delivery is guided by the underlying behavioral philosophy and theory. Patients learn to reduce the dominant influence of the literal meaning of language as the only tool for behavior change. Direct experience is moved to the front of awareness and literal meaning, mental and verbal analysis, and so forth, are moved to the back [20]. In treatment, the therapist models for the patient the behavior change processes that are being targeted and also may use examples from his or her life as well as that of the patient’s to develop psychological flexibility [22]. An example might include a therapist’s response to a person who shows an experience of emotional distress and struggling to manage this distress. Here the therapist, in line with ACT, instead of acting in some way to attempt to lessen the distress, would consciously show openness to the experiences and to their own reactions to helplessness around these experiences.

The therapist might say:

 “I would feel tired and probably in pain too if I did what you just did. Could we do a little closed-eyes exercise? Shall we put the distressing thought you are having on the table, and focus on it, and we can “observe” what your mind does, and what happens in your body and your emotions when that thought shows up? Are you willing?”

 “I’m feeling confused about this issue myself - how about both of us sitting quietly for a moment or two and observe what our minds do in response to this, just slowing things down, and watching?”

 “I feel anxious when I believe that my thoughts about pain are true - like I have to do something to make it go away but I don’t know how. What shows up for you when you believe such thoughts about pain?”

• How and when should ACT be used?

Based on current evidence how and when ACT ought to be used, as opposed to other treatment options, will be largely up to the individual professional and their level of competence. ACT is a form of CBT and many of the same guides pertain. In line with the pragmatic approach of ACT, an approach that makes ACT broadly applicable, there is no one particular manualised or scripted treatment protocol that must be adhered to in treatment for one specific condition or another. As mentioned earlier, the ACT approach does not usually follow a cookbook style of delivery, nor is it rigidly guided by strict protocols. There are protocols shared by researchers to support further development but there is no process by which these are deemed “official” or “recognized” or approved by anyone in particular.

A wide range of metaphors and exercises based on a set of behavioral principles that target a particular function has been proposed in ACT and this is part of its uniqueness as a therapeutic model.

Those developing ACT also have not required a standardised certification process to delivering ACT. Instead, they have chosen to create an open community of contributing researchers and clinicians who are “members” by virtue of their commitment to the same approach to clinical development and the same clinical model. Practicing ACT requires that the clinician is aware of their own competencies and delivers treatment accordingly.

• How effective is ACT?

Numerous studies have supported a general role of psychological flexibility in improving the well-being and physical functioning of patients with chronic pain, including patients in specialty care [24,28] and primary care [26]. Many studies support the particular role of acceptance of pain in adjustment to chronic pain [27–30]. Pain acceptance is a better predictor of outcomes than pain severity itself [31,32].

There are now several relatively large-scale studies conducted in actual clinical practice settings that demonstrate the effectiveness of ACT for chronic pain [25,27,33,34]. A more recent study, also conducted in an actual clinical practice setting, provided support for the specific treatment processes proposed within this approach [35]. This study showed that changes in traditionally conceived methods of pain management were unrelated to treatment improvements of pain intensity, physical disability, anxiety and depression for those who participated in treatment, while changes in psychological flexibility were consistently and significantly related to these improvements, with the exception of the results for depression.

Randomised Controlled Trials (RCTs)

To date, there are a total of 7 RCTs related to ACT and chronic pain [36–42], each providing supportive evidence. For example, in one of the early studies, Dahl and colleagues [36] showed that in comparison to treatment as usual, a group of workers who were at risk of long-term absenteeism from work due to pain or stress had a significant reduction in sick leave and healthcare usage after attending four hours of ACT sessions.

Wicksell and colleagues [37,38] conducted 2 separate RCTs with participants who suffered whiplash-associated disorder (WAD) and fibromyalgia, respectively. Post-treatment results of both RCTs showed an improvement in physical functioning, depression and psychological flexibility in the treatment group with gains maintained at follow-up. In addition, participants in the treatment group with WAD showed an improvement in life satisfaction and fear of movement while those in the treatment group with fibromyalgia showed significant improvements in fibromyalgia impact, self-efficacy and anxiety. There was however no change in pain intensity in those who received the ACT-based treatments.

An ACT-based treatment including a self-help manual showed a significant increase in acceptance, satisfaction in life with a higher level of function and decreased pain intensity compared with a wait-list condition and with applied relaxation (AR) [40]. In comparison to the AR condition, participants in the ACT condition also reported a significantly higher level of engagement in meaningful activities and a willingness to experience pain. Follow-up data support the maintenance of these improvements at first follow-up but differences were not significant at the second follow-up. Both depression and anxiety scores improved in both treatment groups.

Wetherell and colleagues [39] compared the effectiveness of ACT and traditional CBT and found that they both produced positive results. Results from the study also showed higher satisfaction in participants who attended ACT treatment than those that attended CBT treatment, suggesting that ACT “is an effective and acceptable” intervention for patients with chronic pain. Overall acceptance of pain was shown to differentiate patients who could function well with chronic pain from those that continued to suffer with it after treatment.

More recently the first internet-based RCT for ACT with chronic pain was conducted [41]. The authors found a reduction in measures of pain-related distress, depressive symptoms, and anxiety, with these gains maintained at 6 months follow-up in the ACT treatment group compared with controls. The most recent RCT was a pilot trial of a group-based treatment of people with chronic pain recruited from general practices in the UK [42]. Participants were randomised to either an ACT-based treatment or treatment as usual. Participants in the ACT-based group underwent 4 sessions each lasting 4 hours with the first 3 sessions completed in 1 week and the last session completed a week later. At 3 months follow-up, participants in the ACT group had lower disability, depression, and higher pain acceptance.

In general, results from the ACT-based RCTs on chronic pain support the efficacy of the treatment and reflect a high degree of versatility, based on the wide variety of modes of delivery tested. However, RCTs for chronic pain are still relatively few with some studies limited to small sample sizes, thus making it difficult to reach definitive conclusions on the general efficacy of ACT in chronic pain treatment. What the studies do seem to show is that ACT is a good alternative treatment option to more traditionally conceived current CBT-based treatments for chronic pain. Larger sample sizes and higher quality studies are needed to strengthen and establish the effectiveness of ACT and to understand the potential impact of wider implementation in clinical practice.

Meta-Analyses

A total of 4 meta-analyses [43–46] have been conducted on acceptance- or ACT-based treatment studies. Although the earlier meta-analyses [43,44] did not separately report the effectiveness of ACT for chronic pain, they reported a moderate effect size for ACT in general, with no evidence that ACT is more effective than established treatments.

Ruiz [46] conducted a review focusing on outcome or mediation/moderation type studies that compared ACT and CBT treatments. His review was not specific to chronic pain, although one study [39] involving a sample of chronic pain patients was included. Moderate effect sizes were found that favored ACT, with ACT showing a greater impact on change processes (g = 0.38) compared to no impact found in CBT (g = 0.05).

Essentially, only one meta-analysis [45] specifically reviewed the efficacy in chronic pain studies. Pain inten-sity and depression were selected as primary outcome measures, with anxiety, physical well-being, and quality of life selected as secondary outcomes. Out of 22 studies that were included in the review, only 2 studies [36,37] were ACT-based RCTs, with the rest of the studies mindfulness-based interventions. The overall effect size of 0.37 was found for pain and 0.32 for depression. In general, results showed significant effect sizes for both primary and secondary outcome measures in favor of the “acceptance-based treatments.” The authors concluded that at present, mindfulness-based stress reduction programs and ACT-based programs may not be superior to CBT but could be good alternatives for people with chronic pain.

The appropriateness of using pain intensity as a primary outcome measure for ACT-based studies is questionable [45]. The focus of ACT is to increase function rather than to reduce pain symptoms; hence possibly including interference of pain in daily life might be a more appropriate outcome measure.

Other Studies

A particularly important question to answer about ACT concerns its cost-effectivness, and we still know relatively little about this. We do know that when people participate in ACT-based treatments they are able to reduce medication use and health care visits and return to work after extended periods away from work [27,28]. It remains to conduct full health economic analyses of this type of approach for chronic pain.

ACT is known to produce significant benefits widely, in other applications apart from chronic pain, such as in workplace stress [47], psychosis [48], obsessive-compulsive disorder [49], and depression [50], among other mental health conditions [51].

• What are implications for policy makers?

Results from studies of ACT in chronic pain and in other areas are disseminating rapidly. This dissemination is aided in part by a professional organization devoted to ACT and psychological flexibility (Association for Contextual Behavioral Science; www.contextualscience.org), which has a new journal, the Journal of Contextual Behavioral Science, started in 2012.

With the development of ACT a focus on implementation, training, and treatment integrity began early. There was an implementation study of ACT was published by Strosahl and colleagues in 1998. Their study showed that training clinicians in ACT produced better outcomes and better treatment completion rates in an outpatient setting in comparison to clinicians not receiving this training.

Processes of training have also appeared during relatively early phases of research into ACT. Lappalainen and colleagues [52] compared the impact of treatment provided by trainee therapists trained in both a traditional CBT model and ACT. Here each trainee therapist treated one patient with traditional CBT and one with ACT. Although the therapists reported higher confidence in delivering traditional CBT, patients treated within an ACT model showed better symptoms improvement. Also, improved acceptance during treatment significantly predicted improvements across both groups of patients. Essentially, therapists with only a limited amount of training in both models demonstrated better clinical results with ACT.

A group-based ACT intervention has also been shown to be effective in reducing stress and improving the professional performance of clinical psychology trainees [53]. Here the trainees found the intervention personally and professionally useful and a majority showed a significant increase in psychological flexibility. This supports the applicability of ACT not only as a model to guide therapy but also as a model to guide training and professional performance [54]. Other results in a pain management setting show that transitioning to ACT as a treatment model can have similar benefits and may increase job satisfaction and staff well-
being [55].

• What are criticisms of ACT?

Many strong supporters of cognitive therapy and more traditional versions of CBT in the field claim that ACT is not new nor better than other current versions of CBT [56]. The proponents of ACT openly acknowledge that many methods used within ACT are adopted or modified from other established therapies [4]. Criticisms are not specific to the application of ACT with chronic pain but are based on others’ perceptions of ACT as a treatment approach and treatment techniques used in ACT in general.

Ost [43] criticised ACT and the third-wave therapies on 2 main grounds. First, he concluded that ACT and the rest of the third-wave therapies were not meeting the criteria of empirically supported treatments. He further concluded that there is no strong evidence to show that ACT is more effective than cognitive therapy. The methods of the Ost review have been challenged [57], yet to a certain degree the points raised are correct. Most of the limitations noted reflect a difference in the maturity of the evidence base for ACT versus traditional CBT-based approaches. Indeed, in comparison to CBT, which is the most empirically established form of psychotherapy and an active area of research for more than 40 years, ACT can be considered to be in its infancy stage of empirically supported treatments, where treatment evidence and availability of high-quality RCTs in general are few at present. Specific research on ACT for chronic pain though supportive is still preliminary to a certain degree. Even so, ACT for pain is regarded as an empirically supported treatment by the body within the American Psychological Association authorized to make this determination [58].

Conclusion

ACT is essentially a form of CBT, considered broadly. ACT brings with it a different philosophy and approach to science compared with some other forms of CBT—this can lead to some distinctive strategies and methods in treatment for chronic pain. Like traditionally designed CBT, however, ACT similarly aims for behavior change as the end point.

ACT is grounded in specific philosophical assumptions and includes the model of psychological flexibility at its core. Preliminary findings in broad clinical and nonclinical populations support the efficacy, effectiveness, and processes in the psychological flexibility model as mediators of change, in ACT [46,59]. Research has shown that most of the 6 ACT processes, all of those so far investigated, correlate with improved daily functioning and emotional well-being in patients with chronic pain. The evidence base for ACT is still developing. Larger trials, more carefully designed trials, and a continued focus on processes of change will be needed to strengthen this base.

Corresponding author: Su-Yin Yang, Health Psychology Section, Psychology Department, Institute of Psychiatry, King’s College London, 5th Fl, Bermondsey Wing, Guy’s Campus, London SE1 9RT, [email protected].

Financial disclosures: None.

Author contributions: conception and design, SY, LMM; analysis and interpretation of data, SY; drafting of article, SY, LMM; critical revision of the article, LMM; administrative or technical support, LMM; collection and assembly of data, SY.

Abstract

• Objective: To describe Acceptance and Commitment Therapy (ACT) and its application in the treatment of chronic pain.
• Methods: Review of the theoretical and clinical literature and presentation of a case example.
• Results: General cognitive behavioral approaches for chronic pain have a consistent and large evidence base supporting their benefits. Even so, these treatments continue to develop with the aim to improve. One example of a relatively new development within the cognitive behavioral approaches is ACT, a treatment that focuses on increasing psychological flexibility. Here we describe ACT and the therapeutic model on which it is based, present its distinguishing features, and summarize the evidence for it as a treatment for chronic pain. We also discuss such issues as dissemination, implementation, and training.
• Conclusion: There are now 7 randomized controlled trials, a number of innovative uncontrolled trials, and at least 1 systematic review that support the clinical efficacy and effectiveness of ACT for chronic pain. Further research and development of this approach is underway.

The introduction of the gate control theory of pain [1] in 1965, among other events, signaled a shift in our understanding of pain, particularly chronic pain. This shift, which continues today, is a shift from a predominantly biomedical model of chronic pain to a biospsychosocial model. This model, as the name suggests, includes psycho-social influences in a key role in relation to the experience of pain and the impact of this experience. During this same period of time, psychosocial models and treatment methods have also shifted and evolved. This evolution has included the operant approach [2], the cognitive behavioral approach [3], and the latest developments, contextual cognitive behavioral approaches [4,5], among which Acceptance and Commitment Therapy (ACT) and mindfulness-based therapies are key examples.

Until about 10 years ago, the mainstream of psycho-logical treatments for chronic pain and other physical health problems was dominated almost exclusively by concepts and methods of what we will refer to as “traditional” cognitive behavioral therapy (CBT). Specific constructs within what is called the “common sense model” [6], such as illness perceptions, beliefs about control over one’s illness, amongst other constructs such as self-efficacy, catastrophising, fear avoidance, and pain-related anxiety, captured a substantial focus of research and treatment development during most of the past 3 decades [7]. The treatment methods that have emerged and persisted from this work have included relaxation, attention-based and cognitive coping strategies, cognitive restructuring, the use of imagery, and certain activity management strategies [8]. However, despite consistent supportive evidence for CBT interventions for chronic pain [9], there remain gaps and areas of relative weakness, both in the conceptual models underlying this work and in the base of evidence. Research clearly shows that not all patients benefit from traditional CBT interventions, and recent reviews of CBT for chronic pain generally show effect sizes that are usually small or mediumat best [9–11].

The Problem with Pain

Pain hurts and is often viewed as harmful, and this leads to fear or anxiety, avoidance, or attempts to control the pain. Seeking to control pain is entirely natural and even seems necessary to reduce the undesirable effects of pain in one’s life.

Dependent on the situation, pain avoidance, sometimes also referred to as “fear avoidance,” in studies of chronic pain can present itself in many forms. Avoidance behavior can include refusal to engage in any activity believed to cause an increase in pain. It may also include “guarding” or bracing around an area of pain, information seeking, treatment seeking, taking medications, overdosing on medications, using aids like heat or ice, withdrawing from social activity, as well as being unwilling to talk about emotional experiences, amongst others [5]. Today, avoidance is recognized as a key foundation element in pain-related suffering and disability [12], and addressing it effectively has become a prime focus in many or most current treatments.

Acceptance and Psychological Flexibility

In recent years, the concept of “acceptance” has gained prominence as a potentially important process for addressing a broad array of psychological problems, including those associated with chronic pain. From this new interest, a fundamentally different treatment emphasis has emerged. This includes a shift away from a predominant focus on changing thoughts and feelings, a focus sometimes adopted within some traditional CBT methods, towards a focus on reducing the influence of thoughts and feelings on our actions instead. This can be a rather confusing distinction. This is because the influence of our thoughts and feelings is often automatic and even invisible to us as it occurs. As such, the influences of our thoughts and feelings appear directly tied to the content of thoughts and feelings, but the matter is not that simple. Clearly there are occasions when our actions contradict our thoughts and feelings, such as when we have perfectly confident beliefs and fail, or significant anxiety and perform successfully. Such instances illustrate what we might call a “2-dimensional” quality of experience; it is the content of experience and the context of experience that determine the influence exerted. Suffice it to say acceptance-based methods are designed to address the difference between experiences that are difficult to control, such as thoughts and feelings, and things that are easier to control: the actions we take in relation to our thoughts and feelings. They do this by taking a focus on creating changes in context and ultimately in behavior. Acceptance includes especially a focus on allowing or opening up to feelings rather than struggling with them or retreating from them. Here, the capacity for openness is a contextual process.

Acceptance methods are not used in isolation. They are usually used in combination with other traditional behavior change strategies, with methods to facilitate values clarification, committed action, and other methods from ACT. Notions of acceptance have even been incorporated into many behavioral and cognitive therapies before, including dialectical behavior therapy [13] and mindfulness-based treatment [14,15], and so this process is not the exclusive domain of ACT. In implementing acceptance-based methods, patients are taught skills, such as to (a) notice feelings specifically in detail, (b) notice that thoughts about pain are products of thinking and not the same as direct experience, (c) notice urges to struggle with thoughts and feelings, (d) to practice refraining from struggling and adopt an observing, allowing, and “making room”–type posture, and (e) take action in line with their goals [4,5].

The wider processes around acceptance in combination are referred to as psychological flexibility [16]. Psychological flexibility relates to one’s ability to directly contact the present moment; to be aware of the thoughts, feelings and potentially unwanted internal experiences it brings; and to follow through with a behavior change or persist with a chosen behavior in the direction of chosen values. Psychological flexibility is the model for psychological health from an ACT perspective [17].

Psychological Flexibility and the 6 Core ACT Processes

Acceptance

Acceptance involves the patients’ willingness to have pain while remaining able to actively choose to continue participating in their life as they want it to be. ACT encour-ages patients to act in ways that are consistent with direct experiences rather than what the mind interprets these events to mean.

Cognitive Defusion

Cognitive defusion is the process of modifying one’s reaction to thoughts by constructing contexts where the influences of these thoughts on behavior are lessened [18]. Unlike traditional cognitive behavior approaches, in ACT it is not the content and actual validity of these thoughts that is challenged but the functions, or influences, of thoughts [19].

Present Moment Awareness

Contact with the present moment reflects the process wherein the person is aware of the situation in “the now” as opposed to focusing on events that happened in the past or might happen in the future [18]. To be “present” requires the individual to flexibly focus attention on experiences as they are happening in the environment, in real time, and to be fully open to what is taking place [20]. It is important the individual is able to notice when he or she is not acting in relation to the present moment and has the ability to shift attention to the present if this shift benefits them.

Self as Context

The sense of self-as-context or self-as-observer is considered the ability to adopt a perspective or point of view that is separate from and not defined by thoughts and feelings or even the physical body. This contrasts a sense of self as made up of personality characteristics, self-evaluations, or a narrative about who we are [5,16]. In ACT, perspective taking can be trained to help people connect with the experience of a distinction between self and psychological experiences. From this, one can choose to follow one’s inner verbal constructions of what defines us, our “stories” of who we are, in certain situations when it works to do so, and not in situations where it leads to unhealthy responses and behavioral restriction.

Values

Values are defined as guiding principles in one’s life. Values are often contrasted with goals, where the difference is that goals can be achieved while values are part of an ongoing process of action and cannot be completed once and for all. In a sense, goals represent set plans of action to be achieved while values are general life directions. If life is like a journey, then goals would be the chosen destination and values would simply be represented by a general direction of travel. Values are helpful when patients struggle with unwanted internal experiences like pain, as they not only serve as a guide for the client to persist in behavior change but also function as a motivating element. Values clarification exercise in therapy encourages the patient to define their values in specific domains of “career, family, intimate relationships, friendships, health, education and spirituality” [4,21] regardless of the primary problem. Personally chosen and clarified values can function as guides when people have difficulty initiating and maintaining behavior change in the presence of unwanted internal experiences.

Committed Action

Committed action is an ongoing process of redirecting behavior in order to create patterns of flexible and effective action in line with a defined value [22]. Patients are encouraged to follow through with their chosen actions that are in line with their values, and to persist or alter their course flexibly. Without the capacity for committed action, behavior change is less likely to persist and integrate into patterns of behavior more generally.

Case Study

Initial Presentation and History

Ms X, a 45-year-old woman, presents with the chief complaint of low back pain, which she has experienced for 3 years. She works part-time due to her pain problem. When she is not at work, she busies herself with seeking both conventional and alternative treatments for her pain condition. In the past, during periods where she experienced pain relief, she attempted to engage in her hobby of photography. However, this often led to a pain flare the next day and required 2 to 3 days of medical leave with increased medication from her PCP before she is able to return to work. As a result, Ms X chose to give up her hobby and focus on treating her pain instead. Ms X in in a constant struggle with her pain condition and believes that she can only return to photography, and live a more normal life, after her pain is cured.

• What are considerations for applying ACT in this scenario?

From an ACT conceptualization this case shows patterns of avoidance that are apparently not helping the person to reach her goals but are causing her distress and restrictions in functioning. An ACT therapist would approach this scenario by first reflecting how normal it is to struggle with pain and stop activities when in pain. From there they might (a) identify what the patient wants from treatment, (b) look at what has been done so far to attain this, (c) examine how well those things have been working, (d) consider the costs of the approach being taken, and (e) if the approach is not working and the cost is high, see if the patient is willing to stop this approach [23].

Therapist’s Initial Approach

Therapist: By what you have told me, your pain has become a big problem for you and it has been going on a long time—3 years. I can see some of the impacts it has had in your life, such as on your work, your photography, and time spent seeking treatment.

Ms X: Yes, it seems like pain has taken over …

Therapist: Exactly, it seems that is a good way to say it. So, understanding that pain has taken over, can I ask you another question?

Ms X: If your question will help me get over this problem, of course.

Therapist: Ok. What is it you want from coming here to participate in this treatment?

Ms X: Well, I want to get rid of this pain, obviously. It’s ruining my life.

Therapist: Ah, that makes sense. You want to eliminate your pain because it has, as you say, ruined your life, and then I guess your life will be better again.

Ms X: Correct.

Therapist: So, can I check in with the things you have been doing so far to reach this goal to eliminate pain?

 Ms X: You name it, I’ve tried it: acupuncture, medication, herbs, rest, exercise, magnets, yoga, and more.

 Therapist: Ok, you have tried many treatments focused on trying to get rid of the pain. I think that’s a very natural thing to do. In your experience have these methods been successful?

 Ms X: Well, some of them seem to work at the time but it all becomes very confusing, because here I am looking for another treatment. It can feel good to get away from the pain for a little while, but soon I will experience a pain flare bringing me back to square one.

 Therapist: I see what you are saying. Let me ask my earlier question in a different way. What would your life look like, and what would you be doing, if your pain were not the problem it is today?

 Ms X: I would be taking pictures again, be more consistent at work, and spend less time seeking treatments.

Therapist: So, is it your experience that the methods you have been using have helped you to live life this way?

Ms X: … I never thought about it that way ...

• What exercises or techniques are used in ACT?

In practice, ACT is somewhat unique in that it often relies on the use of metaphors and experiential exercises in treatment delivery. Metaphors and stories are used in treatment and communicated in terms that fit with the experience and background of the person seeking treatment. Although therapists can select from among many widely used and often appropriate metaphors and stories, an experienced therapist is likely to create patient specific metaphors “live,” within the context of a particular session. This is consistent with the philosophical underpinning of ACT in its aims for individual tailoring of methods. Unlike other current psychotherapeutic approaches that place a higher value on sticking to a specified protocol, the theory and philosophy behind ACT allow for flexibility and are open to creativity, individual style, and situational sensitivity of the therapist. This is expected to allow the patient to also adopt a similar sensitivity to changing environmental contingencies [19]. In ACT, the techniques typically do not follow a cookbook style of treatment delivery.

Case Continued

Therapist: What if trying to control your thoughts and feelings were not the answer?

Ms X: I have no idea what you mean.

Therapist: Well, you certainly have focused a lot of your effort on trying not to have the thoughts and feelings that seem to block you.

Ms X: What else is there to do, really?

Therapist: If you are willing to experiment with something, try this. Don’t think of a pineapple. (pause for 30 to 60 seconds). Ok, what happens.

Ms X: It didn’t work—I kept thinking about a pineapple.

Therapist: Weird, huh? Notice what is happening here. I wonder if some of your struggles with your experiences are just like this. It’s like by trying to get rid of something, there it is! I wonder if there were another way to do this, do you think you might be willing to test it out?

Ms X: Yes, I can try.

Further ACT Methods

ACT includes numerous experience-based methods and also direct rehearsal of targeted skills. In the previous scen-ario, the therapist might then proceed to instruction and practice of one or another type of acceptance-based skill, something like an “exposure” session or a mindfulness type of exercise that includes having the participant sit with the experience without doing anything else but observe it. The other type of method used includes metaphors that reveal how circumstances and behavior often work in life [4,16].

An Acceptance-Based Metaphor

Therapist: Imagine that you are new to the neighborhood and you invited all your neighbors over to a housewarming party. Everyone in the neighborhood is invited. On that day, the party’s going great, and here comes Joe, who smells and looks like he has not bathed in days. You are embarrassed by the way he looks and smells and try to close the door on him. However, he shows you a flyer that you put up stating that everyone in the neighborhood is invited. So you let him in and quickly shove him to the kitchen so that he will not embarrass you and disrupt your party. However, to stop him from leaving the kitchen, you end up having to stand guard at the doorway. Meanwhile the party is going on and your guests are enjoying themselves, but do you notice what else is happening here?

Ms X: I’ve stopped myself from enjoying my party in order to keep Joe away.

Therapist: What if your pain was like Joe?

Ms X: Huh? … Ah, I think I see what you are saying…

Therapist: It’s like if you allow Joe to simply be another guest, you can do whatever you like at your party. On the other hand, if you say “no” to Joe you also say “no” to the party.

Ms X: Are you saying that it is for me to choose?

• What is the role of therapist in modeling behavior change in ACT?

An important distinction can be made between talking about behavior change and doing behavior change. Within the psychological flexibility model the emphasis is placed on the latter. Here, especially through the use of experiential exercises, clients are put into contact with the experiences that have coordinated unhealthy behavior patterns in the past so that more effective behavior patterns can be acquired. Treatment delivery is guided by the underlying behavioral philosophy and theory. Patients learn to reduce the dominant influence of the literal meaning of language as the only tool for behavior change. Direct experience is moved to the front of awareness and literal meaning, mental and verbal analysis, and so forth, are moved to the back [20]. In treatment, the therapist models for the patient the behavior change processes that are being targeted and also may use examples from his or her life as well as that of the patient’s to develop psychological flexibility [22]. An example might include a therapist’s response to a person who shows an experience of emotional distress and struggling to manage this distress. Here the therapist, in line with ACT, instead of acting in some way to attempt to lessen the distress, would consciously show openness to the experiences and to their own reactions to helplessness around these experiences.

The therapist might say:

 “I would feel tired and probably in pain too if I did what you just did. Could we do a little closed-eyes exercise? Shall we put the distressing thought you are having on the table, and focus on it, and we can “observe” what your mind does, and what happens in your body and your emotions when that thought shows up? Are you willing?”

 “I’m feeling confused about this issue myself - how about both of us sitting quietly for a moment or two and observe what our minds do in response to this, just slowing things down, and watching?”

 “I feel anxious when I believe that my thoughts about pain are true - like I have to do something to make it go away but I don’t know how. What shows up for you when you believe such thoughts about pain?”

• How and when should ACT be used?

Based on current evidence how and when ACT ought to be used, as opposed to other treatment options, will be largely up to the individual professional and their level of competence. ACT is a form of CBT and many of the same guides pertain. In line with the pragmatic approach of ACT, an approach that makes ACT broadly applicable, there is no one particular manualised or scripted treatment protocol that must be adhered to in treatment for one specific condition or another. As mentioned earlier, the ACT approach does not usually follow a cookbook style of delivery, nor is it rigidly guided by strict protocols. There are protocols shared by researchers to support further development but there is no process by which these are deemed “official” or “recognized” or approved by anyone in particular.

A wide range of metaphors and exercises based on a set of behavioral principles that target a particular function has been proposed in ACT and this is part of its uniqueness as a therapeutic model.

Those developing ACT also have not required a standardised certification process to delivering ACT. Instead, they have chosen to create an open community of contributing researchers and clinicians who are “members” by virtue of their commitment to the same approach to clinical development and the same clinical model. Practicing ACT requires that the clinician is aware of their own competencies and delivers treatment accordingly.

• How effective is ACT?

Numerous studies have supported a general role of psychological flexibility in improving the well-being and physical functioning of patients with chronic pain, including patients in specialty care [24,28] and primary care [26]. Many studies support the particular role of acceptance of pain in adjustment to chronic pain [27–30]. Pain acceptance is a better predictor of outcomes than pain severity itself [31,32].

There are now several relatively large-scale studies conducted in actual clinical practice settings that demonstrate the effectiveness of ACT for chronic pain [25,27,33,34]. A more recent study, also conducted in an actual clinical practice setting, provided support for the specific treatment processes proposed within this approach [35]. This study showed that changes in traditionally conceived methods of pain management were unrelated to treatment improvements of pain intensity, physical disability, anxiety and depression for those who participated in treatment, while changes in psychological flexibility were consistently and significantly related to these improvements, with the exception of the results for depression.

Randomised Controlled Trials (RCTs)

To date, there are a total of 7 RCTs related to ACT and chronic pain [36–42], each providing supportive evidence. For example, in one of the early studies, Dahl and colleagues [36] showed that in comparison to treatment as usual, a group of workers who were at risk of long-term absenteeism from work due to pain or stress had a significant reduction in sick leave and healthcare usage after attending four hours of ACT sessions.

Wicksell and colleagues [37,38] conducted 2 separate RCTs with participants who suffered whiplash-associated disorder (WAD) and fibromyalgia, respectively. Post-treatment results of both RCTs showed an improvement in physical functioning, depression and psychological flexibility in the treatment group with gains maintained at follow-up. In addition, participants in the treatment group with WAD showed an improvement in life satisfaction and fear of movement while those in the treatment group with fibromyalgia showed significant improvements in fibromyalgia impact, self-efficacy and anxiety. There was however no change in pain intensity in those who received the ACT-based treatments.

An ACT-based treatment including a self-help manual showed a significant increase in acceptance, satisfaction in life with a higher level of function and decreased pain intensity compared with a wait-list condition and with applied relaxation (AR) [40]. In comparison to the AR condition, participants in the ACT condition also reported a significantly higher level of engagement in meaningful activities and a willingness to experience pain. Follow-up data support the maintenance of these improvements at first follow-up but differences were not significant at the second follow-up. Both depression and anxiety scores improved in both treatment groups.

Wetherell and colleagues [39] compared the effectiveness of ACT and traditional CBT and found that they both produced positive results. Results from the study also showed higher satisfaction in participants who attended ACT treatment than those that attended CBT treatment, suggesting that ACT “is an effective and acceptable” intervention for patients with chronic pain. Overall acceptance of pain was shown to differentiate patients who could function well with chronic pain from those that continued to suffer with it after treatment.

More recently the first internet-based RCT for ACT with chronic pain was conducted [41]. The authors found a reduction in measures of pain-related distress, depressive symptoms, and anxiety, with these gains maintained at 6 months follow-up in the ACT treatment group compared with controls. The most recent RCT was a pilot trial of a group-based treatment of people with chronic pain recruited from general practices in the UK [42]. Participants were randomised to either an ACT-based treatment or treatment as usual. Participants in the ACT-based group underwent 4 sessions each lasting 4 hours with the first 3 sessions completed in 1 week and the last session completed a week later. At 3 months follow-up, participants in the ACT group had lower disability, depression, and higher pain acceptance.

In general, results from the ACT-based RCTs on chronic pain support the efficacy of the treatment and reflect a high degree of versatility, based on the wide variety of modes of delivery tested. However, RCTs for chronic pain are still relatively few with some studies limited to small sample sizes, thus making it difficult to reach definitive conclusions on the general efficacy of ACT in chronic pain treatment. What the studies do seem to show is that ACT is a good alternative treatment option to more traditionally conceived current CBT-based treatments for chronic pain. Larger sample sizes and higher quality studies are needed to strengthen and establish the effectiveness of ACT and to understand the potential impact of wider implementation in clinical practice.

Meta-Analyses

A total of 4 meta-analyses [43–46] have been conducted on acceptance- or ACT-based treatment studies. Although the earlier meta-analyses [43,44] did not separately report the effectiveness of ACT for chronic pain, they reported a moderate effect size for ACT in general, with no evidence that ACT is more effective than established treatments.

Ruiz [46] conducted a review focusing on outcome or mediation/moderation type studies that compared ACT and CBT treatments. His review was not specific to chronic pain, although one study [39] involving a sample of chronic pain patients was included. Moderate effect sizes were found that favored ACT, with ACT showing a greater impact on change processes (g = 0.38) compared to no impact found in CBT (g = 0.05).

Essentially, only one meta-analysis [45] specifically reviewed the efficacy in chronic pain studies. Pain inten-sity and depression were selected as primary outcome measures, with anxiety, physical well-being, and quality of life selected as secondary outcomes. Out of 22 studies that were included in the review, only 2 studies [36,37] were ACT-based RCTs, with the rest of the studies mindfulness-based interventions. The overall effect size of 0.37 was found for pain and 0.32 for depression. In general, results showed significant effect sizes for both primary and secondary outcome measures in favor of the “acceptance-based treatments.” The authors concluded that at present, mindfulness-based stress reduction programs and ACT-based programs may not be superior to CBT but could be good alternatives for people with chronic pain.

The appropriateness of using pain intensity as a primary outcome measure for ACT-based studies is questionable [45]. The focus of ACT is to increase function rather than to reduce pain symptoms; hence possibly including interference of pain in daily life might be a more appropriate outcome measure.

Other Studies

A particularly important question to answer about ACT concerns its cost-effectivness, and we still know relatively little about this. We do know that when people participate in ACT-based treatments they are able to reduce medication use and health care visits and return to work after extended periods away from work [27,28]. It remains to conduct full health economic analyses of this type of approach for chronic pain.

ACT is known to produce significant benefits widely, in other applications apart from chronic pain, such as in workplace stress [47], psychosis [48], obsessive-compulsive disorder [49], and depression [50], among other mental health conditions [51].

• What are implications for policy makers?

Results from studies of ACT in chronic pain and in other areas are disseminating rapidly. This dissemination is aided in part by a professional organization devoted to ACT and psychological flexibility (Association for Contextual Behavioral Science; www.contextualscience.org), which has a new journal, the Journal of Contextual Behavioral Science, started in 2012.

With the development of ACT a focus on implementation, training, and treatment integrity began early. There was an implementation study of ACT was published by Strosahl and colleagues in 1998. Their study showed that training clinicians in ACT produced better outcomes and better treatment completion rates in an outpatient setting in comparison to clinicians not receiving this training.

Processes of training have also appeared during relatively early phases of research into ACT. Lappalainen and colleagues [52] compared the impact of treatment provided by trainee therapists trained in both a traditional CBT model and ACT. Here each trainee therapist treated one patient with traditional CBT and one with ACT. Although the therapists reported higher confidence in delivering traditional CBT, patients treated within an ACT model showed better symptoms improvement. Also, improved acceptance during treatment significantly predicted improvements across both groups of patients. Essentially, therapists with only a limited amount of training in both models demonstrated better clinical results with ACT.

A group-based ACT intervention has also been shown to be effective in reducing stress and improving the professional performance of clinical psychology trainees [53]. Here the trainees found the intervention personally and professionally useful and a majority showed a significant increase in psychological flexibility. This supports the applicability of ACT not only as a model to guide therapy but also as a model to guide training and professional performance [54]. Other results in a pain management setting show that transitioning to ACT as a treatment model can have similar benefits and may increase job satisfaction and staff well-
being [55].

• What are criticisms of ACT?

Many strong supporters of cognitive therapy and more traditional versions of CBT in the field claim that ACT is not new nor better than other current versions of CBT [56]. The proponents of ACT openly acknowledge that many methods used within ACT are adopted or modified from other established therapies [4]. Criticisms are not specific to the application of ACT with chronic pain but are based on others’ perceptions of ACT as a treatment approach and treatment techniques used in ACT in general.

Ost [43] criticised ACT and the third-wave therapies on 2 main grounds. First, he concluded that ACT and the rest of the third-wave therapies were not meeting the criteria of empirically supported treatments. He further concluded that there is no strong evidence to show that ACT is more effective than cognitive therapy. The methods of the Ost review have been challenged [57], yet to a certain degree the points raised are correct. Most of the limitations noted reflect a difference in the maturity of the evidence base for ACT versus traditional CBT-based approaches. Indeed, in comparison to CBT, which is the most empirically established form of psychotherapy and an active area of research for more than 40 years, ACT can be considered to be in its infancy stage of empirically supported treatments, where treatment evidence and availability of high-quality RCTs in general are few at present. Specific research on ACT for chronic pain though supportive is still preliminary to a certain degree. Even so, ACT for pain is regarded as an empirically supported treatment by the body within the American Psychological Association authorized to make this determination [58].

Conclusion

ACT is essentially a form of CBT, considered broadly. ACT brings with it a different philosophy and approach to science compared with some other forms of CBT—this can lead to some distinctive strategies and methods in treatment for chronic pain. Like traditionally designed CBT, however, ACT similarly aims for behavior change as the end point.

ACT is grounded in specific philosophical assumptions and includes the model of psychological flexibility at its core. Preliminary findings in broad clinical and nonclinical populations support the efficacy, effectiveness, and processes in the psychological flexibility model as mediators of change, in ACT [46,59]. Research has shown that most of the 6 ACT processes, all of those so far investigated, correlate with improved daily functioning and emotional well-being in patients with chronic pain. The evidence base for ACT is still developing. Larger trials, more carefully designed trials, and a continued focus on processes of change will be needed to strengthen this base.

Corresponding author: Su-Yin Yang, Health Psychology Section, Psychology Department, Institute of Psychiatry, King’s College London, 5th Fl, Bermondsey Wing, Guy’s Campus, London SE1 9RT, [email protected].

Financial disclosures: None.

Author contributions: conception and design, SY, LMM; analysis and interpretation of data, SY; drafting of article, SY, LMM; critical revision of the article, LMM; administrative or technical support, LMM; collection and assembly of data, SY.

CASE Paranoid and confused

Mr. P, age 46, presents to the emergency department (ED) with a chief complaint of feeling “very weird.” Although he has seen a number of psychiatrists in the past, he does not recall being given a specific diagnosis. He describes his feelings as “1 minute I am fine and the next minute I am confused.” He endorses feeling paranoid for the past 6 to 12 months and reports a history of passive suicidal ideations. On the day he presents to the ED, however, he has a specific plan to shoot himself. He does not report audiovisual hallucinations, but has noticed that he talks to himself often.

Mr. P reports feeling worthless at times. He has a history of manic symptoms, including decreased need for sleep and hypersexuality. He describes verbal and sexual abuse by his foster parents. Mr. P reports using Cannabis and opioids occasionally and to drinking every “now and then” but not every day. He denies using benzodiazepines. When he is evaluated, he is not taking any medication and has no significant medical problems. Mr. P reports a history of several hospitalizations, but he could not describe the reasons or timing of past admissions.

Mr. P has a 10^th-grade education. He lives with his fiancée, who reports that he has been behaving oddly for some time. She noticed that he has memory problems and describes violent behavior, such as shaking his fist at her, breaking the television, and attempting to cut his throat once when he was “intoxicated.” She says she does not feel safe around him because of his labile mood and history of
aggression. She confirms that Mr. P does not drink daily but binge-drinks at times.

Initial mental status examination of evaluation reveals hyperverbal, rapid speech. Mr. P is circumstantial and tangential in his thought process. He has poor judgment and insight and exhibits suicidal ideations with a plan. Toxicology screening reveals a blood alcohol level of 50 mg/dL and is positive for Cannabis and opiates.

Which condition most likely accounts for Mr. P’s presentation?
    a) bipolar disorder, currently manic
    b) substance-induced mood disorder
    c) cognitive disorder
    d) delirium


TREATMENT Rapid improvement

From the ED, Mr. P was admitted to an inpatient psychiatric unit, where he was found initially to be disoriented to time, place, and person. His thought process remained disorganized and irrational, with significant memory difficulties. He is noted to have an unsteady gait. Nursing staff observes that Mr. P has significant difficulties with activities of daily living and requires assistance. He talks in circles
and uses nonsensical words.

His serum vitamin B₁₂ level, folate level, rapid plasma reagin, magnesium level, and thiamine level are within normal limits; CT scan of the brain is unremarkable. Neuropsychological testing reveals significant and diffuse cognitive deficits suggestive of frontal lobe dysfunction. He is deemed to not have decision-making capacity; because he has no family, his fiancée is appointed as his temporary health care proxy.

Thiamine and lorazepam are prescribed as needed because of Mr. P’s history of alcohol abuse. However, it’s determined that he does not need lorazepam because his vital signs are stable and there is no evidence of alcohol withdrawal symptoms.

During the course of his 10-day hospitalization, Mr. P’s cognitive difficulties resolved. He regains orientation to time, place, and person. He gains skill in all his activities of daily living, to the point of independence, and is discharged with minimal supervision. Vitamin B supplementation is prescribed, with close follow up in an outpatient day program. MRI/SPECT scan is considered to rule out frontotemporal dementia as recommended by the results of his neurocognitive testing profile.

Which condition likely account for Mr. P’s presentation during inpatient hospitalization?
    a) Wernicke’s encephalopathy
    b) Korsakoff’s syndrome
    c) malingering
    d) frontotemporal dementia
    e) a neurodegenerative disease

The author's observations

Mr. P’s fluctuating mental status, gait instability, and confabulation create high suspicion for Wernicke’s encephalopathy; his dramatic improvement with IV thiamine supports that diagnosis. Mr. P attends the outpatient day program once after his discharge, and is then lost to follow-up.

During inpatient stay, Mr. P eventually admits to binge drinking several times a week, and drinking early in the morning, which would continue throughout the day. His significant cognitive deficits revealed by neuropsychological testing suggests consideration of a differential diagnosis of multifactorial cognitive dysfunction because of:
   • long-term substance use
   • Korsakoff’s syndrome
   • frontotemporal dementia
   • a neurodegenerative disease
   • malingering (Table 1).

Wernicke’s encephalopathy
Wernicke’s encephalopathy is a life-threatening neurologic disorder caused by thiamine deficiency. The disease is rare, catastrophic in onset, and clinically complex¹; as in Mr. P’s case, diagnosis often is delayed. In autopsy studies, the reported prevalence of Wernicke’s encephalopathy is 0.4% to 2.8%.1 Wernicke’s encephalopathy was suspected before death in 33% of alcohol-dependent patientsand 6% of nonalcoholics.¹ Other causes of Wernicke’s encephalopathy include cancer, gastrointestinal surgery, hyperemesis gravidarum, a starvation or malnutrition state, GI tract disease, AIDS, parenteral nutrition, repetitive vomiting, and infection.¹

Diagnosis. Making the correct diagnosis is challenging because the clinical presentation can be variable. No lab or imaging studies confirm the diagnosis. The triad of signs considered to support the diagnosis include ocular signs such as nystagmus, cerebellar signs, and confusion. These signs occur in only 8% to 10% of patients in whom the diagnosis likely.^1,2

Attempts to increase the likelihood of making an accurate lifetime diagnosis of
Wernicke’s encephalopathy include expanding the focus to 8 clinical domains:
   • dietary deficiency
   • eye signs
   • cerebellar signs
   • seizures
   • frontal lobe dysfunction
   • amnesia
   • mild memory impairment
   • altered mental status.¹

The sensitivity of making a correct diagnosis increases to 85% if at least 2 of 4 features—namely dietary deficiency, eye signs, cerebellar signs, memory impairment, and altered mental status—are present. These criteria can be applied to alcoholic and nonalcoholic patients.¹Table 2_³ lists common and uncommon symptoms of Wernicke’s encephalopathy.

Although CT scan of the brain is not a reliable test for the disorder, MRI can be powerful tool that could support a diagnosis of acute Wernicke’s encephalopathy.¹ We did not consider MRI in Mr. P’s case because the consulting neurologist thought this was unnecessary because of the quick improvement in his cognitive status with IV thiamine—although MRI might have helped to detect the disease earlier. In some studies, brain MRI revealed lesions in two-thirds of Wernicke’s encephalopathy patients.¹ Typically, lesions are symmetrical and seen in the thalamus, mammillary body, and periaqueductal areas.^1,4 Atypical lesions commonly are seen in the cerebellum, dentate nuclei, caudate nucleus, and cerebral cortex.¹

Treatment. Evidence supports use of IV thiamine, 200 mg 3 times a day, when the disease is suspected or established.^1,2 Thiamine has been associated with sporadic anaphylactic reactions, and should be administered when resuscitation facilities are available. Do not delay treatment because resuscitation measures are unavailable because you risk causing irreversible brain damage.¹

In Mr. P’s case, prompt recognition of the need for thiamine likely led to a better outcome. Thiamine supplementation can prevent Wernicke’s encephalopathy in some patients. Prophylactic parenteral administration of thiamine before administration of glucose in the ED is recommended, as well as vitamin B supplementation with thiamine included upon discharge.^1,2 Studies support several treatment regimens for patients with Wernicke’s encephalopathy and those at risk of it.^1,3,5

Neither the optimal dosage of thiamine nor the appropriate duration of treatment have been determined by randomized, double-blind, controlled studies; empirical clinical practice and recommendations by Royal College of Physicians, London, suggest that a more prolonged course of thiamine—administered as long as improvement continues—might be beneficial.⁶

Left untreated, Wernicke’s encephalopathy can lead to irreversible brain damage.²
Mortality has been reported as 17% to 20%; 82% of patients develop Korsakoff’s syndrome, a chronic condition characterized by short-term memory loss. One-quarter of patients who develop Korsakoff’s syndrome require long-term residential care because of permanent brain damage.²

Making a diagnosis of Wernicke’s encephalopathy is a challenge because no specific symptom or diagnostic test can be relied upon to confirm the diagnosis. Also, patients might deny that they have an alcohol problem or give an inaccurate history of their alcohol use,² as Mr. P did. The disorder is substantially underdiagnosed; as a consequence, patients are at risk of brain damage.²

Bottom Line

Not all patients who present with aggressive behavior, mania, and psychiatric
symptoms have a primary psychiatric diagnosis. It is important to consider
nutritional deficiencies caused by chronic alcohol abuse in patients presenting
with acute onset of confusion or altered mental status. Wernicke’s encephalopathy
might be the result of alcohol abuse and can be treated with IV thiamine.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Paranoid and confused

Mr. P, age 46, presents to the emergency department (ED) with a chief complaint of feeling “very weird.” Although he has seen a number of psychiatrists in the past, he does not recall being given a specific diagnosis. He describes his feelings as “1 minute I am fine and the next minute I am confused.” He endorses feeling paranoid for the past 6 to 12 months and reports a history of passive suicidal ideations. On the day he presents to the ED, however, he has a specific plan to shoot himself. He does not report audiovisual hallucinations, but has noticed that he talks to himself often.

Mr. P reports feeling worthless at times. He has a history of manic symptoms, including decreased need for sleep and hypersexuality. He describes verbal and sexual abuse by his foster parents. Mr. P reports using Cannabis and opioids occasionally and to drinking every “now and then” but not every day. He denies using benzodiazepines. When he is evaluated, he is not taking any medication and has no significant medical problems. Mr. P reports a history of several hospitalizations, but he could not describe the reasons or timing of past admissions.

Mr. P has a 10^th-grade education. He lives with his fiancée, who reports that he has been behaving oddly for some time. She noticed that he has memory problems and describes violent behavior, such as shaking his fist at her, breaking the television, and attempting to cut his throat once when he was “intoxicated.” She says she does not feel safe around him because of his labile mood and history of
aggression. She confirms that Mr. P does not drink daily but binge-drinks at times.

Initial mental status examination of evaluation reveals hyperverbal, rapid speech. Mr. P is circumstantial and tangential in his thought process. He has poor judgment and insight and exhibits suicidal ideations with a plan. Toxicology screening reveals a blood alcohol level of 50 mg/dL and is positive for Cannabis and opiates.

Which condition most likely accounts for Mr. P’s presentation?
    a) bipolar disorder, currently manic
    b) substance-induced mood disorder
    c) cognitive disorder
    d) delirium


TREATMENT Rapid improvement

From the ED, Mr. P was admitted to an inpatient psychiatric unit, where he was found initially to be disoriented to time, place, and person. His thought process remained disorganized and irrational, with significant memory difficulties. He is noted to have an unsteady gait. Nursing staff observes that Mr. P has significant difficulties with activities of daily living and requires assistance. He talks in circles
and uses nonsensical words.

His serum vitamin B₁₂ level, folate level, rapid plasma reagin, magnesium level, and thiamine level are within normal limits; CT scan of the brain is unremarkable. Neuropsychological testing reveals significant and diffuse cognitive deficits suggestive of frontal lobe dysfunction. He is deemed to not have decision-making capacity; because he has no family, his fiancée is appointed as his temporary health care proxy.

Thiamine and lorazepam are prescribed as needed because of Mr. P’s history of alcohol abuse. However, it’s determined that he does not need lorazepam because his vital signs are stable and there is no evidence of alcohol withdrawal symptoms.

During the course of his 10-day hospitalization, Mr. P’s cognitive difficulties resolved. He regains orientation to time, place, and person. He gains skill in all his activities of daily living, to the point of independence, and is discharged with minimal supervision. Vitamin B supplementation is prescribed, with close follow up in an outpatient day program. MRI/SPECT scan is considered to rule out frontotemporal dementia as recommended by the results of his neurocognitive testing profile.

Which condition likely account for Mr. P’s presentation during inpatient hospitalization?
    a) Wernicke’s encephalopathy
    b) Korsakoff’s syndrome
    c) malingering
    d) frontotemporal dementia
    e) a neurodegenerative disease

The author's observations

Mr. P’s fluctuating mental status, gait instability, and confabulation create high suspicion for Wernicke’s encephalopathy; his dramatic improvement with IV thiamine supports that diagnosis. Mr. P attends the outpatient day program once after his discharge, and is then lost to follow-up.

During inpatient stay, Mr. P eventually admits to binge drinking several times a week, and drinking early in the morning, which would continue throughout the day. His significant cognitive deficits revealed by neuropsychological testing suggests consideration of a differential diagnosis of multifactorial cognitive dysfunction because of:
   • long-term substance use
   • Korsakoff’s syndrome
   • frontotemporal dementia
   • a neurodegenerative disease
   • malingering (Table 1).

Wernicke’s encephalopathy
Wernicke’s encephalopathy is a life-threatening neurologic disorder caused by thiamine deficiency. The disease is rare, catastrophic in onset, and clinically complex¹; as in Mr. P’s case, diagnosis often is delayed. In autopsy studies, the reported prevalence of Wernicke’s encephalopathy is 0.4% to 2.8%.1 Wernicke’s encephalopathy was suspected before death in 33% of alcohol-dependent patientsand 6% of nonalcoholics.¹ Other causes of Wernicke’s encephalopathy include cancer, gastrointestinal surgery, hyperemesis gravidarum, a starvation or malnutrition state, GI tract disease, AIDS, parenteral nutrition, repetitive vomiting, and infection.¹

Diagnosis. Making the correct diagnosis is challenging because the clinical presentation can be variable. No lab or imaging studies confirm the diagnosis. The triad of signs considered to support the diagnosis include ocular signs such as nystagmus, cerebellar signs, and confusion. These signs occur in only 8% to 10% of patients in whom the diagnosis likely.^1,2

Attempts to increase the likelihood of making an accurate lifetime diagnosis of
Wernicke’s encephalopathy include expanding the focus to 8 clinical domains:
   • dietary deficiency
   • eye signs
   • cerebellar signs
   • seizures
   • frontal lobe dysfunction
   • amnesia
   • mild memory impairment
   • altered mental status.¹

The sensitivity of making a correct diagnosis increases to 85% if at least 2 of 4 features—namely dietary deficiency, eye signs, cerebellar signs, memory impairment, and altered mental status—are present. These criteria can be applied to alcoholic and nonalcoholic patients.¹Table 2_³ lists common and uncommon symptoms of Wernicke’s encephalopathy.

Although CT scan of the brain is not a reliable test for the disorder, MRI can be powerful tool that could support a diagnosis of acute Wernicke’s encephalopathy.¹ We did not consider MRI in Mr. P’s case because the consulting neurologist thought this was unnecessary because of the quick improvement in his cognitive status with IV thiamine—although MRI might have helped to detect the disease earlier. In some studies, brain MRI revealed lesions in two-thirds of Wernicke’s encephalopathy patients.¹ Typically, lesions are symmetrical and seen in the thalamus, mammillary body, and periaqueductal areas.^1,4 Atypical lesions commonly are seen in the cerebellum, dentate nuclei, caudate nucleus, and cerebral cortex.¹

Treatment. Evidence supports use of IV thiamine, 200 mg 3 times a day, when the disease is suspected or established.^1,2 Thiamine has been associated with sporadic anaphylactic reactions, and should be administered when resuscitation facilities are available. Do not delay treatment because resuscitation measures are unavailable because you risk causing irreversible brain damage.¹

In Mr. P’s case, prompt recognition of the need for thiamine likely led to a better outcome. Thiamine supplementation can prevent Wernicke’s encephalopathy in some patients. Prophylactic parenteral administration of thiamine before administration of glucose in the ED is recommended, as well as vitamin B supplementation with thiamine included upon discharge.^1,2 Studies support several treatment regimens for patients with Wernicke’s encephalopathy and those at risk of it.^1,3,5

Neither the optimal dosage of thiamine nor the appropriate duration of treatment have been determined by randomized, double-blind, controlled studies; empirical clinical practice and recommendations by Royal College of Physicians, London, suggest that a more prolonged course of thiamine—administered as long as improvement continues—might be beneficial.⁶

Left untreated, Wernicke’s encephalopathy can lead to irreversible brain damage.²
Mortality has been reported as 17% to 20%; 82% of patients develop Korsakoff’s syndrome, a chronic condition characterized by short-term memory loss. One-quarter of patients who develop Korsakoff’s syndrome require long-term residential care because of permanent brain damage.²

Making a diagnosis of Wernicke’s encephalopathy is a challenge because no specific symptom or diagnostic test can be relied upon to confirm the diagnosis. Also, patients might deny that they have an alcohol problem or give an inaccurate history of their alcohol use,² as Mr. P did. The disorder is substantially underdiagnosed; as a consequence, patients are at risk of brain damage.²

Bottom Line

Not all patients who present with aggressive behavior, mania, and psychiatric
symptoms have a primary psychiatric diagnosis. It is important to consider
nutritional deficiencies caused by chronic alcohol abuse in patients presenting
with acute onset of confusion or altered mental status. Wernicke’s encephalopathy
might be the result of alcohol abuse and can be treated with IV thiamine.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Paranoid and confused

Mr. P, age 46, presents to the emergency department (ED) with a chief complaint of feeling “very weird.” Although he has seen a number of psychiatrists in the past, he does not recall being given a specific diagnosis. He describes his feelings as “1 minute I am fine and the next minute I am confused.” He endorses feeling paranoid for the past 6 to 12 months and reports a history of passive suicidal ideations. On the day he presents to the ED, however, he has a specific plan to shoot himself. He does not report audiovisual hallucinations, but has noticed that he talks to himself often.

Mr. P reports feeling worthless at times. He has a history of manic symptoms, including decreased need for sleep and hypersexuality. He describes verbal and sexual abuse by his foster parents. Mr. P reports using Cannabis and opioids occasionally and to drinking every “now and then” but not every day. He denies using benzodiazepines. When he is evaluated, he is not taking any medication and has no significant medical problems. Mr. P reports a history of several hospitalizations, but he could not describe the reasons or timing of past admissions.

Mr. P has a 10^th-grade education. He lives with his fiancée, who reports that he has been behaving oddly for some time. She noticed that he has memory problems and describes violent behavior, such as shaking his fist at her, breaking the television, and attempting to cut his throat once when he was “intoxicated.” She says she does not feel safe around him because of his labile mood and history of
aggression. She confirms that Mr. P does not drink daily but binge-drinks at times.

Initial mental status examination of evaluation reveals hyperverbal, rapid speech. Mr. P is circumstantial and tangential in his thought process. He has poor judgment and insight and exhibits suicidal ideations with a plan. Toxicology screening reveals a blood alcohol level of 50 mg/dL and is positive for Cannabis and opiates.

Which condition most likely accounts for Mr. P’s presentation?
    a) bipolar disorder, currently manic
    b) substance-induced mood disorder
    c) cognitive disorder
    d) delirium


TREATMENT Rapid improvement

From the ED, Mr. P was admitted to an inpatient psychiatric unit, where he was found initially to be disoriented to time, place, and person. His thought process remained disorganized and irrational, with significant memory difficulties. He is noted to have an unsteady gait. Nursing staff observes that Mr. P has significant difficulties with activities of daily living and requires assistance. He talks in circles
and uses nonsensical words.

His serum vitamin B₁₂ level, folate level, rapid plasma reagin, magnesium level, and thiamine level are within normal limits; CT scan of the brain is unremarkable. Neuropsychological testing reveals significant and diffuse cognitive deficits suggestive of frontal lobe dysfunction. He is deemed to not have decision-making capacity; because he has no family, his fiancée is appointed as his temporary health care proxy.

Thiamine and lorazepam are prescribed as needed because of Mr. P’s history of alcohol abuse. However, it’s determined that he does not need lorazepam because his vital signs are stable and there is no evidence of alcohol withdrawal symptoms.

During the course of his 10-day hospitalization, Mr. P’s cognitive difficulties resolved. He regains orientation to time, place, and person. He gains skill in all his activities of daily living, to the point of independence, and is discharged with minimal supervision. Vitamin B supplementation is prescribed, with close follow up in an outpatient day program. MRI/SPECT scan is considered to rule out frontotemporal dementia as recommended by the results of his neurocognitive testing profile.

Which condition likely account for Mr. P’s presentation during inpatient hospitalization?
    a) Wernicke’s encephalopathy
    b) Korsakoff’s syndrome
    c) malingering
    d) frontotemporal dementia
    e) a neurodegenerative disease

The author's observations

Mr. P’s fluctuating mental status, gait instability, and confabulation create high suspicion for Wernicke’s encephalopathy; his dramatic improvement with IV thiamine supports that diagnosis. Mr. P attends the outpatient day program once after his discharge, and is then lost to follow-up.

During inpatient stay, Mr. P eventually admits to binge drinking several times a week, and drinking early in the morning, which would continue throughout the day. His significant cognitive deficits revealed by neuropsychological testing suggests consideration of a differential diagnosis of multifactorial cognitive dysfunction because of:
   • long-term substance use
   • Korsakoff’s syndrome
   • frontotemporal dementia
   • a neurodegenerative disease
   • malingering (Table 1).

Wernicke’s encephalopathy
Wernicke’s encephalopathy is a life-threatening neurologic disorder caused by thiamine deficiency. The disease is rare, catastrophic in onset, and clinically complex¹; as in Mr. P’s case, diagnosis often is delayed. In autopsy studies, the reported prevalence of Wernicke’s encephalopathy is 0.4% to 2.8%.1 Wernicke’s encephalopathy was suspected before death in 33% of alcohol-dependent patientsand 6% of nonalcoholics.¹ Other causes of Wernicke’s encephalopathy include cancer, gastrointestinal surgery, hyperemesis gravidarum, a starvation or malnutrition state, GI tract disease, AIDS, parenteral nutrition, repetitive vomiting, and infection.¹

Diagnosis. Making the correct diagnosis is challenging because the clinical presentation can be variable. No lab or imaging studies confirm the diagnosis. The triad of signs considered to support the diagnosis include ocular signs such as nystagmus, cerebellar signs, and confusion. These signs occur in only 8% to 10% of patients in whom the diagnosis likely.^1,2

Attempts to increase the likelihood of making an accurate lifetime diagnosis of
Wernicke’s encephalopathy include expanding the focus to 8 clinical domains:
   • dietary deficiency
   • eye signs
   • cerebellar signs
   • seizures
   • frontal lobe dysfunction
   • amnesia
   • mild memory impairment
   • altered mental status.¹

The sensitivity of making a correct diagnosis increases to 85% if at least 2 of 4 features—namely dietary deficiency, eye signs, cerebellar signs, memory impairment, and altered mental status—are present. These criteria can be applied to alcoholic and nonalcoholic patients.¹Table 2_³ lists common and uncommon symptoms of Wernicke’s encephalopathy.

Although CT scan of the brain is not a reliable test for the disorder, MRI can be powerful tool that could support a diagnosis of acute Wernicke’s encephalopathy.¹ We did not consider MRI in Mr. P’s case because the consulting neurologist thought this was unnecessary because of the quick improvement in his cognitive status with IV thiamine—although MRI might have helped to detect the disease earlier. In some studies, brain MRI revealed lesions in two-thirds of Wernicke’s encephalopathy patients.¹ Typically, lesions are symmetrical and seen in the thalamus, mammillary body, and periaqueductal areas.^1,4 Atypical lesions commonly are seen in the cerebellum, dentate nuclei, caudate nucleus, and cerebral cortex.¹

Treatment. Evidence supports use of IV thiamine, 200 mg 3 times a day, when the disease is suspected or established.^1,2 Thiamine has been associated with sporadic anaphylactic reactions, and should be administered when resuscitation facilities are available. Do not delay treatment because resuscitation measures are unavailable because you risk causing irreversible brain damage.¹

In Mr. P’s case, prompt recognition of the need for thiamine likely led to a better outcome. Thiamine supplementation can prevent Wernicke’s encephalopathy in some patients. Prophylactic parenteral administration of thiamine before administration of glucose in the ED is recommended, as well as vitamin B supplementation with thiamine included upon discharge.^1,2 Studies support several treatment regimens for patients with Wernicke’s encephalopathy and those at risk of it.^1,3,5

Neither the optimal dosage of thiamine nor the appropriate duration of treatment have been determined by randomized, double-blind, controlled studies; empirical clinical practice and recommendations by Royal College of Physicians, London, suggest that a more prolonged course of thiamine—administered as long as improvement continues—might be beneficial.⁶

Left untreated, Wernicke’s encephalopathy can lead to irreversible brain damage.²
Mortality has been reported as 17% to 20%; 82% of patients develop Korsakoff’s syndrome, a chronic condition characterized by short-term memory loss. One-quarter of patients who develop Korsakoff’s syndrome require long-term residential care because of permanent brain damage.²

Making a diagnosis of Wernicke’s encephalopathy is a challenge because no specific symptom or diagnostic test can be relied upon to confirm the diagnosis. Also, patients might deny that they have an alcohol problem or give an inaccurate history of their alcohol use,² as Mr. P did. The disorder is substantially underdiagnosed; as a consequence, patients are at risk of brain damage.²

Bottom Line

Not all patients who present with aggressive behavior, mania, and psychiatric
symptoms have a primary psychiatric diagnosis. It is important to consider
nutritional deficiencies caused by chronic alcohol abuse in patients presenting
with acute onset of confusion or altered mental status. Wernicke’s encephalopathy
might be the result of alcohol abuse and can be treated with IV thiamine.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Confused and cold

Ms. K, age 48, is brought to the emergency department (ED) by her husband because she has become increasingly lethargic over the past 2 weeks and cannot attend to activities of daily living. She is incontinent of stool and poorly responsive.

Ms. K’s husband reports that lethargy culminated in his wife sleeping 30 continuous hours. She has a history of a ruptured cerebral arteriovenous malformation (AVM) complicated by a secondary infarct 7 years ago, with residual symptoms of frontal lobe syndrome. Until 2 weeks ago, however, she was in her usual state of health.

Symptoms have included depression, mood lability, impulsivity, disinhibition, poor focus, and apathy. An outpatient psychiatrist has managed these symptoms with antidepressants and atypical antipsychotics.

When Ms. K arrives in the ED, she is taking citalopram, 30 mg/d, and paliperidone,
6 mg/d. Her psychiatrist started paliperidone 2 months ago, increasing the dosage to 6 mg/d 6 weeks before presentation because of worsening mood lability, disinhibition, and paranoia regarding her caregivers. Her husband denies any other medication changes or exposure to environmental toxins.

In the ED, Ms. K is confused and oriented only to person. Vital signs are: pulse 46 bpm; blood pressure, 66/51 mm Hg; respirations, 12/min; and temperature, 29.9ºC (85.8ºF) via bladder probe.

The authors’ observations

Hypothermia is core body temperature <35ºC (95ºF).¹ It often is caused by exposure to low ambient temperature (Table 1),¹ but Ms. K’s husband denied that she had been exposed to cold. Because of Ms. K’s neurologic history, stroke was high on the differential diagnosis, but physical examination did not reveal evidence of focal dysfunction and was significant only for altered mental status.

Ms. K had no posturing, rigidity, negativism, or excessive motor activity that would suggest catatonia. Before she became lethargic, her husband had not noted any deterioration of mood, although she did exhibit other behavioral changes that prompted her outpatient psychiatrist to increase the dosage of paliperidone. Although Ms. K began experiencing persecutory delusions—she believed that her caregivers were trying to harm her—she and her family denied perceptual disturbances. On examination, she did not appear responsive to auditory or visual hallucinations.

Frontal lobe syndrome is defined as a set of changes in the cognitive, behavioral, or emotional domains, often leading to disturbed affect, alteration of attention, aphasia, perseveration, disinhibition, and personality changes.² These symptoms are not specific to lesions in the frontal lobes but can arise from lesions anywhere in the frontal-striatal-thalamic circuit.³ Causes include traumatic brain injury, neurodegenerative disorders, cerebrovascular disease, tumors, and aging.² Recommended treatment incorporates psychosocial interventions with drug treatment to target specific symptoms. Medications reported to be effective include typical and atypical antipsychotics to target aggression and agitation; benzodiazepines to reduce arousal; antidepressants for mood symptoms, dopamine agonists (eg, bromocriptine) to decrease apathy, and mood stabilizers to target mood lability.⁴

Before her AVM rupture, review of Ms. K’s psychiatric history revealed no psychiatric symptoms or impaired functioning. When hospitalized for the AVM repair, she was started on sertraline. She began seeing a psychiatrist 2 years later because of increased agitation and behavioral disturbances, and aripiprazole was added. Persistent agitation prompted a trial of divalproex sodium, which was discontinued because of slurred speech and increased distractibility. Aripiprazole was tapered and replaced with paliperidone because of poor response. Citalopram was initiated 1 year before she presented to the ED.

EVALUATION Hypothermia

Laboratory tests reveal multiple abnormalities, including thrombocytopenia (platelet level, 53 ×10³/μL), altered coagulation (partial thromboplastin time, 55.6 s), elevated levels of hepatic transaminases (aspartate aminotransferase, 168 U/L; alanine aminotransferase, 357 U/L), and increased alkaline phosphatase (206 U/L). Other mild metabolic disturbances include: sodium, 149 mEq/L; CO₂, 33 mEq/L; and blood urea nitrogen, 24 mg/dL.

These laboratory values are consistent with complications of hypothermia.¹

ECG reveals sinus bradycardia (40 bpm) and Osborn waves (additional deflection at the end of the QRS complex), which are seen often in hypothermia.¹ Head CT and brain MRI show chronic changes after Ms. K’s right temporoparietal AVM rupture, but no acute abnormality. Urinalysis, blood cultures, and chest radiographs are negative for infection. Urine toxicology screen is negative. Results of thyroid function tests and pituitary hormones studies are significant only for hyperprolactinemia of 155.7 ng/mL, a known adverse effect of antipsychotics.⁵

Ms. K is admitted and rewarmed passively and with warm IV fluids; by day 10 of hospitalization, temperature is stable (>35.1ºC [95.2ºF]). Thrombocytopenia, transaminitis, and altered mental status resolve.

Ms. K’s oral medications, including citalopram and paliperidone, have been held since admission because of her altered mental status. The psychiatry service is consulted to evaluate whether her presentation could be related to her change of medication.

A literature search reveals no report of paliperidone-induced hypothermia, but we consider it a possible explanation for Ms. K’s presentation. Lamotrigine (titrated to 50 mg/d), a benzodiazepine (oral lorazepam as needed), and discontinuing antipsychotics are recommended. After she returns to her baseline functioning, Ms. K is discharged to a skilled nursing facility.

Ms. K presents to the ED 2 days after discharge with altered mental status. Vital signs are: blood pressure, 90/55 mm Hg; pulse, 59 bpm; respiratory rate, 14/min; and temperature, 34.4ºC (93.9ºF) via bladder probe (Figure). Laboratory tests were significant for hepatic transaminitis (aspartate aminotransferase, 75 U/L; alanine aminotransferase, 122 U/L) and elevated alkaline phosphatase (226 U/L). A review of records from the nursing facility revealed that Ms. K was receiving paliperidone because of an error in the discharge summary, which recommended restarting all prior medications.

The authors’ observations

The Naranjo Causality Scale,⁶ which categorizes the probability that an adverse event is related to a drug (based on several variables, including timing of the drug administration with the onset of event, drug dosage and levels, response relationships to a drug, including re-challenge when possible, and previous patient experience with the medication), often is used to evaluate whether an adverse clinical event has been caused by a drug (Table 2). We applied the Scale to Ms. K’s case, which revealed a score of 7—indicating a probable adverse drug reaction. The sequence of events in Ms. K’s case that led to a paliperidone challenge-dechallenge-rechallenge, and the resulting hypothermia, are, we concluded, evidence of an adverse drug reaction.

Using the World Health Organization database for adverse drug reactions, van Marum et al⁷ found 480 reports hypothermia with antipsychotics as of 2007 (compared with 524 reports of hyperthermia in the same period); 55% involved atypical antipsychotics, mainly risperidone. There are no case reports of paliperidone-induced hypothermia; however, several reports of hypothermia have been attributed to risperidone, and paliperidone is the primary active metabolite of risperidone.⁵

To identify risk factors for hypothermia with antipsychotic use, van Marum et al⁷ performed a literature search for case reports of antipsychotic-induced hypothermia, which revealed no association with age or sex. The most common diagnosis in cases of antipsychotic-induced hypothermia was schizophrenia (51%). In 73% of the cases, hypothermia followed the start or dosage increase of the antipsychotic. These observations have been noted in case reports and case series of hypothermia associated with antipsychotic use.^8-12

Mechanism of action

One proposed mechanism for antipsychotic-induced hypothermia includes preferential 5-HT2A receptor antagonism over D2 receptor antagonism.^7,12 It has been believed that, under normal conditions, the action of dopamine to reduce body temperature and the action of serotonin to elevate it are in balance.⁹

Another possible mechanism is peripheral á2-adrenergic blockade, which might increase the hypothermic effect by inhibiting peripheral responses to cooling, such as vasoconstriction and shivering.^7,8 Boschi et al¹³ found that antipsychotics cause hypothermia in rats when the drug is administered intraperitoneally but not when given intrathecally. Perhaps for these reasons, in the early 1950s, before its psychotropic properties were known, chlorpromazine was used during surgery to induce artificial hibernation and suppress the body’s response to cooling.⁷ The therapeutic activity of paliperidone is mediated though a D2, 5-HT2A, and á2-receptor antagonism⁵; these mechanisms could, therefore, be contributing to Ms. K’s hypothermia.

Patients with preexisting brain damage— such as Ms. K—might be at increased risk of antipsychotic-induced hypothermia.^7,8 This includes focal damage to central thermoregulatory centers, such as the pre-optic anterior hypothalamic region,¹⁴ and more diffuse damage seen in patients with cognitive impairment or a seizure disorder.⁸

Studies of people with schizophrenia show a decrease in core temperature after administration of an antipsychotic,¹⁵ raising the possibility of an impairment of baseline thermoregulatory control. Such thermal dysregulation in patients with schizophrenia might be explained by changes in neurotensin levels.⁷

The neuropeptide neurotensin has been implicated in the regulation of prolactin release and interacts to a significant degree with the dopaminergic system.¹⁶ When administered to animals, neurotensin suppresses heat production and increases heat loss.¹⁷ The neurotensin level in CSF was found to be lower in non-medicated patients with schizophrenia than in healthy controls, with an inverse correlation between the severity of symptoms and the neurotensin level.¹⁸

Additionally, persons with schizophrenia might be at increased risk of developing hypothermia when exposed to a low environmental temperature.^7,8 Kudoh et al¹⁹ investigated temperature regulation during anesthesia in patients with chronic (≥7 years) schizophrenia receiving antipsychotics, and compared findings against what was seen in controls. The team reported that patients with schizophrenia had significantly lower intraoperative temperatures.

A published analysis of cases and studies of antipsychotic-induced hypothermia describes the combination of drug variables, patient variables, and environmental variables that contribute to thermal dysregulation (Table 3).^7-12,15 The recommendation for practitioners is that, when considering an antipsychotic for a patient at high risk of thermal dysregulation, your choice of an agent should take that risk into account, especially when that drug is one that has comparatively stronger serotonergic and peripheral á-adrenergic effects. You should monitor patients closely for hypothermia after starting and when increasing the dosage of the drug. In patients with schizophrenia who might have a problem with baseline thermoregulation, advise them to take measures to counteract their increased susceptibility to low ambient temperatures.

OUTCOME Readmission

Ms. K was readmitted, rewarmed, and discharged to a skilled nursing facility 4 days later, after baseline function returned to normal and temperature stabilized. Paliperidone is now listed in her electronic medical record as “drug intolerance.”

This case also highlights the importance of adequate medication reconciliation at
admission and discharge, especially when using an electronic medical record system, because what might otherwise be considered a minor mistake can have devastating consequences.

Bottom Line

Thermal dysregulation—hyperthermia and hypothermia—can occur secondary to an antipsychotic. Determining whether a patient is at increased risk of either of these adverse effects is important when deciding to use antipsychotics. Recognizing agents that can cause hypothermia is essential, because management requires prompt discontinuation of the offending drug.

Related Resource

• Espay AJ, et al. Frontal lobe syndromes. http://emedicine.medscape.com/article/1135866-overview. Updated September 17, 2012. Accessed November 3, 2012.

Drug Brand Names

Aripiprazole • Abilify                    Lamotrigine • Lamictal
Bromocriptine • Parlodel              Lorazepam • Ativan
Chlorpromazine • Thorazine         Paliperidone • Invega
Citalopram • Celexa                    Risperidone • Risperdal
Clozapine • Clozaril                     Sertraline • Zoloft
Divalproex sodium • Depakote     Thioridazine • Mellaril

Disclosure

The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Confused and cold

Ms. K, age 48, is brought to the emergency department (ED) by her husband because she has become increasingly lethargic over the past 2 weeks and cannot attend to activities of daily living. She is incontinent of stool and poorly responsive.

Ms. K’s husband reports that lethargy culminated in his wife sleeping 30 continuous hours. She has a history of a ruptured cerebral arteriovenous malformation (AVM) complicated by a secondary infarct 7 years ago, with residual symptoms of frontal lobe syndrome. Until 2 weeks ago, however, she was in her usual state of health.

Symptoms have included depression, mood lability, impulsivity, disinhibition, poor focus, and apathy. An outpatient psychiatrist has managed these symptoms with antidepressants and atypical antipsychotics.

When Ms. K arrives in the ED, she is taking citalopram, 30 mg/d, and paliperidone,
6 mg/d. Her psychiatrist started paliperidone 2 months ago, increasing the dosage to 6 mg/d 6 weeks before presentation because of worsening mood lability, disinhibition, and paranoia regarding her caregivers. Her husband denies any other medication changes or exposure to environmental toxins.

In the ED, Ms. K is confused and oriented only to person. Vital signs are: pulse 46 bpm; blood pressure, 66/51 mm Hg; respirations, 12/min; and temperature, 29.9ºC (85.8ºF) via bladder probe.

The authors’ observations

Hypothermia is core body temperature <35ºC (95ºF).¹ It often is caused by exposure to low ambient temperature (Table 1),¹ but Ms. K’s husband denied that she had been exposed to cold. Because of Ms. K’s neurologic history, stroke was high on the differential diagnosis, but physical examination did not reveal evidence of focal dysfunction and was significant only for altered mental status.

Ms. K had no posturing, rigidity, negativism, or excessive motor activity that would suggest catatonia. Before she became lethargic, her husband had not noted any deterioration of mood, although she did exhibit other behavioral changes that prompted her outpatient psychiatrist to increase the dosage of paliperidone. Although Ms. K began experiencing persecutory delusions—she believed that her caregivers were trying to harm her—she and her family denied perceptual disturbances. On examination, she did not appear responsive to auditory or visual hallucinations.

Frontal lobe syndrome is defined as a set of changes in the cognitive, behavioral, or emotional domains, often leading to disturbed affect, alteration of attention, aphasia, perseveration, disinhibition, and personality changes.² These symptoms are not specific to lesions in the frontal lobes but can arise from lesions anywhere in the frontal-striatal-thalamic circuit.³ Causes include traumatic brain injury, neurodegenerative disorders, cerebrovascular disease, tumors, and aging.² Recommended treatment incorporates psychosocial interventions with drug treatment to target specific symptoms. Medications reported to be effective include typical and atypical antipsychotics to target aggression and agitation; benzodiazepines to reduce arousal; antidepressants for mood symptoms, dopamine agonists (eg, bromocriptine) to decrease apathy, and mood stabilizers to target mood lability.⁴

Before her AVM rupture, review of Ms. K’s psychiatric history revealed no psychiatric symptoms or impaired functioning. When hospitalized for the AVM repair, she was started on sertraline. She began seeing a psychiatrist 2 years later because of increased agitation and behavioral disturbances, and aripiprazole was added. Persistent agitation prompted a trial of divalproex sodium, which was discontinued because of slurred speech and increased distractibility. Aripiprazole was tapered and replaced with paliperidone because of poor response. Citalopram was initiated 1 year before she presented to the ED.

EVALUATION Hypothermia

Laboratory tests reveal multiple abnormalities, including thrombocytopenia (platelet level, 53 ×10³/μL), altered coagulation (partial thromboplastin time, 55.6 s), elevated levels of hepatic transaminases (aspartate aminotransferase, 168 U/L; alanine aminotransferase, 357 U/L), and increased alkaline phosphatase (206 U/L). Other mild metabolic disturbances include: sodium, 149 mEq/L; CO₂, 33 mEq/L; and blood urea nitrogen, 24 mg/dL.

These laboratory values are consistent with complications of hypothermia.¹

ECG reveals sinus bradycardia (40 bpm) and Osborn waves (additional deflection at the end of the QRS complex), which are seen often in hypothermia.¹ Head CT and brain MRI show chronic changes after Ms. K’s right temporoparietal AVM rupture, but no acute abnormality. Urinalysis, blood cultures, and chest radiographs are negative for infection. Urine toxicology screen is negative. Results of thyroid function tests and pituitary hormones studies are significant only for hyperprolactinemia of 155.7 ng/mL, a known adverse effect of antipsychotics.⁵

Ms. K is admitted and rewarmed passively and with warm IV fluids; by day 10 of hospitalization, temperature is stable (>35.1ºC [95.2ºF]). Thrombocytopenia, transaminitis, and altered mental status resolve.

Ms. K’s oral medications, including citalopram and paliperidone, have been held since admission because of her altered mental status. The psychiatry service is consulted to evaluate whether her presentation could be related to her change of medication.

A literature search reveals no report of paliperidone-induced hypothermia, but we consider it a possible explanation for Ms. K’s presentation. Lamotrigine (titrated to 50 mg/d), a benzodiazepine (oral lorazepam as needed), and discontinuing antipsychotics are recommended. After she returns to her baseline functioning, Ms. K is discharged to a skilled nursing facility.

Ms. K presents to the ED 2 days after discharge with altered mental status. Vital signs are: blood pressure, 90/55 mm Hg; pulse, 59 bpm; respiratory rate, 14/min; and temperature, 34.4ºC (93.9ºF) via bladder probe (Figure). Laboratory tests were significant for hepatic transaminitis (aspartate aminotransferase, 75 U/L; alanine aminotransferase, 122 U/L) and elevated alkaline phosphatase (226 U/L). A review of records from the nursing facility revealed that Ms. K was receiving paliperidone because of an error in the discharge summary, which recommended restarting all prior medications.

The authors’ observations

The Naranjo Causality Scale,⁶ which categorizes the probability that an adverse event is related to a drug (based on several variables, including timing of the drug administration with the onset of event, drug dosage and levels, response relationships to a drug, including re-challenge when possible, and previous patient experience with the medication), often is used to evaluate whether an adverse clinical event has been caused by a drug (Table 2). We applied the Scale to Ms. K’s case, which revealed a score of 7—indicating a probable adverse drug reaction. The sequence of events in Ms. K’s case that led to a paliperidone challenge-dechallenge-rechallenge, and the resulting hypothermia, are, we concluded, evidence of an adverse drug reaction.

Using the World Health Organization database for adverse drug reactions, van Marum et al⁷ found 480 reports hypothermia with antipsychotics as of 2007 (compared with 524 reports of hyperthermia in the same period); 55% involved atypical antipsychotics, mainly risperidone. There are no case reports of paliperidone-induced hypothermia; however, several reports of hypothermia have been attributed to risperidone, and paliperidone is the primary active metabolite of risperidone.⁵

To identify risk factors for hypothermia with antipsychotic use, van Marum et al⁷ performed a literature search for case reports of antipsychotic-induced hypothermia, which revealed no association with age or sex. The most common diagnosis in cases of antipsychotic-induced hypothermia was schizophrenia (51%). In 73% of the cases, hypothermia followed the start or dosage increase of the antipsychotic. These observations have been noted in case reports and case series of hypothermia associated with antipsychotic use.^8-12

Mechanism of action

One proposed mechanism for antipsychotic-induced hypothermia includes preferential 5-HT2A receptor antagonism over D2 receptor antagonism.^7,12 It has been believed that, under normal conditions, the action of dopamine to reduce body temperature and the action of serotonin to elevate it are in balance.⁹

Another possible mechanism is peripheral á2-adrenergic blockade, which might increase the hypothermic effect by inhibiting peripheral responses to cooling, such as vasoconstriction and shivering.^7,8 Boschi et al¹³ found that antipsychotics cause hypothermia in rats when the drug is administered intraperitoneally but not when given intrathecally. Perhaps for these reasons, in the early 1950s, before its psychotropic properties were known, chlorpromazine was used during surgery to induce artificial hibernation and suppress the body’s response to cooling.⁷ The therapeutic activity of paliperidone is mediated though a D2, 5-HT2A, and á2-receptor antagonism⁵; these mechanisms could, therefore, be contributing to Ms. K’s hypothermia.

Patients with preexisting brain damage— such as Ms. K—might be at increased risk of antipsychotic-induced hypothermia.^7,8 This includes focal damage to central thermoregulatory centers, such as the pre-optic anterior hypothalamic region,¹⁴ and more diffuse damage seen in patients with cognitive impairment or a seizure disorder.⁸

Studies of people with schizophrenia show a decrease in core temperature after administration of an antipsychotic,¹⁵ raising the possibility of an impairment of baseline thermoregulatory control. Such thermal dysregulation in patients with schizophrenia might be explained by changes in neurotensin levels.⁷

The neuropeptide neurotensin has been implicated in the regulation of prolactin release and interacts to a significant degree with the dopaminergic system.¹⁶ When administered to animals, neurotensin suppresses heat production and increases heat loss.¹⁷ The neurotensin level in CSF was found to be lower in non-medicated patients with schizophrenia than in healthy controls, with an inverse correlation between the severity of symptoms and the neurotensin level.¹⁸

Additionally, persons with schizophrenia might be at increased risk of developing hypothermia when exposed to a low environmental temperature.^7,8 Kudoh et al¹⁹ investigated temperature regulation during anesthesia in patients with chronic (≥7 years) schizophrenia receiving antipsychotics, and compared findings against what was seen in controls. The team reported that patients with schizophrenia had significantly lower intraoperative temperatures.

A published analysis of cases and studies of antipsychotic-induced hypothermia describes the combination of drug variables, patient variables, and environmental variables that contribute to thermal dysregulation (Table 3).^7-12,15 The recommendation for practitioners is that, when considering an antipsychotic for a patient at high risk of thermal dysregulation, your choice of an agent should take that risk into account, especially when that drug is one that has comparatively stronger serotonergic and peripheral á-adrenergic effects. You should monitor patients closely for hypothermia after starting and when increasing the dosage of the drug. In patients with schizophrenia who might have a problem with baseline thermoregulation, advise them to take measures to counteract their increased susceptibility to low ambient temperatures.

OUTCOME Readmission

Ms. K was readmitted, rewarmed, and discharged to a skilled nursing facility 4 days later, after baseline function returned to normal and temperature stabilized. Paliperidone is now listed in her electronic medical record as “drug intolerance.”

This case also highlights the importance of adequate medication reconciliation at
admission and discharge, especially when using an electronic medical record system, because what might otherwise be considered a minor mistake can have devastating consequences.

Bottom Line

Thermal dysregulation—hyperthermia and hypothermia—can occur secondary to an antipsychotic. Determining whether a patient is at increased risk of either of these adverse effects is important when deciding to use antipsychotics. Recognizing agents that can cause hypothermia is essential, because management requires prompt discontinuation of the offending drug.

Related Resource

• Espay AJ, et al. Frontal lobe syndromes. http://emedicine.medscape.com/article/1135866-overview. Updated September 17, 2012. Accessed November 3, 2012.

Drug Brand Names

Aripiprazole • Abilify                    Lamotrigine • Lamictal
Bromocriptine • Parlodel              Lorazepam • Ativan
Chlorpromazine • Thorazine         Paliperidone • Invega
Citalopram • Celexa                    Risperidone • Risperdal
Clozapine • Clozaril                     Sertraline • Zoloft
Divalproex sodium • Depakote     Thioridazine • Mellaril

Disclosure

The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Confused and cold

Ms. K, age 48, is brought to the emergency department (ED) by her husband because she has become increasingly lethargic over the past 2 weeks and cannot attend to activities of daily living. She is incontinent of stool and poorly responsive.

Ms. K’s husband reports that lethargy culminated in his wife sleeping 30 continuous hours. She has a history of a ruptured cerebral arteriovenous malformation (AVM) complicated by a secondary infarct 7 years ago, with residual symptoms of frontal lobe syndrome. Until 2 weeks ago, however, she was in her usual state of health.

Symptoms have included depression, mood lability, impulsivity, disinhibition, poor focus, and apathy. An outpatient psychiatrist has managed these symptoms with antidepressants and atypical antipsychotics.

When Ms. K arrives in the ED, she is taking citalopram, 30 mg/d, and paliperidone,
6 mg/d. Her psychiatrist started paliperidone 2 months ago, increasing the dosage to 6 mg/d 6 weeks before presentation because of worsening mood lability, disinhibition, and paranoia regarding her caregivers. Her husband denies any other medication changes or exposure to environmental toxins.

In the ED, Ms. K is confused and oriented only to person. Vital signs are: pulse 46 bpm; blood pressure, 66/51 mm Hg; respirations, 12/min; and temperature, 29.9ºC (85.8ºF) via bladder probe.

The authors’ observations

Hypothermia is core body temperature <35ºC (95ºF).¹ It often is caused by exposure to low ambient temperature (Table 1),¹ but Ms. K’s husband denied that she had been exposed to cold. Because of Ms. K’s neurologic history, stroke was high on the differential diagnosis, but physical examination did not reveal evidence of focal dysfunction and was significant only for altered mental status.

Ms. K had no posturing, rigidity, negativism, or excessive motor activity that would suggest catatonia. Before she became lethargic, her husband had not noted any deterioration of mood, although she did exhibit other behavioral changes that prompted her outpatient psychiatrist to increase the dosage of paliperidone. Although Ms. K began experiencing persecutory delusions—she believed that her caregivers were trying to harm her—she and her family denied perceptual disturbances. On examination, she did not appear responsive to auditory or visual hallucinations.

Frontal lobe syndrome is defined as a set of changes in the cognitive, behavioral, or emotional domains, often leading to disturbed affect, alteration of attention, aphasia, perseveration, disinhibition, and personality changes.² These symptoms are not specific to lesions in the frontal lobes but can arise from lesions anywhere in the frontal-striatal-thalamic circuit.³ Causes include traumatic brain injury, neurodegenerative disorders, cerebrovascular disease, tumors, and aging.² Recommended treatment incorporates psychosocial interventions with drug treatment to target specific symptoms. Medications reported to be effective include typical and atypical antipsychotics to target aggression and agitation; benzodiazepines to reduce arousal; antidepressants for mood symptoms, dopamine agonists (eg, bromocriptine) to decrease apathy, and mood stabilizers to target mood lability.⁴

Before her AVM rupture, review of Ms. K’s psychiatric history revealed no psychiatric symptoms or impaired functioning. When hospitalized for the AVM repair, she was started on sertraline. She began seeing a psychiatrist 2 years later because of increased agitation and behavioral disturbances, and aripiprazole was added. Persistent agitation prompted a trial of divalproex sodium, which was discontinued because of slurred speech and increased distractibility. Aripiprazole was tapered and replaced with paliperidone because of poor response. Citalopram was initiated 1 year before she presented to the ED.

EVALUATION Hypothermia

Laboratory tests reveal multiple abnormalities, including thrombocytopenia (platelet level, 53 ×10³/μL), altered coagulation (partial thromboplastin time, 55.6 s), elevated levels of hepatic transaminases (aspartate aminotransferase, 168 U/L; alanine aminotransferase, 357 U/L), and increased alkaline phosphatase (206 U/L). Other mild metabolic disturbances include: sodium, 149 mEq/L; CO₂, 33 mEq/L; and blood urea nitrogen, 24 mg/dL.

These laboratory values are consistent with complications of hypothermia.¹

ECG reveals sinus bradycardia (40 bpm) and Osborn waves (additional deflection at the end of the QRS complex), which are seen often in hypothermia.¹ Head CT and brain MRI show chronic changes after Ms. K’s right temporoparietal AVM rupture, but no acute abnormality. Urinalysis, blood cultures, and chest radiographs are negative for infection. Urine toxicology screen is negative. Results of thyroid function tests and pituitary hormones studies are significant only for hyperprolactinemia of 155.7 ng/mL, a known adverse effect of antipsychotics.⁵

Ms. K is admitted and rewarmed passively and with warm IV fluids; by day 10 of hospitalization, temperature is stable (>35.1ºC [95.2ºF]). Thrombocytopenia, transaminitis, and altered mental status resolve.

Ms. K’s oral medications, including citalopram and paliperidone, have been held since admission because of her altered mental status. The psychiatry service is consulted to evaluate whether her presentation could be related to her change of medication.

A literature search reveals no report of paliperidone-induced hypothermia, but we consider it a possible explanation for Ms. K’s presentation. Lamotrigine (titrated to 50 mg/d), a benzodiazepine (oral lorazepam as needed), and discontinuing antipsychotics are recommended. After she returns to her baseline functioning, Ms. K is discharged to a skilled nursing facility.

Ms. K presents to the ED 2 days after discharge with altered mental status. Vital signs are: blood pressure, 90/55 mm Hg; pulse, 59 bpm; respiratory rate, 14/min; and temperature, 34.4ºC (93.9ºF) via bladder probe (Figure). Laboratory tests were significant for hepatic transaminitis (aspartate aminotransferase, 75 U/L; alanine aminotransferase, 122 U/L) and elevated alkaline phosphatase (226 U/L). A review of records from the nursing facility revealed that Ms. K was receiving paliperidone because of an error in the discharge summary, which recommended restarting all prior medications.

The authors’ observations

The Naranjo Causality Scale,⁶ which categorizes the probability that an adverse event is related to a drug (based on several variables, including timing of the drug administration with the onset of event, drug dosage and levels, response relationships to a drug, including re-challenge when possible, and previous patient experience with the medication), often is used to evaluate whether an adverse clinical event has been caused by a drug (Table 2). We applied the Scale to Ms. K’s case, which revealed a score of 7—indicating a probable adverse drug reaction. The sequence of events in Ms. K’s case that led to a paliperidone challenge-dechallenge-rechallenge, and the resulting hypothermia, are, we concluded, evidence of an adverse drug reaction.

Using the World Health Organization database for adverse drug reactions, van Marum et al⁷ found 480 reports hypothermia with antipsychotics as of 2007 (compared with 524 reports of hyperthermia in the same period); 55% involved atypical antipsychotics, mainly risperidone. There are no case reports of paliperidone-induced hypothermia; however, several reports of hypothermia have been attributed to risperidone, and paliperidone is the primary active metabolite of risperidone.⁵

To identify risk factors for hypothermia with antipsychotic use, van Marum et al⁷ performed a literature search for case reports of antipsychotic-induced hypothermia, which revealed no association with age or sex. The most common diagnosis in cases of antipsychotic-induced hypothermia was schizophrenia (51%). In 73% of the cases, hypothermia followed the start or dosage increase of the antipsychotic. These observations have been noted in case reports and case series of hypothermia associated with antipsychotic use.^8-12

Mechanism of action

One proposed mechanism for antipsychotic-induced hypothermia includes preferential 5-HT2A receptor antagonism over D2 receptor antagonism.^7,12 It has been believed that, under normal conditions, the action of dopamine to reduce body temperature and the action of serotonin to elevate it are in balance.⁹

Another possible mechanism is peripheral á2-adrenergic blockade, which might increase the hypothermic effect by inhibiting peripheral responses to cooling, such as vasoconstriction and shivering.^7,8 Boschi et al¹³ found that antipsychotics cause hypothermia in rats when the drug is administered intraperitoneally but not when given intrathecally. Perhaps for these reasons, in the early 1950s, before its psychotropic properties were known, chlorpromazine was used during surgery to induce artificial hibernation and suppress the body’s response to cooling.⁷ The therapeutic activity of paliperidone is mediated though a D2, 5-HT2A, and á2-receptor antagonism⁵; these mechanisms could, therefore, be contributing to Ms. K’s hypothermia.

Patients with preexisting brain damage— such as Ms. K—might be at increased risk of antipsychotic-induced hypothermia.^7,8 This includes focal damage to central thermoregulatory centers, such as the pre-optic anterior hypothalamic region,¹⁴ and more diffuse damage seen in patients with cognitive impairment or a seizure disorder.⁸

Studies of people with schizophrenia show a decrease in core temperature after administration of an antipsychotic,¹⁵ raising the possibility of an impairment of baseline thermoregulatory control. Such thermal dysregulation in patients with schizophrenia might be explained by changes in neurotensin levels.⁷

The neuropeptide neurotensin has been implicated in the regulation of prolactin release and interacts to a significant degree with the dopaminergic system.¹⁶ When administered to animals, neurotensin suppresses heat production and increases heat loss.¹⁷ The neurotensin level in CSF was found to be lower in non-medicated patients with schizophrenia than in healthy controls, with an inverse correlation between the severity of symptoms and the neurotensin level.¹⁸

Additionally, persons with schizophrenia might be at increased risk of developing hypothermia when exposed to a low environmental temperature.^7,8 Kudoh et al¹⁹ investigated temperature regulation during anesthesia in patients with chronic (≥7 years) schizophrenia receiving antipsychotics, and compared findings against what was seen in controls. The team reported that patients with schizophrenia had significantly lower intraoperative temperatures.

A published analysis of cases and studies of antipsychotic-induced hypothermia describes the combination of drug variables, patient variables, and environmental variables that contribute to thermal dysregulation (Table 3).^7-12,15 The recommendation for practitioners is that, when considering an antipsychotic for a patient at high risk of thermal dysregulation, your choice of an agent should take that risk into account, especially when that drug is one that has comparatively stronger serotonergic and peripheral á-adrenergic effects. You should monitor patients closely for hypothermia after starting and when increasing the dosage of the drug. In patients with schizophrenia who might have a problem with baseline thermoregulation, advise them to take measures to counteract their increased susceptibility to low ambient temperatures.

OUTCOME Readmission

Ms. K was readmitted, rewarmed, and discharged to a skilled nursing facility 4 days later, after baseline function returned to normal and temperature stabilized. Paliperidone is now listed in her electronic medical record as “drug intolerance.”

This case also highlights the importance of adequate medication reconciliation at
admission and discharge, especially when using an electronic medical record system, because what might otherwise be considered a minor mistake can have devastating consequences.

Bottom Line

Thermal dysregulation—hyperthermia and hypothermia—can occur secondary to an antipsychotic. Determining whether a patient is at increased risk of either of these adverse effects is important when deciding to use antipsychotics. Recognizing agents that can cause hypothermia is essential, because management requires prompt discontinuation of the offending drug.

Related Resource

• Espay AJ, et al. Frontal lobe syndromes. http://emedicine.medscape.com/article/1135866-overview. Updated September 17, 2012. Accessed November 3, 2012.

Drug Brand Names

Aripiprazole • Abilify                    Lamotrigine • Lamictal
Bromocriptine • Parlodel              Lorazepam • Ativan
Chlorpromazine • Thorazine         Paliperidone • Invega
Citalopram • Celexa                    Risperidone • Risperdal
Clozapine • Clozaril                     Sertraline • Zoloft
Divalproex sodium • Depakote     Thioridazine • Mellaril

Disclosure

The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

From Children’s Mercy Kansas City, Kansas City, MO.

Abstract

• Objective: To review functional gastrointestinal disorders (FGIDs) in children, with an emphasis on evidence-based diagnostic and treatment approaches.
• Methods: Review of the literature.
• Results: Chronic or recurrent abdominal pain is a common condition in children. No clinical practice guidelines currently exist for pediatric functional abdominal pain broadly or FGIDs more specifically. The Rome classification system includes several discrete diagnostic entities that are diagnosed based on symptom criteria in the absence of red flags. The prevailing biopsychosocial model of pediatric functional abdominal pain suggests that intervening to address biological factors, while providing coping skills and environmental supports to encourage functioning, offers the greatest likelihood of positive treatment outcomes and decreased disability.
• Conclusion: Simultaneously treating all contributors to pain maintenance in FGIDs offers the greatest promise in effectively breaking the pain cycle.

From Children’s Mercy Kansas City, Kansas City, MO.

Abstract

• Objective: To review functional gastrointestinal disorders (FGIDs) in children, with an emphasis on evidence-based diagnostic and treatment approaches.
• Methods: Review of the literature.
• Results: Chronic or recurrent abdominal pain is a common condition in children. No clinical practice guidelines currently exist for pediatric functional abdominal pain broadly or FGIDs more specifically. The Rome classification system includes several discrete diagnostic entities that are diagnosed based on symptom criteria in the absence of red flags. The prevailing biopsychosocial model of pediatric functional abdominal pain suggests that intervening to address biological factors, while providing coping skills and environmental supports to encourage functioning, offers the greatest likelihood of positive treatment outcomes and decreased disability.
• Conclusion: Simultaneously treating all contributors to pain maintenance in FGIDs offers the greatest promise in effectively breaking the pain cycle.

From Children’s Mercy Kansas City, Kansas City, MO.

Abstract

• Objective: To review functional gastrointestinal disorders (FGIDs) in children, with an emphasis on evidence-based diagnostic and treatment approaches.
• Methods: Review of the literature.
• Results: Chronic or recurrent abdominal pain is a common condition in children. No clinical practice guidelines currently exist for pediatric functional abdominal pain broadly or FGIDs more specifically. The Rome classification system includes several discrete diagnostic entities that are diagnosed based on symptom criteria in the absence of red flags. The prevailing biopsychosocial model of pediatric functional abdominal pain suggests that intervening to address biological factors, while providing coping skills and environmental supports to encourage functioning, offers the greatest likelihood of positive treatment outcomes and decreased disability.
• Conclusion: Simultaneously treating all contributors to pain maintenance in FGIDs offers the greatest promise in effectively breaking the pain cycle.

CASE Grief and confusion

Mr. P, age 47, is arrested for entering the apartment of a woman he does not know and tossing her belongings out the window. When he is assessed to determine if he can participate in his legal defense, examiners find an attentive, courteous man who is baffled by his own behavior.

Mr. P says that he had been “stressed out” after the recent death of his grandmother, with whom he was close. He says he entered the apartment because voices told him to do so. He has no recent history of substance abuse or psychiatric hospitalizations, but he had a similar episode of “confusion” years before, when another close family member died.

Mr. P is found not fit to stand trial and the charges are dropped. He accepts haloperidol, 10 mg/d, and benztropine, 2 mg/d, and is transferred to a hospital for psychiatric treatment.

On interview, Mr. P is well groomed, soft-spoken, and shy, without formal thought disorder. Physical exam and routine lab tests are within normal limits. He says that 18 months before his arrest, he and his frail grandmother moved to a large city in hopes that he would find a wife. Both depended on the grandmother’s Social Security benefits while he cared for her.

In the 2 months after she died, he reports that he felt sad and alone and slept poorly, but made efforts to find a job and keep his apartment. When his efforts failed and he lost the apartment, he stayed with various friends for a few days at a time, then spent several days in the subway before ending up on the streets.

His arrest on the current charge occurred 4 days after he began walking the streets.

HISTORY Imagining nonsense

Mr. P cannot explain why he started “trashing” the woman’s apartment, but says he entered it because he thought it was his apartment. With embarrassment and regret, he admits he has been depressed and confused, “imagining things”—“foolish things,” he admits—such as being in a different “time zone.”

Contradicting his earlier statements, Mr. P now admits that he had “a few beers” and denies that he experienced auditory hallucinations, saying he only talks to himself. He now says that within 2 days after his arrest, he was “all over it.” Mr. P denies current symptoms, including hallucinations, but, when pressed, waffles, then admits to a strange belief: that some people, including him, can move from one “time zone” to another.

Mr. P says he was treated for psychiatric problems 4 years earlier when his parents were killed in a car crash. By his recollection, his reaction to their death was similar to his reaction to his grandmother’s death: He became upset and wandered the streets for a few days, “moving between time zones” and talking to himself but not experiencing hallucinations. After he was taken to a hospital and “given an injection,” he calmed down and was released. Within a few days he recovered and returned to supporting himself and caring for his grandmother. Mr. P says the idea of travelling between “time zones” is embarrassing and nonsensical but adds that he was affected in this way because he “bickered” with his mother.

Mr. P’s grandmother raised him until he was age 15, although he frequently visited his parents, who lived nearby and worked during the day. Mr. P initially denies substance abuse, then admits to smoking marijuana every day for about a year before admission. He also admits to cocaine abuse in his 20s. He denies a history of suicide attempts.

The author’s observations

Mr. P reported only 2 episodes of “confusion” (or psychosis) and strange behavior in his life, both precipitated by the loss of a loved one, and at least 1 while under the influence of alcohol and Cannabis. He gave an inconsistent and ambiguous history of auditory hallucinations associated with episodes of confusion. He believes that time travel is possible, an idea that he acknowledged is nonsense. This alone was not enough to warrant long-term antipsychotic treatment. The most likely diagnosis seemed to be brief psychotic episode induced by Cannabis and the stressors of homelessness and his grandmother’s death. 

EVALUATION Changing stories

No longer taking haloperidol, Mr. P continues to deny hallucinations and depressed mood, but keeps to himself. Nine days after admission he becomes tearful after he informs his aunt of his grandmother’s death in a telephone call, then approaches a nurse and complains of sadness and auditory hallucinations.

Mr. P confesses that he denied hallucinations on admission because he feared he would remain in the hospital for years if he revealed the truth that he had been experiencing auditory hallucinations almost continuously from age 10. He reports that the voices distracted him when he worked; seem to be male; often spoke gibberish; and alternate between deprecating and positive and supportive. Mr. P is reluctant to disclose more about what the voices actually say, although he acknowledges that they are not commenting or conversing with him, and that he has never believed the voices were his own thoughts but did believe that they came from inside his brain.

With haloperidol, the voices stopped. They resumed, however, when haloperidol was discontinued.

When we ask what happened to him at age 10, Mr. P shrugs.

The author’s observations

In community samples of children and adolescents, auditory hallucinations are not rare and usually do not cause distress or dysfunction. In a study of 3,870 children age 7 and 8,¹ 9% endorsed auditory hallucinations. Most heard 1 voice, once a week or less, at low volume. In 85% of children who experienced hallucinations, they caused minimal or no suffering; 97% reported minimal or no interference with daily functioning. Among children who experienced auditory hallucinations at age 7 or 8, 24% continued to hallucinate 5 years later.² Persistent hallucinations were associated with more problematic behaviors at baseline and follow up.

In a group of 12-year-old twins, 4.2% reported auditory hallucinations.³ In that study, hallucinations were not related to Cannabis use; rather, they were heritable and related to risk factors such as cognitive impairment; behavioral, emotional, and educational problems at age 5; and a history of physical abuse and self-harm at age 12. The authors noted that these are risk factors and correlates of schizophrenia, but are not specific to schizophrenia.

Hallucinations and delusions have been found in 4% to 8% of children and adolescents referred for psychiatric treatment,⁴ far more than the prevalence of childhood-onset schizophrenia (0.01% of children).⁵ Psychotic symptoms in children have been associated with bipolar disorder, but also with anxiety disorders, obsessive-compulsive disorder, PTSD, pervasive developmental disorder, conduct disorder, and substance abuse.⁴

Childhood-onset schizophrenia is rare and would require that Mr. P have a diagnosis of schizophrenia as an adult. It is possible that Mr. P’s childhood symptoms were related to substance abuse but he was not asked for this history because it seemed unlikely in a 10-year-old boy. A PTSD diagnosis requires a traumatic event, which Mr. P did not reveal. It is possible that at age 10 he did not have a psychiatric disorder.

Among adults in the general population, 10% to 15% report auditory hallucinations.⁶ Hallucinations could be caused by substance abuse or psychiatric conditions other than schizophrenia; however, in adults—as in children—auditory hallucinations can occur in the absence of these conditions (Table 1) and rarely cause distress or dysfunction.⁶ In Sommer and colleagues’⁶ study of 103 healthy persons, none who heard voices had disorganization or negative symptoms. Those who heard voices had significantly more schizotypal symptoms and more childhood trauma, including emotional, physical, and sexual abuse, than those who did not hear voices.⁶

Conditions associated with hallucinations

PTSD is associated with auditory hallucinations and other psychotic symptoms.⁷ Most studies are of combat veterans with PTSD, in whom auditory hallucinations and delusions were associated with major depressive disorder, not a thought disorder or inappropriate affect.⁸ In a community sample,⁹ psychotic symptoms—particularly auditory hallucinations—were associated with PTSD. Subjects with PTSD and psychotic symptoms were more likely to have other psychiatric disorders, including major depressive disorder and substance use disorder, than patients with PTSD but no psychotic symptoms; however, the relationship between PTSD and psychosis remained after controlling for other psychiatric disorders.

Hallucinations can occur in persons with dissociative disorders in the absence of distinct personality states.¹⁰ Hallucinations have been seen transiently and chronically in persons with borderline personality disorder and can be associated with comorbid conditions such as substance abuse disorders, mood disorders, and PTSD.¹¹

Mr. P lacked the reduced capacity for interpersonal relationships required for a schizotypal personality disorder diagnosis. A diagnosis of PTSD or dissociative disorder requires a history of trauma, which Mr. P did not report.

“Time travelling” with incomprehensible behavior could be interpreted as dissociation, but dissociative fugue or dissociative disorder not otherwise specified (NOS) cannot be diagnosed if symptoms might be the direct effect of a substance, such as Cannabis. Mr. P admitted to substance abuse. We can rule out borderline personality disorder because he did not display or admit to tempestuous interpersonal relationships.

A schizophrenia diagnosis requires the presence of auditory hallucinations that commented on his behavior or conversed among themselves, a second psychotic symptom for ≥1 month, or negative symptoms, which Mr. P lacked (unless belief in time travel is considered delusional).

Last, a physician might have considered malingering or a factitious disorder when Mr. P was found not able to participate in his own defense, but this seemed less likely after he revealed that he experienced auditory hallucinations since age 10.

HISTORY Bad beatings

With a few days of beginning risperidone, 4 mg/d, Mr. P reports that his hallucinations have stopped and he feels less sad. He reveals that, at age 10, when the hallucinations began, his mother hit him over the head with a high-heeled shoe, causing a scalp laceration that required a visit to the emergency room for suturing. His mother beat Mr. P for as long as he could remember. She beat him “bad” at least twice weekly, and he was taken to the hospital 7 or 8 times for injury, but she also beat him “constantly” with a belt buckle, sometimes striking his head. She instructed him to tell nobody.

The author’s observations

Auditory hallucinations in adults have been associated with childhood abuse, particularly childhood sexual abuse,¹² in clinical and non-clinical samples.¹³ Some argue¹³ that child abuse itself causes hallucinations and other psychotic symptoms.

OUTCOME Depressed and sleepless

Mr. P admits that he had been smoking marijuana 2 to 3 times daily for a year. He also reports insomnia, sleeping approximately 4 hours a night and spending hours awake in bed thinking of his grandmother, with depressed mood and tearfulness. He denies suicidal ideas and hallucinations. He is treated for depressive disorder NOS first with amitriptyline, 50 mg at bedtime, for sleep, then paroxetine, 20 mg/d, for depressive symptoms, in addition to risperidone, 4 mg/d. Although Mr. P does not describe re-experiencing his childhood trauma, avoidance of stimuli associated with the trauma, or symptoms of increased arousal (except for insomnia), the treatment team did not ask, so it remains uncertain if he has PTSD (Table 2).

When Mr. P is discharged to a clinic, he smiles easily and is positive and supportive with other patients. He spruces up his appearance by wearing jewelry and works in the hospital kitchen.

Bottom Line

Chronic auditory hallucinations are associated with psychiatric illnesses other than chronic schizophrenia, particularly those resulting from trauma such as posttraumatic stress disorder. They can also occur in the absence of diagnosable psychiatric illness and rarely cause distress or functional impairment. Auditory hallucinations in adults have been associated with childhood abuse.

Related Resources

• Moskowitz A, Schafer I, Dorahy MJ. Psychosis, trauma and dissociation: emerging perspectives on severe psychopathology. West Sussex, UK: John Wiley and Sons, Ltd.; 2008.
• The International Hearing Voices Network. www.intervoiceonline.org.

Drug Brand Names

Amitriptyline • Elavil               Paroxetine • Paxil

Benztropine • Cogentin           Risperidone • Risperdal

Haloperidol • Haldol

Disclosure

Dr. Crowner reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Grief and confusion

Mr. P, age 47, is arrested for entering the apartment of a woman he does not know and tossing her belongings out the window. When he is assessed to determine if he can participate in his legal defense, examiners find an attentive, courteous man who is baffled by his own behavior.

Mr. P says that he had been “stressed out” after the recent death of his grandmother, with whom he was close. He says he entered the apartment because voices told him to do so. He has no recent history of substance abuse or psychiatric hospitalizations, but he had a similar episode of “confusion” years before, when another close family member died.

Mr. P is found not fit to stand trial and the charges are dropped. He accepts haloperidol, 10 mg/d, and benztropine, 2 mg/d, and is transferred to a hospital for psychiatric treatment.

On interview, Mr. P is well groomed, soft-spoken, and shy, without formal thought disorder. Physical exam and routine lab tests are within normal limits. He says that 18 months before his arrest, he and his frail grandmother moved to a large city in hopes that he would find a wife. Both depended on the grandmother’s Social Security benefits while he cared for her.

In the 2 months after she died, he reports that he felt sad and alone and slept poorly, but made efforts to find a job and keep his apartment. When his efforts failed and he lost the apartment, he stayed with various friends for a few days at a time, then spent several days in the subway before ending up on the streets.

His arrest on the current charge occurred 4 days after he began walking the streets.

HISTORY Imagining nonsense

Mr. P cannot explain why he started “trashing” the woman’s apartment, but says he entered it because he thought it was his apartment. With embarrassment and regret, he admits he has been depressed and confused, “imagining things”—“foolish things,” he admits—such as being in a different “time zone.”

Contradicting his earlier statements, Mr. P now admits that he had “a few beers” and denies that he experienced auditory hallucinations, saying he only talks to himself. He now says that within 2 days after his arrest, he was “all over it.” Mr. P denies current symptoms, including hallucinations, but, when pressed, waffles, then admits to a strange belief: that some people, including him, can move from one “time zone” to another.

Mr. P says he was treated for psychiatric problems 4 years earlier when his parents were killed in a car crash. By his recollection, his reaction to their death was similar to his reaction to his grandmother’s death: He became upset and wandered the streets for a few days, “moving between time zones” and talking to himself but not experiencing hallucinations. After he was taken to a hospital and “given an injection,” he calmed down and was released. Within a few days he recovered and returned to supporting himself and caring for his grandmother. Mr. P says the idea of travelling between “time zones” is embarrassing and nonsensical but adds that he was affected in this way because he “bickered” with his mother.

Mr. P’s grandmother raised him until he was age 15, although he frequently visited his parents, who lived nearby and worked during the day. Mr. P initially denies substance abuse, then admits to smoking marijuana every day for about a year before admission. He also admits to cocaine abuse in his 20s. He denies a history of suicide attempts.

The author’s observations

Mr. P reported only 2 episodes of “confusion” (or psychosis) and strange behavior in his life, both precipitated by the loss of a loved one, and at least 1 while under the influence of alcohol and Cannabis. He gave an inconsistent and ambiguous history of auditory hallucinations associated with episodes of confusion. He believes that time travel is possible, an idea that he acknowledged is nonsense. This alone was not enough to warrant long-term antipsychotic treatment. The most likely diagnosis seemed to be brief psychotic episode induced by Cannabis and the stressors of homelessness and his grandmother’s death. 

EVALUATION Changing stories

No longer taking haloperidol, Mr. P continues to deny hallucinations and depressed mood, but keeps to himself. Nine days after admission he becomes tearful after he informs his aunt of his grandmother’s death in a telephone call, then approaches a nurse and complains of sadness and auditory hallucinations.

Mr. P confesses that he denied hallucinations on admission because he feared he would remain in the hospital for years if he revealed the truth that he had been experiencing auditory hallucinations almost continuously from age 10. He reports that the voices distracted him when he worked; seem to be male; often spoke gibberish; and alternate between deprecating and positive and supportive. Mr. P is reluctant to disclose more about what the voices actually say, although he acknowledges that they are not commenting or conversing with him, and that he has never believed the voices were his own thoughts but did believe that they came from inside his brain.

With haloperidol, the voices stopped. They resumed, however, when haloperidol was discontinued.

When we ask what happened to him at age 10, Mr. P shrugs.

The author’s observations

In community samples of children and adolescents, auditory hallucinations are not rare and usually do not cause distress or dysfunction. In a study of 3,870 children age 7 and 8,¹ 9% endorsed auditory hallucinations. Most heard 1 voice, once a week or less, at low volume. In 85% of children who experienced hallucinations, they caused minimal or no suffering; 97% reported minimal or no interference with daily functioning. Among children who experienced auditory hallucinations at age 7 or 8, 24% continued to hallucinate 5 years later.² Persistent hallucinations were associated with more problematic behaviors at baseline and follow up.

In a group of 12-year-old twins, 4.2% reported auditory hallucinations.³ In that study, hallucinations were not related to Cannabis use; rather, they were heritable and related to risk factors such as cognitive impairment; behavioral, emotional, and educational problems at age 5; and a history of physical abuse and self-harm at age 12. The authors noted that these are risk factors and correlates of schizophrenia, but are not specific to schizophrenia.

Hallucinations and delusions have been found in 4% to 8% of children and adolescents referred for psychiatric treatment,⁴ far more than the prevalence of childhood-onset schizophrenia (0.01% of children).⁵ Psychotic symptoms in children have been associated with bipolar disorder, but also with anxiety disorders, obsessive-compulsive disorder, PTSD, pervasive developmental disorder, conduct disorder, and substance abuse.⁴

Childhood-onset schizophrenia is rare and would require that Mr. P have a diagnosis of schizophrenia as an adult. It is possible that Mr. P’s childhood symptoms were related to substance abuse but he was not asked for this history because it seemed unlikely in a 10-year-old boy. A PTSD diagnosis requires a traumatic event, which Mr. P did not reveal. It is possible that at age 10 he did not have a psychiatric disorder.

Among adults in the general population, 10% to 15% report auditory hallucinations.⁶ Hallucinations could be caused by substance abuse or psychiatric conditions other than schizophrenia; however, in adults—as in children—auditory hallucinations can occur in the absence of these conditions (Table 1) and rarely cause distress or dysfunction.⁶ In Sommer and colleagues’⁶ study of 103 healthy persons, none who heard voices had disorganization or negative symptoms. Those who heard voices had significantly more schizotypal symptoms and more childhood trauma, including emotional, physical, and sexual abuse, than those who did not hear voices.⁶

Conditions associated with hallucinations

PTSD is associated with auditory hallucinations and other psychotic symptoms.⁷ Most studies are of combat veterans with PTSD, in whom auditory hallucinations and delusions were associated with major depressive disorder, not a thought disorder or inappropriate affect.⁸ In a community sample,⁹ psychotic symptoms—particularly auditory hallucinations—were associated with PTSD. Subjects with PTSD and psychotic symptoms were more likely to have other psychiatric disorders, including major depressive disorder and substance use disorder, than patients with PTSD but no psychotic symptoms; however, the relationship between PTSD and psychosis remained after controlling for other psychiatric disorders.

Hallucinations can occur in persons with dissociative disorders in the absence of distinct personality states.¹⁰ Hallucinations have been seen transiently and chronically in persons with borderline personality disorder and can be associated with comorbid conditions such as substance abuse disorders, mood disorders, and PTSD.¹¹

Mr. P lacked the reduced capacity for interpersonal relationships required for a schizotypal personality disorder diagnosis. A diagnosis of PTSD or dissociative disorder requires a history of trauma, which Mr. P did not report.

“Time travelling” with incomprehensible behavior could be interpreted as dissociation, but dissociative fugue or dissociative disorder not otherwise specified (NOS) cannot be diagnosed if symptoms might be the direct effect of a substance, such as Cannabis. Mr. P admitted to substance abuse. We can rule out borderline personality disorder because he did not display or admit to tempestuous interpersonal relationships.

A schizophrenia diagnosis requires the presence of auditory hallucinations that commented on his behavior or conversed among themselves, a second psychotic symptom for ≥1 month, or negative symptoms, which Mr. P lacked (unless belief in time travel is considered delusional).

Last, a physician might have considered malingering or a factitious disorder when Mr. P was found not able to participate in his own defense, but this seemed less likely after he revealed that he experienced auditory hallucinations since age 10.

HISTORY Bad beatings

With a few days of beginning risperidone, 4 mg/d, Mr. P reports that his hallucinations have stopped and he feels less sad. He reveals that, at age 10, when the hallucinations began, his mother hit him over the head with a high-heeled shoe, causing a scalp laceration that required a visit to the emergency room for suturing. His mother beat Mr. P for as long as he could remember. She beat him “bad” at least twice weekly, and he was taken to the hospital 7 or 8 times for injury, but she also beat him “constantly” with a belt buckle, sometimes striking his head. She instructed him to tell nobody.

The author’s observations

Auditory hallucinations in adults have been associated with childhood abuse, particularly childhood sexual abuse,¹² in clinical and non-clinical samples.¹³ Some argue¹³ that child abuse itself causes hallucinations and other psychotic symptoms.

OUTCOME Depressed and sleepless

Mr. P admits that he had been smoking marijuana 2 to 3 times daily for a year. He also reports insomnia, sleeping approximately 4 hours a night and spending hours awake in bed thinking of his grandmother, with depressed mood and tearfulness. He denies suicidal ideas and hallucinations. He is treated for depressive disorder NOS first with amitriptyline, 50 mg at bedtime, for sleep, then paroxetine, 20 mg/d, for depressive symptoms, in addition to risperidone, 4 mg/d. Although Mr. P does not describe re-experiencing his childhood trauma, avoidance of stimuli associated with the trauma, or symptoms of increased arousal (except for insomnia), the treatment team did not ask, so it remains uncertain if he has PTSD (Table 2).

When Mr. P is discharged to a clinic, he smiles easily and is positive and supportive with other patients. He spruces up his appearance by wearing jewelry and works in the hospital kitchen.

Bottom Line

Chronic auditory hallucinations are associated with psychiatric illnesses other than chronic schizophrenia, particularly those resulting from trauma such as posttraumatic stress disorder. They can also occur in the absence of diagnosable psychiatric illness and rarely cause distress or functional impairment. Auditory hallucinations in adults have been associated with childhood abuse.

Related Resources

• Moskowitz A, Schafer I, Dorahy MJ. Psychosis, trauma and dissociation: emerging perspectives on severe psychopathology. West Sussex, UK: John Wiley and Sons, Ltd.; 2008.
• The International Hearing Voices Network. www.intervoiceonline.org.

Drug Brand Names

Amitriptyline • Elavil               Paroxetine • Paxil

Benztropine • Cogentin           Risperidone • Risperdal

Haloperidol • Haldol

Disclosure

Dr. Crowner reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Grief and confusion

Mr. P, age 47, is arrested for entering the apartment of a woman he does not know and tossing her belongings out the window. When he is assessed to determine if he can participate in his legal defense, examiners find an attentive, courteous man who is baffled by his own behavior.

Mr. P says that he had been “stressed out” after the recent death of his grandmother, with whom he was close. He says he entered the apartment because voices told him to do so. He has no recent history of substance abuse or psychiatric hospitalizations, but he had a similar episode of “confusion” years before, when another close family member died.

Mr. P is found not fit to stand trial and the charges are dropped. He accepts haloperidol, 10 mg/d, and benztropine, 2 mg/d, and is transferred to a hospital for psychiatric treatment.

On interview, Mr. P is well groomed, soft-spoken, and shy, without formal thought disorder. Physical exam and routine lab tests are within normal limits. He says that 18 months before his arrest, he and his frail grandmother moved to a large city in hopes that he would find a wife. Both depended on the grandmother’s Social Security benefits while he cared for her.

In the 2 months after she died, he reports that he felt sad and alone and slept poorly, but made efforts to find a job and keep his apartment. When his efforts failed and he lost the apartment, he stayed with various friends for a few days at a time, then spent several days in the subway before ending up on the streets.

His arrest on the current charge occurred 4 days after he began walking the streets.

HISTORY Imagining nonsense

Mr. P cannot explain why he started “trashing” the woman’s apartment, but says he entered it because he thought it was his apartment. With embarrassment and regret, he admits he has been depressed and confused, “imagining things”—“foolish things,” he admits—such as being in a different “time zone.”

Contradicting his earlier statements, Mr. P now admits that he had “a few beers” and denies that he experienced auditory hallucinations, saying he only talks to himself. He now says that within 2 days after his arrest, he was “all over it.” Mr. P denies current symptoms, including hallucinations, but, when pressed, waffles, then admits to a strange belief: that some people, including him, can move from one “time zone” to another.

Mr. P says he was treated for psychiatric problems 4 years earlier when his parents were killed in a car crash. By his recollection, his reaction to their death was similar to his reaction to his grandmother’s death: He became upset and wandered the streets for a few days, “moving between time zones” and talking to himself but not experiencing hallucinations. After he was taken to a hospital and “given an injection,” he calmed down and was released. Within a few days he recovered and returned to supporting himself and caring for his grandmother. Mr. P says the idea of travelling between “time zones” is embarrassing and nonsensical but adds that he was affected in this way because he “bickered” with his mother.

Mr. P’s grandmother raised him until he was age 15, although he frequently visited his parents, who lived nearby and worked during the day. Mr. P initially denies substance abuse, then admits to smoking marijuana every day for about a year before admission. He also admits to cocaine abuse in his 20s. He denies a history of suicide attempts.

The author’s observations

Mr. P reported only 2 episodes of “confusion” (or psychosis) and strange behavior in his life, both precipitated by the loss of a loved one, and at least 1 while under the influence of alcohol and Cannabis. He gave an inconsistent and ambiguous history of auditory hallucinations associated with episodes of confusion. He believes that time travel is possible, an idea that he acknowledged is nonsense. This alone was not enough to warrant long-term antipsychotic treatment. The most likely diagnosis seemed to be brief psychotic episode induced by Cannabis and the stressors of homelessness and his grandmother’s death. 

EVALUATION Changing stories

No longer taking haloperidol, Mr. P continues to deny hallucinations and depressed mood, but keeps to himself. Nine days after admission he becomes tearful after he informs his aunt of his grandmother’s death in a telephone call, then approaches a nurse and complains of sadness and auditory hallucinations.

Mr. P confesses that he denied hallucinations on admission because he feared he would remain in the hospital for years if he revealed the truth that he had been experiencing auditory hallucinations almost continuously from age 10. He reports that the voices distracted him when he worked; seem to be male; often spoke gibberish; and alternate between deprecating and positive and supportive. Mr. P is reluctant to disclose more about what the voices actually say, although he acknowledges that they are not commenting or conversing with him, and that he has never believed the voices were his own thoughts but did believe that they came from inside his brain.

With haloperidol, the voices stopped. They resumed, however, when haloperidol was discontinued.

When we ask what happened to him at age 10, Mr. P shrugs.

The author’s observations

In community samples of children and adolescents, auditory hallucinations are not rare and usually do not cause distress or dysfunction. In a study of 3,870 children age 7 and 8,¹ 9% endorsed auditory hallucinations. Most heard 1 voice, once a week or less, at low volume. In 85% of children who experienced hallucinations, they caused minimal or no suffering; 97% reported minimal or no interference with daily functioning. Among children who experienced auditory hallucinations at age 7 or 8, 24% continued to hallucinate 5 years later.² Persistent hallucinations were associated with more problematic behaviors at baseline and follow up.

In a group of 12-year-old twins, 4.2% reported auditory hallucinations.³ In that study, hallucinations were not related to Cannabis use; rather, they were heritable and related to risk factors such as cognitive impairment; behavioral, emotional, and educational problems at age 5; and a history of physical abuse and self-harm at age 12. The authors noted that these are risk factors and correlates of schizophrenia, but are not specific to schizophrenia.

Hallucinations and delusions have been found in 4% to 8% of children and adolescents referred for psychiatric treatment,⁴ far more than the prevalence of childhood-onset schizophrenia (0.01% of children).⁵ Psychotic symptoms in children have been associated with bipolar disorder, but also with anxiety disorders, obsessive-compulsive disorder, PTSD, pervasive developmental disorder, conduct disorder, and substance abuse.⁴

Childhood-onset schizophrenia is rare and would require that Mr. P have a diagnosis of schizophrenia as an adult. It is possible that Mr. P’s childhood symptoms were related to substance abuse but he was not asked for this history because it seemed unlikely in a 10-year-old boy. A PTSD diagnosis requires a traumatic event, which Mr. P did not reveal. It is possible that at age 10 he did not have a psychiatric disorder.

Among adults in the general population, 10% to 15% report auditory hallucinations.⁶ Hallucinations could be caused by substance abuse or psychiatric conditions other than schizophrenia; however, in adults—as in children—auditory hallucinations can occur in the absence of these conditions (Table 1) and rarely cause distress or dysfunction.⁶ In Sommer and colleagues’⁶ study of 103 healthy persons, none who heard voices had disorganization or negative symptoms. Those who heard voices had significantly more schizotypal symptoms and more childhood trauma, including emotional, physical, and sexual abuse, than those who did not hear voices.⁶

Conditions associated with hallucinations

PTSD is associated with auditory hallucinations and other psychotic symptoms.⁷ Most studies are of combat veterans with PTSD, in whom auditory hallucinations and delusions were associated with major depressive disorder, not a thought disorder or inappropriate affect.⁸ In a community sample,⁹ psychotic symptoms—particularly auditory hallucinations—were associated with PTSD. Subjects with PTSD and psychotic symptoms were more likely to have other psychiatric disorders, including major depressive disorder and substance use disorder, than patients with PTSD but no psychotic symptoms; however, the relationship between PTSD and psychosis remained after controlling for other psychiatric disorders.

Hallucinations can occur in persons with dissociative disorders in the absence of distinct personality states.¹⁰ Hallucinations have been seen transiently and chronically in persons with borderline personality disorder and can be associated with comorbid conditions such as substance abuse disorders, mood disorders, and PTSD.¹¹

Mr. P lacked the reduced capacity for interpersonal relationships required for a schizotypal personality disorder diagnosis. A diagnosis of PTSD or dissociative disorder requires a history of trauma, which Mr. P did not report.

“Time travelling” with incomprehensible behavior could be interpreted as dissociation, but dissociative fugue or dissociative disorder not otherwise specified (NOS) cannot be diagnosed if symptoms might be the direct effect of a substance, such as Cannabis. Mr. P admitted to substance abuse. We can rule out borderline personality disorder because he did not display or admit to tempestuous interpersonal relationships.

A schizophrenia diagnosis requires the presence of auditory hallucinations that commented on his behavior or conversed among themselves, a second psychotic symptom for ≥1 month, or negative symptoms, which Mr. P lacked (unless belief in time travel is considered delusional).

Last, a physician might have considered malingering or a factitious disorder when Mr. P was found not able to participate in his own defense, but this seemed less likely after he revealed that he experienced auditory hallucinations since age 10.

HISTORY Bad beatings

With a few days of beginning risperidone, 4 mg/d, Mr. P reports that his hallucinations have stopped and he feels less sad. He reveals that, at age 10, when the hallucinations began, his mother hit him over the head with a high-heeled shoe, causing a scalp laceration that required a visit to the emergency room for suturing. His mother beat Mr. P for as long as he could remember. She beat him “bad” at least twice weekly, and he was taken to the hospital 7 or 8 times for injury, but she also beat him “constantly” with a belt buckle, sometimes striking his head. She instructed him to tell nobody.

The author’s observations

Auditory hallucinations in adults have been associated with childhood abuse, particularly childhood sexual abuse,¹² in clinical and non-clinical samples.¹³ Some argue¹³ that child abuse itself causes hallucinations and other psychotic symptoms.

OUTCOME Depressed and sleepless

Mr. P admits that he had been smoking marijuana 2 to 3 times daily for a year. He also reports insomnia, sleeping approximately 4 hours a night and spending hours awake in bed thinking of his grandmother, with depressed mood and tearfulness. He denies suicidal ideas and hallucinations. He is treated for depressive disorder NOS first with amitriptyline, 50 mg at bedtime, for sleep, then paroxetine, 20 mg/d, for depressive symptoms, in addition to risperidone, 4 mg/d. Although Mr. P does not describe re-experiencing his childhood trauma, avoidance of stimuli associated with the trauma, or symptoms of increased arousal (except for insomnia), the treatment team did not ask, so it remains uncertain if he has PTSD (Table 2).

When Mr. P is discharged to a clinic, he smiles easily and is positive and supportive with other patients. He spruces up his appearance by wearing jewelry and works in the hospital kitchen.

Bottom Line

Chronic auditory hallucinations are associated with psychiatric illnesses other than chronic schizophrenia, particularly those resulting from trauma such as posttraumatic stress disorder. They can also occur in the absence of diagnosable psychiatric illness and rarely cause distress or functional impairment. Auditory hallucinations in adults have been associated with childhood abuse.

Related Resources

• Moskowitz A, Schafer I, Dorahy MJ. Psychosis, trauma and dissociation: emerging perspectives on severe psychopathology. West Sussex, UK: John Wiley and Sons, Ltd.; 2008.
• The International Hearing Voices Network. www.intervoiceonline.org.

Drug Brand Names

Amitriptyline • Elavil               Paroxetine • Paxil

Benztropine • Cogentin           Risperidone • Risperdal

Haloperidol • Haldol

Disclosure

Dr. Crowner reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.