Current Psychiatry

CASE Insurer denies drug coverage
Ms. X, age 65, has a 35-year history of bipolar I disorder (BD I) characterized by psychotic mania and severe suicidal depression. For the past year, her symptoms have been well controlled with aripiprazole, 5 mg/d; trazodone, 50 mg at bedtime; and citalopram, 20 mg/d. Because her health insurance has changed, Ms. X asks to be switched to an alternative antipsychotic because the new provider denied coverage of aripiprazole.

While taking aripiprazole, Ms. X did not report any extrapyramidal side effects, including tardive dyskinesia. Her Abnormal Involuntary Movement Scale (AIMS) score is 4. No significant abnormal movements were noted on examination during previous medica­tion management sessions.

We decide to replace aripiprazole with que­tiapine, 50 mg/d. At a 2-week follow-up visit, Ms. X is noted to have euphoric mood and reduced need to sleep, flight of ideas, increased talkativeness, and paranoia. We also notice that she has significant tongue rolling and lip smacking, which she says started 10 days after changing from aripiprazole to quetiapine. Her AIMS score is 17.

What could be causing Ms. X’s tongue rolling and lip smacking?
   a) an irreversible syndrome usually starting after 1 or 2 years of continuous exposure to antipsychotics
   b) a self-limited condition expected to resolve completely within 12 weeks
   c) an acute manifestation of an antipsychotic that can respond to an anticholinergic agent
   d) none of the above

The authors’ observations
Tardive dyskinesia (TD) refers to at least moderate abnormal involuntary move­ments in ≥1 areas of the body or at least mild movements in ≥2 areas of the body, developing after ≥3 months of cumulative exposure (continuous or discontinuous) to dopamine D2 receptor-blocking agents.¹ AIMS is a 14-item, clinician-administered questionnaire designed to evaluate such movements and track their severity over time. The first 10 items are rated on 5-point scale (0 = none; 1 = minimal; 2 = mild; 3 = moderate; 4 = severe), with items 1 to 4 assessing orofacial movements, 5 to 7 assess­ing extremity and truncal movements, and 8 to 10 assessing overall severity, impair­ment, and subjective distress. Items 11 to 13 assess dental status because lack of teeth can result in oral movements mimicking TDs. The last item assesses whether these move­ments disappear during sleep.

HISTORY Poor response
Ms. X was given a diagnosis of BD I at age 30; she first started taking antipsychotics 10 years later. Previous psychotropic trials included lamotrigine, divalproex sodium, risperidone, and ziprasidone, which were ineffective or poorly tolerated. Her medical history includes obstructive sleep apnea, narcolepsy, type 2 diabetes mellitus, hypertension, dyslipid­emia, fibromyalgia, gastroesophageal reflux disease, and hypothyroidism. She takes met­formin, omeprazole, pravastatin, carvedilol, insulin, levothyroxine, methylphenidate (for hypersomnia), and enalapril.

What is the next best step in management?
   a) discontinue quetiapine
   b) replace quetiapine with clozapine
   c) increase quetiapine to target manic symptoms and reassess in a few weeks
   d) continue quetiapine and treat abnormal movements with benztropine

TREATMENT Increase dosage
We increase quetiapine to 150 mg/d to target Ms. X’s manic symptoms. She is scheduled for a follow-up visit in 4 weeks but is instructed to return to the clinic earlier if her manic symp­toms do not improve. At the 4-week follow-up visit, Ms. X does not have any abnormal move­ments and her manic symptoms have resolved. Her AIMS score is 4. Her husband reports that her abnormal movements resolved 4 days after increasing quetiapine to 150 mg/d.

The authors’ observations
Second-generation antipsychotics are known to have a lower risk of extrapyrami­dal adverse reactions compared with older first-generation antipsychotics.^2,3 TD differs from other extrapyramidal symptoms (EPS) because of its delayed onset. Risk factors for TD include:
   • female sex
   • age >50
   • history of brain damage
   • long-term antipsychotic use
   • diagnosis of a mood disorder.

Gardos et al⁴ described 2 other forms of delayed dyskinesias related to antipsy­chotic use but resulting from antipsychotic discontinuation: withdrawal dyskinesia and covert dyskinesia. Evidence for these types of antipsychotic discontinuation syn­dromes mostly is anecdotal.^5,6Table 1 high­lights 3 different types of dyskinesias and their management.

Withdrawal dyskinesia has been described as a syndrome resembling TD that appears after discontinuation or dos­age reduction of an antipsychotic in a patient who does not have an earlier TD diagnosis.⁷ The prevalence of withdrawal dyskinesia among patients undergoing antipsychotic discontinuation is approximately 30%.⁸ Cases of withdrawal dyskinesia are self-limited and resolve in 1 to 3 months.^9,10 We believe that Ms. X’s movement disorder was withdrawal dyskinesia from aripiprazole because her symptoms started 10 days after the drug was discontinued, and was self-limited and reversible.

Similar to TD, withdrawal dyskinesia can present in different forms:
   • tongue protrusion movements
   • facial grimacing
   • ticks
   • chorea
   • tremors
   • athetosis
   • involuntary vocalizations
   • abnormal movements of hands and legs
   • “dyspnea” due to involvement of respiratory musculature.^5,11

There may be a sex difference in duration of withdrawal dyskinesias, because symp­toms persist longer in females.⁹

Although covert dyskinesia also develops after discontinuation or dosage reduction of a dopamine-blocking agent, the symptoms usually are permanent, and could require reintroducing the antipsychotic or manage­ment with evidence-based treatments for TD, such as tetrabenazine or amantadine.^6,12

What is the cause of Ms. X’s abnormal involuntary movements?
   a) quetiapine-induced D2 receptor hypersensitivity
   b) aripiprazole-induced cholinergic overactivity
   c) quetiapine-induced cholinergic overactivity
   d) aripiprazole-induced D2 receptor hypersensitivity

The authors’ observations
Pathophysiology of this condition is unknown but different theories have been proposed. D2 receptor up-regulation and hypersensitivity to compensate for chronic D2 receptor blockade by antipsychotics is a commonly cited theory.^7,13 Discontinuation of an antipsychotic can make this D2 recep­tor up-regulation and hypersensitivity manifest as withdrawal dyskinesia by cre­ating a temporary hyperdopaminergic state in basal ganglia. Other theories implicate decrease of γ-aminobutyric acid (GABA) in the globus pallidus (GP) and substantia nigra (SN) regions of the brain, and oxida­tive damage to GABAergic interneurons in GP and SN from excess production of cat­echolamines in response to chronic dopa­mine blockade.¹⁴

It has been proposed that patients with withdrawal dyskinesia might be in an early phase of D2 receptor modulation that, if con­tinued because of use of the antipsychotic implicated in withdrawal dyskinesia, can lead to development of TD.^4,7,8 A feature of withdrawal dyskinesia that differentiates it from TD is that it usually remits spontane­ously within several weeks to a few months.^4,7 Because of this characteristic, Schultz et al⁸ propose that, if withdrawal dyskinesia is identified early in treatment, it may be possi­ble to prevent development of persistent TD.

Look carefully for dyskinetic movements in patients who have recently discontinued or decreased the dosage of their antipsy­chotic. Non-compliance and partial compliance are common problems among patients taking an antipsychotic.¹⁵ Therefore, careful watchfulness for withdrawal dyskinesias at all times can be beneficial. Inquiring about recent history of these dyskinesias in such patients is probably more useful than an exam because the dyskinesias may not be evident on exam when these patients show up for their follow-up visit, because of their self-limited nature.⁸

Treatment options
If a patient is noted to have a withdrawal-emergent dyskinesia, a clinician has options to prevent TD, including:
   • decreasing the dosage of the antipsychotic
   • switching from a typical antipsychotic to an atypical antipsychotic
   • switching from one atypical to another with lesser affinity for striatal D2 recep­tor, such as clozapine or quetiapine.^16,17

In addition, researchers are investigating the use of vitamin B6, Ginkgo biloba, aman­tadine, levetiracetam, melatonin, tetrabena­zine, zonisamide, branched chain amino acids, clonazepam, and vitamin E as treat­ment alternatives for TD.

Tetrabenazine acts by blocking vesicu­lar monoamine transporter type 2, thereby inhibiting release of monoamines, includ­ing dopamine into synaptic cleft area in basal ganglia.¹⁸ Clonazepam’s benefit for TD relates to its facilitation of GABAergic neuro­transmission, because reduced GABAergic transmission in GP and SN has been associ­ ated with hyperkinetic movements, includ­ing TD.¹⁴Ginkgo biloba and melatonin exert their beneficial effects in TD through their antioxidant function.¹⁴

The agents listed in Table 2¹⁹ could be used on a short-term basis for symptomatic treatment of withdrawal dyskinesias.^1,18,20

Withdrawal dyskinesia has been reported with aripiprazole discontinuation and is thought to be related to aripiprazole’s strong affinity for D2 receptors.²¹ Aripiprazole at dosages of 15 to 30 mg/d can occupy more than 80% of the striatal D2 dopamine recep­tors. The dosage of ≥30 mg/d can lead to receptor occupancy of >90%.²² Studies have shown that EPS correlate with D2 receptor occupancy in steady-state conditions, and occupancy exceeding 80% results in these symptoms.²²

Compared with aripiprazole, quetiapine has weak affinity for D2 receptors (Table 3), making it an unlikely culprit if dyskine­sia emerges within 2 weeks of initation.²² We believe that, in Ms. X’s case, quetiapine might have masked the severity of aripip­razole withdrawal dyskinesia by causing some degree of D2 receptor blockade. It may have decreased the duration of withdrawal dyskinesia by the same effect on D2 recep­tors. It may have lasted longer if aripiprazole was not replaced by another antipsychotic. This is particularly evident because dys­kinesia improved quickly when quetiap­ine was titrated to 150 mg/d. The higher quetiapine dosage of 150 mg/d is closer to 5 mg/d of aripiprazole in terms of D2 recep­tor occupancy and affinity. However, que­tiapine is weaker than aripiprazole in terms of D2 receptor occupancy at all dosages, and therefore less likely to cause EPS.¹⁶

Evidence suggests that reversible withdrawal dyskinesia could represent a prodrome to irreversible TD. Therefore, keeping a watchful eye for these move­ments during the exam, along with spe­cific inquiry about withdrawal dyskinesias while taking a history at every follow-up visit, is important because doing so can:
   • inform the clinician about partial compliance or noncompliance to these medications, which could lead to treat­ment failure
   • help prevent development of irrevers­ible TD syndrome.

Ms. X’s case reminds clinicians (1) to be aware of this unexpected side effect occur­ring even with second-generation antipsy­chotics and (2) that they should consider EPS in patients while they are discontinu­ing their drugs. Furthermore, it is impor­tant for clinical and medicolegal reasons to inform our patients that different forms of dyskinesias can be potential side effects of antipsychotics.

Bottom Line
Dyskinesias can result from withdrawal of both typical and atypical antipsychotics, and usually are self-limited. Withdrawal dyskinesia may represent a prodrome to tardive dyskinesia; early recognition may aid in preventing development of persistent tardive dyskinesia.

Related Resources
• Abnormal Involuntary Movement Scale. http://www.cqaimh.org/pdf/toolaims.pdf.
• Goldberg JF, Ernst CL. Managing the side effects of psychotro­pic medications. Arlington, VA: American Psychiatric Publishing, Inc; 2012.
• Tarsay D. Tardive dyskinesia: prevention and treatment. http:// www.uptodate.com/contents/tardive-dyskinesia-prevention-and-treatment?topicKey=NEURO%2F4908&elapsedTimeMs=3 &view=print&displayedView=full#.

Drug Brand Names
Amantadine • Symmetrel
Aripiprazole • Abilify
Benztropine • Cogentin
Carvedilol • Coreg
Citalopram • Celexa
Clonazepam • Klonopin
Clozapine • Clozaril
Divalproex sodium • Depakote
Donepezil • Aricept
Enalapril • Vasotec
Haloperidol • Haldol
Lamotrigine • Lamictal
Levetiracetam • Keppra
Levothyroxine • Levoxyl, Synthroid
Metformin • Glucophage
Methylphenidate • Ritalin
Olanzapine • Zyprexa
Omeprazole • Prilosec
Pravastatin • Pravachol
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trazodone • Desyrel, Oleptro
Ziprasidone • Geodon
Zonisamide • Zonegran

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

CASE Insurer denies drug coverage
Ms. X, age 65, has a 35-year history of bipolar I disorder (BD I) characterized by psychotic mania and severe suicidal depression. For the past year, her symptoms have been well controlled with aripiprazole, 5 mg/d; trazodone, 50 mg at bedtime; and citalopram, 20 mg/d. Because her health insurance has changed, Ms. X asks to be switched to an alternative antipsychotic because the new provider denied coverage of aripiprazole.

While taking aripiprazole, Ms. X did not report any extrapyramidal side effects, including tardive dyskinesia. Her Abnormal Involuntary Movement Scale (AIMS) score is 4. No significant abnormal movements were noted on examination during previous medica­tion management sessions.

We decide to replace aripiprazole with que­tiapine, 50 mg/d. At a 2-week follow-up visit, Ms. X is noted to have euphoric mood and reduced need to sleep, flight of ideas, increased talkativeness, and paranoia. We also notice that she has significant tongue rolling and lip smacking, which she says started 10 days after changing from aripiprazole to quetiapine. Her AIMS score is 17.

What could be causing Ms. X’s tongue rolling and lip smacking?
   a) an irreversible syndrome usually starting after 1 or 2 years of continuous exposure to antipsychotics
   b) a self-limited condition expected to resolve completely within 12 weeks
   c) an acute manifestation of an antipsychotic that can respond to an anticholinergic agent
   d) none of the above

The authors’ observations
Tardive dyskinesia (TD) refers to at least moderate abnormal involuntary move­ments in ≥1 areas of the body or at least mild movements in ≥2 areas of the body, developing after ≥3 months of cumulative exposure (continuous or discontinuous) to dopamine D2 receptor-blocking agents.¹ AIMS is a 14-item, clinician-administered questionnaire designed to evaluate such movements and track their severity over time. The first 10 items are rated on 5-point scale (0 = none; 1 = minimal; 2 = mild; 3 = moderate; 4 = severe), with items 1 to 4 assessing orofacial movements, 5 to 7 assess­ing extremity and truncal movements, and 8 to 10 assessing overall severity, impair­ment, and subjective distress. Items 11 to 13 assess dental status because lack of teeth can result in oral movements mimicking TDs. The last item assesses whether these move­ments disappear during sleep.

HISTORY Poor response
Ms. X was given a diagnosis of BD I at age 30; she first started taking antipsychotics 10 years later. Previous psychotropic trials included lamotrigine, divalproex sodium, risperidone, and ziprasidone, which were ineffective or poorly tolerated. Her medical history includes obstructive sleep apnea, narcolepsy, type 2 diabetes mellitus, hypertension, dyslipid­emia, fibromyalgia, gastroesophageal reflux disease, and hypothyroidism. She takes met­formin, omeprazole, pravastatin, carvedilol, insulin, levothyroxine, methylphenidate (for hypersomnia), and enalapril.

What is the next best step in management?
   a) discontinue quetiapine
   b) replace quetiapine with clozapine
   c) increase quetiapine to target manic symptoms and reassess in a few weeks
   d) continue quetiapine and treat abnormal movements with benztropine

TREATMENT Increase dosage
We increase quetiapine to 150 mg/d to target Ms. X’s manic symptoms. She is scheduled for a follow-up visit in 4 weeks but is instructed to return to the clinic earlier if her manic symp­toms do not improve. At the 4-week follow-up visit, Ms. X does not have any abnormal move­ments and her manic symptoms have resolved. Her AIMS score is 4. Her husband reports that her abnormal movements resolved 4 days after increasing quetiapine to 150 mg/d.

The authors’ observations
Second-generation antipsychotics are known to have a lower risk of extrapyrami­dal adverse reactions compared with older first-generation antipsychotics.^2,3 TD differs from other extrapyramidal symptoms (EPS) because of its delayed onset. Risk factors for TD include:
   • female sex
   • age >50
   • history of brain damage
   • long-term antipsychotic use
   • diagnosis of a mood disorder.

Gardos et al⁴ described 2 other forms of delayed dyskinesias related to antipsy­chotic use but resulting from antipsychotic discontinuation: withdrawal dyskinesia and covert dyskinesia. Evidence for these types of antipsychotic discontinuation syn­dromes mostly is anecdotal.^5,6Table 1 high­lights 3 different types of dyskinesias and their management.

Withdrawal dyskinesia has been described as a syndrome resembling TD that appears after discontinuation or dos­age reduction of an antipsychotic in a patient who does not have an earlier TD diagnosis.⁷ The prevalence of withdrawal dyskinesia among patients undergoing antipsychotic discontinuation is approximately 30%.⁸ Cases of withdrawal dyskinesia are self-limited and resolve in 1 to 3 months.^9,10 We believe that Ms. X’s movement disorder was withdrawal dyskinesia from aripiprazole because her symptoms started 10 days after the drug was discontinued, and was self-limited and reversible.

Similar to TD, withdrawal dyskinesia can present in different forms:
   • tongue protrusion movements
   • facial grimacing
   • ticks
   • chorea
   • tremors
   • athetosis
   • involuntary vocalizations
   • abnormal movements of hands and legs
   • “dyspnea” due to involvement of respiratory musculature.^5,11

There may be a sex difference in duration of withdrawal dyskinesias, because symp­toms persist longer in females.⁹

Although covert dyskinesia also develops after discontinuation or dosage reduction of a dopamine-blocking agent, the symptoms usually are permanent, and could require reintroducing the antipsychotic or manage­ment with evidence-based treatments for TD, such as tetrabenazine or amantadine.^6,12

What is the cause of Ms. X’s abnormal involuntary movements?
   a) quetiapine-induced D2 receptor hypersensitivity
   b) aripiprazole-induced cholinergic overactivity
   c) quetiapine-induced cholinergic overactivity
   d) aripiprazole-induced D2 receptor hypersensitivity

The authors’ observations
Pathophysiology of this condition is unknown but different theories have been proposed. D2 receptor up-regulation and hypersensitivity to compensate for chronic D2 receptor blockade by antipsychotics is a commonly cited theory.^7,13 Discontinuation of an antipsychotic can make this D2 recep­tor up-regulation and hypersensitivity manifest as withdrawal dyskinesia by cre­ating a temporary hyperdopaminergic state in basal ganglia. Other theories implicate decrease of γ-aminobutyric acid (GABA) in the globus pallidus (GP) and substantia nigra (SN) regions of the brain, and oxida­tive damage to GABAergic interneurons in GP and SN from excess production of cat­echolamines in response to chronic dopa­mine blockade.¹⁴

It has been proposed that patients with withdrawal dyskinesia might be in an early phase of D2 receptor modulation that, if con­tinued because of use of the antipsychotic implicated in withdrawal dyskinesia, can lead to development of TD.^4,7,8 A feature of withdrawal dyskinesia that differentiates it from TD is that it usually remits spontane­ously within several weeks to a few months.^4,7 Because of this characteristic, Schultz et al⁸ propose that, if withdrawal dyskinesia is identified early in treatment, it may be possi­ble to prevent development of persistent TD.

Look carefully for dyskinetic movements in patients who have recently discontinued or decreased the dosage of their antipsy­chotic. Non-compliance and partial compliance are common problems among patients taking an antipsychotic.¹⁵ Therefore, careful watchfulness for withdrawal dyskinesias at all times can be beneficial. Inquiring about recent history of these dyskinesias in such patients is probably more useful than an exam because the dyskinesias may not be evident on exam when these patients show up for their follow-up visit, because of their self-limited nature.⁸

Treatment options
If a patient is noted to have a withdrawal-emergent dyskinesia, a clinician has options to prevent TD, including:
   • decreasing the dosage of the antipsychotic
   • switching from a typical antipsychotic to an atypical antipsychotic
   • switching from one atypical to another with lesser affinity for striatal D2 recep­tor, such as clozapine or quetiapine.^16,17

In addition, researchers are investigating the use of vitamin B6, Ginkgo biloba, aman­tadine, levetiracetam, melatonin, tetrabena­zine, zonisamide, branched chain amino acids, clonazepam, and vitamin E as treat­ment alternatives for TD.

Tetrabenazine acts by blocking vesicu­lar monoamine transporter type 2, thereby inhibiting release of monoamines, includ­ing dopamine into synaptic cleft area in basal ganglia.¹⁸ Clonazepam’s benefit for TD relates to its facilitation of GABAergic neuro­transmission, because reduced GABAergic transmission in GP and SN has been associ­ ated with hyperkinetic movements, includ­ing TD.¹⁴Ginkgo biloba and melatonin exert their beneficial effects in TD through their antioxidant function.¹⁴

The agents listed in Table 2¹⁹ could be used on a short-term basis for symptomatic treatment of withdrawal dyskinesias.^1,18,20

Withdrawal dyskinesia has been reported with aripiprazole discontinuation and is thought to be related to aripiprazole’s strong affinity for D2 receptors.²¹ Aripiprazole at dosages of 15 to 30 mg/d can occupy more than 80% of the striatal D2 dopamine recep­tors. The dosage of ≥30 mg/d can lead to receptor occupancy of >90%.²² Studies have shown that EPS correlate with D2 receptor occupancy in steady-state conditions, and occupancy exceeding 80% results in these symptoms.²²

Compared with aripiprazole, quetiapine has weak affinity for D2 receptors (Table 3), making it an unlikely culprit if dyskine­sia emerges within 2 weeks of initation.²² We believe that, in Ms. X’s case, quetiapine might have masked the severity of aripip­razole withdrawal dyskinesia by causing some degree of D2 receptor blockade. It may have decreased the duration of withdrawal dyskinesia by the same effect on D2 recep­tors. It may have lasted longer if aripiprazole was not replaced by another antipsychotic. This is particularly evident because dys­kinesia improved quickly when quetiap­ine was titrated to 150 mg/d. The higher quetiapine dosage of 150 mg/d is closer to 5 mg/d of aripiprazole in terms of D2 recep­tor occupancy and affinity. However, que­tiapine is weaker than aripiprazole in terms of D2 receptor occupancy at all dosages, and therefore less likely to cause EPS.¹⁶

Evidence suggests that reversible withdrawal dyskinesia could represent a prodrome to irreversible TD. Therefore, keeping a watchful eye for these move­ments during the exam, along with spe­cific inquiry about withdrawal dyskinesias while taking a history at every follow-up visit, is important because doing so can:
   • inform the clinician about partial compliance or noncompliance to these medications, which could lead to treat­ment failure
   • help prevent development of irrevers­ible TD syndrome.

Ms. X’s case reminds clinicians (1) to be aware of this unexpected side effect occur­ring even with second-generation antipsy­chotics and (2) that they should consider EPS in patients while they are discontinu­ing their drugs. Furthermore, it is impor­tant for clinical and medicolegal reasons to inform our patients that different forms of dyskinesias can be potential side effects of antipsychotics.

Bottom Line
Dyskinesias can result from withdrawal of both typical and atypical antipsychotics, and usually are self-limited. Withdrawal dyskinesia may represent a prodrome to tardive dyskinesia; early recognition may aid in preventing development of persistent tardive dyskinesia.

Related Resources
• Abnormal Involuntary Movement Scale. http://www.cqaimh.org/pdf/toolaims.pdf.
• Goldberg JF, Ernst CL. Managing the side effects of psychotro­pic medications. Arlington, VA: American Psychiatric Publishing, Inc; 2012.
• Tarsay D. Tardive dyskinesia: prevention and treatment. http:// www.uptodate.com/contents/tardive-dyskinesia-prevention-and-treatment?topicKey=NEURO%2F4908&elapsedTimeMs=3 &view=print&displayedView=full#.

Drug Brand Names
Amantadine • Symmetrel
Aripiprazole • Abilify
Benztropine • Cogentin
Carvedilol • Coreg
Citalopram • Celexa
Clonazepam • Klonopin
Clozapine • Clozaril
Divalproex sodium • Depakote
Donepezil • Aricept
Enalapril • Vasotec
Haloperidol • Haldol
Lamotrigine • Lamictal
Levetiracetam • Keppra
Levothyroxine • Levoxyl, Synthroid
Metformin • Glucophage
Methylphenidate • Ritalin
Olanzapine • Zyprexa
Omeprazole • Prilosec
Pravastatin • Pravachol
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trazodone • Desyrel, Oleptro
Ziprasidone • Geodon
Zonisamide • Zonegran

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

CASE Insurer denies drug coverage
Ms. X, age 65, has a 35-year history of bipolar I disorder (BD I) characterized by psychotic mania and severe suicidal depression. For the past year, her symptoms have been well controlled with aripiprazole, 5 mg/d; trazodone, 50 mg at bedtime; and citalopram, 20 mg/d. Because her health insurance has changed, Ms. X asks to be switched to an alternative antipsychotic because the new provider denied coverage of aripiprazole.

While taking aripiprazole, Ms. X did not report any extrapyramidal side effects, including tardive dyskinesia. Her Abnormal Involuntary Movement Scale (AIMS) score is 4. No significant abnormal movements were noted on examination during previous medica­tion management sessions.

We decide to replace aripiprazole with que­tiapine, 50 mg/d. At a 2-week follow-up visit, Ms. X is noted to have euphoric mood and reduced need to sleep, flight of ideas, increased talkativeness, and paranoia. We also notice that she has significant tongue rolling and lip smacking, which she says started 10 days after changing from aripiprazole to quetiapine. Her AIMS score is 17.

What could be causing Ms. X’s tongue rolling and lip smacking?
   a) an irreversible syndrome usually starting after 1 or 2 years of continuous exposure to antipsychotics
   b) a self-limited condition expected to resolve completely within 12 weeks
   c) an acute manifestation of an antipsychotic that can respond to an anticholinergic agent
   d) none of the above

The authors’ observations
Tardive dyskinesia (TD) refers to at least moderate abnormal involuntary move­ments in ≥1 areas of the body or at least mild movements in ≥2 areas of the body, developing after ≥3 months of cumulative exposure (continuous or discontinuous) to dopamine D2 receptor-blocking agents.¹ AIMS is a 14-item, clinician-administered questionnaire designed to evaluate such movements and track their severity over time. The first 10 items are rated on 5-point scale (0 = none; 1 = minimal; 2 = mild; 3 = moderate; 4 = severe), with items 1 to 4 assessing orofacial movements, 5 to 7 assess­ing extremity and truncal movements, and 8 to 10 assessing overall severity, impair­ment, and subjective distress. Items 11 to 13 assess dental status because lack of teeth can result in oral movements mimicking TDs. The last item assesses whether these move­ments disappear during sleep.

HISTORY Poor response
Ms. X was given a diagnosis of BD I at age 30; she first started taking antipsychotics 10 years later. Previous psychotropic trials included lamotrigine, divalproex sodium, risperidone, and ziprasidone, which were ineffective or poorly tolerated. Her medical history includes obstructive sleep apnea, narcolepsy, type 2 diabetes mellitus, hypertension, dyslipid­emia, fibromyalgia, gastroesophageal reflux disease, and hypothyroidism. She takes met­formin, omeprazole, pravastatin, carvedilol, insulin, levothyroxine, methylphenidate (for hypersomnia), and enalapril.

What is the next best step in management?
   a) discontinue quetiapine
   b) replace quetiapine with clozapine
   c) increase quetiapine to target manic symptoms and reassess in a few weeks
   d) continue quetiapine and treat abnormal movements with benztropine

TREATMENT Increase dosage
We increase quetiapine to 150 mg/d to target Ms. X’s manic symptoms. She is scheduled for a follow-up visit in 4 weeks but is instructed to return to the clinic earlier if her manic symp­toms do not improve. At the 4-week follow-up visit, Ms. X does not have any abnormal move­ments and her manic symptoms have resolved. Her AIMS score is 4. Her husband reports that her abnormal movements resolved 4 days after increasing quetiapine to 150 mg/d.

The authors’ observations
Second-generation antipsychotics are known to have a lower risk of extrapyrami­dal adverse reactions compared with older first-generation antipsychotics.^2,3 TD differs from other extrapyramidal symptoms (EPS) because of its delayed onset. Risk factors for TD include:
   • female sex
   • age >50
   • history of brain damage
   • long-term antipsychotic use
   • diagnosis of a mood disorder.

Gardos et al⁴ described 2 other forms of delayed dyskinesias related to antipsy­chotic use but resulting from antipsychotic discontinuation: withdrawal dyskinesia and covert dyskinesia. Evidence for these types of antipsychotic discontinuation syn­dromes mostly is anecdotal.^5,6Table 1 high­lights 3 different types of dyskinesias and their management.

Withdrawal dyskinesia has been described as a syndrome resembling TD that appears after discontinuation or dos­age reduction of an antipsychotic in a patient who does not have an earlier TD diagnosis.⁷ The prevalence of withdrawal dyskinesia among patients undergoing antipsychotic discontinuation is approximately 30%.⁸ Cases of withdrawal dyskinesia are self-limited and resolve in 1 to 3 months.^9,10 We believe that Ms. X’s movement disorder was withdrawal dyskinesia from aripiprazole because her symptoms started 10 days after the drug was discontinued, and was self-limited and reversible.

Similar to TD, withdrawal dyskinesia can present in different forms:
   • tongue protrusion movements
   • facial grimacing
   • ticks
   • chorea
   • tremors
   • athetosis
   • involuntary vocalizations
   • abnormal movements of hands and legs
   • “dyspnea” due to involvement of respiratory musculature.^5,11

There may be a sex difference in duration of withdrawal dyskinesias, because symp­toms persist longer in females.⁹

Although covert dyskinesia also develops after discontinuation or dosage reduction of a dopamine-blocking agent, the symptoms usually are permanent, and could require reintroducing the antipsychotic or manage­ment with evidence-based treatments for TD, such as tetrabenazine or amantadine.^6,12

What is the cause of Ms. X’s abnormal involuntary movements?
   a) quetiapine-induced D2 receptor hypersensitivity
   b) aripiprazole-induced cholinergic overactivity
   c) quetiapine-induced cholinergic overactivity
   d) aripiprazole-induced D2 receptor hypersensitivity

The authors’ observations
Pathophysiology of this condition is unknown but different theories have been proposed. D2 receptor up-regulation and hypersensitivity to compensate for chronic D2 receptor blockade by antipsychotics is a commonly cited theory.^7,13 Discontinuation of an antipsychotic can make this D2 recep­tor up-regulation and hypersensitivity manifest as withdrawal dyskinesia by cre­ating a temporary hyperdopaminergic state in basal ganglia. Other theories implicate decrease of γ-aminobutyric acid (GABA) in the globus pallidus (GP) and substantia nigra (SN) regions of the brain, and oxida­tive damage to GABAergic interneurons in GP and SN from excess production of cat­echolamines in response to chronic dopa­mine blockade.¹⁴

It has been proposed that patients with withdrawal dyskinesia might be in an early phase of D2 receptor modulation that, if con­tinued because of use of the antipsychotic implicated in withdrawal dyskinesia, can lead to development of TD.^4,7,8 A feature of withdrawal dyskinesia that differentiates it from TD is that it usually remits spontane­ously within several weeks to a few months.^4,7 Because of this characteristic, Schultz et al⁸ propose that, if withdrawal dyskinesia is identified early in treatment, it may be possi­ble to prevent development of persistent TD.

Look carefully for dyskinetic movements in patients who have recently discontinued or decreased the dosage of their antipsy­chotic. Non-compliance and partial compliance are common problems among patients taking an antipsychotic.¹⁵ Therefore, careful watchfulness for withdrawal dyskinesias at all times can be beneficial. Inquiring about recent history of these dyskinesias in such patients is probably more useful than an exam because the dyskinesias may not be evident on exam when these patients show up for their follow-up visit, because of their self-limited nature.⁸

Treatment options
If a patient is noted to have a withdrawal-emergent dyskinesia, a clinician has options to prevent TD, including:
   • decreasing the dosage of the antipsychotic
   • switching from a typical antipsychotic to an atypical antipsychotic
   • switching from one atypical to another with lesser affinity for striatal D2 recep­tor, such as clozapine or quetiapine.^16,17

In addition, researchers are investigating the use of vitamin B6, Ginkgo biloba, aman­tadine, levetiracetam, melatonin, tetrabena­zine, zonisamide, branched chain amino acids, clonazepam, and vitamin E as treat­ment alternatives for TD.

Tetrabenazine acts by blocking vesicu­lar monoamine transporter type 2, thereby inhibiting release of monoamines, includ­ing dopamine into synaptic cleft area in basal ganglia.¹⁸ Clonazepam’s benefit for TD relates to its facilitation of GABAergic neuro­transmission, because reduced GABAergic transmission in GP and SN has been associ­ ated with hyperkinetic movements, includ­ing TD.¹⁴Ginkgo biloba and melatonin exert their beneficial effects in TD through their antioxidant function.¹⁴

The agents listed in Table 2¹⁹ could be used on a short-term basis for symptomatic treatment of withdrawal dyskinesias.^1,18,20

Withdrawal dyskinesia has been reported with aripiprazole discontinuation and is thought to be related to aripiprazole’s strong affinity for D2 receptors.²¹ Aripiprazole at dosages of 15 to 30 mg/d can occupy more than 80% of the striatal D2 dopamine recep­tors. The dosage of ≥30 mg/d can lead to receptor occupancy of >90%.²² Studies have shown that EPS correlate with D2 receptor occupancy in steady-state conditions, and occupancy exceeding 80% results in these symptoms.²²

Compared with aripiprazole, quetiapine has weak affinity for D2 receptors (Table 3), making it an unlikely culprit if dyskine­sia emerges within 2 weeks of initation.²² We believe that, in Ms. X’s case, quetiapine might have masked the severity of aripip­razole withdrawal dyskinesia by causing some degree of D2 receptor blockade. It may have decreased the duration of withdrawal dyskinesia by the same effect on D2 recep­tors. It may have lasted longer if aripiprazole was not replaced by another antipsychotic. This is particularly evident because dys­kinesia improved quickly when quetiap­ine was titrated to 150 mg/d. The higher quetiapine dosage of 150 mg/d is closer to 5 mg/d of aripiprazole in terms of D2 recep­tor occupancy and affinity. However, que­tiapine is weaker than aripiprazole in terms of D2 receptor occupancy at all dosages, and therefore less likely to cause EPS.¹⁶

Evidence suggests that reversible withdrawal dyskinesia could represent a prodrome to irreversible TD. Therefore, keeping a watchful eye for these move­ments during the exam, along with spe­cific inquiry about withdrawal dyskinesias while taking a history at every follow-up visit, is important because doing so can:
   • inform the clinician about partial compliance or noncompliance to these medications, which could lead to treat­ment failure
   • help prevent development of irrevers­ible TD syndrome.

Ms. X’s case reminds clinicians (1) to be aware of this unexpected side effect occur­ring even with second-generation antipsy­chotics and (2) that they should consider EPS in patients while they are discontinu­ing their drugs. Furthermore, it is impor­tant for clinical and medicolegal reasons to inform our patients that different forms of dyskinesias can be potential side effects of antipsychotics.

Bottom Line
Dyskinesias can result from withdrawal of both typical and atypical antipsychotics, and usually are self-limited. Withdrawal dyskinesia may represent a prodrome to tardive dyskinesia; early recognition may aid in preventing development of persistent tardive dyskinesia.

Related Resources
• Abnormal Involuntary Movement Scale. http://www.cqaimh.org/pdf/toolaims.pdf.
• Goldberg JF, Ernst CL. Managing the side effects of psychotro­pic medications. Arlington, VA: American Psychiatric Publishing, Inc; 2012.
• Tarsay D. Tardive dyskinesia: prevention and treatment. http:// www.uptodate.com/contents/tardive-dyskinesia-prevention-and-treatment?topicKey=NEURO%2F4908&elapsedTimeMs=3 &view=print&displayedView=full#.

Drug Brand Names
Amantadine • Symmetrel
Aripiprazole • Abilify
Benztropine • Cogentin
Carvedilol • Coreg
Citalopram • Celexa
Clonazepam • Klonopin
Clozapine • Clozaril
Divalproex sodium • Depakote
Donepezil • Aricept
Enalapril • Vasotec
Haloperidol • Haldol
Lamotrigine • Lamictal
Levetiracetam • Keppra
Levothyroxine • Levoxyl, Synthroid
Metformin • Glucophage
Methylphenidate • Ritalin
Olanzapine • Zyprexa
Omeprazole • Prilosec
Pravastatin • Pravachol
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trazodone • Desyrel, Oleptro
Ziprasidone • Geodon
Zonisamide • Zonegran

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

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

SPECT of 32 boys with previously untreated ADHD. Kim et al²¹ found that the presence of reduced right or left, or both, frontal rCBF, which normal­ized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improve­ment of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,^16,22 suggesting increased responsiveness to extraneous environmental input.)

SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al²³ reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somato­sensory area.

After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improve­ment occurred in 64% of patients—suggest­ing methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activ­ity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.

O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al²⁴ found that participants who demonstrated improve­ment in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.

PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly simi­lar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.

Studies using PET to assess rCGM were some of the earliest molecular imaging appli­cations in ADHD. Zametkin et al²⁵ reported low global cerebral glucose utilization in adults, but not adolescents,²⁶ with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents²⁶ and adults,²⁷ indicating hypometabolism of cortical areas associated with impulse con­trol and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.

Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopami­nergic synapse, including:
   • dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
   • dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
   • the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).

All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imag­ing agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.²⁸ This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imag­ing (Figure 4).

Dopamine transporter imaging
Because the site of action of methylpheni­date is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.²⁹ By reversibly bind­ing to, and occupying sites on, the DaT, methylphenidate impedes dopamine reup­take, which results in increased availability of dopamine at the synapse.³⁰

By demonstrating an increase in stria­tal DaT density in patients with ADHD— first reported by Dougherty et al³¹ using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—inves­tigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environ­mental factors, is a central causative agent of ADHD.³² Subsequent studies, however, have yielded contradictory findings: Hesse et al,³³ using SPECT imaging, and Volkow et al,³⁴ using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.

To clarify the role of DaT levels in the eti­ology of ADHD and to explain discrepant results, Fusar-Poli et al³⁵ performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 differ­ent imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT con­centration correlated with a history of stimu­lant exposure, and that the drug-naïve group had a reduced DaT level.

Fusar-Poli’s hypothesis? Elevated DaT lev­els result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.³⁶

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

SPECT of 32 boys with previously untreated ADHD. Kim et al²¹ found that the presence of reduced right or left, or both, frontal rCBF, which normal­ized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improve­ment of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,^16,22 suggesting increased responsiveness to extraneous environmental input.)

SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al²³ reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somato­sensory area.

After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improve­ment occurred in 64% of patients—suggest­ing methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activ­ity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.

O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al²⁴ found that participants who demonstrated improve­ment in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.

PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly simi­lar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.

Studies using PET to assess rCGM were some of the earliest molecular imaging appli­cations in ADHD. Zametkin et al²⁵ reported low global cerebral glucose utilization in adults, but not adolescents,²⁶ with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents²⁶ and adults,²⁷ indicating hypometabolism of cortical areas associated with impulse con­trol and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.

Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopami­nergic synapse, including:
   • dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
   • dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
   • the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).

All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imag­ing agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.²⁸ This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imag­ing (Figure 4).

Dopamine transporter imaging
Because the site of action of methylpheni­date is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.²⁹ By reversibly bind­ing to, and occupying sites on, the DaT, methylphenidate impedes dopamine reup­take, which results in increased availability of dopamine at the synapse.³⁰

By demonstrating an increase in stria­tal DaT density in patients with ADHD— first reported by Dougherty et al³¹ using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—inves­tigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environ­mental factors, is a central causative agent of ADHD.³² Subsequent studies, however, have yielded contradictory findings: Hesse et al,³³ using SPECT imaging, and Volkow et al,³⁴ using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.

To clarify the role of DaT levels in the eti­ology of ADHD and to explain discrepant results, Fusar-Poli et al³⁵ performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 differ­ent imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT con­centration correlated with a history of stimu­lant exposure, and that the drug-naïve group had a reduced DaT level.

Fusar-Poli’s hypothesis? Elevated DaT lev­els result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.³⁶

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

SPECT of 32 boys with previously untreated ADHD. Kim et al²¹ found that the presence of reduced right or left, or both, frontal rCBF, which normal­ized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improve­ment of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,^16,22 suggesting increased responsiveness to extraneous environmental input.)

SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al²³ reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somato­sensory area.

After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improve­ment occurred in 64% of patients—suggest­ing methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activ­ity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.

O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al²⁴ found that participants who demonstrated improve­ment in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.

PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly simi­lar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.

Studies using PET to assess rCGM were some of the earliest molecular imaging appli­cations in ADHD. Zametkin et al²⁵ reported low global cerebral glucose utilization in adults, but not adolescents,²⁶ with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents²⁶ and adults,²⁷ indicating hypometabolism of cortical areas associated with impulse con­trol and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.

Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopami­nergic synapse, including:
   • dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
   • dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
   • the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).

All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imag­ing agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.²⁸ This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imag­ing (Figure 4).

Dopamine transporter imaging
Because the site of action of methylpheni­date is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.²⁹ By reversibly bind­ing to, and occupying sites on, the DaT, methylphenidate impedes dopamine reup­take, which results in increased availability of dopamine at the synapse.³⁰

By demonstrating an increase in stria­tal DaT density in patients with ADHD— first reported by Dougherty et al³¹ using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—inves­tigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environ­mental factors, is a central causative agent of ADHD.³² Subsequent studies, however, have yielded contradictory findings: Hesse et al,³³ using SPECT imaging, and Volkow et al,³⁴ using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.

To clarify the role of DaT levels in the eti­ology of ADHD and to explain discrepant results, Fusar-Poli et al³⁵ performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 differ­ent imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT con­centration correlated with a history of stimu­lant exposure, and that the drug-naïve group had a reduced DaT level.

Fusar-Poli’s hypothesis? Elevated DaT lev­els result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.³⁶

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

A 3-month paliperidone palmitate (PPM-3) extended-release inject­able suspension was approved by the FDA in May 2015 for preventing relapse among patients with schizophre­nia, under the brand name Invega Trinza (Table 1). Administered 4 times a year, PPM-3 provides the longest interval of any approved long-acting injectable anti­psychotic (LAIA). PPM-3 can be adminis­tered to patients with schizophrenia who have been taking 1-month paliperidone palmitate (PPM-1) extended-release inject­able suspension (brand name, Invega Sustenna), once a month, for at least 4 months.

How it works
PPM-3 is a LAIA injection. Because of its low solubility in water, paliperidone palmitate dissolves slowly once injected before being hydrolyzed as paliperidone and absorbed into the bloodstream. From time of release on Day 1, PPM-3 remains active for as long 18 months.

PPM-3 reaches a maximum plasma con­centration between Day 30 and Day 33. In clinical trials, PPM-3 had a median half-life of 84 to 95 days when injected into the del­toid muscle and a median half-life of 118 to 139 days when injected into the gluteal muscle.

Paliperidone is not extensively metabo­lized in the liver. Although results of a study suggest that cytochrome P450 (CYP) 2D6 and CYP3A4 might play a role in metabolizing paliperidone, there is no evi­dence that it has a significant role.

Dosing and administration
PPM-3 is administered intramuscularly by a licensed health care professional, once every 3 months. The recommended dosage is based on the patient’s previous dosage of PPM-1 (Table 2).

See the prescribing information for administration instructions.

Efficacy
The efficacy of PPM-3 was assessed in a long-term double-blind, placebo-controlled, randomized-withdrawal trial in adult patients with acute symptoms (previously treated with an oral antipsy­chotic) or adequately treated with a LAIA, either PPM-1 or another agent; patients receiving PPM-1, 39 mg, injections were ineligible. All patients entering the study received PPM-1 in place of the next sched­uled injection.

The study comprised 3 treatment periods:
   • 17-Week flexible-dose open-label period with PPM-1 (ie, first part of a 29-week open-label stabilization phase): Patients (N = 506) received PPM-1 with a flexible dose based on symptom response, tolerabil­ity, and medication history. Patients had to achieve a Positive and Negative Syndrome Scale (PANSS) total score of <70 at Week 17 to enter the second phase.
   • 12-Week open-label with PPM-3 (ie, sec­ond part of the 29-week open-label stabili­zation phase): Patients (N = 379) received a single injection of PPM-3 that was 3.5 times the last dose of PPM-1. Patients had to achieve a PANSS total score of <70 and ≤4 for 7 specific PANSS items.
   • A variable length double-blind treat­ment period: Patients (N = 305) were ran­domized 1:1 to continue treatment with PPM-3 (273 mg, 410 mg, 546 mg, or 819 mg) or placebo (administered once every 12 weeks) until relapse, early with­drawal, or end of the study. The primary efficacy measure was time to first relapse, defined as psychiatric hospitalization, ≥25% increase or a 10-point increase in total PANSS score on 2 consecutive assessments, deliberate self-injury, violent behavior, sui­cidal or homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on 2 consecutive assessments of the specific PANSS items.

Among the patients in the third treat­ment period, 23% of those who received placebo and 7.4% of those who received PPM-3 experienced a relapse event. The time to relapse was significantly longer for patients who received PPM-3 than for those who received placebo.

See Table 3 for adverse reactions reported in patients who received PPM-3 and those taking placebo in the study.

Contraindications
Allergic reactions. Patients who have a hypersensitivity to paliperidone, ris­peridone, or their components should not receive PPM-3. Anaphylactic reac­tions have been reported in patients who previously tolerated risperidone or oral paliperidone, which could be significant because the drug is slowly released over 3 months. Other adverse reactions, includ­ing angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary reten­tion, were reported post-approval of paliperidone; however, these adverse effects were reported voluntarily from an unknown population size and, therefore, it is unknown whether there is a causal rela­tionship to the drug or its frequency.

Drug-drug interactions. Although pali­peridone is not expected to cause drug– drug interactions with medications that are metabolized by CYP isoenzymes, it is recommended to avoid using a strong inducer of CYP3A4 and/or P-glycoprotein.

Overdose. When assessing treatment options and recovery, consider the half-life of PPM-3 and its long-lasting effects.

Because PPM-3 is administered by a licensed health care provider, the potential for overdose is low. However, if overdose occurs, general treatment and manage­ment measures should be employed as with overdose of any drug and the pos­sibility of multiple drug overdose should be considered. There is no specific antidote to paliperidone. Contact a certified poi­son control center for guidance on man­aging paliperidone and PPM-3 overdose. Generally, management consists of sup­portive care.

Black-box warning in dementia. As with all atypical antipsychotics, the black-box warning for PPM-3 states that it is not approved for, and should not be used in, patients with dementia-related psychosis. An analysis of placebo-controlled studies revealed that patients taking an antipsy­chotic had (1) 1.6 to 1.7 times the risk of death than those who received placebo and (2) a higher incidence of cerebrovas­cular adverse reactions.

Adverse reactions
The safety profile of PPM-3 is similar to that of PPM-1. The most common adverse reactions are:
   • reaction at the injection site
   • weight gain
   • headache
   • upper respiratory tract infection
   • akathisia
   • parkinsonism.

See the full prescribing information for a complete list of adverse effects.

Related Resources
• Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone pal­mitate: once monthly treatment option for schizophrenia. Current Psychiatry. 2010;9(3):48-49.
• Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clini­cal trial [published online March 29, 2015]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2015.0241.

Drug Brand Names
Paliperidone palmitate • Invega Sustenna, Invega Trinza
Risperidone • Risperdal

A 3-month paliperidone palmitate (PPM-3) extended-release inject­able suspension was approved by the FDA in May 2015 for preventing relapse among patients with schizophre­nia, under the brand name Invega Trinza (Table 1). Administered 4 times a year, PPM-3 provides the longest interval of any approved long-acting injectable anti­psychotic (LAIA). PPM-3 can be adminis­tered to patients with schizophrenia who have been taking 1-month paliperidone palmitate (PPM-1) extended-release inject­able suspension (brand name, Invega Sustenna), once a month, for at least 4 months.

How it works
PPM-3 is a LAIA injection. Because of its low solubility in water, paliperidone palmitate dissolves slowly once injected before being hydrolyzed as paliperidone and absorbed into the bloodstream. From time of release on Day 1, PPM-3 remains active for as long 18 months.

PPM-3 reaches a maximum plasma con­centration between Day 30 and Day 33. In clinical trials, PPM-3 had a median half-life of 84 to 95 days when injected into the del­toid muscle and a median half-life of 118 to 139 days when injected into the gluteal muscle.

Paliperidone is not extensively metabo­lized in the liver. Although results of a study suggest that cytochrome P450 (CYP) 2D6 and CYP3A4 might play a role in metabolizing paliperidone, there is no evi­dence that it has a significant role.

Dosing and administration
PPM-3 is administered intramuscularly by a licensed health care professional, once every 3 months. The recommended dosage is based on the patient’s previous dosage of PPM-1 (Table 2).

See the prescribing information for administration instructions.

Efficacy
The efficacy of PPM-3 was assessed in a long-term double-blind, placebo-controlled, randomized-withdrawal trial in adult patients with acute symptoms (previously treated with an oral antipsy­chotic) or adequately treated with a LAIA, either PPM-1 or another agent; patients receiving PPM-1, 39 mg, injections were ineligible. All patients entering the study received PPM-1 in place of the next sched­uled injection.

The study comprised 3 treatment periods:
   • 17-Week flexible-dose open-label period with PPM-1 (ie, first part of a 29-week open-label stabilization phase): Patients (N = 506) received PPM-1 with a flexible dose based on symptom response, tolerabil­ity, and medication history. Patients had to achieve a Positive and Negative Syndrome Scale (PANSS) total score of <70 at Week 17 to enter the second phase.
   • 12-Week open-label with PPM-3 (ie, sec­ond part of the 29-week open-label stabili­zation phase): Patients (N = 379) received a single injection of PPM-3 that was 3.5 times the last dose of PPM-1. Patients had to achieve a PANSS total score of <70 and ≤4 for 7 specific PANSS items.
   • A variable length double-blind treat­ment period: Patients (N = 305) were ran­domized 1:1 to continue treatment with PPM-3 (273 mg, 410 mg, 546 mg, or 819 mg) or placebo (administered once every 12 weeks) until relapse, early with­drawal, or end of the study. The primary efficacy measure was time to first relapse, defined as psychiatric hospitalization, ≥25% increase or a 10-point increase in total PANSS score on 2 consecutive assessments, deliberate self-injury, violent behavior, sui­cidal or homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on 2 consecutive assessments of the specific PANSS items.

Among the patients in the third treat­ment period, 23% of those who received placebo and 7.4% of those who received PPM-3 experienced a relapse event. The time to relapse was significantly longer for patients who received PPM-3 than for those who received placebo.

See Table 3 for adverse reactions reported in patients who received PPM-3 and those taking placebo in the study.

Contraindications
Allergic reactions. Patients who have a hypersensitivity to paliperidone, ris­peridone, or their components should not receive PPM-3. Anaphylactic reac­tions have been reported in patients who previously tolerated risperidone or oral paliperidone, which could be significant because the drug is slowly released over 3 months. Other adverse reactions, includ­ing angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary reten­tion, were reported post-approval of paliperidone; however, these adverse effects were reported voluntarily from an unknown population size and, therefore, it is unknown whether there is a causal rela­tionship to the drug or its frequency.

Drug-drug interactions. Although pali­peridone is not expected to cause drug– drug interactions with medications that are metabolized by CYP isoenzymes, it is recommended to avoid using a strong inducer of CYP3A4 and/or P-glycoprotein.

Overdose. When assessing treatment options and recovery, consider the half-life of PPM-3 and its long-lasting effects.

Because PPM-3 is administered by a licensed health care provider, the potential for overdose is low. However, if overdose occurs, general treatment and manage­ment measures should be employed as with overdose of any drug and the pos­sibility of multiple drug overdose should be considered. There is no specific antidote to paliperidone. Contact a certified poi­son control center for guidance on man­aging paliperidone and PPM-3 overdose. Generally, management consists of sup­portive care.

Black-box warning in dementia. As with all atypical antipsychotics, the black-box warning for PPM-3 states that it is not approved for, and should not be used in, patients with dementia-related psychosis. An analysis of placebo-controlled studies revealed that patients taking an antipsy­chotic had (1) 1.6 to 1.7 times the risk of death than those who received placebo and (2) a higher incidence of cerebrovas­cular adverse reactions.

Adverse reactions
The safety profile of PPM-3 is similar to that of PPM-1. The most common adverse reactions are:
   • reaction at the injection site
   • weight gain
   • headache
   • upper respiratory tract infection
   • akathisia
   • parkinsonism.

See the full prescribing information for a complete list of adverse effects.

Related Resources
• Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone pal­mitate: once monthly treatment option for schizophrenia. Current Psychiatry. 2010;9(3):48-49.
• Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clini­cal trial [published online March 29, 2015]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2015.0241.

Drug Brand Names
Paliperidone palmitate • Invega Sustenna, Invega Trinza
Risperidone • Risperdal

A 3-month paliperidone palmitate (PPM-3) extended-release inject­able suspension was approved by the FDA in May 2015 for preventing relapse among patients with schizophre­nia, under the brand name Invega Trinza (Table 1). Administered 4 times a year, PPM-3 provides the longest interval of any approved long-acting injectable anti­psychotic (LAIA). PPM-3 can be adminis­tered to patients with schizophrenia who have been taking 1-month paliperidone palmitate (PPM-1) extended-release inject­able suspension (brand name, Invega Sustenna), once a month, for at least 4 months.

How it works
PPM-3 is a LAIA injection. Because of its low solubility in water, paliperidone palmitate dissolves slowly once injected before being hydrolyzed as paliperidone and absorbed into the bloodstream. From time of release on Day 1, PPM-3 remains active for as long 18 months.

PPM-3 reaches a maximum plasma con­centration between Day 30 and Day 33. In clinical trials, PPM-3 had a median half-life of 84 to 95 days when injected into the del­toid muscle and a median half-life of 118 to 139 days when injected into the gluteal muscle.

Paliperidone is not extensively metabo­lized in the liver. Although results of a study suggest that cytochrome P450 (CYP) 2D6 and CYP3A4 might play a role in metabolizing paliperidone, there is no evi­dence that it has a significant role.

Dosing and administration
PPM-3 is administered intramuscularly by a licensed health care professional, once every 3 months. The recommended dosage is based on the patient’s previous dosage of PPM-1 (Table 2).

See the prescribing information for administration instructions.

Efficacy
The efficacy of PPM-3 was assessed in a long-term double-blind, placebo-controlled, randomized-withdrawal trial in adult patients with acute symptoms (previously treated with an oral antipsy­chotic) or adequately treated with a LAIA, either PPM-1 or another agent; patients receiving PPM-1, 39 mg, injections were ineligible. All patients entering the study received PPM-1 in place of the next sched­uled injection.

The study comprised 3 treatment periods:
   • 17-Week flexible-dose open-label period with PPM-1 (ie, first part of a 29-week open-label stabilization phase): Patients (N = 506) received PPM-1 with a flexible dose based on symptom response, tolerabil­ity, and medication history. Patients had to achieve a Positive and Negative Syndrome Scale (PANSS) total score of <70 at Week 17 to enter the second phase.
   • 12-Week open-label with PPM-3 (ie, sec­ond part of the 29-week open-label stabili­zation phase): Patients (N = 379) received a single injection of PPM-3 that was 3.5 times the last dose of PPM-1. Patients had to achieve a PANSS total score of <70 and ≤4 for 7 specific PANSS items.
   • A variable length double-blind treat­ment period: Patients (N = 305) were ran­domized 1:1 to continue treatment with PPM-3 (273 mg, 410 mg, 546 mg, or 819 mg) or placebo (administered once every 12 weeks) until relapse, early with­drawal, or end of the study. The primary efficacy measure was time to first relapse, defined as psychiatric hospitalization, ≥25% increase or a 10-point increase in total PANSS score on 2 consecutive assessments, deliberate self-injury, violent behavior, sui­cidal or homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on 2 consecutive assessments of the specific PANSS items.

Among the patients in the third treat­ment period, 23% of those who received placebo and 7.4% of those who received PPM-3 experienced a relapse event. The time to relapse was significantly longer for patients who received PPM-3 than for those who received placebo.

See Table 3 for adverse reactions reported in patients who received PPM-3 and those taking placebo in the study.

Contraindications
Allergic reactions. Patients who have a hypersensitivity to paliperidone, ris­peridone, or their components should not receive PPM-3. Anaphylactic reac­tions have been reported in patients who previously tolerated risperidone or oral paliperidone, which could be significant because the drug is slowly released over 3 months. Other adverse reactions, includ­ing angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary reten­tion, were reported post-approval of paliperidone; however, these adverse effects were reported voluntarily from an unknown population size and, therefore, it is unknown whether there is a causal rela­tionship to the drug or its frequency.

Drug-drug interactions. Although pali­peridone is not expected to cause drug– drug interactions with medications that are metabolized by CYP isoenzymes, it is recommended to avoid using a strong inducer of CYP3A4 and/or P-glycoprotein.

Overdose. When assessing treatment options and recovery, consider the half-life of PPM-3 and its long-lasting effects.

Because PPM-3 is administered by a licensed health care provider, the potential for overdose is low. However, if overdose occurs, general treatment and manage­ment measures should be employed as with overdose of any drug and the pos­sibility of multiple drug overdose should be considered. There is no specific antidote to paliperidone. Contact a certified poi­son control center for guidance on man­aging paliperidone and PPM-3 overdose. Generally, management consists of sup­portive care.

Black-box warning in dementia. As with all atypical antipsychotics, the black-box warning for PPM-3 states that it is not approved for, and should not be used in, patients with dementia-related psychosis. An analysis of placebo-controlled studies revealed that patients taking an antipsy­chotic had (1) 1.6 to 1.7 times the risk of death than those who received placebo and (2) a higher incidence of cerebrovas­cular adverse reactions.

Adverse reactions
The safety profile of PPM-3 is similar to that of PPM-1. The most common adverse reactions are:
   • reaction at the injection site
   • weight gain
   • headache
   • upper respiratory tract infection
   • akathisia
   • parkinsonism.

See the full prescribing information for a complete list of adverse effects.

Related Resources
• Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone pal­mitate: once monthly treatment option for schizophrenia. Current Psychiatry. 2010;9(3):48-49.
• Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clini­cal trial [published online March 29, 2015]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2015.0241.

Drug Brand Names
Paliperidone palmitate • Invega Sustenna, Invega Trinza
Risperidone • Risperdal

More than 45% of people worldwide suffer from headache at some point in their life.¹ Head pain can lead to disabil­ity and functional decline, yet headache disorders often are underdiagnosed and poorly assessed. For example, 60% of migraine and tension-type headaches go undiagnosed and 50% of persons suffering from migraine have severe functional dis­ability or require bed rest.^2-4

Because head pain can be associated with secondary medical and psy­chiatric conditions, diagnosis can be challenging. This article reviews the medical and psychological aspects of major headaches and assists with clinical assessment. We present clinical interviewing tools and a diagram to enhance focused, efficient assessment and inform treatment plans.

Classification of headache
Headache is a common complaint, yet it is often underdiagnosed and ineffectively treated. The World Health Organization estimates that, globally, 50% of people with headache self-treat their pain.⁵ The International Headache Society classifies headache as primary or sec­ondary; approximately 90% of complaints are from primary headache.⁶

Assessment and diagnosis of headache can be complex because of overlapping, subjective symptoms. It is important to have a general understanding of primary and secondary causes of headache so that interrelated symptoms do not obscure the most accurate diagnosis and effective treatment course. Although most headache complaints are benign, ruling out secondary causes helps gauge the likelihood of developing severe sequelae from underlying pathology.

By definition, primary headaches are idiopathic and commonly include migraine, tension-type, cluster, and hemicrania conti­nua headache. Secondary headaches have an underlying pathology, which could improve by targeting the disorder. Common secondary causes of headache include:
   • trauma
   • vascular abnormalities
   • structural abnormalities
   • chemical (including medications)
   • inflammation or infection
   • metabolic conditions
   • diseases of the neck and pericranial and intracranial structures
   • psychiatric conditions.

Table 1 illustrates common causes of head pain. More definitive criteria for symptoms and diagnosis can be found in the International Classification of Headache Disorders.⁷

Migraine typically causes pulsating pain in a localized area of the head that lasts as long as 72 hours and can be associated with nausea, vomiting, photophobia, phono-phobia, and aura. Patients report varying precipitating factors but commonly cite cer­tain foods, menstruation, and sleep depri­vation. Although rare, migraine with aura has been linked to ischemic stroke; most cases have been reported in female smokers and oral contraceptive users age <45.⁹

Because migraines can be debilitat­ing, some patients—typically those with ≥4 attacks a month—opt for prophylactic medication. Effective prophylactics include amitriptyline, propranolol, divalproex sodium, and topiramate, which should be monitored closely and given a trial for sev­eral months before switching to another drug. Commonly used abortive treatments include triptans and anti-emetics such as metoclopramide.

Meperidine and ketorolac are popular second-line agents for migraine. Botulinum toxin A also has been used in severe cases to reduce the number of headache days in chronic migraine patients.⁶ 

Cluster headache is rare, but typically exhibits repeated burning and intense unilateral periorbital or retro-orbital pain that lasts 15 minutes to 3 hours over several weeks. Men are predominantly affected. Cluster headaches typically improve with oxygen treatment.
 

Biopsychosocial model of head pain
The biomedical model has helped iden­ tify pathophysiological pain mechanisms and pharmacotherapeutic agents for headache. However, during assessment, limiting one’s attention to the linear rela­tionship between pathology, mechanism of action, and pain oversimplifies common questions clinicians face when assessing chronic head pain.

Advancements in the last 3 decades have expanded the conceptualization of head pain to integrate sociocultural, envi­ronmental, behavioral, affective, cogni­tive, and biological variables—otherwise known as the biopsychosocial model.^10,11 The biopsychosocial model is a multidi­mensional theory that helps answer dif­ficult clinical assessment questions and complex patient presentations (Table 2).^10-13 Many unusual responses to pain treatment, questionable validity of pain behavior, and disproportionate pain perception and functional decline are explained by non-pathophysiological and non-biomechani­cal models.

Psychiatric comorbidity and head pain
Psychiatric conditions are highly prevalent among persons with primary headache. Verri et al¹⁴ found that 90% of chronic daily headache patients had ≥1 psychiatric con­dition; depression and anxiety were most common. Of concern, 1 study found that headache is associated with increased frequency of suicidal ideation among patients with chronic pain.¹⁵ It is critical for clinicians to screen for psychiatric comor­bidities in patients with chronic head­ache. Conversely, clinicians might want to screen for headache in their patients with psychiatric illness.

Migraine. Mood disorders are com­mon among patients who suffer from migraine. The rate of depression is 2 to 4 times higher in those with migraine compared with healthy controls.^16,17 In a large-scale study, patients with migraine had a 1.9-fold higher risk (compared with controls) of having a comorbid depres­sive episode; a 2-fold higher risk of manic episodes; and a 3-fold higher risk of both mania and depression.¹⁸ In a study of 62 inpatients, Fasmer¹⁹ reported that 46% of patients with unipolar depression and 44% of patients with bipolar disorder experienced migraine (77% of the bipolar disorder patients with migraine had bipo­lar II disorder). Patients with migraine are at increased risk of suicide attempts (odds ratio 4.3; 95% CI, 1.2-15.7).²⁰ 

Tension-type headache. The relationship between psychiatric comorbidity in tension-type headache is well established. In con­trast to what is seen with migraines, Puca et al²¹ found a higher prevalence of anxiety disorders (52.5%) than depressive disorders (36.4%) in patients with tension-type head­ache. Generalized anxiety disorder was one of the most prevalent anxiety conditions (83.3%), and dysthymia was the most prev­alent mood disorder (45.6%). In the same study, 21.7% of patients were found to have a comorbid somatoform disorder.²¹

Emotional and cognitive factors can co-occur in patients with tension-type head­ache and a comorbid psychiatric condition. For example, difficulty identifying or rec­ognizing emotions—commonly referred to as alexithymia—has been linked to tension-type headache.²² Additionally, maladap­tive cognitive appraisal of stress is more common among patients with tension-type headache when compared with those without headaches.²³ Being mindful of and recognizing these co-occurring emotional and cognitive factors will help clinicians construct a more accurate assessment and effective behavioral treatment plan.

Clinical assessment with a useful mnemonic
Clinical assessment of psychiatric illness is essential when evaluating chronic pain patients. Using the acronym AMPS (Anxiety, Mood, Psychosis, and Substance use disor­ders) (Table 3) is an efficient way for the cli­nician to ask pertinent questions regarding common psychiatric conditions that could have a direct effect on chronic pain.²⁴ Head pain can be more intense when combined with untreated anxiety, depression, psycho­sis, or a substance use disorder. Untreated anxiety, for example, can amplify sympathetic response to pain and complicate treatment.

Investigating head pain patients for an underlying mood disorder is essential to providing successful treatment. Consider:
   • starting psychotherapy modalities that address both pain and psychiatric illness, such as cognitive-behavioral therapy (CBT)
   • reframing unhelpful pain beliefs
   • managing activity-rest levels
   • biofeedback
   • supportive group therapy
   • reducing family members’ reinforce­ment of the patient’s pain behavior or sick role.²⁵

Assessing for somatic symptom disorders
In addition to using the AMPS approach for psychiatric assessment, clinicians should evaluate for somatization, which can pres­ent as head pain. Somatic symptom dis­orders (SSD) are a class of conditions that are impacted by affective, cognitive, and reinforcing factors that might or might not be consciously or intentionally produced. Patients with an SSD have somatic symp­toms that are distressing or cause significant disruption of daily life because of excessive thoughts, feelings, or behaviors related to the somatic symptoms, for ≥6 months. The Figure outlines SSD, related conditions, and their respective prominent symptoms to assist in the differential diagnosis.²⁶

Note that some headache conditions present with severe distress because of their abrupt onset and severity of symptoms (eg, cluster headaches). Therefore, the expectation and likelihood of psychological disturbance should be factored into a diag­nosis of SSD and related conditions as seen in the Figure.

Secondary factors of unusual pain behavior or treatment response. The role of thoughts, affect, and behaviors is clinically meaningful in understand­ing SSD and similar conditions. Specific questions about cultural beliefs and ritu­als as they relate to exacerbations of head pain are of value. Table 4^13,27 lists behavioral, cognitive, and affective dimen­sions of head pain using the biopsychoso­cial model, and further clarifies common questions that arise with unusual pain response and complex patient presenta­tions, which were outlined in the begin­ning of the article.

Functional assessment to rule out the disproportional impact of pain on daily activities is helpful in understanding the somatization process. Neurocognitive functioning should be assessed, particu­larly because frontal and subcortical dys­regulation has been observed in head pain sufferers.^29,30 Patients with cognitive changes as a result of a medical illness (eg, stroke, head concussion, brain tumor, or seizures) are especially at risk for neuro­cognitive dysfunction.

Neuropsychological assessment can be useful, not only to assess neurocogni­tive functioning (eg, Repeated Battery for the Assessment of Neuropsychological Status) but to identify objective test pro­files associated with altered motivation (eg, Rey 15-Item Test, Minnesota Multiphasic Personality Inventory-2-Restructured Form F Scale, Personality Assessment Inventory [PAI] Negative Impression Management) and somatization processes (eg, PAI Somatization Scale). These instruments help to identify the severity of psychiatric and neurocognitive symptoms by com­paring scores to normative (eg, healthy control group), clinical (eg, somatization, traumatic brain injury, mild cognitive impairment), and altered motivation (eg, persons instructed to exaggerate symp­toms) databases.

If the clinician pursues neurocognitive assessment, direct referral to a neuropsy­chologist, referral to neurologist, or admin­istration of a cognitive screening tool such as the Montreal Cognitive Assessment, Saint Louis University Mental Status, or Cognitive Log is recommended. If the cognitive screening is positive, next steps include: referring for full neuropsycholog­ical assessment, which includes complete cognitive and motor testing, personality testing, and integration of neuroimaging data (eg, MRI, CT scans, and/or EEG).

Assessing the patients’ self-talk or thought patterns as they describe their head pain will help clinicians understand belief systems that may be distorting the reality of the medical condition. For exam­ple, a patient might report that “my pain feels like someone is hitting me with an axe”; this is a catastrophic thought that can distort the clarity and perceptibility of pain. Encouraging patients to monitor and analyze their anxiety and associated negative thoughts is an important strat­egy for improving mood and decreasing somatization. Recording daily thoughts and CBT can help the patient identify and appropriately address his (her) cognitive distortions and futile thinking.

When implementing a treatment plan for somatization disorder, we propose the mnemonic device CARE MD:
   • CBT
   • Assess (by ruling out a medical cause for somatic complaints)
   • Regular visits
   • Empathy
   • Med-psych interface (help the patient connect physical complaints and emotional stressors)
   • Do no harm.

Clinical recommendations
Chronic head pain can be debilitating; psy­chodiagnostic assessment should therefore be considered an important part of the diagnosis and treatment plan. After rul­ing out common and emergent primary or secondary causes of head pain, consider psychiatric comorbidities. Depression and anxiety have a strong bidirectional rela­tionship with chronic headache; therefore, we suggest evaluating patients with the intention of alleviating both psychiatric symptoms and head pain.

It is important to diligently assess for common psychiatric comorbidities; using the AMPS and CARE MD mnemonics, along with screening for somatization disorders, is an easy and effective way to evaluate for relevant psychiatric conditions associated with chronic head pain. Because many patients have unusual and compli­cated responses to head pain that can be explained by non-pathophysiological and non-biomechanical models, using the bio­psychosocial model is essential for effec­tive diagnosis, assessment, and treatment. Abortive and prophylactic medical inter­ventions, as well as behavioral, sociocul­tural, and cognitive assessment, are vital to a comprehensive treatment approach.

Bottom Line
The psychodiagnostic assessment can help the astute clinician identify comorbid psychiatric conditions, psychological factors, and somatic symptoms to develop a comprehensive biopsychosocial treatment plan for patients with chronic head pain. Rule out primary and secondary causes of pain and screen for somatization disorders. Consider medication and psychotherapeutic treatment options.

Related Resources
• Pompili M, Di Cosimo D, Innamorati M, et al. Psychiatric co­morbidity in patients with chronic daily headache and mi­graine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283-290.
• Sinclair AJ, Sturrock A, Davies B, et al. Headache manage­ment: pharmacological approaches [published online July 3, 2015]. Pract Neurol. doi: 10.1136/practneurol-2015-001167.

Drug Brand Names
Amitriptyline • Elavil                            Meperidine • Demerol
Botulinum toxin A • Botox                   Metoclopramide • Reglan
Divalproex sodium • Depakote             Propranolol • Inderide
Ketorolac • Toradol                              Topiramate • Topamax

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

More than 45% of people worldwide suffer from headache at some point in their life.¹ Head pain can lead to disabil­ity and functional decline, yet headache disorders often are underdiagnosed and poorly assessed. For example, 60% of migraine and tension-type headaches go undiagnosed and 50% of persons suffering from migraine have severe functional dis­ability or require bed rest.^2-4

Because head pain can be associated with secondary medical and psy­chiatric conditions, diagnosis can be challenging. This article reviews the medical and psychological aspects of major headaches and assists with clinical assessment. We present clinical interviewing tools and a diagram to enhance focused, efficient assessment and inform treatment plans.

Classification of headache
Headache is a common complaint, yet it is often underdiagnosed and ineffectively treated. The World Health Organization estimates that, globally, 50% of people with headache self-treat their pain.⁵ The International Headache Society classifies headache as primary or sec­ondary; approximately 90% of complaints are from primary headache.⁶

Assessment and diagnosis of headache can be complex because of overlapping, subjective symptoms. It is important to have a general understanding of primary and secondary causes of headache so that interrelated symptoms do not obscure the most accurate diagnosis and effective treatment course. Although most headache complaints are benign, ruling out secondary causes helps gauge the likelihood of developing severe sequelae from underlying pathology.

By definition, primary headaches are idiopathic and commonly include migraine, tension-type, cluster, and hemicrania conti­nua headache. Secondary headaches have an underlying pathology, which could improve by targeting the disorder. Common secondary causes of headache include:
   • trauma
   • vascular abnormalities
   • structural abnormalities
   • chemical (including medications)
   • inflammation or infection
   • metabolic conditions
   • diseases of the neck and pericranial and intracranial structures
   • psychiatric conditions.

Table 1 illustrates common causes of head pain. More definitive criteria for symptoms and diagnosis can be found in the International Classification of Headache Disorders.⁷

Migraine typically causes pulsating pain in a localized area of the head that lasts as long as 72 hours and can be associated with nausea, vomiting, photophobia, phono-phobia, and aura. Patients report varying precipitating factors but commonly cite cer­tain foods, menstruation, and sleep depri­vation. Although rare, migraine with aura has been linked to ischemic stroke; most cases have been reported in female smokers and oral contraceptive users age <45.⁹

Because migraines can be debilitat­ing, some patients—typically those with ≥4 attacks a month—opt for prophylactic medication. Effective prophylactics include amitriptyline, propranolol, divalproex sodium, and topiramate, which should be monitored closely and given a trial for sev­eral months before switching to another drug. Commonly used abortive treatments include triptans and anti-emetics such as metoclopramide.

Meperidine and ketorolac are popular second-line agents for migraine. Botulinum toxin A also has been used in severe cases to reduce the number of headache days in chronic migraine patients.⁶ 

Cluster headache is rare, but typically exhibits repeated burning and intense unilateral periorbital or retro-orbital pain that lasts 15 minutes to 3 hours over several weeks. Men are predominantly affected. Cluster headaches typically improve with oxygen treatment.
 

Biopsychosocial model of head pain
The biomedical model has helped iden­ tify pathophysiological pain mechanisms and pharmacotherapeutic agents for headache. However, during assessment, limiting one’s attention to the linear rela­tionship between pathology, mechanism of action, and pain oversimplifies common questions clinicians face when assessing chronic head pain.

Advancements in the last 3 decades have expanded the conceptualization of head pain to integrate sociocultural, envi­ronmental, behavioral, affective, cogni­tive, and biological variables—otherwise known as the biopsychosocial model.^10,11 The biopsychosocial model is a multidi­mensional theory that helps answer dif­ficult clinical assessment questions and complex patient presentations (Table 2).^10-13 Many unusual responses to pain treatment, questionable validity of pain behavior, and disproportionate pain perception and functional decline are explained by non-pathophysiological and non-biomechani­cal models.

Psychiatric comorbidity and head pain
Psychiatric conditions are highly prevalent among persons with primary headache. Verri et al¹⁴ found that 90% of chronic daily headache patients had ≥1 psychiatric con­dition; depression and anxiety were most common. Of concern, 1 study found that headache is associated with increased frequency of suicidal ideation among patients with chronic pain.¹⁵ It is critical for clinicians to screen for psychiatric comor­bidities in patients with chronic head­ache. Conversely, clinicians might want to screen for headache in their patients with psychiatric illness.

Migraine. Mood disorders are com­mon among patients who suffer from migraine. The rate of depression is 2 to 4 times higher in those with migraine compared with healthy controls.^16,17 In a large-scale study, patients with migraine had a 1.9-fold higher risk (compared with controls) of having a comorbid depres­sive episode; a 2-fold higher risk of manic episodes; and a 3-fold higher risk of both mania and depression.¹⁸ In a study of 62 inpatients, Fasmer¹⁹ reported that 46% of patients with unipolar depression and 44% of patients with bipolar disorder experienced migraine (77% of the bipolar disorder patients with migraine had bipo­lar II disorder). Patients with migraine are at increased risk of suicide attempts (odds ratio 4.3; 95% CI, 1.2-15.7).²⁰ 

Tension-type headache. The relationship between psychiatric comorbidity in tension-type headache is well established. In con­trast to what is seen with migraines, Puca et al²¹ found a higher prevalence of anxiety disorders (52.5%) than depressive disorders (36.4%) in patients with tension-type head­ache. Generalized anxiety disorder was one of the most prevalent anxiety conditions (83.3%), and dysthymia was the most prev­alent mood disorder (45.6%). In the same study, 21.7% of patients were found to have a comorbid somatoform disorder.²¹

Emotional and cognitive factors can co-occur in patients with tension-type head­ache and a comorbid psychiatric condition. For example, difficulty identifying or rec­ognizing emotions—commonly referred to as alexithymia—has been linked to tension-type headache.²² Additionally, maladap­tive cognitive appraisal of stress is more common among patients with tension-type headache when compared with those without headaches.²³ Being mindful of and recognizing these co-occurring emotional and cognitive factors will help clinicians construct a more accurate assessment and effective behavioral treatment plan.

Clinical assessment with a useful mnemonic
Clinical assessment of psychiatric illness is essential when evaluating chronic pain patients. Using the acronym AMPS (Anxiety, Mood, Psychosis, and Substance use disor­ders) (Table 3) is an efficient way for the cli­nician to ask pertinent questions regarding common psychiatric conditions that could have a direct effect on chronic pain.²⁴ Head pain can be more intense when combined with untreated anxiety, depression, psycho­sis, or a substance use disorder. Untreated anxiety, for example, can amplify sympathetic response to pain and complicate treatment.

Investigating head pain patients for an underlying mood disorder is essential to providing successful treatment. Consider:
   • starting psychotherapy modalities that address both pain and psychiatric illness, such as cognitive-behavioral therapy (CBT)
   • reframing unhelpful pain beliefs
   • managing activity-rest levels
   • biofeedback
   • supportive group therapy
   • reducing family members’ reinforce­ment of the patient’s pain behavior or sick role.²⁵

Assessing for somatic symptom disorders
In addition to using the AMPS approach for psychiatric assessment, clinicians should evaluate for somatization, which can pres­ent as head pain. Somatic symptom dis­orders (SSD) are a class of conditions that are impacted by affective, cognitive, and reinforcing factors that might or might not be consciously or intentionally produced. Patients with an SSD have somatic symp­toms that are distressing or cause significant disruption of daily life because of excessive thoughts, feelings, or behaviors related to the somatic symptoms, for ≥6 months. The Figure outlines SSD, related conditions, and their respective prominent symptoms to assist in the differential diagnosis.²⁶

Note that some headache conditions present with severe distress because of their abrupt onset and severity of symptoms (eg, cluster headaches). Therefore, the expectation and likelihood of psychological disturbance should be factored into a diag­nosis of SSD and related conditions as seen in the Figure.

Secondary factors of unusual pain behavior or treatment response. The role of thoughts, affect, and behaviors is clinically meaningful in understand­ing SSD and similar conditions. Specific questions about cultural beliefs and ritu­als as they relate to exacerbations of head pain are of value. Table 4^13,27 lists behavioral, cognitive, and affective dimen­sions of head pain using the biopsychoso­cial model, and further clarifies common questions that arise with unusual pain response and complex patient presenta­tions, which were outlined in the begin­ning of the article.

Functional assessment to rule out the disproportional impact of pain on daily activities is helpful in understanding the somatization process. Neurocognitive functioning should be assessed, particu­larly because frontal and subcortical dys­regulation has been observed in head pain sufferers.^29,30 Patients with cognitive changes as a result of a medical illness (eg, stroke, head concussion, brain tumor, or seizures) are especially at risk for neuro­cognitive dysfunction.

Neuropsychological assessment can be useful, not only to assess neurocogni­tive functioning (eg, Repeated Battery for the Assessment of Neuropsychological Status) but to identify objective test pro­files associated with altered motivation (eg, Rey 15-Item Test, Minnesota Multiphasic Personality Inventory-2-Restructured Form F Scale, Personality Assessment Inventory [PAI] Negative Impression Management) and somatization processes (eg, PAI Somatization Scale). These instruments help to identify the severity of psychiatric and neurocognitive symptoms by com­paring scores to normative (eg, healthy control group), clinical (eg, somatization, traumatic brain injury, mild cognitive impairment), and altered motivation (eg, persons instructed to exaggerate symp­toms) databases.

If the clinician pursues neurocognitive assessment, direct referral to a neuropsy­chologist, referral to neurologist, or admin­istration of a cognitive screening tool such as the Montreal Cognitive Assessment, Saint Louis University Mental Status, or Cognitive Log is recommended. If the cognitive screening is positive, next steps include: referring for full neuropsycholog­ical assessment, which includes complete cognitive and motor testing, personality testing, and integration of neuroimaging data (eg, MRI, CT scans, and/or EEG).

Assessing the patients’ self-talk or thought patterns as they describe their head pain will help clinicians understand belief systems that may be distorting the reality of the medical condition. For exam­ple, a patient might report that “my pain feels like someone is hitting me with an axe”; this is a catastrophic thought that can distort the clarity and perceptibility of pain. Encouraging patients to monitor and analyze their anxiety and associated negative thoughts is an important strat­egy for improving mood and decreasing somatization. Recording daily thoughts and CBT can help the patient identify and appropriately address his (her) cognitive distortions and futile thinking.

When implementing a treatment plan for somatization disorder, we propose the mnemonic device CARE MD:
   • CBT
   • Assess (by ruling out a medical cause for somatic complaints)
   • Regular visits
   • Empathy
   • Med-psych interface (help the patient connect physical complaints and emotional stressors)
   • Do no harm.

Clinical recommendations
Chronic head pain can be debilitating; psy­chodiagnostic assessment should therefore be considered an important part of the diagnosis and treatment plan. After rul­ing out common and emergent primary or secondary causes of head pain, consider psychiatric comorbidities. Depression and anxiety have a strong bidirectional rela­tionship with chronic headache; therefore, we suggest evaluating patients with the intention of alleviating both psychiatric symptoms and head pain.

It is important to diligently assess for common psychiatric comorbidities; using the AMPS and CARE MD mnemonics, along with screening for somatization disorders, is an easy and effective way to evaluate for relevant psychiatric conditions associated with chronic head pain. Because many patients have unusual and compli­cated responses to head pain that can be explained by non-pathophysiological and non-biomechanical models, using the bio­psychosocial model is essential for effec­tive diagnosis, assessment, and treatment. Abortive and prophylactic medical inter­ventions, as well as behavioral, sociocul­tural, and cognitive assessment, are vital to a comprehensive treatment approach.

Bottom Line
The psychodiagnostic assessment can help the astute clinician identify comorbid psychiatric conditions, psychological factors, and somatic symptoms to develop a comprehensive biopsychosocial treatment plan for patients with chronic head pain. Rule out primary and secondary causes of pain and screen for somatization disorders. Consider medication and psychotherapeutic treatment options.

Related Resources
• Pompili M, Di Cosimo D, Innamorati M, et al. Psychiatric co­morbidity in patients with chronic daily headache and mi­graine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283-290.
• Sinclair AJ, Sturrock A, Davies B, et al. Headache manage­ment: pharmacological approaches [published online July 3, 2015]. Pract Neurol. doi: 10.1136/practneurol-2015-001167.

Drug Brand Names
Amitriptyline • Elavil                            Meperidine • Demerol
Botulinum toxin A • Botox                   Metoclopramide • Reglan
Divalproex sodium • Depakote             Propranolol • Inderide
Ketorolac • Toradol                              Topiramate • Topamax

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

More than 45% of people worldwide suffer from headache at some point in their life.¹ Head pain can lead to disabil­ity and functional decline, yet headache disorders often are underdiagnosed and poorly assessed. For example, 60% of migraine and tension-type headaches go undiagnosed and 50% of persons suffering from migraine have severe functional dis­ability or require bed rest.^2-4

Because head pain can be associated with secondary medical and psy­chiatric conditions, diagnosis can be challenging. This article reviews the medical and psychological aspects of major headaches and assists with clinical assessment. We present clinical interviewing tools and a diagram to enhance focused, efficient assessment and inform treatment plans.

Classification of headache
Headache is a common complaint, yet it is often underdiagnosed and ineffectively treated. The World Health Organization estimates that, globally, 50% of people with headache self-treat their pain.⁵ The International Headache Society classifies headache as primary or sec­ondary; approximately 90% of complaints are from primary headache.⁶

Assessment and diagnosis of headache can be complex because of overlapping, subjective symptoms. It is important to have a general understanding of primary and secondary causes of headache so that interrelated symptoms do not obscure the most accurate diagnosis and effective treatment course. Although most headache complaints are benign, ruling out secondary causes helps gauge the likelihood of developing severe sequelae from underlying pathology.

By definition, primary headaches are idiopathic and commonly include migraine, tension-type, cluster, and hemicrania conti­nua headache. Secondary headaches have an underlying pathology, which could improve by targeting the disorder. Common secondary causes of headache include:
   • trauma
   • vascular abnormalities
   • structural abnormalities
   • chemical (including medications)
   • inflammation or infection
   • metabolic conditions
   • diseases of the neck and pericranial and intracranial structures
   • psychiatric conditions.

Table 1 illustrates common causes of head pain. More definitive criteria for symptoms and diagnosis can be found in the International Classification of Headache Disorders.⁷

Migraine typically causes pulsating pain in a localized area of the head that lasts as long as 72 hours and can be associated with nausea, vomiting, photophobia, phono-phobia, and aura. Patients report varying precipitating factors but commonly cite cer­tain foods, menstruation, and sleep depri­vation. Although rare, migraine with aura has been linked to ischemic stroke; most cases have been reported in female smokers and oral contraceptive users age <45.⁹

Because migraines can be debilitat­ing, some patients—typically those with ≥4 attacks a month—opt for prophylactic medication. Effective prophylactics include amitriptyline, propranolol, divalproex sodium, and topiramate, which should be monitored closely and given a trial for sev­eral months before switching to another drug. Commonly used abortive treatments include triptans and anti-emetics such as metoclopramide.

Meperidine and ketorolac are popular second-line agents for migraine. Botulinum toxin A also has been used in severe cases to reduce the number of headache days in chronic migraine patients.⁶ 

Cluster headache is rare, but typically exhibits repeated burning and intense unilateral periorbital or retro-orbital pain that lasts 15 minutes to 3 hours over several weeks. Men are predominantly affected. Cluster headaches typically improve with oxygen treatment.
 

Biopsychosocial model of head pain
The biomedical model has helped iden­ tify pathophysiological pain mechanisms and pharmacotherapeutic agents for headache. However, during assessment, limiting one’s attention to the linear rela­tionship between pathology, mechanism of action, and pain oversimplifies common questions clinicians face when assessing chronic head pain.

Advancements in the last 3 decades have expanded the conceptualization of head pain to integrate sociocultural, envi­ronmental, behavioral, affective, cogni­tive, and biological variables—otherwise known as the biopsychosocial model.^10,11 The biopsychosocial model is a multidi­mensional theory that helps answer dif­ficult clinical assessment questions and complex patient presentations (Table 2).^10-13 Many unusual responses to pain treatment, questionable validity of pain behavior, and disproportionate pain perception and functional decline are explained by non-pathophysiological and non-biomechani­cal models.

Psychiatric comorbidity and head pain
Psychiatric conditions are highly prevalent among persons with primary headache. Verri et al¹⁴ found that 90% of chronic daily headache patients had ≥1 psychiatric con­dition; depression and anxiety were most common. Of concern, 1 study found that headache is associated with increased frequency of suicidal ideation among patients with chronic pain.¹⁵ It is critical for clinicians to screen for psychiatric comor­bidities in patients with chronic head­ache. Conversely, clinicians might want to screen for headache in their patients with psychiatric illness.

Migraine. Mood disorders are com­mon among patients who suffer from migraine. The rate of depression is 2 to 4 times higher in those with migraine compared with healthy controls.^16,17 In a large-scale study, patients with migraine had a 1.9-fold higher risk (compared with controls) of having a comorbid depres­sive episode; a 2-fold higher risk of manic episodes; and a 3-fold higher risk of both mania and depression.¹⁸ In a study of 62 inpatients, Fasmer¹⁹ reported that 46% of patients with unipolar depression and 44% of patients with bipolar disorder experienced migraine (77% of the bipolar disorder patients with migraine had bipo­lar II disorder). Patients with migraine are at increased risk of suicide attempts (odds ratio 4.3; 95% CI, 1.2-15.7).²⁰ 

Tension-type headache. The relationship between psychiatric comorbidity in tension-type headache is well established. In con­trast to what is seen with migraines, Puca et al²¹ found a higher prevalence of anxiety disorders (52.5%) than depressive disorders (36.4%) in patients with tension-type head­ache. Generalized anxiety disorder was one of the most prevalent anxiety conditions (83.3%), and dysthymia was the most prev­alent mood disorder (45.6%). In the same study, 21.7% of patients were found to have a comorbid somatoform disorder.²¹

Emotional and cognitive factors can co-occur in patients with tension-type head­ache and a comorbid psychiatric condition. For example, difficulty identifying or rec­ognizing emotions—commonly referred to as alexithymia—has been linked to tension-type headache.²² Additionally, maladap­tive cognitive appraisal of stress is more common among patients with tension-type headache when compared with those without headaches.²³ Being mindful of and recognizing these co-occurring emotional and cognitive factors will help clinicians construct a more accurate assessment and effective behavioral treatment plan.

Clinical assessment with a useful mnemonic
Clinical assessment of psychiatric illness is essential when evaluating chronic pain patients. Using the acronym AMPS (Anxiety, Mood, Psychosis, and Substance use disor­ders) (Table 3) is an efficient way for the cli­nician to ask pertinent questions regarding common psychiatric conditions that could have a direct effect on chronic pain.²⁴ Head pain can be more intense when combined with untreated anxiety, depression, psycho­sis, or a substance use disorder. Untreated anxiety, for example, can amplify sympathetic response to pain and complicate treatment.

Investigating head pain patients for an underlying mood disorder is essential to providing successful treatment. Consider:
   • starting psychotherapy modalities that address both pain and psychiatric illness, such as cognitive-behavioral therapy (CBT)
   • reframing unhelpful pain beliefs
   • managing activity-rest levels
   • biofeedback
   • supportive group therapy
   • reducing family members’ reinforce­ment of the patient’s pain behavior or sick role.²⁵

Assessing for somatic symptom disorders
In addition to using the AMPS approach for psychiatric assessment, clinicians should evaluate for somatization, which can pres­ent as head pain. Somatic symptom dis­orders (SSD) are a class of conditions that are impacted by affective, cognitive, and reinforcing factors that might or might not be consciously or intentionally produced. Patients with an SSD have somatic symp­toms that are distressing or cause significant disruption of daily life because of excessive thoughts, feelings, or behaviors related to the somatic symptoms, for ≥6 months. The Figure outlines SSD, related conditions, and their respective prominent symptoms to assist in the differential diagnosis.²⁶

Note that some headache conditions present with severe distress because of their abrupt onset and severity of symptoms (eg, cluster headaches). Therefore, the expectation and likelihood of psychological disturbance should be factored into a diag­nosis of SSD and related conditions as seen in the Figure.

Secondary factors of unusual pain behavior or treatment response. The role of thoughts, affect, and behaviors is clinically meaningful in understand­ing SSD and similar conditions. Specific questions about cultural beliefs and ritu­als as they relate to exacerbations of head pain are of value. Table 4^13,27 lists behavioral, cognitive, and affective dimen­sions of head pain using the biopsychoso­cial model, and further clarifies common questions that arise with unusual pain response and complex patient presenta­tions, which were outlined in the begin­ning of the article.

Functional assessment to rule out the disproportional impact of pain on daily activities is helpful in understanding the somatization process. Neurocognitive functioning should be assessed, particu­larly because frontal and subcortical dys­regulation has been observed in head pain sufferers.^29,30 Patients with cognitive changes as a result of a medical illness (eg, stroke, head concussion, brain tumor, or seizures) are especially at risk for neuro­cognitive dysfunction.

Neuropsychological assessment can be useful, not only to assess neurocogni­tive functioning (eg, Repeated Battery for the Assessment of Neuropsychological Status) but to identify objective test pro­files associated with altered motivation (eg, Rey 15-Item Test, Minnesota Multiphasic Personality Inventory-2-Restructured Form F Scale, Personality Assessment Inventory [PAI] Negative Impression Management) and somatization processes (eg, PAI Somatization Scale). These instruments help to identify the severity of psychiatric and neurocognitive symptoms by com­paring scores to normative (eg, healthy control group), clinical (eg, somatization, traumatic brain injury, mild cognitive impairment), and altered motivation (eg, persons instructed to exaggerate symp­toms) databases.

If the clinician pursues neurocognitive assessment, direct referral to a neuropsy­chologist, referral to neurologist, or admin­istration of a cognitive screening tool such as the Montreal Cognitive Assessment, Saint Louis University Mental Status, or Cognitive Log is recommended. If the cognitive screening is positive, next steps include: referring for full neuropsycholog­ical assessment, which includes complete cognitive and motor testing, personality testing, and integration of neuroimaging data (eg, MRI, CT scans, and/or EEG).

Assessing the patients’ self-talk or thought patterns as they describe their head pain will help clinicians understand belief systems that may be distorting the reality of the medical condition. For exam­ple, a patient might report that “my pain feels like someone is hitting me with an axe”; this is a catastrophic thought that can distort the clarity and perceptibility of pain. Encouraging patients to monitor and analyze their anxiety and associated negative thoughts is an important strat­egy for improving mood and decreasing somatization. Recording daily thoughts and CBT can help the patient identify and appropriately address his (her) cognitive distortions and futile thinking.

When implementing a treatment plan for somatization disorder, we propose the mnemonic device CARE MD:
   • CBT
   • Assess (by ruling out a medical cause for somatic complaints)
   • Regular visits
   • Empathy
   • Med-psych interface (help the patient connect physical complaints and emotional stressors)
   • Do no harm.

Clinical recommendations
Chronic head pain can be debilitating; psy­chodiagnostic assessment should therefore be considered an important part of the diagnosis and treatment plan. After rul­ing out common and emergent primary or secondary causes of head pain, consider psychiatric comorbidities. Depression and anxiety have a strong bidirectional rela­tionship with chronic headache; therefore, we suggest evaluating patients with the intention of alleviating both psychiatric symptoms and head pain.

It is important to diligently assess for common psychiatric comorbidities; using the AMPS and CARE MD mnemonics, along with screening for somatization disorders, is an easy and effective way to evaluate for relevant psychiatric conditions associated with chronic head pain. Because many patients have unusual and compli­cated responses to head pain that can be explained by non-pathophysiological and non-biomechanical models, using the bio­psychosocial model is essential for effec­tive diagnosis, assessment, and treatment. Abortive and prophylactic medical inter­ventions, as well as behavioral, sociocul­tural, and cognitive assessment, are vital to a comprehensive treatment approach.

Bottom Line
The psychodiagnostic assessment can help the astute clinician identify comorbid psychiatric conditions, psychological factors, and somatic symptoms to develop a comprehensive biopsychosocial treatment plan for patients with chronic head pain. Rule out primary and secondary causes of pain and screen for somatization disorders. Consider medication and psychotherapeutic treatment options.

Related Resources
• Pompili M, Di Cosimo D, Innamorati M, et al. Psychiatric co­morbidity in patients with chronic daily headache and mi­graine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283-290.
• Sinclair AJ, Sturrock A, Davies B, et al. Headache manage­ment: pharmacological approaches [published online July 3, 2015]. Pract Neurol. doi: 10.1136/practneurol-2015-001167.

Drug Brand Names
Amitriptyline • Elavil                            Meperidine • Demerol
Botulinum toxin A • Botox                   Metoclopramide • Reglan
Divalproex sodium • Depakote             Propranolol • Inderide
Ketorolac • Toradol                              Topiramate • Topamax

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

With few exceptions, I have found that patients who have chronic moder­ate or severe mental illness tend to be relatively more vulnerable in terms of (1) receiving suboptimal primary medical care and (2) suffering a result­ing increase in morbidity, mortality, and disability.

Across the board, I’ve found, psychiatrists are more likely to treat patients who are chronically vulnerable.

Why are they so vulnerable?
The unique vulnerability of patients with severe mental illness stems from several causative factors:
   • the stigma attached to mental illness
   • poor implementation of parity in reimbursement for mental health services
   • a suboptimal-sized mental health workforce
   • related poor patient-centered support
   • most important, these patients’ lack of primary and preventive medical care.

Here are a few examples that dem­onstrate how dire the situation is:

Smoking cigarettes is one of the most dangerous modifiable risk factors for vascular disease and early death. People with mental illness smoke almost half (44%) of the cigarettes sold in the United States and are twice as likely to smoke than those who do not have a mental illness.^1,2

HIV infection is at least 2 or 3 times more prevalent among people with severe mental illness as it is in the gen­eral population.³

Hepatitis C infection is at least twice as prevalent in people with a diagno­sis of schizophrenia as it is in the gen­eral population.⁴

Schizophrenia. As many as 60% of premature deaths among people with schizophrenia are attributable to a medical illness.⁵ For example, those with schizophrenia have an increased 10-year cardiac mortality; compara­tively higher rates of hypertension, diabetes, and smoking; and, on aver­age, a lower level of high-density lipoprotein cholesterol. Nasrallah et al reported that the rate of untreated hypertension among patients with schizophrenia is 62.4%.⁶

Premature death. People who have a diagnosis of severe mental illness are at risk of dying prematurely by as much as 25 years.^5,7-10

Who should take the lead?
How can psychiatrists address this ongoing vulnerability within the men­tally ill patient population, and advo­cate for their patients? A comprehensive answer to this question is beyond the scope of this article, but I can offer this prescription for your consideration.

Be an advocate. You, as a psychiatrist, are well positioned to counter the men­tal health-related stigma and advocate for implementation of mental health parity nationwide. In addition to par­ticipating in community education and outreach, become a member of, and get involved in, established organiza­tions, such as the American Psychiatric Association, that advocates for psychi­atric patients at all levels.

Keep patients connected. Make sure your patients are connected with a pri­mary care provider, and use your psy­chotherapeutic skills to help patients understand the importance of receiv­ing primary and secondary preventive medical care.

Monitor health and disease. As a phy­sician first and a psychiatrist second, closely monitor your patients for general medical conditions that are related to the presence and treatment of psychiatric disorders. Consider routinely reviewing pertinent lab work with patients—even results of tests ordered by a primary care provider (eg, the metabolic panel and a thyroid-stimulating hormone level in patients taking lithium).

Collaborate with your primary care col­leagues; they need your help as much as you can use their help! Make sure your patients witness this collaboration, because it mirrors how you would like them to interact with their primary care provider.

Educate yourself. Education in the essentials of psychiatry-based preven­tive medical care is key, as we work to more effectively address the increased disability, morbidity, mortality, and overall vulnerability in our patients. Stay “current” on general medical top­ics by reading the “Med/Psych Update” section of Current Psychiatry and relevant articles in other clinical guides to both integrated and preventive medicine.¹¹

With few exceptions, I have found that patients who have chronic moder­ate or severe mental illness tend to be relatively more vulnerable in terms of (1) receiving suboptimal primary medical care and (2) suffering a result­ing increase in morbidity, mortality, and disability.

Across the board, I’ve found, psychiatrists are more likely to treat patients who are chronically vulnerable.

Why are they so vulnerable?
The unique vulnerability of patients with severe mental illness stems from several causative factors:
   • the stigma attached to mental illness
   • poor implementation of parity in reimbursement for mental health services
   • a suboptimal-sized mental health workforce
   • related poor patient-centered support
   • most important, these patients’ lack of primary and preventive medical care.

Here are a few examples that dem­onstrate how dire the situation is:

Smoking cigarettes is one of the most dangerous modifiable risk factors for vascular disease and early death. People with mental illness smoke almost half (44%) of the cigarettes sold in the United States and are twice as likely to smoke than those who do not have a mental illness.^1,2

HIV infection is at least 2 or 3 times more prevalent among people with severe mental illness as it is in the gen­eral population.³

Hepatitis C infection is at least twice as prevalent in people with a diagno­sis of schizophrenia as it is in the gen­eral population.⁴

Schizophrenia. As many as 60% of premature deaths among people with schizophrenia are attributable to a medical illness.⁵ For example, those with schizophrenia have an increased 10-year cardiac mortality; compara­tively higher rates of hypertension, diabetes, and smoking; and, on aver­age, a lower level of high-density lipoprotein cholesterol. Nasrallah et al reported that the rate of untreated hypertension among patients with schizophrenia is 62.4%.⁶

Premature death. People who have a diagnosis of severe mental illness are at risk of dying prematurely by as much as 25 years.^5,7-10

Who should take the lead?
How can psychiatrists address this ongoing vulnerability within the men­tally ill patient population, and advo­cate for their patients? A comprehensive answer to this question is beyond the scope of this article, but I can offer this prescription for your consideration.

Be an advocate. You, as a psychiatrist, are well positioned to counter the men­tal health-related stigma and advocate for implementation of mental health parity nationwide. In addition to par­ticipating in community education and outreach, become a member of, and get involved in, established organiza­tions, such as the American Psychiatric Association, that advocates for psychi­atric patients at all levels.

Keep patients connected. Make sure your patients are connected with a pri­mary care provider, and use your psy­chotherapeutic skills to help patients understand the importance of receiv­ing primary and secondary preventive medical care.

Monitor health and disease. As a phy­sician first and a psychiatrist second, closely monitor your patients for general medical conditions that are related to the presence and treatment of psychiatric disorders. Consider routinely reviewing pertinent lab work with patients—even results of tests ordered by a primary care provider (eg, the metabolic panel and a thyroid-stimulating hormone level in patients taking lithium).

Collaborate with your primary care col­leagues; they need your help as much as you can use their help! Make sure your patients witness this collaboration, because it mirrors how you would like them to interact with their primary care provider.

Educate yourself. Education in the essentials of psychiatry-based preven­tive medical care is key, as we work to more effectively address the increased disability, morbidity, mortality, and overall vulnerability in our patients. Stay “current” on general medical top­ics by reading the “Med/Psych Update” section of Current Psychiatry and relevant articles in other clinical guides to both integrated and preventive medicine.¹¹

With few exceptions, I have found that patients who have chronic moder­ate or severe mental illness tend to be relatively more vulnerable in terms of (1) receiving suboptimal primary medical care and (2) suffering a result­ing increase in morbidity, mortality, and disability.

Across the board, I’ve found, psychiatrists are more likely to treat patients who are chronically vulnerable.

Why are they so vulnerable?
The unique vulnerability of patients with severe mental illness stems from several causative factors:
   • the stigma attached to mental illness
   • poor implementation of parity in reimbursement for mental health services
   • a suboptimal-sized mental health workforce
   • related poor patient-centered support
   • most important, these patients’ lack of primary and preventive medical care.

Here are a few examples that dem­onstrate how dire the situation is:

Smoking cigarettes is one of the most dangerous modifiable risk factors for vascular disease and early death. People with mental illness smoke almost half (44%) of the cigarettes sold in the United States and are twice as likely to smoke than those who do not have a mental illness.^1,2

HIV infection is at least 2 or 3 times more prevalent among people with severe mental illness as it is in the gen­eral population.³

Hepatitis C infection is at least twice as prevalent in people with a diagno­sis of schizophrenia as it is in the gen­eral population.⁴

Schizophrenia. As many as 60% of premature deaths among people with schizophrenia are attributable to a medical illness.⁵ For example, those with schizophrenia have an increased 10-year cardiac mortality; compara­tively higher rates of hypertension, diabetes, and smoking; and, on aver­age, a lower level of high-density lipoprotein cholesterol. Nasrallah et al reported that the rate of untreated hypertension among patients with schizophrenia is 62.4%.⁶

Premature death. People who have a diagnosis of severe mental illness are at risk of dying prematurely by as much as 25 years.^5,7-10

Who should take the lead?
How can psychiatrists address this ongoing vulnerability within the men­tally ill patient population, and advo­cate for their patients? A comprehensive answer to this question is beyond the scope of this article, but I can offer this prescription for your consideration.

Be an advocate. You, as a psychiatrist, are well positioned to counter the men­tal health-related stigma and advocate for implementation of mental health parity nationwide. In addition to par­ticipating in community education and outreach, become a member of, and get involved in, established organiza­tions, such as the American Psychiatric Association, that advocates for psychi­atric patients at all levels.

Keep patients connected. Make sure your patients are connected with a pri­mary care provider, and use your psy­chotherapeutic skills to help patients understand the importance of receiv­ing primary and secondary preventive medical care.

Monitor health and disease. As a phy­sician first and a psychiatrist second, closely monitor your patients for general medical conditions that are related to the presence and treatment of psychiatric disorders. Consider routinely reviewing pertinent lab work with patients—even results of tests ordered by a primary care provider (eg, the metabolic panel and a thyroid-stimulating hormone level in patients taking lithium).

Collaborate with your primary care col­leagues; they need your help as much as you can use their help! Make sure your patients witness this collaboration, because it mirrors how you would like them to interact with their primary care provider.

Educate yourself. Education in the essentials of psychiatry-based preven­tive medical care is key, as we work to more effectively address the increased disability, morbidity, mortality, and overall vulnerability in our patients. Stay “current” on general medical top­ics by reading the “Med/Psych Update” section of Current Psychiatry and relevant articles in other clinical guides to both integrated and preventive medicine.¹¹

Methadone maintenance therapy is widely used for helping patients recover from an opioid use disor­der. When these patients develop an acute medical problem that requires hospital­ization, there often is confusion among providers regarding methadone pharma­cology, regulations, and general safety issues. We have observed that the lack of awareness of these practices can lead to poor medical and surgical outcomes, increased length of stay, and diminished patient satisfaction.

Consider the following common pit­falls—all of which we have encountered on our psychiatry consult service—and ways to avoid them when treating methadone-maintained patients.

Don’t give a full methadone maintenance dosage without verifying the dosage and the date when it was last administered. Methadone typically has a long, but vari­able, half-life, with ranges of 4 to 130 hours being reported.¹ Do not rush to give the full dose without verification from the patient’s methadone maintenance treatment pro­gram (MMTP). Small doses—not to exceed 40 mg in 24 hours—can be administered until you verify the dosage. Multiple days of missed dosing result in decreased toler­ance and will require a dosage reduction.

Consult with the MMTP when restarting methadone in a patient who has missed any days of outpatient dosing. Because metha­done can take days to reach a serum steady state, it can cause oversedation or obtunda­tion after it’s restarted in a person who has lost tolerance due to multiple consecutive days of missed doses.

Don’t automatically give the full, veri­fied dose if the patient appears sedated. A variety of other substances (benzodiaz­epines, heroin, tricyclic antidepressants) can increase the effects of methadone. Even the verified methadone maintenance dos­age may need to be reduced or held until these other substances are cleared from the patient’s system.

Don’t be afraid to adjust the metha­done dosage if medically indicated. Medically hospitalized patients might be placed on medications that can alter metha­done metabolism. The primary enzyme responsible for methadone metabolism is cytochrome P450 3A4, which can cre­ate significant drug-drug interactions with rifampin, carbamazepine, phenytoin, and barbiturates, among others.²

Don’t taper methadone just because the patient does not want to be on it any longer. A patient’s methadone dosage should be adjusted in the hospital only if there is an acute medical indication to do so. Otherwise, all dosage changes must be made on an outpatient basis at the MMTP.

Don’t be afraid to give opioids to treat acute pain. Methadone maintenance does not treat acute pain. In fact, compared with the general population, these patients likely will need a higher-than-expected opioid dosage to treat acute pain.³

Don’t initiate methadone maintenance in the hospital. Methadone maintenance can be initiated only at an MMTP that has been certified by appropriate federal and state agencies.⁴ Small doses of methadone can be given to treat or prevent opioid withdrawal in patients admitted to the hospital for conditions other than an opi­oid use disorder. An exception: A pregnant woman with an opioid use disorder who seeks methadone initiation in the hospital.

Don’t forget to monitor the QTc interval. Methadone can prolong the QTc interval. Although the overall rate of cardiac toxicity is low, it is reasonable to obtain an electro­cardiogram in patients with heart disease, those predisposed to prolonged QTc, or those taking another QT-prolonging agent.5

Don’t let negative countertransference prevent you from giving quality care. Patients with a drug addiction can be challenging. They can elicit anger among members of their treatment team because of their character pathology or a provid­er’s discomfort and unfamiliarity. One might be tempted to spend less time with so-called “difficult” patients, but keep in mind that methadone-maintained patients often carry chaotic medical and social issues that require a thoughtful and thor­ough approach to treatment.

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

Methadone maintenance therapy is widely used for helping patients recover from an opioid use disor­der. When these patients develop an acute medical problem that requires hospital­ization, there often is confusion among providers regarding methadone pharma­cology, regulations, and general safety issues. We have observed that the lack of awareness of these practices can lead to poor medical and surgical outcomes, increased length of stay, and diminished patient satisfaction.

Consider the following common pit­falls—all of which we have encountered on our psychiatry consult service—and ways to avoid them when treating methadone-maintained patients.

Don’t give a full methadone maintenance dosage without verifying the dosage and the date when it was last administered. Methadone typically has a long, but vari­able, half-life, with ranges of 4 to 130 hours being reported.¹ Do not rush to give the full dose without verification from the patient’s methadone maintenance treatment pro­gram (MMTP). Small doses—not to exceed 40 mg in 24 hours—can be administered until you verify the dosage. Multiple days of missed dosing result in decreased toler­ance and will require a dosage reduction.

Consult with the MMTP when restarting methadone in a patient who has missed any days of outpatient dosing. Because metha­done can take days to reach a serum steady state, it can cause oversedation or obtunda­tion after it’s restarted in a person who has lost tolerance due to multiple consecutive days of missed doses.

Don’t automatically give the full, veri­fied dose if the patient appears sedated. A variety of other substances (benzodiaz­epines, heroin, tricyclic antidepressants) can increase the effects of methadone. Even the verified methadone maintenance dos­age may need to be reduced or held until these other substances are cleared from the patient’s system.

Don’t be afraid to adjust the metha­done dosage if medically indicated. Medically hospitalized patients might be placed on medications that can alter metha­done metabolism. The primary enzyme responsible for methadone metabolism is cytochrome P450 3A4, which can cre­ate significant drug-drug interactions with rifampin, carbamazepine, phenytoin, and barbiturates, among others.²

Don’t taper methadone just because the patient does not want to be on it any longer. A patient’s methadone dosage should be adjusted in the hospital only if there is an acute medical indication to do so. Otherwise, all dosage changes must be made on an outpatient basis at the MMTP.

Don’t be afraid to give opioids to treat acute pain. Methadone maintenance does not treat acute pain. In fact, compared with the general population, these patients likely will need a higher-than-expected opioid dosage to treat acute pain.³

Don’t initiate methadone maintenance in the hospital. Methadone maintenance can be initiated only at an MMTP that has been certified by appropriate federal and state agencies.⁴ Small doses of methadone can be given to treat or prevent opioid withdrawal in patients admitted to the hospital for conditions other than an opi­oid use disorder. An exception: A pregnant woman with an opioid use disorder who seeks methadone initiation in the hospital.

Don’t forget to monitor the QTc interval. Methadone can prolong the QTc interval. Although the overall rate of cardiac toxicity is low, it is reasonable to obtain an electro­cardiogram in patients with heart disease, those predisposed to prolonged QTc, or those taking another QT-prolonging agent.5

Don’t let negative countertransference prevent you from giving quality care. Patients with a drug addiction can be challenging. They can elicit anger among members of their treatment team because of their character pathology or a provid­er’s discomfort and unfamiliarity. One might be tempted to spend less time with so-called “difficult” patients, but keep in mind that methadone-maintained patients often carry chaotic medical and social issues that require a thoughtful and thor­ough approach to treatment.

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

Methadone maintenance therapy is widely used for helping patients recover from an opioid use disor­der. When these patients develop an acute medical problem that requires hospital­ization, there often is confusion among providers regarding methadone pharma­cology, regulations, and general safety issues. We have observed that the lack of awareness of these practices can lead to poor medical and surgical outcomes, increased length of stay, and diminished patient satisfaction.

Consider the following common pit­falls—all of which we have encountered on our psychiatry consult service—and ways to avoid them when treating methadone-maintained patients.

Don’t give a full methadone maintenance dosage without verifying the dosage and the date when it was last administered. Methadone typically has a long, but vari­able, half-life, with ranges of 4 to 130 hours being reported.¹ Do not rush to give the full dose without verification from the patient’s methadone maintenance treatment pro­gram (MMTP). Small doses—not to exceed 40 mg in 24 hours—can be administered until you verify the dosage. Multiple days of missed dosing result in decreased toler­ance and will require a dosage reduction.

Consult with the MMTP when restarting methadone in a patient who has missed any days of outpatient dosing. Because metha­done can take days to reach a serum steady state, it can cause oversedation or obtunda­tion after it’s restarted in a person who has lost tolerance due to multiple consecutive days of missed doses.

Don’t automatically give the full, veri­fied dose if the patient appears sedated. A variety of other substances (benzodiaz­epines, heroin, tricyclic antidepressants) can increase the effects of methadone. Even the verified methadone maintenance dos­age may need to be reduced or held until these other substances are cleared from the patient’s system.

Don’t be afraid to adjust the metha­done dosage if medically indicated. Medically hospitalized patients might be placed on medications that can alter metha­done metabolism. The primary enzyme responsible for methadone metabolism is cytochrome P450 3A4, which can cre­ate significant drug-drug interactions with rifampin, carbamazepine, phenytoin, and barbiturates, among others.²

Don’t taper methadone just because the patient does not want to be on it any longer. A patient’s methadone dosage should be adjusted in the hospital only if there is an acute medical indication to do so. Otherwise, all dosage changes must be made on an outpatient basis at the MMTP.

Don’t be afraid to give opioids to treat acute pain. Methadone maintenance does not treat acute pain. In fact, compared with the general population, these patients likely will need a higher-than-expected opioid dosage to treat acute pain.³

Don’t initiate methadone maintenance in the hospital. Methadone maintenance can be initiated only at an MMTP that has been certified by appropriate federal and state agencies.⁴ Small doses of methadone can be given to treat or prevent opioid withdrawal in patients admitted to the hospital for conditions other than an opi­oid use disorder. An exception: A pregnant woman with an opioid use disorder who seeks methadone initiation in the hospital.

Don’t forget to monitor the QTc interval. Methadone can prolong the QTc interval. Although the overall rate of cardiac toxicity is low, it is reasonable to obtain an electro­cardiogram in patients with heart disease, those predisposed to prolonged QTc, or those taking another QT-prolonging agent.5

Don’t let negative countertransference prevent you from giving quality care. Patients with a drug addiction can be challenging. They can elicit anger among members of their treatment team because of their character pathology or a provid­er’s discomfort and unfamiliarity. One might be tempted to spend less time with so-called “difficult” patients, but keep in mind that methadone-maintained patients often carry chaotic medical and social issues that require a thoughtful and thor­ough approach to treatment.

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

Mindfulness has become an impor­tant supportive psychotherapeutic intervention for a variety of psychi­atric conditions,^1-3 regardless of what other modalities the psychiatrist employs (eg, phar­macotherapy, other psychotherapeutic inter­ventions). In general, mindfulness involves engaging in meditation exercises, analogous to working out in the gym, to strengthen “mindfulness muscles.” These exercises increase the patient’s ability to remain in the moment, “as is,” and without judgment.

I think of mindfulness exercises as an “ego gym” for the patient as he (she) gets to exercise the ego functions of agency, atten­tion, awareness, acceptance, and empathy. Advising and helping patients to be present and exist with their thoughts is a psycho-educational approach and form of advice consistent with principles of supportive therapy. In this article, I provide a practical framework for doing and teaching mind­fulness using the mnemonic BREATHE.

Flow is more important than sequence
The 7 elements of mindfulness exercises contained in BREATHE do not need to be done in order. Rather, mindfulness gener­ally involves each of the following elements flowing, or tumbling, into each other, not standing as a distinct entity.

Being in the now, “as is,” without judg­ment (eg, being present/being vs doing; Buddhist origins; diaphragmatic breath­ing/body scans; “breathing-space” medi­tation exercises). In general, mindfulness meditation exercises focus on some sen­sory experience (eg, the physical sensa­tion of breathing or of a difficult emotion, or sounds and smells in the environment). Some mindfulness meditations are called “body scans.”

A patient can shift his (her) focus during mindfulness meditation to a sound or some other stimulus intruding on his original meditative focus, such as an intense emo­tion or pain, that might arise and become the new focus of mindfulness meditation. Ideally, mindfulness exercises are done without the intention of achieving anything (ie, there is no “striving” for anything when being mindful). Striving, after all, is doing; mindfulness is being.

R(AIN). Mindfulness, as operationalized by Kabat-Zinn,⁴ starts with a focus on breath­ing similar to many meditation practices in Buddhism. When the patient wanders into intense emotions, such as suffering, that become the focus of mindfulness, use the mnemonic-within-a-mnemonic RAIN as a guide; typically, this involves first anchoring with a few deep breaths, and then becoming mindful by:
   • Recognizing (and labeling, nam­ing, “tagging”) the emotion (eg, sad, hurt, angry, embarrassed); this engages frontal lobe processes that diminishes amygdaloid limbic system overactivity¹
   • Allowing (ie, accepting suffering)
   • Investigating, with an open and curious attitude, using one’s senses to experience, feel, and explore thoughts and emotions
   • Non-identifying with one’s thoughts, feelings, emotions, or suffering (expressed in the important mindfulness refrain: “You are not your thoughts or emotions. You are the entity that simply is aware of them.”).

Experiencing. The patient stops at the perceived experience or sensation and does not automatically react with thoughts, emo­tions, distress, or judgments. Mindfulness is a psychotherapeutic intervention that is “more experiential than cognitive.” Encourage the patient to stop at the “door of experience” and not enter the doors of thinking, emotion, and feeling.

Accepting without judgment—also called “awarenessing” or “avoid avoiding.” This involves being aware of the experi­ence regardless of what it entails, whether suffering, thoughts, emotions, or pain, and not trying to escape or avoid the difficult experience. Psychodynamic principles help us understand how psychological defenses designed to avoid the experience of the “unbearable affect” often lead to more problems for patients. In mindfulness, only avoiding is to be avoided.

Thoughts. People tend to over-identify with their thoughts and emotions. In mindfulness, you emphasize to the patient that (1) he is not his thoughts or emotions and (2) these cognitive processes do not represent facts.

Heartfulness—or, healthy, happy, free from harm. Mindfulness from the Buddhist tradition also includes “heartfulness” and “loving-kindness” and the development of compassion and kindness for one’s self and others. Mindfulness meditation there­fore also involves development of loving-kindness/compassion toward oneself and others—even one’s enemies (eg, “May I be healthy, happy, and free from harm.”). I have found this aspect of mindfulness useful for patients who feel angry or entitled, with characterological problems.

Empathy for others. As an extension of, or further emphasis on, loving-kindness, medi­tation focuses on understanding the suffer­ing of others. In certain monastic practices, this mindfulness meditation involves “tak­ing on” the suffering of another.

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

Mindfulness has become an impor­tant supportive psychotherapeutic intervention for a variety of psychi­atric conditions,^1-3 regardless of what other modalities the psychiatrist employs (eg, phar­macotherapy, other psychotherapeutic inter­ventions). In general, mindfulness involves engaging in meditation exercises, analogous to working out in the gym, to strengthen “mindfulness muscles.” These exercises increase the patient’s ability to remain in the moment, “as is,” and without judgment.

I think of mindfulness exercises as an “ego gym” for the patient as he (she) gets to exercise the ego functions of agency, atten­tion, awareness, acceptance, and empathy. Advising and helping patients to be present and exist with their thoughts is a psycho-educational approach and form of advice consistent with principles of supportive therapy. In this article, I provide a practical framework for doing and teaching mind­fulness using the mnemonic BREATHE.

Flow is more important than sequence
The 7 elements of mindfulness exercises contained in BREATHE do not need to be done in order. Rather, mindfulness gener­ally involves each of the following elements flowing, or tumbling, into each other, not standing as a distinct entity.

Being in the now, “as is,” without judg­ment (eg, being present/being vs doing; Buddhist origins; diaphragmatic breath­ing/body scans; “breathing-space” medi­tation exercises). In general, mindfulness meditation exercises focus on some sen­sory experience (eg, the physical sensa­tion of breathing or of a difficult emotion, or sounds and smells in the environment). Some mindfulness meditations are called “body scans.”

A patient can shift his (her) focus during mindfulness meditation to a sound or some other stimulus intruding on his original meditative focus, such as an intense emo­tion or pain, that might arise and become the new focus of mindfulness meditation. Ideally, mindfulness exercises are done without the intention of achieving anything (ie, there is no “striving” for anything when being mindful). Striving, after all, is doing; mindfulness is being.

R(AIN). Mindfulness, as operationalized by Kabat-Zinn,⁴ starts with a focus on breath­ing similar to many meditation practices in Buddhism. When the patient wanders into intense emotions, such as suffering, that become the focus of mindfulness, use the mnemonic-within-a-mnemonic RAIN as a guide; typically, this involves first anchoring with a few deep breaths, and then becoming mindful by:
   • Recognizing (and labeling, nam­ing, “tagging”) the emotion (eg, sad, hurt, angry, embarrassed); this engages frontal lobe processes that diminishes amygdaloid limbic system overactivity¹
   • Allowing (ie, accepting suffering)
   • Investigating, with an open and curious attitude, using one’s senses to experience, feel, and explore thoughts and emotions
   • Non-identifying with one’s thoughts, feelings, emotions, or suffering (expressed in the important mindfulness refrain: “You are not your thoughts or emotions. You are the entity that simply is aware of them.”).

Experiencing. The patient stops at the perceived experience or sensation and does not automatically react with thoughts, emo­tions, distress, or judgments. Mindfulness is a psychotherapeutic intervention that is “more experiential than cognitive.” Encourage the patient to stop at the “door of experience” and not enter the doors of thinking, emotion, and feeling.

Accepting without judgment—also called “awarenessing” or “avoid avoiding.” This involves being aware of the experi­ence regardless of what it entails, whether suffering, thoughts, emotions, or pain, and not trying to escape or avoid the difficult experience. Psychodynamic principles help us understand how psychological defenses designed to avoid the experience of the “unbearable affect” often lead to more problems for patients. In mindfulness, only avoiding is to be avoided.

Thoughts. People tend to over-identify with their thoughts and emotions. In mindfulness, you emphasize to the patient that (1) he is not his thoughts or emotions and (2) these cognitive processes do not represent facts.

Heartfulness—or, healthy, happy, free from harm. Mindfulness from the Buddhist tradition also includes “heartfulness” and “loving-kindness” and the development of compassion and kindness for one’s self and others. Mindfulness meditation there­fore also involves development of loving-kindness/compassion toward oneself and others—even one’s enemies (eg, “May I be healthy, happy, and free from harm.”). I have found this aspect of mindfulness useful for patients who feel angry or entitled, with characterological problems.

Empathy for others. As an extension of, or further emphasis on, loving-kindness, medi­tation focuses on understanding the suffer­ing of others. In certain monastic practices, this mindfulness meditation involves “tak­ing on” the suffering of another.

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

Mindfulness has become an impor­tant supportive psychotherapeutic intervention for a variety of psychi­atric conditions,^1-3 regardless of what other modalities the psychiatrist employs (eg, phar­macotherapy, other psychotherapeutic inter­ventions). In general, mindfulness involves engaging in meditation exercises, analogous to working out in the gym, to strengthen “mindfulness muscles.” These exercises increase the patient’s ability to remain in the moment, “as is,” and without judgment.

I think of mindfulness exercises as an “ego gym” for the patient as he (she) gets to exercise the ego functions of agency, atten­tion, awareness, acceptance, and empathy. Advising and helping patients to be present and exist with their thoughts is a psycho-educational approach and form of advice consistent with principles of supportive therapy. In this article, I provide a practical framework for doing and teaching mind­fulness using the mnemonic BREATHE.

Flow is more important than sequence
The 7 elements of mindfulness exercises contained in BREATHE do not need to be done in order. Rather, mindfulness gener­ally involves each of the following elements flowing, or tumbling, into each other, not standing as a distinct entity.

Being in the now, “as is,” without judg­ment (eg, being present/being vs doing; Buddhist origins; diaphragmatic breath­ing/body scans; “breathing-space” medi­tation exercises). In general, mindfulness meditation exercises focus on some sen­sory experience (eg, the physical sensa­tion of breathing or of a difficult emotion, or sounds and smells in the environment). Some mindfulness meditations are called “body scans.”

A patient can shift his (her) focus during mindfulness meditation to a sound or some other stimulus intruding on his original meditative focus, such as an intense emo­tion or pain, that might arise and become the new focus of mindfulness meditation. Ideally, mindfulness exercises are done without the intention of achieving anything (ie, there is no “striving” for anything when being mindful). Striving, after all, is doing; mindfulness is being.

R(AIN). Mindfulness, as operationalized by Kabat-Zinn,⁴ starts with a focus on breath­ing similar to many meditation practices in Buddhism. When the patient wanders into intense emotions, such as suffering, that become the focus of mindfulness, use the mnemonic-within-a-mnemonic RAIN as a guide; typically, this involves first anchoring with a few deep breaths, and then becoming mindful by:
   • Recognizing (and labeling, nam­ing, “tagging”) the emotion (eg, sad, hurt, angry, embarrassed); this engages frontal lobe processes that diminishes amygdaloid limbic system overactivity¹
   • Allowing (ie, accepting suffering)
   • Investigating, with an open and curious attitude, using one’s senses to experience, feel, and explore thoughts and emotions
   • Non-identifying with one’s thoughts, feelings, emotions, or suffering (expressed in the important mindfulness refrain: “You are not your thoughts or emotions. You are the entity that simply is aware of them.”).

Experiencing. The patient stops at the perceived experience or sensation and does not automatically react with thoughts, emo­tions, distress, or judgments. Mindfulness is a psychotherapeutic intervention that is “more experiential than cognitive.” Encourage the patient to stop at the “door of experience” and not enter the doors of thinking, emotion, and feeling.

Accepting without judgment—also called “awarenessing” or “avoid avoiding.” This involves being aware of the experi­ence regardless of what it entails, whether suffering, thoughts, emotions, or pain, and not trying to escape or avoid the difficult experience. Psychodynamic principles help us understand how psychological defenses designed to avoid the experience of the “unbearable affect” often lead to more problems for patients. In mindfulness, only avoiding is to be avoided.

Thoughts. People tend to over-identify with their thoughts and emotions. In mindfulness, you emphasize to the patient that (1) he is not his thoughts or emotions and (2) these cognitive processes do not represent facts.

Heartfulness—or, healthy, happy, free from harm. Mindfulness from the Buddhist tradition also includes “heartfulness” and “loving-kindness” and the development of compassion and kindness for one’s self and others. Mindfulness meditation there­fore also involves development of loving-kindness/compassion toward oneself and others—even one’s enemies (eg, “May I be healthy, happy, and free from harm.”). I have found this aspect of mindfulness useful for patients who feel angry or entitled, with characterological problems.

Empathy for others. As an extension of, or further emphasis on, loving-kindness, medi­tation focuses on understanding the suffer­ing of others. In certain monastic practices, this mindfulness meditation involves “tak­ing on” the suffering of another.

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

Asenapine an atypical antipsychotic sold under the brand name Saphris, was granted a second, pediatric indi­cation by the FDA in March 2015 as mono­therapy for acute treatment of manic or mixed episodes of bipolar I disorder in chil­dren and adolescents age 10 to 17 (Table 1).¹ (Asenapine was first approved in August 2009 as monotherapy or adjunctive therapy to lithium or valproate in adults for schizo­phrenia and bipolar I disorder.^1,2)

Dosage and administration
Asenapine is available as 2.5-, 5-, and 10-mg sublingual tablets, the only atypical anti­psychotic with this formulation.¹ The rec­ommended dosage for the new indication is 2.5 mg twice daily for 3 days, titrated to 5 mg twice daily, titrated again to 10 mg twice daily after 3 days.³ In a phase I study, pedi­atric patients appeared to be more sensitive to dystonia when the recommended dosage escalation schedule was not followed.³

In clinical trials, drinking water 2 to 5 minutes after taking asenapine decreased exposure to the drug. Instruct patients not to swallow the tablet and to avoid eating and drinking for 10 minutes after administration.³

For full prescribing information for pediat­ric and adult patients, see Reference 3.

Safety and efficacy
In a 3-week, placebo-controlled, double-blind trial of 403 patients, 302 children and adolescents age 10 to 17 received asenap­ine at fixed dosages of 2.5 to 10 mg twice daily; the remainder were given placebo. The Young Mania Rating Scale (YMRS) total score and Clinical Global Impressions Severity of Illness scores of patients who received asenapine improved significantly compared with those who received placebo, as measured by change from baseline to week 3 (Table 2).¹

Asenapine was not shown to be effective in pediatric patients with schizophrenia in an 8-week, placebo-controlled, double-blind trial.

The pharmacokinetics of asenapine in pediatric patients are similar to those seen in adults.

Adverse effects
In pediatric patients, the most common reported adverse effects of asenapine are:
   • dizziness
   • dysgeusia
   • fatigue
   • increased appetite
   • increased weight
   • nausea
   • oral paresthesia
   • somnolence.

Similar adverse effects were reported in the pediatric bipolar disorder and adult bipolar disorder clinical trials (Table 3).³ A complete list of reported adverse effects is given in the package insert.³

When treating pediatric patients, moni­tor the child’s weight gain against expected normal weight gain.

Asenapine is contraindicated in patients with hepatic impairment and those who have a hypersensitivity to asenapine or any components in its formulation.³

Asenapine an atypical antipsychotic sold under the brand name Saphris, was granted a second, pediatric indi­cation by the FDA in March 2015 as mono­therapy for acute treatment of manic or mixed episodes of bipolar I disorder in chil­dren and adolescents age 10 to 17 (Table 1).¹ (Asenapine was first approved in August 2009 as monotherapy or adjunctive therapy to lithium or valproate in adults for schizo­phrenia and bipolar I disorder.^1,2)

Dosage and administration
Asenapine is available as 2.5-, 5-, and 10-mg sublingual tablets, the only atypical anti­psychotic with this formulation.¹ The rec­ommended dosage for the new indication is 2.5 mg twice daily for 3 days, titrated to 5 mg twice daily, titrated again to 10 mg twice daily after 3 days.³ In a phase I study, pedi­atric patients appeared to be more sensitive to dystonia when the recommended dosage escalation schedule was not followed.³

In clinical trials, drinking water 2 to 5 minutes after taking asenapine decreased exposure to the drug. Instruct patients not to swallow the tablet and to avoid eating and drinking for 10 minutes after administration.³

For full prescribing information for pediat­ric and adult patients, see Reference 3.

Safety and efficacy
In a 3-week, placebo-controlled, double-blind trial of 403 patients, 302 children and adolescents age 10 to 17 received asenap­ine at fixed dosages of 2.5 to 10 mg twice daily; the remainder were given placebo. The Young Mania Rating Scale (YMRS) total score and Clinical Global Impressions Severity of Illness scores of patients who received asenapine improved significantly compared with those who received placebo, as measured by change from baseline to week 3 (Table 2).¹

Asenapine was not shown to be effective in pediatric patients with schizophrenia in an 8-week, placebo-controlled, double-blind trial.

The pharmacokinetics of asenapine in pediatric patients are similar to those seen in adults.

Adverse effects
In pediatric patients, the most common reported adverse effects of asenapine are:
   • dizziness
   • dysgeusia
   • fatigue
   • increased appetite
   • increased weight
   • nausea
   • oral paresthesia
   • somnolence.

Similar adverse effects were reported in the pediatric bipolar disorder and adult bipolar disorder clinical trials (Table 3).³ A complete list of reported adverse effects is given in the package insert.³

When treating pediatric patients, moni­tor the child’s weight gain against expected normal weight gain.

Asenapine is contraindicated in patients with hepatic impairment and those who have a hypersensitivity to asenapine or any components in its formulation.³

Asenapine an atypical antipsychotic sold under the brand name Saphris, was granted a second, pediatric indi­cation by the FDA in March 2015 as mono­therapy for acute treatment of manic or mixed episodes of bipolar I disorder in chil­dren and adolescents age 10 to 17 (Table 1).¹ (Asenapine was first approved in August 2009 as monotherapy or adjunctive therapy to lithium or valproate in adults for schizo­phrenia and bipolar I disorder.^1,2)

Dosage and administration
Asenapine is available as 2.5-, 5-, and 10-mg sublingual tablets, the only atypical anti­psychotic with this formulation.¹ The rec­ommended dosage for the new indication is 2.5 mg twice daily for 3 days, titrated to 5 mg twice daily, titrated again to 10 mg twice daily after 3 days.³ In a phase I study, pedi­atric patients appeared to be more sensitive to dystonia when the recommended dosage escalation schedule was not followed.³

In clinical trials, drinking water 2 to 5 minutes after taking asenapine decreased exposure to the drug. Instruct patients not to swallow the tablet and to avoid eating and drinking for 10 minutes after administration.³

For full prescribing information for pediat­ric and adult patients, see Reference 3.

Safety and efficacy
In a 3-week, placebo-controlled, double-blind trial of 403 patients, 302 children and adolescents age 10 to 17 received asenap­ine at fixed dosages of 2.5 to 10 mg twice daily; the remainder were given placebo. The Young Mania Rating Scale (YMRS) total score and Clinical Global Impressions Severity of Illness scores of patients who received asenapine improved significantly compared with those who received placebo, as measured by change from baseline to week 3 (Table 2).¹

Asenapine was not shown to be effective in pediatric patients with schizophrenia in an 8-week, placebo-controlled, double-blind trial.

The pharmacokinetics of asenapine in pediatric patients are similar to those seen in adults.

Adverse effects
In pediatric patients, the most common reported adverse effects of asenapine are:
   • dizziness
   • dysgeusia
   • fatigue
   • increased appetite
   • increased weight
   • nausea
   • oral paresthesia
   • somnolence.

Similar adverse effects were reported in the pediatric bipolar disorder and adult bipolar disorder clinical trials (Table 3).³ A complete list of reported adverse effects is given in the package insert.³

When treating pediatric patients, moni­tor the child’s weight gain against expected normal weight gain.

Asenapine is contraindicated in patients with hepatic impairment and those who have a hypersensitivity to asenapine or any components in its formulation.³