Current Psychiatry

CASE Mute and nonresponsive
Mr. R, a 19-year-old African-American man, is brought to the emergency room (ER) because he has reduced oral intake and mutism, and is not attending to activities of daily living (ADL). His family reports gradual onset of symptoms over the past month after he began using “Spice,” a synthetic cannabinoid (Box^1-8).

Mr. R has been using marijuana regularly for a few years. He has no history of psychiatric illness. The family history is positive for schizophrenia (mother).

Mr. R slowly stopped speaking and eating, and no longer responds to verbal stimulation. On examination, he responds only with unintelligible mumbling. Mr. R exhibits blunted affect and fails to maintain eye contact, looking to the side of the interviewer. He exhibits severe psychomotor retardation but without posturing or waxy flexibility. It takes him approximately 3 minutes to transfer between chairs, and he is incontinent of bladder and bowel.

Mr. R has not experienced a similar episode in the past, although he had exhibited brief paranoia while intoxicated with marijuana.

Before this episode, Mr. R had been moving between his grandmother’s and father’s homes and was attending high school classes. Recent stressful events include his brother’s incarceration and his father having re-entered his life after a long absence.

Which treatment would you initiate for Mr. R’s symptoms of catatonia?
   a) dantrolene
   b) a benzodiazepine
   c) an antipsychotic
   d) electroconvulsive therapy (ECT)

The authors’ observations
Catatonia is a common complication in a variety of psychiatric and medical contexts. It can be a feature of mood disorders, schizophrenia, metabolic disturbances, drug intoxication, neuroleptic malignant syndrome (NMS), and encephalopathy. The most common psychiatric comorbidity is bipolar disorder; as many as 25% of cases are caused by a medical or neurological condition.⁹ When accompanied by fever and autonomic instability, so-called malignant catatonia can lead to respiratory failure, coma, and death.

Catatonia is characterized by ≥3 of the elements outlined in Table 1.¹⁰

In DSM-5, catatonia is no longer considered a subtype of schizophrenia, but is a specifier in the following disorders: brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, and substance-induced psychotic disorder. In addition, catatonia not otherwise specified is reserved for cases when the cause is not apparent; this diagnosis is intended to lead to greater recognition of catatonia and prompt initiation of treatment. DSM-5 stops short of classifying catatonia as an independent syndrome, however. Changes in clinical status can be charted with instruments such as the Bush-Francis Catatonia Rating Scale.

Workup and treatment
The initial workup of patients with catatonia is extensive. A basic metabolic panel can detect electrolyte disturbances and acute renal failure. Monitoring creatine kinase (CK) allows clinicians to assess for rhabdomyolysis. Patients should also undergo an infectious workup, including complete blood count (CBC) and chest radiography, because patients can develop pneumonia due to atelectasis or aspiration. Additional workup could include EEG, erythrocyte sedimentation rate, D-dimer, urinalysis, urine drug screen, antinuclear antibodies, magnetic resonance imaging, cerebrospinal fluid analysis, anti-N-methyl-D-aspartate receptor antibodies, and serum iron, which could predict development of NMS in patients treated with an antipsychotic.¹¹

Treatment. In addition to supportive measures, the initial treatment of choice for catatonia is a benzodiazepine, lorazepam being the most commonly used agent; dramatic improvement in symptoms can be seen within minutes of IV administration. A high dosage of lorazepam (14 to 16 mg/d) sometimes is required for symptomatic relief. Zolpidem also has been used successfully to treat catatonia, although the supporting literature is less extensive.¹²

Antipsychotics generally are held during the initial stages of catatonia treatment because they can exacerbate symptoms and increase the likelihood of NMS. Glutamate antagonists, such as amantadine and memantine, also are being investigated for treating catatonia.⁹

ECT is effective but is reserved for when pharmacotherapy has failed or when a rapid response is required. ECT is associated with cognitive and medical complications, although current techniques have greatly mitigated the risks. Mortality is estimated to be 1 in every 10,000 patients or 1 for every 80,000 treatments, most often due to a cardiac or pulmonary cause.¹³ Patients receiving ECT could experience temporary anterograde amnesia and confusion as well as retrograde amnesia, particularly memories formed around the time of treatment.

Response to benzodiazepine therapy varies: Some patients experience significant improvement after 1 dose; others require a high dosage for an extended period. More than 70% of cases remit with benzodiazepines; ECT should be considered after several days or earlier if indicated.⁹ Some patients with catatonia require a slow benzodiazepine taper to prevent symptoms from recurring.

Patients with catatonia are at risk of dehydration and malnutrition, and might require IV fluids or parenteral nutrition. These patients also are at risk of constipation, ileus, decubitus ulcers, deep vein thrombosis, and pulmonary embolism. Encourage early ambulation and consider prescribing an antithrombotic. Some patients might require physical therapy to prevent or treat muscle contractures.

TREATMENT Benzodiazepines, ECT
Mr. R is admitted for stabilization of catatonic symptoms. A basic metabolic panel, CBC with differential, urine drug screen, urinalysis, folate level, thyroid-stimulating hormone level, vitamin B₁₂, EEG, and a stool culture are unremarkable. Ammonia level is slightly elevated at 40 µmol/L.

Mr. R is started on IM lorazepam, 1 mg every 8 hours. Antipsychotics are held in part because of an elevated CK level (614 U/L). CK is rechecked daily and increases to 5,681 U/L by the second week. Internal medicine is consulted because Mr. R could develop NMS. However, the treatment team thinks that CK elevation is caused by immobility, because Mr. R remains afebrile, normotensive, and without leukocytosis.

After 4 days of treatment, Mr. R can follow simple commands. He nods or shakes his head when questioned. IV fluids are started because of limited oral intake. As the month progresses, Mr. R’s CK levels slowly trend downward, toward 500 U/L.

Mr. R progresses slowly with benzodiazepine therapy. He begins to ambulate, make eye contact, and look at interviewers. Lorazepam is slowly titrated to 4 mg IM every 8 hours. On hospital Day 20, his functioning reaches a plateau; Mr. R’s cognition continues to fluctuate with periods of unresponsiveness, immobility, and incontinence.

The treatment team obtains consent from the family to begin ECT. On hospital Day 24, bilateral transtemporal ECT is initiated and continued 3 times a week. Mr. R tolerates the procedure without complications. After the first treatment, he demonstrates spontaneous speech for the first time since admission. He continues to improve overall but has a variable clinical course.

By Day 30, Mr. R can state the day, month, year, and that he is in the “psych” unit. He remembers being on the unit for a long time and says that he had been attempting to talk but “it wasn’t coming out.” When further questioned about substance use, he admits to using Spice for the month before admission and marijuana regularly over several years. He denies using other illicit drugs or alcohol.

Mr. R is started on olanzapine, 2.5 mg/d, titrated to 15 mg/d. He becomes increasingly interactive, although with occasional bouts of confusion, and regains bladder and bowel control. He receives a total of 12 ECT treatments. The family is adamant that Mr. R should not receive more ECT treatments, and is not interested in maintenance therapy. Mr. R’s father and grandmother visit and believe that he is back to baseline functioning. After 51 days of inpatient treatment, Mr. R is discharged on olanzapine, 15 mg/d, and oral lorazepam, 1 mg/d.

Nine days later, Mr. R is brought to the ER because of unresponsiveness, poor oral intake, refusal of medication, bowel and bladder incontinence, and inability to perform ADL. His father reports that he administered olanzapine but, because he only recognized the brand name of lorazepam, he did not get that prescription filled. Mr. R slowly decompensates and, by the time of readmission, refuses all medications.

Over the next few months, Mr. R is readmitted several times for similar symptoms. Again, the family states they do not want further ECT; the father believes that these treatments have caused his son’s condition. Complicating the matter is that the father had been out of his son’s life for an extended period and is unaccustomed to his son’s display of psychiatric symptoms.

The authors’ observations
The use of ECT for drug-induced psychosis is not well described in the literature because substance abuse is exclusionary in many trials. The safety and efficacy of ECT has been established for adolescents with first-episode psychosis¹⁴ and with catatonia.^15,16

The use of ECT in Spice-induced catatonia has been reported in 2 case studies.^17,18

Case 1. A 36-year-old man with schizophrenia and Cannabis dependence was admitted for auditory hallucinations, disorganization, paranoia, and manic symptoms, which progressed to catatonia.¹⁷ His symptoms were profound, including psychomotor retardation, rigidity, posturing, waxy flexibility, and inability to perform ADL.

The patient later reported that, 3 weeks prior, he had stopped taking his psychotropic medications and started smoking “K2,” a synthetic cannabinoid, because it was cheaper and easier to obtain than Cannabis. He had never experienced disturbances in motor function or speech in the past, even during episodes of Cannabis use and medication non-adherence.

After clozapine and benzodiazepine treatment (as high as 12 mg/d of lorazepam) did not resolve his symptoms, the patient received 6 bilateral ECT treatments over 16 days, with complete resolution of catatonic symptoms. He showed marked improvement, including resumption of speech after the first treatment, although he required an additional 20 days of inpatient care. As in our case, exposure to synthetic cannabinoids was self-reported; no confirmatory tests were performed.

Case 2. A 17-year-old male with no history of psychosis exhibited catatonic symptoms after smoking an estimated 2 to 3 g/d of K2 over 2 months.¹⁸ Similar to the case of Mr. R, he plateaued after lorazepam treatment, and then received 6 ECT treatments, which resulted in complete resolution of symptoms. He was discharged with olanzapine.

As our patient, and the 2 cases cited, show, ECT seems to be an effective option for Spice-induced catatonia. Unlike those published cases, however, our patient achieved only brief resolution of symptoms after an acute course of ECT. There appears to be a subset of patients who require maintenance ECT or prolonged benzodiazepine therapy after Spice-induced catatonia.

CASE Mute and nonresponsive
Mr. R, a 19-year-old African-American man, is brought to the emergency room (ER) because he has reduced oral intake and mutism, and is not attending to activities of daily living (ADL). His family reports gradual onset of symptoms over the past month after he began using “Spice,” a synthetic cannabinoid (Box^1-8).

Mr. R has been using marijuana regularly for a few years. He has no history of psychiatric illness. The family history is positive for schizophrenia (mother).

Mr. R slowly stopped speaking and eating, and no longer responds to verbal stimulation. On examination, he responds only with unintelligible mumbling. Mr. R exhibits blunted affect and fails to maintain eye contact, looking to the side of the interviewer. He exhibits severe psychomotor retardation but without posturing or waxy flexibility. It takes him approximately 3 minutes to transfer between chairs, and he is incontinent of bladder and bowel.

Mr. R has not experienced a similar episode in the past, although he had exhibited brief paranoia while intoxicated with marijuana.

Before this episode, Mr. R had been moving between his grandmother’s and father’s homes and was attending high school classes. Recent stressful events include his brother’s incarceration and his father having re-entered his life after a long absence.

Which treatment would you initiate for Mr. R’s symptoms of catatonia?
   a) dantrolene
   b) a benzodiazepine
   c) an antipsychotic
   d) electroconvulsive therapy (ECT)

The authors’ observations
Catatonia is a common complication in a variety of psychiatric and medical contexts. It can be a feature of mood disorders, schizophrenia, metabolic disturbances, drug intoxication, neuroleptic malignant syndrome (NMS), and encephalopathy. The most common psychiatric comorbidity is bipolar disorder; as many as 25% of cases are caused by a medical or neurological condition.⁹ When accompanied by fever and autonomic instability, so-called malignant catatonia can lead to respiratory failure, coma, and death.

Catatonia is characterized by ≥3 of the elements outlined in Table 1.¹⁰

In DSM-5, catatonia is no longer considered a subtype of schizophrenia, but is a specifier in the following disorders: brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, and substance-induced psychotic disorder. In addition, catatonia not otherwise specified is reserved for cases when the cause is not apparent; this diagnosis is intended to lead to greater recognition of catatonia and prompt initiation of treatment. DSM-5 stops short of classifying catatonia as an independent syndrome, however. Changes in clinical status can be charted with instruments such as the Bush-Francis Catatonia Rating Scale.

Workup and treatment
The initial workup of patients with catatonia is extensive. A basic metabolic panel can detect electrolyte disturbances and acute renal failure. Monitoring creatine kinase (CK) allows clinicians to assess for rhabdomyolysis. Patients should also undergo an infectious workup, including complete blood count (CBC) and chest radiography, because patients can develop pneumonia due to atelectasis or aspiration. Additional workup could include EEG, erythrocyte sedimentation rate, D-dimer, urinalysis, urine drug screen, antinuclear antibodies, magnetic resonance imaging, cerebrospinal fluid analysis, anti-N-methyl-D-aspartate receptor antibodies, and serum iron, which could predict development of NMS in patients treated with an antipsychotic.¹¹

Treatment. In addition to supportive measures, the initial treatment of choice for catatonia is a benzodiazepine, lorazepam being the most commonly used agent; dramatic improvement in symptoms can be seen within minutes of IV administration. A high dosage of lorazepam (14 to 16 mg/d) sometimes is required for symptomatic relief. Zolpidem also has been used successfully to treat catatonia, although the supporting literature is less extensive.¹²

Antipsychotics generally are held during the initial stages of catatonia treatment because they can exacerbate symptoms and increase the likelihood of NMS. Glutamate antagonists, such as amantadine and memantine, also are being investigated for treating catatonia.⁹

ECT is effective but is reserved for when pharmacotherapy has failed or when a rapid response is required. ECT is associated with cognitive and medical complications, although current techniques have greatly mitigated the risks. Mortality is estimated to be 1 in every 10,000 patients or 1 for every 80,000 treatments, most often due to a cardiac or pulmonary cause.¹³ Patients receiving ECT could experience temporary anterograde amnesia and confusion as well as retrograde amnesia, particularly memories formed around the time of treatment.

Response to benzodiazepine therapy varies: Some patients experience significant improvement after 1 dose; others require a high dosage for an extended period. More than 70% of cases remit with benzodiazepines; ECT should be considered after several days or earlier if indicated.⁹ Some patients with catatonia require a slow benzodiazepine taper to prevent symptoms from recurring.

Patients with catatonia are at risk of dehydration and malnutrition, and might require IV fluids or parenteral nutrition. These patients also are at risk of constipation, ileus, decubitus ulcers, deep vein thrombosis, and pulmonary embolism. Encourage early ambulation and consider prescribing an antithrombotic. Some patients might require physical therapy to prevent or treat muscle contractures.

TREATMENT Benzodiazepines, ECT
Mr. R is admitted for stabilization of catatonic symptoms. A basic metabolic panel, CBC with differential, urine drug screen, urinalysis, folate level, thyroid-stimulating hormone level, vitamin B₁₂, EEG, and a stool culture are unremarkable. Ammonia level is slightly elevated at 40 µmol/L.

Mr. R is started on IM lorazepam, 1 mg every 8 hours. Antipsychotics are held in part because of an elevated CK level (614 U/L). CK is rechecked daily and increases to 5,681 U/L by the second week. Internal medicine is consulted because Mr. R could develop NMS. However, the treatment team thinks that CK elevation is caused by immobility, because Mr. R remains afebrile, normotensive, and without leukocytosis.

After 4 days of treatment, Mr. R can follow simple commands. He nods or shakes his head when questioned. IV fluids are started because of limited oral intake. As the month progresses, Mr. R’s CK levels slowly trend downward, toward 500 U/L.

Mr. R progresses slowly with benzodiazepine therapy. He begins to ambulate, make eye contact, and look at interviewers. Lorazepam is slowly titrated to 4 mg IM every 8 hours. On hospital Day 20, his functioning reaches a plateau; Mr. R’s cognition continues to fluctuate with periods of unresponsiveness, immobility, and incontinence.

The treatment team obtains consent from the family to begin ECT. On hospital Day 24, bilateral transtemporal ECT is initiated and continued 3 times a week. Mr. R tolerates the procedure without complications. After the first treatment, he demonstrates spontaneous speech for the first time since admission. He continues to improve overall but has a variable clinical course.

By Day 30, Mr. R can state the day, month, year, and that he is in the “psych” unit. He remembers being on the unit for a long time and says that he had been attempting to talk but “it wasn’t coming out.” When further questioned about substance use, he admits to using Spice for the month before admission and marijuana regularly over several years. He denies using other illicit drugs or alcohol.

Mr. R is started on olanzapine, 2.5 mg/d, titrated to 15 mg/d. He becomes increasingly interactive, although with occasional bouts of confusion, and regains bladder and bowel control. He receives a total of 12 ECT treatments. The family is adamant that Mr. R should not receive more ECT treatments, and is not interested in maintenance therapy. Mr. R’s father and grandmother visit and believe that he is back to baseline functioning. After 51 days of inpatient treatment, Mr. R is discharged on olanzapine, 15 mg/d, and oral lorazepam, 1 mg/d.

Nine days later, Mr. R is brought to the ER because of unresponsiveness, poor oral intake, refusal of medication, bowel and bladder incontinence, and inability to perform ADL. His father reports that he administered olanzapine but, because he only recognized the brand name of lorazepam, he did not get that prescription filled. Mr. R slowly decompensates and, by the time of readmission, refuses all medications.

Over the next few months, Mr. R is readmitted several times for similar symptoms. Again, the family states they do not want further ECT; the father believes that these treatments have caused his son’s condition. Complicating the matter is that the father had been out of his son’s life for an extended period and is unaccustomed to his son’s display of psychiatric symptoms.

The authors’ observations
The use of ECT for drug-induced psychosis is not well described in the literature because substance abuse is exclusionary in many trials. The safety and efficacy of ECT has been established for adolescents with first-episode psychosis¹⁴ and with catatonia.^15,16

The use of ECT in Spice-induced catatonia has been reported in 2 case studies.^17,18

Case 1. A 36-year-old man with schizophrenia and Cannabis dependence was admitted for auditory hallucinations, disorganization, paranoia, and manic symptoms, which progressed to catatonia.¹⁷ His symptoms were profound, including psychomotor retardation, rigidity, posturing, waxy flexibility, and inability to perform ADL.

The patient later reported that, 3 weeks prior, he had stopped taking his psychotropic medications and started smoking “K2,” a synthetic cannabinoid, because it was cheaper and easier to obtain than Cannabis. He had never experienced disturbances in motor function or speech in the past, even during episodes of Cannabis use and medication non-adherence.

After clozapine and benzodiazepine treatment (as high as 12 mg/d of lorazepam) did not resolve his symptoms, the patient received 6 bilateral ECT treatments over 16 days, with complete resolution of catatonic symptoms. He showed marked improvement, including resumption of speech after the first treatment, although he required an additional 20 days of inpatient care. As in our case, exposure to synthetic cannabinoids was self-reported; no confirmatory tests were performed.

Case 2. A 17-year-old male with no history of psychosis exhibited catatonic symptoms after smoking an estimated 2 to 3 g/d of K2 over 2 months.¹⁸ Similar to the case of Mr. R, he plateaued after lorazepam treatment, and then received 6 ECT treatments, which resulted in complete resolution of symptoms. He was discharged with olanzapine.

As our patient, and the 2 cases cited, show, ECT seems to be an effective option for Spice-induced catatonia. Unlike those published cases, however, our patient achieved only brief resolution of symptoms after an acute course of ECT. There appears to be a subset of patients who require maintenance ECT or prolonged benzodiazepine therapy after Spice-induced catatonia.

CASE Mute and nonresponsive
Mr. R, a 19-year-old African-American man, is brought to the emergency room (ER) because he has reduced oral intake and mutism, and is not attending to activities of daily living (ADL). His family reports gradual onset of symptoms over the past month after he began using “Spice,” a synthetic cannabinoid (Box^1-8).

Mr. R has been using marijuana regularly for a few years. He has no history of psychiatric illness. The family history is positive for schizophrenia (mother).

Mr. R slowly stopped speaking and eating, and no longer responds to verbal stimulation. On examination, he responds only with unintelligible mumbling. Mr. R exhibits blunted affect and fails to maintain eye contact, looking to the side of the interviewer. He exhibits severe psychomotor retardation but without posturing or waxy flexibility. It takes him approximately 3 minutes to transfer between chairs, and he is incontinent of bladder and bowel.

Mr. R has not experienced a similar episode in the past, although he had exhibited brief paranoia while intoxicated with marijuana.

Before this episode, Mr. R had been moving between his grandmother’s and father’s homes and was attending high school classes. Recent stressful events include his brother’s incarceration and his father having re-entered his life after a long absence.

Which treatment would you initiate for Mr. R’s symptoms of catatonia?
   a) dantrolene
   b) a benzodiazepine
   c) an antipsychotic
   d) electroconvulsive therapy (ECT)

The authors’ observations
Catatonia is a common complication in a variety of psychiatric and medical contexts. It can be a feature of mood disorders, schizophrenia, metabolic disturbances, drug intoxication, neuroleptic malignant syndrome (NMS), and encephalopathy. The most common psychiatric comorbidity is bipolar disorder; as many as 25% of cases are caused by a medical or neurological condition.⁹ When accompanied by fever and autonomic instability, so-called malignant catatonia can lead to respiratory failure, coma, and death.

Catatonia is characterized by ≥3 of the elements outlined in Table 1.¹⁰

In DSM-5, catatonia is no longer considered a subtype of schizophrenia, but is a specifier in the following disorders: brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, and substance-induced psychotic disorder. In addition, catatonia not otherwise specified is reserved for cases when the cause is not apparent; this diagnosis is intended to lead to greater recognition of catatonia and prompt initiation of treatment. DSM-5 stops short of classifying catatonia as an independent syndrome, however. Changes in clinical status can be charted with instruments such as the Bush-Francis Catatonia Rating Scale.

Workup and treatment
The initial workup of patients with catatonia is extensive. A basic metabolic panel can detect electrolyte disturbances and acute renal failure. Monitoring creatine kinase (CK) allows clinicians to assess for rhabdomyolysis. Patients should also undergo an infectious workup, including complete blood count (CBC) and chest radiography, because patients can develop pneumonia due to atelectasis or aspiration. Additional workup could include EEG, erythrocyte sedimentation rate, D-dimer, urinalysis, urine drug screen, antinuclear antibodies, magnetic resonance imaging, cerebrospinal fluid analysis, anti-N-methyl-D-aspartate receptor antibodies, and serum iron, which could predict development of NMS in patients treated with an antipsychotic.¹¹

Treatment. In addition to supportive measures, the initial treatment of choice for catatonia is a benzodiazepine, lorazepam being the most commonly used agent; dramatic improvement in symptoms can be seen within minutes of IV administration. A high dosage of lorazepam (14 to 16 mg/d) sometimes is required for symptomatic relief. Zolpidem also has been used successfully to treat catatonia, although the supporting literature is less extensive.¹²

Antipsychotics generally are held during the initial stages of catatonia treatment because they can exacerbate symptoms and increase the likelihood of NMS. Glutamate antagonists, such as amantadine and memantine, also are being investigated for treating catatonia.⁹

ECT is effective but is reserved for when pharmacotherapy has failed or when a rapid response is required. ECT is associated with cognitive and medical complications, although current techniques have greatly mitigated the risks. Mortality is estimated to be 1 in every 10,000 patients or 1 for every 80,000 treatments, most often due to a cardiac or pulmonary cause.¹³ Patients receiving ECT could experience temporary anterograde amnesia and confusion as well as retrograde amnesia, particularly memories formed around the time of treatment.

Response to benzodiazepine therapy varies: Some patients experience significant improvement after 1 dose; others require a high dosage for an extended period. More than 70% of cases remit with benzodiazepines; ECT should be considered after several days or earlier if indicated.⁹ Some patients with catatonia require a slow benzodiazepine taper to prevent symptoms from recurring.

Patients with catatonia are at risk of dehydration and malnutrition, and might require IV fluids or parenteral nutrition. These patients also are at risk of constipation, ileus, decubitus ulcers, deep vein thrombosis, and pulmonary embolism. Encourage early ambulation and consider prescribing an antithrombotic. Some patients might require physical therapy to prevent or treat muscle contractures.

TREATMENT Benzodiazepines, ECT
Mr. R is admitted for stabilization of catatonic symptoms. A basic metabolic panel, CBC with differential, urine drug screen, urinalysis, folate level, thyroid-stimulating hormone level, vitamin B₁₂, EEG, and a stool culture are unremarkable. Ammonia level is slightly elevated at 40 µmol/L.

Mr. R is started on IM lorazepam, 1 mg every 8 hours. Antipsychotics are held in part because of an elevated CK level (614 U/L). CK is rechecked daily and increases to 5,681 U/L by the second week. Internal medicine is consulted because Mr. R could develop NMS. However, the treatment team thinks that CK elevation is caused by immobility, because Mr. R remains afebrile, normotensive, and without leukocytosis.

After 4 days of treatment, Mr. R can follow simple commands. He nods or shakes his head when questioned. IV fluids are started because of limited oral intake. As the month progresses, Mr. R’s CK levels slowly trend downward, toward 500 U/L.

Mr. R progresses slowly with benzodiazepine therapy. He begins to ambulate, make eye contact, and look at interviewers. Lorazepam is slowly titrated to 4 mg IM every 8 hours. On hospital Day 20, his functioning reaches a plateau; Mr. R’s cognition continues to fluctuate with periods of unresponsiveness, immobility, and incontinence.

The treatment team obtains consent from the family to begin ECT. On hospital Day 24, bilateral transtemporal ECT is initiated and continued 3 times a week. Mr. R tolerates the procedure without complications. After the first treatment, he demonstrates spontaneous speech for the first time since admission. He continues to improve overall but has a variable clinical course.

By Day 30, Mr. R can state the day, month, year, and that he is in the “psych” unit. He remembers being on the unit for a long time and says that he had been attempting to talk but “it wasn’t coming out.” When further questioned about substance use, he admits to using Spice for the month before admission and marijuana regularly over several years. He denies using other illicit drugs or alcohol.

Mr. R is started on olanzapine, 2.5 mg/d, titrated to 15 mg/d. He becomes increasingly interactive, although with occasional bouts of confusion, and regains bladder and bowel control. He receives a total of 12 ECT treatments. The family is adamant that Mr. R should not receive more ECT treatments, and is not interested in maintenance therapy. Mr. R’s father and grandmother visit and believe that he is back to baseline functioning. After 51 days of inpatient treatment, Mr. R is discharged on olanzapine, 15 mg/d, and oral lorazepam, 1 mg/d.

Nine days later, Mr. R is brought to the ER because of unresponsiveness, poor oral intake, refusal of medication, bowel and bladder incontinence, and inability to perform ADL. His father reports that he administered olanzapine but, because he only recognized the brand name of lorazepam, he did not get that prescription filled. Mr. R slowly decompensates and, by the time of readmission, refuses all medications.

Over the next few months, Mr. R is readmitted several times for similar symptoms. Again, the family states they do not want further ECT; the father believes that these treatments have caused his son’s condition. Complicating the matter is that the father had been out of his son’s life for an extended period and is unaccustomed to his son’s display of psychiatric symptoms.

The authors’ observations
The use of ECT for drug-induced psychosis is not well described in the literature because substance abuse is exclusionary in many trials. The safety and efficacy of ECT has been established for adolescents with first-episode psychosis¹⁴ and with catatonia.^15,16

The use of ECT in Spice-induced catatonia has been reported in 2 case studies.^17,18

Case 1. A 36-year-old man with schizophrenia and Cannabis dependence was admitted for auditory hallucinations, disorganization, paranoia, and manic symptoms, which progressed to catatonia.¹⁷ His symptoms were profound, including psychomotor retardation, rigidity, posturing, waxy flexibility, and inability to perform ADL.

The patient later reported that, 3 weeks prior, he had stopped taking his psychotropic medications and started smoking “K2,” a synthetic cannabinoid, because it was cheaper and easier to obtain than Cannabis. He had never experienced disturbances in motor function or speech in the past, even during episodes of Cannabis use and medication non-adherence.

After clozapine and benzodiazepine treatment (as high as 12 mg/d of lorazepam) did not resolve his symptoms, the patient received 6 bilateral ECT treatments over 16 days, with complete resolution of catatonic symptoms. He showed marked improvement, including resumption of speech after the first treatment, although he required an additional 20 days of inpatient care. As in our case, exposure to synthetic cannabinoids was self-reported; no confirmatory tests were performed.

Case 2. A 17-year-old male with no history of psychosis exhibited catatonic symptoms after smoking an estimated 2 to 3 g/d of K2 over 2 months.¹⁸ Similar to the case of Mr. R, he plateaued after lorazepam treatment, and then received 6 ECT treatments, which resulted in complete resolution of symptoms. He was discharged with olanzapine.

As our patient, and the 2 cases cited, show, ECT seems to be an effective option for Spice-induced catatonia. Unlike those published cases, however, our patient achieved only brief resolution of symptoms after an acute course of ECT. There appears to be a subset of patients who require maintenance ECT or prolonged benzodiazepine therapy after Spice-induced catatonia.

Patients who have chronic pain and those with a major depressive disorder (MDD) share clinical features, including fatigue, cognitive complaints, and functional limitation. Sleep disturbance and anxiety are common with both disorders. Because pain and depression share common neurobiological pathways (see Part 1 of this article in the February 2016 issue and at CurrentPsychiatry.com) and clinical manifestations, you can use similar strategies and, often, the same agents to treat both conditions when they occur together (Table 1).

What are the medical options?
Antidepressants. Using an antidepressant to treat chronic pain is a common practice in primary care and specialty practice. Antidepressants that modulate multiple neurotransmitters appear to be more efficacious than those with a single mechanism of action.¹ Convergent evidence from preclinical and clinical studies supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) as more effective analgesic agents, compared with the mostly noradrenergic antidepressants, which, in turn, are more effective than selective serotonin reuptake inhibitors (SSRIs).² The mechanism of the analgesic action of antidepressants appears to rely on their inhibitory effects of norepinephrine and serotonin reuptake, thereby elevating the performance of endogenous descending pain regulatory pathways.³

Tricyclic antidepressants (TCAs), primarily amitriptyline, nortriptyline, and desipramine, have the advantage of years of clinical experience and low cost. Their side effect burden, however, is higher, especially in geriatric patients. Dose-dependent side effects include sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension.

TCAs must be used with caution in patients with suicidal ideation because of the risk of a potentially lethal intentional overdose.

The key to using a TCA is to start with a low dosage, followed by slow titration. Typically, the dosages of TCAs used in clinical trials that focused on pain have been lower (25 to 100 mg/d of amitriptyline or equivalent) than the dosage typically necessary for treating depression; however, some experts have found that titrating TCAs to higher dosages with an option of monitoring serum levels may benefit some patients.⁴

SNRIs are considered first-line agents for both neuropathic pain and fibromyalgia. Duloxetine has been shown to be effective in both conditions⁵; venlafaxine also has shown efficacy in neuropathic pain.⁶ Milnacipran, another SNRI that blocks 5-HT, and norepinephrine equally and exerts a mild N-methyl-D-aspartate inhibition, has proven efficacy in fibromyalgia.^7,8

SSRIs for alleviating central pain or neuropathic pain are supported by minimal evidence only.⁹ A review of the effectiveness of various antidepressants on pain in diabetic neuropathy concluded that fluoxetine was no more effective than placebo.^10,11 Schreiber and Pick¹¹ evaluated the antinociceptive properties of several SSRIs and offered the opinion that fluoxetine, fluvoxamine, and citalopram were, at best, weak antinociceptors.

Opioids. Data on the long-term benefits of opioids are limited, except for use in carefully selected patients; in any case, risk of abuse, diversion, and even death with these agents is quite high.¹² Also, there is evidence that opioid-induced hyperalgesia might limit the usefulness of opioids for controlling chronic pain.¹³

Gabapentin and pregabalin, both anticonvulsants, act by binding to the α-2-σ subunit of voltage-gated calcium channels within the CNS.¹⁴ By reducing calcium influx at nerve terminals, the drugs diminish the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. This mechanism is thought to be the basis for the analgesic, anticonvulsant, and anxiolytic effects of these drugs.¹⁵

Gabapentin and pregabalin have been shown to decrease pain intensity and improve quality of life and function in patients with neuropathic pain conditions. Pregabalin also has shown efficacy in treating central neuropathic pain and fibromyalgia.¹⁶

Added benefits of these drugs is that they have (1) a better side effect profile than TCAs and (2) fewer drug interactions when they are used as a component of combination therapy. Pregabalin has the additional advantage of less-frequent dosing, linear pharmacokinetics, and a predictable dose-response relationship.¹⁷

Addressing other comorbid psychiatric conditions
Sleep disturbance is common among patients with chronic pain. Sleep deprivation causes a hyperexcitable state that amplifies the pain response.¹⁸

When a patient presents with chronic pain, depression, and disturbed sleep, consider using a sedating antidepressant, such as a TCA. Alternatively, gabapentin or pregabalin can be added to an SNRI; anticonvulsants have been shown to improve quality of sleep.¹⁹ Cognitive-behavioral interventions targeting sleep disturbance may be a helpful adjunct in these patients.²⁰

When anxiety is comorbid with chronic pain, antidepressants with proven efficacy in treating anxiety disorders, such as duloxetine or venlafaxine, can be used. When chronic pain coexists with a specific anxiety disorder (social anxiety disorder, obsessive-compulsive disorder, panic disorder), an SSRI might be more advantageous than an SNRI,²¹ especially if it is combined with a more efficacious analgesic.

Benzodiazepines should be avoided as a routine treatment for comorbid anxiety and pain, because these agents can produce sedation and cognitive interference, and carry the potential for dependence.

Fatigue. In patients who, in addition to pain and depression, complain of fatigue, an activating agent such as milnacipran or adjunct bupropion might be preferable to other agents. Modafinil has been shown to be a well-tolerated and potentially effective augmenting agent for antidepressants when fatigue and sleepiness are present as residual symptoms²²; consider them as adjuncts when managing patients who have chronic pain and depression that manifests as excessive sleepiness and/or fatigue.

Cognitive complaints. We have noted that disturbances of cognition are common in patients with depression and chronic pain, and that cognitive dysfunction might improve after antidepressant treatment.

Studies suggest that SSRIs, duloxetine, and other antidepressants, such as bupropion, might exert a positive effect on learning, memory, and executive function in depressed patients.²³ Beneficial effects of antidepressants may be “pseudo-specific,” however—that is, predominantly a reflection of overall improvement in mood, not on specific amelioration of the cognitive disturbance.

Vortioxetine has shown promise in improving cognitive function in adults with MDD; its cognitive benefits are largely independent of its antidepressant effect.²⁴ The utility of vortioxetine in chronic pain patients has not been studied, but its positive impact on mood, anxiety, sleep, and cognition might make it a consideration for patients with comorbid depression—although it is uncertain at this time whether putative noradrenergic activity makes it suitable for use in chronic pain disorders.

Last, avoid TCAs in patients who have cognitive complaints. These agents have anticholinergic effects that can have an adverse impact on cognitive function.

Cautions: Drug−drug interactions, suicide risk, disrupted sleep
Avoiding drug−drug interactions is an important consideration when treating comorbid disorders. Many chronic pain patients take over-the-counter or prescribed nonsteroidal anti-inflammatory drugs for analgesia; these agents can increase the risk of gastrointestinal bleeding when they are combined with an SSRI or an SNRI.

The use of the opioid tramadol with an SNRI or a TCA is discouraged because of the risk of serotonin syndrome.

Combining a sedating antidepressant, such as a TCA, with gabapentin or pregabalin can increase the risk of CNS depression and psychomotor impairment, especially in geriatric patients. An opioid analgesic is likely to amplify these effects.

Suicidal ideation is not uncommon in patients with chronic pain and depression. To minimize the risk of suicide in patients with a chronic pain disorder, you should ensure optimal pain control by combining the most efficacious analgesic agent with psychotherapeutic interventions and optimal antidepressant treatment. Furthermore, cognitive-behavioral therapy (CBT) (see the discussion below) might not only improve pain coping skills, but also ameliorate catastrophizing, anxiety, and concomitant sleep disturbance.

Complaints of sleep disturbance and anxiety can compound the risk of suicide in a chronic pain patient. When possible, these complex patients should be treated by a multidisciplinary team that includes a pain management specialist, psychotherapist, and primary care clinician. It is important to strengthen the clinician−patient relationship to facilitate close monitoring of symptoms and to provide a trusting environment in which patients feel free to discuss thoughts of suicide or self-harm. For such patients, prescribing opiates and TCAs in small quantities is a prudent action.

When a patient struggles with suicidal thoughts, his (her) family might need to dispense these medications. Most important, if a patient is actively suicidal, consider referral to an inpatient facility or intensive outpatient program, where aggressive treatment of depressive symptoms and intensive monitoring and support can be provided.²⁵

Usefulness of non-drug interventions
There is, of course, a diversity of non-drug treatments for MDD and for chronic pain; discussion here focuses primarily on modalities with established efficacy in both disease states (Table 2). On rare occasions, non-drug treatments can constitute a stand-alone approach; most often, they are incorporated into a multimodal treatment plan or applied as an adjunct intervention.²⁶

Psychotherapy. The most robust evidence supports the use of CBT in addressing MDD and chronic pain—occurring individually and comorbidly.^26-28 Efficacy is well established in MDD, as monotherapy and adjunct treatment, spanning acute and maintenance phases.

Furthermore, CBT also has support from randomized trials, meta-analyses, and treatment guidelines, either as monotherapy or co-therapy for both short-term relief and long-term pain reduction. Additionally, CBT has demonstrated value for relieving pain-related disability.^26,28

Combination of a special form of CBT, rumination-focused CBT with ongoing pharmacological therapy over a 26-week period in a group of medication-refractory MDD patients produced a remission rate of 62%, compared with 21% in a treatment-as-usual group.²⁹ This is of particular interest in chronic pain patients, because rumination-related phenomena of pain catastrophizing and avoidance facilitate a transition from acute to chronic pain, while augmenting pain severity and associated disability.³⁰

Catastrophizing also has been implicated in mediating the relationship between pain and sleep disturbance. Not surprisingly, a randomized controlled study demonstrated the benefit of 8-week, Internet-delivered CBT in patients suffering from comorbid chronic pain, depression, and anxiety. Treatment significantly diminished pain catastrophizing, depression, and anxiety; maintenance of improvement was demonstrated after 1 year of follow-up.³¹

Other behavioral and psychological approaches. Biofeedback, mindfulness-based stress reduction, relaxation training and diaphragmatic breathing, guided imagery, hypnosis, and supportive groups might play an important role as components of an integrated mind−body approach to chronic pain,^28,32,33 while also providing mood benefits.

Exercise. The role of exercise as a primary treatment of MDD continues to be controversial, but its benefits as an add-on intervention are indisputable. Exercise not only complements pharmacotherapy to produce greater reduction in depressive scores and improvement in quality of life, it might aid in reestablishing social contacts when conducted in a group setting—an effect that can be of great value in both MDD and chronic pain.³⁴

Exercise and restorative therapies provide several benefits for chronic pain patients, including:

• improved pain control, cognition, and mood
• greater strength and endurance
• cardiovascular and metabolic benefits
• improved bone health and functionality.^{26,28,32,33,35}

To achieve optimal benefit, an exercise program must be customized to fit the patient’s physical condition, level of fitness, and specific type of pain.³⁵ Preliminary evidence suggests that, beyond improvement in pain and functionality, exercise might reduce depressive symptoms in chronic pain patients.³⁶

Patients who have chronic pain and those with a major depressive disorder (MDD) share clinical features, including fatigue, cognitive complaints, and functional limitation. Sleep disturbance and anxiety are common with both disorders. Because pain and depression share common neurobiological pathways (see Part 1 of this article in the February 2016 issue and at CurrentPsychiatry.com) and clinical manifestations, you can use similar strategies and, often, the same agents to treat both conditions when they occur together (Table 1).

What are the medical options?
Antidepressants. Using an antidepressant to treat chronic pain is a common practice in primary care and specialty practice. Antidepressants that modulate multiple neurotransmitters appear to be more efficacious than those with a single mechanism of action.¹ Convergent evidence from preclinical and clinical studies supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) as more effective analgesic agents, compared with the mostly noradrenergic antidepressants, which, in turn, are more effective than selective serotonin reuptake inhibitors (SSRIs).² The mechanism of the analgesic action of antidepressants appears to rely on their inhibitory effects of norepinephrine and serotonin reuptake, thereby elevating the performance of endogenous descending pain regulatory pathways.³

Tricyclic antidepressants (TCAs), primarily amitriptyline, nortriptyline, and desipramine, have the advantage of years of clinical experience and low cost. Their side effect burden, however, is higher, especially in geriatric patients. Dose-dependent side effects include sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension.

TCAs must be used with caution in patients with suicidal ideation because of the risk of a potentially lethal intentional overdose.

The key to using a TCA is to start with a low dosage, followed by slow titration. Typically, the dosages of TCAs used in clinical trials that focused on pain have been lower (25 to 100 mg/d of amitriptyline or equivalent) than the dosage typically necessary for treating depression; however, some experts have found that titrating TCAs to higher dosages with an option of monitoring serum levels may benefit some patients.⁴

SNRIs are considered first-line agents for both neuropathic pain and fibromyalgia. Duloxetine has been shown to be effective in both conditions⁵; venlafaxine also has shown efficacy in neuropathic pain.⁶ Milnacipran, another SNRI that blocks 5-HT, and norepinephrine equally and exerts a mild N-methyl-D-aspartate inhibition, has proven efficacy in fibromyalgia.^7,8

SSRIs for alleviating central pain or neuropathic pain are supported by minimal evidence only.⁹ A review of the effectiveness of various antidepressants on pain in diabetic neuropathy concluded that fluoxetine was no more effective than placebo.^10,11 Schreiber and Pick¹¹ evaluated the antinociceptive properties of several SSRIs and offered the opinion that fluoxetine, fluvoxamine, and citalopram were, at best, weak antinociceptors.

Opioids. Data on the long-term benefits of opioids are limited, except for use in carefully selected patients; in any case, risk of abuse, diversion, and even death with these agents is quite high.¹² Also, there is evidence that opioid-induced hyperalgesia might limit the usefulness of opioids for controlling chronic pain.¹³

Gabapentin and pregabalin, both anticonvulsants, act by binding to the α-2-σ subunit of voltage-gated calcium channels within the CNS.¹⁴ By reducing calcium influx at nerve terminals, the drugs diminish the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. This mechanism is thought to be the basis for the analgesic, anticonvulsant, and anxiolytic effects of these drugs.¹⁵

Gabapentin and pregabalin have been shown to decrease pain intensity and improve quality of life and function in patients with neuropathic pain conditions. Pregabalin also has shown efficacy in treating central neuropathic pain and fibromyalgia.¹⁶

Added benefits of these drugs is that they have (1) a better side effect profile than TCAs and (2) fewer drug interactions when they are used as a component of combination therapy. Pregabalin has the additional advantage of less-frequent dosing, linear pharmacokinetics, and a predictable dose-response relationship.¹⁷

Addressing other comorbid psychiatric conditions
Sleep disturbance is common among patients with chronic pain. Sleep deprivation causes a hyperexcitable state that amplifies the pain response.¹⁸

When a patient presents with chronic pain, depression, and disturbed sleep, consider using a sedating antidepressant, such as a TCA. Alternatively, gabapentin or pregabalin can be added to an SNRI; anticonvulsants have been shown to improve quality of sleep.¹⁹ Cognitive-behavioral interventions targeting sleep disturbance may be a helpful adjunct in these patients.²⁰

When anxiety is comorbid with chronic pain, antidepressants with proven efficacy in treating anxiety disorders, such as duloxetine or venlafaxine, can be used. When chronic pain coexists with a specific anxiety disorder (social anxiety disorder, obsessive-compulsive disorder, panic disorder), an SSRI might be more advantageous than an SNRI,²¹ especially if it is combined with a more efficacious analgesic.

Benzodiazepines should be avoided as a routine treatment for comorbid anxiety and pain, because these agents can produce sedation and cognitive interference, and carry the potential for dependence.

Fatigue. In patients who, in addition to pain and depression, complain of fatigue, an activating agent such as milnacipran or adjunct bupropion might be preferable to other agents. Modafinil has been shown to be a well-tolerated and potentially effective augmenting agent for antidepressants when fatigue and sleepiness are present as residual symptoms²²; consider them as adjuncts when managing patients who have chronic pain and depression that manifests as excessive sleepiness and/or fatigue.

Cognitive complaints. We have noted that disturbances of cognition are common in patients with depression and chronic pain, and that cognitive dysfunction might improve after antidepressant treatment.

Studies suggest that SSRIs, duloxetine, and other antidepressants, such as bupropion, might exert a positive effect on learning, memory, and executive function in depressed patients.²³ Beneficial effects of antidepressants may be “pseudo-specific,” however—that is, predominantly a reflection of overall improvement in mood, not on specific amelioration of the cognitive disturbance.

Vortioxetine has shown promise in improving cognitive function in adults with MDD; its cognitive benefits are largely independent of its antidepressant effect.²⁴ The utility of vortioxetine in chronic pain patients has not been studied, but its positive impact on mood, anxiety, sleep, and cognition might make it a consideration for patients with comorbid depression—although it is uncertain at this time whether putative noradrenergic activity makes it suitable for use in chronic pain disorders.

Last, avoid TCAs in patients who have cognitive complaints. These agents have anticholinergic effects that can have an adverse impact on cognitive function.

Cautions: Drug−drug interactions, suicide risk, disrupted sleep
Avoiding drug−drug interactions is an important consideration when treating comorbid disorders. Many chronic pain patients take over-the-counter or prescribed nonsteroidal anti-inflammatory drugs for analgesia; these agents can increase the risk of gastrointestinal bleeding when they are combined with an SSRI or an SNRI.

The use of the opioid tramadol with an SNRI or a TCA is discouraged because of the risk of serotonin syndrome.

Combining a sedating antidepressant, such as a TCA, with gabapentin or pregabalin can increase the risk of CNS depression and psychomotor impairment, especially in geriatric patients. An opioid analgesic is likely to amplify these effects.

Suicidal ideation is not uncommon in patients with chronic pain and depression. To minimize the risk of suicide in patients with a chronic pain disorder, you should ensure optimal pain control by combining the most efficacious analgesic agent with psychotherapeutic interventions and optimal antidepressant treatment. Furthermore, cognitive-behavioral therapy (CBT) (see the discussion below) might not only improve pain coping skills, but also ameliorate catastrophizing, anxiety, and concomitant sleep disturbance.

Complaints of sleep disturbance and anxiety can compound the risk of suicide in a chronic pain patient. When possible, these complex patients should be treated by a multidisciplinary team that includes a pain management specialist, psychotherapist, and primary care clinician. It is important to strengthen the clinician−patient relationship to facilitate close monitoring of symptoms and to provide a trusting environment in which patients feel free to discuss thoughts of suicide or self-harm. For such patients, prescribing opiates and TCAs in small quantities is a prudent action.

When a patient struggles with suicidal thoughts, his (her) family might need to dispense these medications. Most important, if a patient is actively suicidal, consider referral to an inpatient facility or intensive outpatient program, where aggressive treatment of depressive symptoms and intensive monitoring and support can be provided.²⁵

Usefulness of non-drug interventions
There is, of course, a diversity of non-drug treatments for MDD and for chronic pain; discussion here focuses primarily on modalities with established efficacy in both disease states (Table 2). On rare occasions, non-drug treatments can constitute a stand-alone approach; most often, they are incorporated into a multimodal treatment plan or applied as an adjunct intervention.²⁶

Psychotherapy. The most robust evidence supports the use of CBT in addressing MDD and chronic pain—occurring individually and comorbidly.^26-28 Efficacy is well established in MDD, as monotherapy and adjunct treatment, spanning acute and maintenance phases.

Furthermore, CBT also has support from randomized trials, meta-analyses, and treatment guidelines, either as monotherapy or co-therapy for both short-term relief and long-term pain reduction. Additionally, CBT has demonstrated value for relieving pain-related disability.^26,28

Combination of a special form of CBT, rumination-focused CBT with ongoing pharmacological therapy over a 26-week period in a group of medication-refractory MDD patients produced a remission rate of 62%, compared with 21% in a treatment-as-usual group.²⁹ This is of particular interest in chronic pain patients, because rumination-related phenomena of pain catastrophizing and avoidance facilitate a transition from acute to chronic pain, while augmenting pain severity and associated disability.³⁰

Catastrophizing also has been implicated in mediating the relationship between pain and sleep disturbance. Not surprisingly, a randomized controlled study demonstrated the benefit of 8-week, Internet-delivered CBT in patients suffering from comorbid chronic pain, depression, and anxiety. Treatment significantly diminished pain catastrophizing, depression, and anxiety; maintenance of improvement was demonstrated after 1 year of follow-up.³¹

Other behavioral and psychological approaches. Biofeedback, mindfulness-based stress reduction, relaxation training and diaphragmatic breathing, guided imagery, hypnosis, and supportive groups might play an important role as components of an integrated mind−body approach to chronic pain,^28,32,33 while also providing mood benefits.

Exercise. The role of exercise as a primary treatment of MDD continues to be controversial, but its benefits as an add-on intervention are indisputable. Exercise not only complements pharmacotherapy to produce greater reduction in depressive scores and improvement in quality of life, it might aid in reestablishing social contacts when conducted in a group setting—an effect that can be of great value in both MDD and chronic pain.³⁴

Exercise and restorative therapies provide several benefits for chronic pain patients, including:

• improved pain control, cognition, and mood
• greater strength and endurance
• cardiovascular and metabolic benefits
• improved bone health and functionality.^{26,28,32,33,35}

To achieve optimal benefit, an exercise program must be customized to fit the patient’s physical condition, level of fitness, and specific type of pain.³⁵ Preliminary evidence suggests that, beyond improvement in pain and functionality, exercise might reduce depressive symptoms in chronic pain patients.³⁶

Patients who have chronic pain and those with a major depressive disorder (MDD) share clinical features, including fatigue, cognitive complaints, and functional limitation. Sleep disturbance and anxiety are common with both disorders. Because pain and depression share common neurobiological pathways (see Part 1 of this article in the February 2016 issue and at CurrentPsychiatry.com) and clinical manifestations, you can use similar strategies and, often, the same agents to treat both conditions when they occur together (Table 1).

What are the medical options?
Antidepressants. Using an antidepressant to treat chronic pain is a common practice in primary care and specialty practice. Antidepressants that modulate multiple neurotransmitters appear to be more efficacious than those with a single mechanism of action.¹ Convergent evidence from preclinical and clinical studies supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) as more effective analgesic agents, compared with the mostly noradrenergic antidepressants, which, in turn, are more effective than selective serotonin reuptake inhibitors (SSRIs).² The mechanism of the analgesic action of antidepressants appears to rely on their inhibitory effects of norepinephrine and serotonin reuptake, thereby elevating the performance of endogenous descending pain regulatory pathways.³

Tricyclic antidepressants (TCAs), primarily amitriptyline, nortriptyline, and desipramine, have the advantage of years of clinical experience and low cost. Their side effect burden, however, is higher, especially in geriatric patients. Dose-dependent side effects include sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension.

TCAs must be used with caution in patients with suicidal ideation because of the risk of a potentially lethal intentional overdose.

The key to using a TCA is to start with a low dosage, followed by slow titration. Typically, the dosages of TCAs used in clinical trials that focused on pain have been lower (25 to 100 mg/d of amitriptyline or equivalent) than the dosage typically necessary for treating depression; however, some experts have found that titrating TCAs to higher dosages with an option of monitoring serum levels may benefit some patients.⁴

SNRIs are considered first-line agents for both neuropathic pain and fibromyalgia. Duloxetine has been shown to be effective in both conditions⁵; venlafaxine also has shown efficacy in neuropathic pain.⁶ Milnacipran, another SNRI that blocks 5-HT, and norepinephrine equally and exerts a mild N-methyl-D-aspartate inhibition, has proven efficacy in fibromyalgia.^7,8

SSRIs for alleviating central pain or neuropathic pain are supported by minimal evidence only.⁹ A review of the effectiveness of various antidepressants on pain in diabetic neuropathy concluded that fluoxetine was no more effective than placebo.^10,11 Schreiber and Pick¹¹ evaluated the antinociceptive properties of several SSRIs and offered the opinion that fluoxetine, fluvoxamine, and citalopram were, at best, weak antinociceptors.

Opioids. Data on the long-term benefits of opioids are limited, except for use in carefully selected patients; in any case, risk of abuse, diversion, and even death with these agents is quite high.¹² Also, there is evidence that opioid-induced hyperalgesia might limit the usefulness of opioids for controlling chronic pain.¹³

Gabapentin and pregabalin, both anticonvulsants, act by binding to the α-2-σ subunit of voltage-gated calcium channels within the CNS.¹⁴ By reducing calcium influx at nerve terminals, the drugs diminish the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. This mechanism is thought to be the basis for the analgesic, anticonvulsant, and anxiolytic effects of these drugs.¹⁵

Gabapentin and pregabalin have been shown to decrease pain intensity and improve quality of life and function in patients with neuropathic pain conditions. Pregabalin also has shown efficacy in treating central neuropathic pain and fibromyalgia.¹⁶

Added benefits of these drugs is that they have (1) a better side effect profile than TCAs and (2) fewer drug interactions when they are used as a component of combination therapy. Pregabalin has the additional advantage of less-frequent dosing, linear pharmacokinetics, and a predictable dose-response relationship.¹⁷

Addressing other comorbid psychiatric conditions
Sleep disturbance is common among patients with chronic pain. Sleep deprivation causes a hyperexcitable state that amplifies the pain response.¹⁸

When a patient presents with chronic pain, depression, and disturbed sleep, consider using a sedating antidepressant, such as a TCA. Alternatively, gabapentin or pregabalin can be added to an SNRI; anticonvulsants have been shown to improve quality of sleep.¹⁹ Cognitive-behavioral interventions targeting sleep disturbance may be a helpful adjunct in these patients.²⁰

When anxiety is comorbid with chronic pain, antidepressants with proven efficacy in treating anxiety disorders, such as duloxetine or venlafaxine, can be used. When chronic pain coexists with a specific anxiety disorder (social anxiety disorder, obsessive-compulsive disorder, panic disorder), an SSRI might be more advantageous than an SNRI,²¹ especially if it is combined with a more efficacious analgesic.

Benzodiazepines should be avoided as a routine treatment for comorbid anxiety and pain, because these agents can produce sedation and cognitive interference, and carry the potential for dependence.

Fatigue. In patients who, in addition to pain and depression, complain of fatigue, an activating agent such as milnacipran or adjunct bupropion might be preferable to other agents. Modafinil has been shown to be a well-tolerated and potentially effective augmenting agent for antidepressants when fatigue and sleepiness are present as residual symptoms²²; consider them as adjuncts when managing patients who have chronic pain and depression that manifests as excessive sleepiness and/or fatigue.

Cognitive complaints. We have noted that disturbances of cognition are common in patients with depression and chronic pain, and that cognitive dysfunction might improve after antidepressant treatment.

Studies suggest that SSRIs, duloxetine, and other antidepressants, such as bupropion, might exert a positive effect on learning, memory, and executive function in depressed patients.²³ Beneficial effects of antidepressants may be “pseudo-specific,” however—that is, predominantly a reflection of overall improvement in mood, not on specific amelioration of the cognitive disturbance.

Vortioxetine has shown promise in improving cognitive function in adults with MDD; its cognitive benefits are largely independent of its antidepressant effect.²⁴ The utility of vortioxetine in chronic pain patients has not been studied, but its positive impact on mood, anxiety, sleep, and cognition might make it a consideration for patients with comorbid depression—although it is uncertain at this time whether putative noradrenergic activity makes it suitable for use in chronic pain disorders.

Last, avoid TCAs in patients who have cognitive complaints. These agents have anticholinergic effects that can have an adverse impact on cognitive function.

Cautions: Drug−drug interactions, suicide risk, disrupted sleep
Avoiding drug−drug interactions is an important consideration when treating comorbid disorders. Many chronic pain patients take over-the-counter or prescribed nonsteroidal anti-inflammatory drugs for analgesia; these agents can increase the risk of gastrointestinal bleeding when they are combined with an SSRI or an SNRI.

The use of the opioid tramadol with an SNRI or a TCA is discouraged because of the risk of serotonin syndrome.

Combining a sedating antidepressant, such as a TCA, with gabapentin or pregabalin can increase the risk of CNS depression and psychomotor impairment, especially in geriatric patients. An opioid analgesic is likely to amplify these effects.

Suicidal ideation is not uncommon in patients with chronic pain and depression. To minimize the risk of suicide in patients with a chronic pain disorder, you should ensure optimal pain control by combining the most efficacious analgesic agent with psychotherapeutic interventions and optimal antidepressant treatment. Furthermore, cognitive-behavioral therapy (CBT) (see the discussion below) might not only improve pain coping skills, but also ameliorate catastrophizing, anxiety, and concomitant sleep disturbance.

Complaints of sleep disturbance and anxiety can compound the risk of suicide in a chronic pain patient. When possible, these complex patients should be treated by a multidisciplinary team that includes a pain management specialist, psychotherapist, and primary care clinician. It is important to strengthen the clinician−patient relationship to facilitate close monitoring of symptoms and to provide a trusting environment in which patients feel free to discuss thoughts of suicide or self-harm. For such patients, prescribing opiates and TCAs in small quantities is a prudent action.

When a patient struggles with suicidal thoughts, his (her) family might need to dispense these medications. Most important, if a patient is actively suicidal, consider referral to an inpatient facility or intensive outpatient program, where aggressive treatment of depressive symptoms and intensive monitoring and support can be provided.²⁵

Usefulness of non-drug interventions
There is, of course, a diversity of non-drug treatments for MDD and for chronic pain; discussion here focuses primarily on modalities with established efficacy in both disease states (Table 2). On rare occasions, non-drug treatments can constitute a stand-alone approach; most often, they are incorporated into a multimodal treatment plan or applied as an adjunct intervention.²⁶

Psychotherapy. The most robust evidence supports the use of CBT in addressing MDD and chronic pain—occurring individually and comorbidly.^26-28 Efficacy is well established in MDD, as monotherapy and adjunct treatment, spanning acute and maintenance phases.

Furthermore, CBT also has support from randomized trials, meta-analyses, and treatment guidelines, either as monotherapy or co-therapy for both short-term relief and long-term pain reduction. Additionally, CBT has demonstrated value for relieving pain-related disability.^26,28

Combination of a special form of CBT, rumination-focused CBT with ongoing pharmacological therapy over a 26-week period in a group of medication-refractory MDD patients produced a remission rate of 62%, compared with 21% in a treatment-as-usual group.²⁹ This is of particular interest in chronic pain patients, because rumination-related phenomena of pain catastrophizing and avoidance facilitate a transition from acute to chronic pain, while augmenting pain severity and associated disability.³⁰

Catastrophizing also has been implicated in mediating the relationship between pain and sleep disturbance. Not surprisingly, a randomized controlled study demonstrated the benefit of 8-week, Internet-delivered CBT in patients suffering from comorbid chronic pain, depression, and anxiety. Treatment significantly diminished pain catastrophizing, depression, and anxiety; maintenance of improvement was demonstrated after 1 year of follow-up.³¹

Other behavioral and psychological approaches. Biofeedback, mindfulness-based stress reduction, relaxation training and diaphragmatic breathing, guided imagery, hypnosis, and supportive groups might play an important role as components of an integrated mind−body approach to chronic pain,^28,32,33 while also providing mood benefits.

Exercise. The role of exercise as a primary treatment of MDD continues to be controversial, but its benefits as an add-on intervention are indisputable. Exercise not only complements pharmacotherapy to produce greater reduction in depressive scores and improvement in quality of life, it might aid in reestablishing social contacts when conducted in a group setting—an effect that can be of great value in both MDD and chronic pain.³⁴

Exercise and restorative therapies provide several benefits for chronic pain patients, including:

• improved pain control, cognition, and mood
• greater strength and endurance
• cardiovascular and metabolic benefits
• improved bone health and functionality.^{26,28,32,33,35}

To achieve optimal benefit, an exercise program must be customized to fit the patient’s physical condition, level of fitness, and specific type of pain.³⁵ Preliminary evidence suggests that, beyond improvement in pain and functionality, exercise might reduce depressive symptoms in chronic pain patients.³⁶

The National Football League (NFL) had its highest concussion tally last year: 182 such injuries reported¹ in the 2014-2015 regular season. The true rate of concussion in the NFL is likely higher, as a result of multiple factors (fear of “letting the team [or the coach] down,” fear of retaliation from team owners,² etc.).

To simply call a head injury a “concussion” is a disservice to players and their family: Any blow to the head, severe or otherwise, has the potential to cause microvascular disruption in the brain; repeated blows to the head undoubtedly cause further damage.

In reality, a “concussion” is a mild traumatic brain injury (mTBI). With repeated blows, an mTBI can lead to chronic traumatic encephalopathy (CTE). In 2015, eighty-seven of 91 brains from autopsied former NFL players displayed some stage of CTE.³

Pathophysiology and presentation
CTE comprises 4 histological stages; Stage 4 is the most advanced. Alzheimer’s disease (AD) and CTE display similarities, which suggests a separate classification of CTE-AD; the presence of amyloid β plaques correlates with (1) more severe hyperphosphorylated tau (pTau) pathology and (2) advanced stages of the disease and clinical presentations. Death tends to occur 10 years earlier in CTE-AD than in AD, suggesting that repetitive mTBI might change the deposition and accumulation of amyloid β plaques, and even accelerate the aging process in the brain.⁴

Symptoms. The case series by Omalu et al⁴ (which inspired the 2015 motion picture Concussion) and the case series presented by McKee et al⁵ described severe psychiatric symptoms associated with CTE:

• decreased speed of information processing
• increase in religiosity
• lack of insight
• poor judgment
• involvement in illegal activities
• substance abuse
• indiscretion
• verbal and physical abuse
• problems with interpersonal relationships
• isolation
• restlessness and hyperactivity
• somatic complaints.

The 2 groups of researchers also noted hopelessness, social phobia, anxiety, agitation, mania, labile mood, insomnia, explosivity, and suicidal ideation, attempt, and completion.^4,5

By Stage 4, all affected patients are symptomatic. Cognitive impairment is severe; many are described as having “severe memory loss with dementia,”⁵ “profound” inattention and loss of concentration,⁵ and dysarthria. Paranoia may develop. Mood symptoms can be severe: Approximately 31% of subjects studied have contemplated suicide; of those, 26% had “suicidal tendencies” and 14% completed suicide.⁵

Two distinct types of CTE progression are apparent:

• patients who display cognitive deficits first; they progress to dementia but live longer
• patients who display mood and behavioral symptoms first; they tend to be younger, more violent, depressed, and explosive.⁶

CTE cannot be diagnosed with imaging. There are, however, a few positron emission tomography (PET) ligands for pTau that show promise:

• [F-18]FDDNP, which consistently identifies pTau deposits in brains in which CTE is clinically suspected, in the same distribution of pTau neurofibrillary tangles on autopsy.
• [11C]DPA-713, which detected TBI-related inflammation of neurons in 9 former NFL players in whom CTE was suspected based on the clinical presentation.
• PiB amyloid ligand, under investigation for use in PET neuroimaging.⁷

Casualties
In January 2016 alone, at least 3 former NFL players were found to have CTE posthumously.

Earl Morrall. Former quarterback who had a 21-year NFL career. Official cause of death in 2014 at age 79 was recorded as “complications of Parkinson’s disease.” In 2016, Stage-4 CTE was discovered on autopsy.⁸

Ken Stabler. Former quarterback for several NFL teams over 15 seasons. Died of colon cancer at age 69 in 2015. On autopsy, was found to have Stage-3 CTE.⁹

Tyler Sash. Former University of Iowa and New York Giants football player. Died in September 2015 at age 27 of an apparent drug overdose; post­humously, determined to have Stage-2 CTE. His family reported memory loss, minor fits of rage, confusion, inattention, lack of focus, and chronic pain.

Sash’s mother said, “My son knew something was wrong, but he couldn’t express it. He was such a good person, and it’s sad that he struggled so with this—not knowing where to go with it. Now it makes sense.”¹⁰ Sash played 16 years of football in all, sustaining at least 5 concussions. (“If you’ve played football, you know there are often other incidents [of head trauma],” Sash’s father said.¹⁰)

Cultural and medical mindsets about contact sports
In the United States, children as young as age 5, with a low weight limit of 35 pounds, routinely are introduced to football.¹¹ Reports of 5 high school players dying from football-related injury in the 2014 season, and 3 deaths in the 2015 season, led a St. Louis, Missouri, area school district to defund their football program entirely. The district’s 2015 homecoming game was a soccer match; students and parents seemed to embrace the change.¹²

On its face, soccer seems a good alternative to football. When children are instructed to “head” the ball, however, concern arises about CTE: Mild CTE changes have been reported in 2 young soccer players, and late-stage CTE changes were seen in a retired soccer player with dementia.¹³

Perhaps most disturbing is that players who develop symptoms of CTE, or are at risk, are unlikely to seek psychiatric help. We, as psychiatric clinicians, must be diligent about questioning young patients about their extracurricular activities. It is not enough to simply ask about a history of head trauma: Ask patients about any blow to the head, and don’t limit your questioning to whether they sustained a “concussion” during practice or play.

When speaking with adult and geriatric patients, ask about a history of playing interscholastic or collegiate contact sports, such as football, hockey, and soccer.

Is the solution to better shield the head?
That is not a solution: Helmets and other protective headgear appear to be insufficient to protect the brain from traumatic injury. Perhaps keeping children from engaging in violent sports that put them at high risk of CTE later is the preventive approach that merits the most attention.

The National Football League (NFL) had its highest concussion tally last year: 182 such injuries reported¹ in the 2014-2015 regular season. The true rate of concussion in the NFL is likely higher, as a result of multiple factors (fear of “letting the team [or the coach] down,” fear of retaliation from team owners,² etc.).

To simply call a head injury a “concussion” is a disservice to players and their family: Any blow to the head, severe or otherwise, has the potential to cause microvascular disruption in the brain; repeated blows to the head undoubtedly cause further damage.

In reality, a “concussion” is a mild traumatic brain injury (mTBI). With repeated blows, an mTBI can lead to chronic traumatic encephalopathy (CTE). In 2015, eighty-seven of 91 brains from autopsied former NFL players displayed some stage of CTE.³

Pathophysiology and presentation
CTE comprises 4 histological stages; Stage 4 is the most advanced. Alzheimer’s disease (AD) and CTE display similarities, which suggests a separate classification of CTE-AD; the presence of amyloid β plaques correlates with (1) more severe hyperphosphorylated tau (pTau) pathology and (2) advanced stages of the disease and clinical presentations. Death tends to occur 10 years earlier in CTE-AD than in AD, suggesting that repetitive mTBI might change the deposition and accumulation of amyloid β plaques, and even accelerate the aging process in the brain.⁴

Symptoms. The case series by Omalu et al⁴ (which inspired the 2015 motion picture Concussion) and the case series presented by McKee et al⁵ described severe psychiatric symptoms associated with CTE:

• decreased speed of information processing
• increase in religiosity
• lack of insight
• poor judgment
• involvement in illegal activities
• substance abuse
• indiscretion
• verbal and physical abuse
• problems with interpersonal relationships
• isolation
• restlessness and hyperactivity
• somatic complaints.

The 2 groups of researchers also noted hopelessness, social phobia, anxiety, agitation, mania, labile mood, insomnia, explosivity, and suicidal ideation, attempt, and completion.^4,5

By Stage 4, all affected patients are symptomatic. Cognitive impairment is severe; many are described as having “severe memory loss with dementia,”⁵ “profound” inattention and loss of concentration,⁵ and dysarthria. Paranoia may develop. Mood symptoms can be severe: Approximately 31% of subjects studied have contemplated suicide; of those, 26% had “suicidal tendencies” and 14% completed suicide.⁵

Two distinct types of CTE progression are apparent:

• patients who display cognitive deficits first; they progress to dementia but live longer
• patients who display mood and behavioral symptoms first; they tend to be younger, more violent, depressed, and explosive.⁶

CTE cannot be diagnosed with imaging. There are, however, a few positron emission tomography (PET) ligands for pTau that show promise:

• [F-18]FDDNP, which consistently identifies pTau deposits in brains in which CTE is clinically suspected, in the same distribution of pTau neurofibrillary tangles on autopsy.
• [11C]DPA-713, which detected TBI-related inflammation of neurons in 9 former NFL players in whom CTE was suspected based on the clinical presentation.
• PiB amyloid ligand, under investigation for use in PET neuroimaging.⁷

Casualties
In January 2016 alone, at least 3 former NFL players were found to have CTE posthumously.

Earl Morrall. Former quarterback who had a 21-year NFL career. Official cause of death in 2014 at age 79 was recorded as “complications of Parkinson’s disease.” In 2016, Stage-4 CTE was discovered on autopsy.⁸

Ken Stabler. Former quarterback for several NFL teams over 15 seasons. Died of colon cancer at age 69 in 2015. On autopsy, was found to have Stage-3 CTE.⁹

Tyler Sash. Former University of Iowa and New York Giants football player. Died in September 2015 at age 27 of an apparent drug overdose; post­humously, determined to have Stage-2 CTE. His family reported memory loss, minor fits of rage, confusion, inattention, lack of focus, and chronic pain.

Sash’s mother said, “My son knew something was wrong, but he couldn’t express it. He was such a good person, and it’s sad that he struggled so with this—not knowing where to go with it. Now it makes sense.”¹⁰ Sash played 16 years of football in all, sustaining at least 5 concussions. (“If you’ve played football, you know there are often other incidents [of head trauma],” Sash’s father said.¹⁰)

Cultural and medical mindsets about contact sports
In the United States, children as young as age 5, with a low weight limit of 35 pounds, routinely are introduced to football.¹¹ Reports of 5 high school players dying from football-related injury in the 2014 season, and 3 deaths in the 2015 season, led a St. Louis, Missouri, area school district to defund their football program entirely. The district’s 2015 homecoming game was a soccer match; students and parents seemed to embrace the change.¹²

On its face, soccer seems a good alternative to football. When children are instructed to “head” the ball, however, concern arises about CTE: Mild CTE changes have been reported in 2 young soccer players, and late-stage CTE changes were seen in a retired soccer player with dementia.¹³

Perhaps most disturbing is that players who develop symptoms of CTE, or are at risk, are unlikely to seek psychiatric help. We, as psychiatric clinicians, must be diligent about questioning young patients about their extracurricular activities. It is not enough to simply ask about a history of head trauma: Ask patients about any blow to the head, and don’t limit your questioning to whether they sustained a “concussion” during practice or play.

When speaking with adult and geriatric patients, ask about a history of playing interscholastic or collegiate contact sports, such as football, hockey, and soccer.

Is the solution to better shield the head?
That is not a solution: Helmets and other protective headgear appear to be insufficient to protect the brain from traumatic injury. Perhaps keeping children from engaging in violent sports that put them at high risk of CTE later is the preventive approach that merits the most attention.

The National Football League (NFL) had its highest concussion tally last year: 182 such injuries reported¹ in the 2014-2015 regular season. The true rate of concussion in the NFL is likely higher, as a result of multiple factors (fear of “letting the team [or the coach] down,” fear of retaliation from team owners,² etc.).

To simply call a head injury a “concussion” is a disservice to players and their family: Any blow to the head, severe or otherwise, has the potential to cause microvascular disruption in the brain; repeated blows to the head undoubtedly cause further damage.

In reality, a “concussion” is a mild traumatic brain injury (mTBI). With repeated blows, an mTBI can lead to chronic traumatic encephalopathy (CTE). In 2015, eighty-seven of 91 brains from autopsied former NFL players displayed some stage of CTE.³

Pathophysiology and presentation
CTE comprises 4 histological stages; Stage 4 is the most advanced. Alzheimer’s disease (AD) and CTE display similarities, which suggests a separate classification of CTE-AD; the presence of amyloid β plaques correlates with (1) more severe hyperphosphorylated tau (pTau) pathology and (2) advanced stages of the disease and clinical presentations. Death tends to occur 10 years earlier in CTE-AD than in AD, suggesting that repetitive mTBI might change the deposition and accumulation of amyloid β plaques, and even accelerate the aging process in the brain.⁴

Symptoms. The case series by Omalu et al⁴ (which inspired the 2015 motion picture Concussion) and the case series presented by McKee et al⁵ described severe psychiatric symptoms associated with CTE:

• decreased speed of information processing
• increase in religiosity
• lack of insight
• poor judgment
• involvement in illegal activities
• substance abuse
• indiscretion
• verbal and physical abuse
• problems with interpersonal relationships
• isolation
• restlessness and hyperactivity
• somatic complaints.

The 2 groups of researchers also noted hopelessness, social phobia, anxiety, agitation, mania, labile mood, insomnia, explosivity, and suicidal ideation, attempt, and completion.^4,5

By Stage 4, all affected patients are symptomatic. Cognitive impairment is severe; many are described as having “severe memory loss with dementia,”⁵ “profound” inattention and loss of concentration,⁵ and dysarthria. Paranoia may develop. Mood symptoms can be severe: Approximately 31% of subjects studied have contemplated suicide; of those, 26% had “suicidal tendencies” and 14% completed suicide.⁵

Two distinct types of CTE progression are apparent:

• patients who display cognitive deficits first; they progress to dementia but live longer
• patients who display mood and behavioral symptoms first; they tend to be younger, more violent, depressed, and explosive.⁶

CTE cannot be diagnosed with imaging. There are, however, a few positron emission tomography (PET) ligands for pTau that show promise:

• [F-18]FDDNP, which consistently identifies pTau deposits in brains in which CTE is clinically suspected, in the same distribution of pTau neurofibrillary tangles on autopsy.
• [11C]DPA-713, which detected TBI-related inflammation of neurons in 9 former NFL players in whom CTE was suspected based on the clinical presentation.
• PiB amyloid ligand, under investigation for use in PET neuroimaging.⁷

Casualties
In January 2016 alone, at least 3 former NFL players were found to have CTE posthumously.

Earl Morrall. Former quarterback who had a 21-year NFL career. Official cause of death in 2014 at age 79 was recorded as “complications of Parkinson’s disease.” In 2016, Stage-4 CTE was discovered on autopsy.⁸

Ken Stabler. Former quarterback for several NFL teams over 15 seasons. Died of colon cancer at age 69 in 2015. On autopsy, was found to have Stage-3 CTE.⁹

Tyler Sash. Former University of Iowa and New York Giants football player. Died in September 2015 at age 27 of an apparent drug overdose; post­humously, determined to have Stage-2 CTE. His family reported memory loss, minor fits of rage, confusion, inattention, lack of focus, and chronic pain.

Sash’s mother said, “My son knew something was wrong, but he couldn’t express it. He was such a good person, and it’s sad that he struggled so with this—not knowing where to go with it. Now it makes sense.”¹⁰ Sash played 16 years of football in all, sustaining at least 5 concussions. (“If you’ve played football, you know there are often other incidents [of head trauma],” Sash’s father said.¹⁰)

Cultural and medical mindsets about contact sports
In the United States, children as young as age 5, with a low weight limit of 35 pounds, routinely are introduced to football.¹¹ Reports of 5 high school players dying from football-related injury in the 2014 season, and 3 deaths in the 2015 season, led a St. Louis, Missouri, area school district to defund their football program entirely. The district’s 2015 homecoming game was a soccer match; students and parents seemed to embrace the change.¹²

On its face, soccer seems a good alternative to football. When children are instructed to “head” the ball, however, concern arises about CTE: Mild CTE changes have been reported in 2 young soccer players, and late-stage CTE changes were seen in a retired soccer player with dementia.¹³

Perhaps most disturbing is that players who develop symptoms of CTE, or are at risk, are unlikely to seek psychiatric help. We, as psychiatric clinicians, must be diligent about questioning young patients about their extracurricular activities. It is not enough to simply ask about a history of head trauma: Ask patients about any blow to the head, and don’t limit your questioning to whether they sustained a “concussion” during practice or play.

When speaking with adult and geriatric patients, ask about a history of playing interscholastic or collegiate contact sports, such as football, hockey, and soccer.

Is the solution to better shield the head?
That is not a solution: Helmets and other protective headgear appear to be insufficient to protect the brain from traumatic injury. Perhaps keeping children from engaging in violent sports that put them at high risk of CTE later is the preventive approach that merits the most attention.

Dear Dr. Mossman,

At the general hospital where I perform consultations, the medical service asked me to fill out psychiatric “hold” documents to keep a severely malnourished young woman with anorexia nervosa from leaving the hospital. Ms. Q, whose body mass index (BMI) was 12 (yes, 12), came to the hospital to have her “electrolytes fixed.” She was willing to stay the night for electrolyte repletion, but insisted she could gain weight on her own at home.

I’m worried that she might die without prompt inpatient treatment; she needs to stay on the medical service. Should I fill out a psychiatric hold to keep her there? What legal risks could I face if Ms. Q is detained and force-fed against her will? What are the legal risks of letting her leave the hospital before she is medically stable?

Submitted by “Dr. F”

When a severely malnourished patient with an eating disorder arrives on a medical floor, treatment teams often ask psychiatric consultants to help them impose care the patient desperately needs but doesn’t want. This reaction is understandable. After all, an eating disorder is a psychiatric illness, and hospital-based psychiatrists have experience with treating involuntary patients. A psychiatric hold may seem like a sensible way to save the life of a hospitalized patient with a mental illness.

But filling out a psychiatric hold only scratches the surface of what a psychiatric consultant’s contribution should include; in Ms. Q’s case, initiating a psychiatric hold is probably the wrong thing to do.

Why would filling out a psychiatric hold be inappropriate for Ms. Q? What clinical factors and legal issues should a psychiatrist consider when helping medical colleagues provide unwanted treatment to a severely malnourished patient with an eating disorder? We’ll explore these matters as we consider the case of Ms. Q (Figure) and the following questions:

• What type of care is most appropriate for her now?
• Can she refuse medical treatment?
• What are the medicolegal risks of letting her leave the hospital?
• What are the medicolegal risks of detaining and force-feeding her against her will?
• When is a psychiatric “hold” appropriate?

What care is appropriate?
Given her state of self-starvation, Ms. Q’s treatment plan could require close monitoring of her electrolytes and cardiac status, as well as watching her for signs of “refeeding syndrome”—rapid, potentially fatal fluid shifts and metabolic derangements that malnourished patients could experience when they receive artificial refeeding.¹

First, the physicians who are caring for Ms. Q should determine whether she needs more intensive medical supervision than is usually available on a psychiatric unit. If she does, but she won’t agree to stay on a medical unit for care, a psychiatric hold is the wrong step, for 2 reasons:

• Once a psychiatric hold has been executed, state statutes require the patient to be placed in a psychiatric facility—a state-approved psychiatric treatment setting, such as a psychiatric unit or free-standing psychiatric hospital—within a specified period.^2,3 Most nonpsychiatric medical units would not meet state’s statutory definition for such a facility.
• A psychiatric hold only permits short-term detention. It does not provide legal authority to impose unwanted medical treatment.

Does Ms. Q have capacity?
In the United States, Ms. Q has a legal right to refuse medical care—even if she needs it urgently—provided that her refusal is made competently.⁴ As Appelbaum and Grisso⁵ explained in a now-classic 1988 article:

The legal standards for competence include the four related skills of communicating a choice, understanding relevant information, appreciating the current situation and its consequences, and manipulating information rationally.

The Table⁵ describes these abilities in more detail.

Only courts can make legal determinations of competence, so physicians refer to an evaluation of a patient’s competence-related abilities as a “capacity assessment.” The decision as to whether a patient has capacity ultimately rests with the primary treatment team; however, physicians in other specialties often enlist psychiatrists’ help with this matter because of their interviewing skills and knowledge of how mental illness can impair capacity.

No easy-to-use instrument for evaluating capacity is available. However, Appelbaum⁶ provides examples of questions that often prove useful in such assessments, and a review by Sessums et al⁷ on several capacity evaluation tools suggests that the Aid to Capacity Evaluation⁸ may be the best instrument for performing capacity assessments.

Patients with anorexia nervosa often differ substantially from healthy people in how they assign values to life and death,⁹ which can make it difficult to evaluate their capacity to refuse life-saving treatment. Malnutrition can alter patients’ ability to think clearly, a phenomenon that some patients with anorexia mention as a reason they are grateful (in retrospect) for the compulsory treatment they received.¹⁰ Yet, if an evaluation shows that the patient has the decision-making capacity to refuse care, then her (his) caregivers should carefully document this conclusion and the basis for it. Although caregivers might encourage her to accept the treatment they believe she needs, they should not provide treatment that conflicts with their patient’s wishes.

If evaluation shows that the patient lacks capacity, however, the findings that support this conclusion should be documented clearly. The team then should consult the hospital attorney to determine how to best proceed. The attorney might recommend that a physician on the primary treatment team initiate a “medical hold”—an order that the patient may not leave against medical advice (AMA)—and then seek an emergency guardianship to permit medical treatment, such as refeeding.

To treat or not to treat?
What are the legal risks of allowing Ms. Q to leave AMA before she reaches medical stability?

Powers and Cloak¹¹ describe a case of a 26-year-old woman with anorexia nervosa who came to the hospital with dizziness, weakness, and a very low blood glucose level. She was discharged after 6 days without having received any feeding, only to return to the emergency department 2 days later. This time, she had a letter from her physician stating that she needed medical supervision to start refeeding, yet she was discharged from the emergency department within a few hours. She was re-admitted to the hospital the next day.

Powers and Cloak¹¹ do not report this woman’s medical outcome. But what if she had suffered a fatal cardiac arrhythmia before her third presentation to the emergency department or suffered another injury attributable to her nutritional state: Could her physicians be found at fault?

On Cohen & Associates’ Web site, they essentially answer, “Yes.” They describe a case of “Miss McIntosh,” who had anorexia nervosa and was discharged home from a hospital despite “chronic metabolic problems and not eating properly.” She went into a “hypoglycemic encephalopathic coma” and “suffered irreversible brain damage.” A subsequent lawsuit against the hospital resulted in a 7-figure settlement,¹² illustrating the potential for adverse medicolegal consequences if failure to treat a patient with anorexia nervosa could be linked to subsequent physical harm. On the other hand, could a patient with anorexia who is being force-fed take legal action against her providers? At least 3 recent British cases suggest that this is possible.^13-15 A British medical student with anorexia, E, made an emergency application to the Court of Protection in London, claiming that being fed against her will was akin to reliving her past experience of sexual abuse. In E’s case, the judge ruled “that the balance tips slowly but unmistakably in the direction of life preserving treatment” and authorized feeding over her objection.⁶ In 2 other cases, however, British courts have ruled that force-feeding anorexic patients would be futile and disallowed the practice.^14,15

Faced with possible legal action, no matter what course you take, how should you respond? Getting legal and ethical consultation is prudent if time allows. In many cases, hospital attorneys might prefer that physicians err on the side of preserving life(D. Vanderpool, MBA, JD, personal communication, February 3, 2016)—even if that means detaining a patient without clear legal authorization to do so—because attorneys would prefer to defend a doctor who acted to save someone’s life than to defend a doctor who knowingly allowed a patient to die.

When might persons with an eating disorder be civilly committed?
Suppose that Ms. Q does not need urgent nonpsychiatric medical care, or that her life-threatening physical problems now have been addressed. Her physicians strongly recommend that she undergo inpatient psychiatric treatment for her eating disorder, but she wants to leave. Would it now be appropriate to fill out paperwork to initiate a psychiatric hold?

All U.S. jurisdictions authorize “civil commitment” proceedings that can lead to involuntary psychiatric hospitalization of people who have a mental disorder and pose a risk to themselves or others because of the disorder.¹⁶

In general, to be subject to civil commitment, a person must have a substantial disorder of thought, mood, perception, orientation, or memory. In addition, that disorder must grossly impair her (his) judgment, behavior, reality testing, or ability to meet the demands of everyday life.¹⁷

People with psychosis, a severe mood disorder, or dementia often meet these criteria. However, psychiatrists do not usually consider anorexia nervosa to be a thought disorder, mood disorder, or memory disorder. Does this mean that people with anorexia nervosa cannot meet the “substantial” mental disorder criterion?

It does not. Courts interpret the words in statutes based on their “ordinary and natural meaning.”¹⁸ If Ms. Q perceived herself as fat, despite having a BMI that was far below the healthy range, most people would regard her thinking to be disordered. If, in addition, her mental disorder impaired her “judgment, behavior, and capacity to meet the ordinary demands of sustaining existence,” then her anorexia nervosa “would qualify as a mental disorder for commitment purposes.”¹⁹

To be subject to civil commitment, a person with a substantial mental disorder also must pose a risk of harm to herself or others because of the disorder. That risk can be evidenced via an action, attempt, or threat to do direct physical harm, or it might inhere in the potential for developing grave disability through neglect of one’s basic needs, such as failing to eat adequately. In Ms. Q’s case, if the evidence shows her eating-disordered behavior has placed her at imminent risk of permanent injury or death, she has satisfied the legal criteria that justify court-ordered psychiatric hospitalization.

Bottom Line
When a severely malnourished patient with anorexia nervosa does not agree to allow recommended care, an appropriate clinical response should include judgment about the urgency of the proposed treatment, what treatment setting is best suited to the patient’s condition, and whether the patient has the mental capacity to refuse potentially life-saving care.

Dear Dr. Mossman,

At the general hospital where I perform consultations, the medical service asked me to fill out psychiatric “hold” documents to keep a severely malnourished young woman with anorexia nervosa from leaving the hospital. Ms. Q, whose body mass index (BMI) was 12 (yes, 12), came to the hospital to have her “electrolytes fixed.” She was willing to stay the night for electrolyte repletion, but insisted she could gain weight on her own at home.

I’m worried that she might die without prompt inpatient treatment; she needs to stay on the medical service. Should I fill out a psychiatric hold to keep her there? What legal risks could I face if Ms. Q is detained and force-fed against her will? What are the legal risks of letting her leave the hospital before she is medically stable?

Submitted by “Dr. F”

When a severely malnourished patient with an eating disorder arrives on a medical floor, treatment teams often ask psychiatric consultants to help them impose care the patient desperately needs but doesn’t want. This reaction is understandable. After all, an eating disorder is a psychiatric illness, and hospital-based psychiatrists have experience with treating involuntary patients. A psychiatric hold may seem like a sensible way to save the life of a hospitalized patient with a mental illness.

But filling out a psychiatric hold only scratches the surface of what a psychiatric consultant’s contribution should include; in Ms. Q’s case, initiating a psychiatric hold is probably the wrong thing to do.

Why would filling out a psychiatric hold be inappropriate for Ms. Q? What clinical factors and legal issues should a psychiatrist consider when helping medical colleagues provide unwanted treatment to a severely malnourished patient with an eating disorder? We’ll explore these matters as we consider the case of Ms. Q (Figure) and the following questions:

• What type of care is most appropriate for her now?
• Can she refuse medical treatment?
• What are the medicolegal risks of letting her leave the hospital?
• What are the medicolegal risks of detaining and force-feeding her against her will?
• When is a psychiatric “hold” appropriate?

What care is appropriate?
Given her state of self-starvation, Ms. Q’s treatment plan could require close monitoring of her electrolytes and cardiac status, as well as watching her for signs of “refeeding syndrome”—rapid, potentially fatal fluid shifts and metabolic derangements that malnourished patients could experience when they receive artificial refeeding.¹

First, the physicians who are caring for Ms. Q should determine whether she needs more intensive medical supervision than is usually available on a psychiatric unit. If she does, but she won’t agree to stay on a medical unit for care, a psychiatric hold is the wrong step, for 2 reasons:

• Once a psychiatric hold has been executed, state statutes require the patient to be placed in a psychiatric facility—a state-approved psychiatric treatment setting, such as a psychiatric unit or free-standing psychiatric hospital—within a specified period.^2,3 Most nonpsychiatric medical units would not meet state’s statutory definition for such a facility.
• A psychiatric hold only permits short-term detention. It does not provide legal authority to impose unwanted medical treatment.

Does Ms. Q have capacity?
In the United States, Ms. Q has a legal right to refuse medical care—even if she needs it urgently—provided that her refusal is made competently.⁴ As Appelbaum and Grisso⁵ explained in a now-classic 1988 article:

The legal standards for competence include the four related skills of communicating a choice, understanding relevant information, appreciating the current situation and its consequences, and manipulating information rationally.

The Table⁵ describes these abilities in more detail.

Only courts can make legal determinations of competence, so physicians refer to an evaluation of a patient’s competence-related abilities as a “capacity assessment.” The decision as to whether a patient has capacity ultimately rests with the primary treatment team; however, physicians in other specialties often enlist psychiatrists’ help with this matter because of their interviewing skills and knowledge of how mental illness can impair capacity.

No easy-to-use instrument for evaluating capacity is available. However, Appelbaum⁶ provides examples of questions that often prove useful in such assessments, and a review by Sessums et al⁷ on several capacity evaluation tools suggests that the Aid to Capacity Evaluation⁸ may be the best instrument for performing capacity assessments.

Patients with anorexia nervosa often differ substantially from healthy people in how they assign values to life and death,⁹ which can make it difficult to evaluate their capacity to refuse life-saving treatment. Malnutrition can alter patients’ ability to think clearly, a phenomenon that some patients with anorexia mention as a reason they are grateful (in retrospect) for the compulsory treatment they received.¹⁰ Yet, if an evaluation shows that the patient has the decision-making capacity to refuse care, then her (his) caregivers should carefully document this conclusion and the basis for it. Although caregivers might encourage her to accept the treatment they believe she needs, they should not provide treatment that conflicts with their patient’s wishes.

If evaluation shows that the patient lacks capacity, however, the findings that support this conclusion should be documented clearly. The team then should consult the hospital attorney to determine how to best proceed. The attorney might recommend that a physician on the primary treatment team initiate a “medical hold”—an order that the patient may not leave against medical advice (AMA)—and then seek an emergency guardianship to permit medical treatment, such as refeeding.

To treat or not to treat?
What are the legal risks of allowing Ms. Q to leave AMA before she reaches medical stability?

Powers and Cloak¹¹ describe a case of a 26-year-old woman with anorexia nervosa who came to the hospital with dizziness, weakness, and a very low blood glucose level. She was discharged after 6 days without having received any feeding, only to return to the emergency department 2 days later. This time, she had a letter from her physician stating that she needed medical supervision to start refeeding, yet she was discharged from the emergency department within a few hours. She was re-admitted to the hospital the next day.

Powers and Cloak¹¹ do not report this woman’s medical outcome. But what if she had suffered a fatal cardiac arrhythmia before her third presentation to the emergency department or suffered another injury attributable to her nutritional state: Could her physicians be found at fault?

On Cohen & Associates’ Web site, they essentially answer, “Yes.” They describe a case of “Miss McIntosh,” who had anorexia nervosa and was discharged home from a hospital despite “chronic metabolic problems and not eating properly.” She went into a “hypoglycemic encephalopathic coma” and “suffered irreversible brain damage.” A subsequent lawsuit against the hospital resulted in a 7-figure settlement,¹² illustrating the potential for adverse medicolegal consequences if failure to treat a patient with anorexia nervosa could be linked to subsequent physical harm. On the other hand, could a patient with anorexia who is being force-fed take legal action against her providers? At least 3 recent British cases suggest that this is possible.^13-15 A British medical student with anorexia, E, made an emergency application to the Court of Protection in London, claiming that being fed against her will was akin to reliving her past experience of sexual abuse. In E’s case, the judge ruled “that the balance tips slowly but unmistakably in the direction of life preserving treatment” and authorized feeding over her objection.⁶ In 2 other cases, however, British courts have ruled that force-feeding anorexic patients would be futile and disallowed the practice.^14,15

Faced with possible legal action, no matter what course you take, how should you respond? Getting legal and ethical consultation is prudent if time allows. In many cases, hospital attorneys might prefer that physicians err on the side of preserving life(D. Vanderpool, MBA, JD, personal communication, February 3, 2016)—even if that means detaining a patient without clear legal authorization to do so—because attorneys would prefer to defend a doctor who acted to save someone’s life than to defend a doctor who knowingly allowed a patient to die.

When might persons with an eating disorder be civilly committed?
Suppose that Ms. Q does not need urgent nonpsychiatric medical care, or that her life-threatening physical problems now have been addressed. Her physicians strongly recommend that she undergo inpatient psychiatric treatment for her eating disorder, but she wants to leave. Would it now be appropriate to fill out paperwork to initiate a psychiatric hold?

All U.S. jurisdictions authorize “civil commitment” proceedings that can lead to involuntary psychiatric hospitalization of people who have a mental disorder and pose a risk to themselves or others because of the disorder.¹⁶

In general, to be subject to civil commitment, a person must have a substantial disorder of thought, mood, perception, orientation, or memory. In addition, that disorder must grossly impair her (his) judgment, behavior, reality testing, or ability to meet the demands of everyday life.¹⁷

People with psychosis, a severe mood disorder, or dementia often meet these criteria. However, psychiatrists do not usually consider anorexia nervosa to be a thought disorder, mood disorder, or memory disorder. Does this mean that people with anorexia nervosa cannot meet the “substantial” mental disorder criterion?

It does not. Courts interpret the words in statutes based on their “ordinary and natural meaning.”¹⁸ If Ms. Q perceived herself as fat, despite having a BMI that was far below the healthy range, most people would regard her thinking to be disordered. If, in addition, her mental disorder impaired her “judgment, behavior, and capacity to meet the ordinary demands of sustaining existence,” then her anorexia nervosa “would qualify as a mental disorder for commitment purposes.”¹⁹

To be subject to civil commitment, a person with a substantial mental disorder also must pose a risk of harm to herself or others because of the disorder. That risk can be evidenced via an action, attempt, or threat to do direct physical harm, or it might inhere in the potential for developing grave disability through neglect of one’s basic needs, such as failing to eat adequately. In Ms. Q’s case, if the evidence shows her eating-disordered behavior has placed her at imminent risk of permanent injury or death, she has satisfied the legal criteria that justify court-ordered psychiatric hospitalization.

Bottom Line
When a severely malnourished patient with anorexia nervosa does not agree to allow recommended care, an appropriate clinical response should include judgment about the urgency of the proposed treatment, what treatment setting is best suited to the patient’s condition, and whether the patient has the mental capacity to refuse potentially life-saving care.

Dear Dr. Mossman,

At the general hospital where I perform consultations, the medical service asked me to fill out psychiatric “hold” documents to keep a severely malnourished young woman with anorexia nervosa from leaving the hospital. Ms. Q, whose body mass index (BMI) was 12 (yes, 12), came to the hospital to have her “electrolytes fixed.” She was willing to stay the night for electrolyte repletion, but insisted she could gain weight on her own at home.

I’m worried that she might die without prompt inpatient treatment; she needs to stay on the medical service. Should I fill out a psychiatric hold to keep her there? What legal risks could I face if Ms. Q is detained and force-fed against her will? What are the legal risks of letting her leave the hospital before she is medically stable?

Submitted by “Dr. F”

When a severely malnourished patient with an eating disorder arrives on a medical floor, treatment teams often ask psychiatric consultants to help them impose care the patient desperately needs but doesn’t want. This reaction is understandable. After all, an eating disorder is a psychiatric illness, and hospital-based psychiatrists have experience with treating involuntary patients. A psychiatric hold may seem like a sensible way to save the life of a hospitalized patient with a mental illness.

But filling out a psychiatric hold only scratches the surface of what a psychiatric consultant’s contribution should include; in Ms. Q’s case, initiating a psychiatric hold is probably the wrong thing to do.

Why would filling out a psychiatric hold be inappropriate for Ms. Q? What clinical factors and legal issues should a psychiatrist consider when helping medical colleagues provide unwanted treatment to a severely malnourished patient with an eating disorder? We’ll explore these matters as we consider the case of Ms. Q (Figure) and the following questions:

• What type of care is most appropriate for her now?
• Can she refuse medical treatment?
• What are the medicolegal risks of letting her leave the hospital?
• What are the medicolegal risks of detaining and force-feeding her against her will?
• When is a psychiatric “hold” appropriate?

What care is appropriate?
Given her state of self-starvation, Ms. Q’s treatment plan could require close monitoring of her electrolytes and cardiac status, as well as watching her for signs of “refeeding syndrome”—rapid, potentially fatal fluid shifts and metabolic derangements that malnourished patients could experience when they receive artificial refeeding.¹

First, the physicians who are caring for Ms. Q should determine whether she needs more intensive medical supervision than is usually available on a psychiatric unit. If she does, but she won’t agree to stay on a medical unit for care, a psychiatric hold is the wrong step, for 2 reasons:

• Once a psychiatric hold has been executed, state statutes require the patient to be placed in a psychiatric facility—a state-approved psychiatric treatment setting, such as a psychiatric unit or free-standing psychiatric hospital—within a specified period.^2,3 Most nonpsychiatric medical units would not meet state’s statutory definition for such a facility.
• A psychiatric hold only permits short-term detention. It does not provide legal authority to impose unwanted medical treatment.

Does Ms. Q have capacity?
In the United States, Ms. Q has a legal right to refuse medical care—even if she needs it urgently—provided that her refusal is made competently.⁴ As Appelbaum and Grisso⁵ explained in a now-classic 1988 article:

The legal standards for competence include the four related skills of communicating a choice, understanding relevant information, appreciating the current situation and its consequences, and manipulating information rationally.

The Table⁵ describes these abilities in more detail.

Only courts can make legal determinations of competence, so physicians refer to an evaluation of a patient’s competence-related abilities as a “capacity assessment.” The decision as to whether a patient has capacity ultimately rests with the primary treatment team; however, physicians in other specialties often enlist psychiatrists’ help with this matter because of their interviewing skills and knowledge of how mental illness can impair capacity.

No easy-to-use instrument for evaluating capacity is available. However, Appelbaum⁶ provides examples of questions that often prove useful in such assessments, and a review by Sessums et al⁷ on several capacity evaluation tools suggests that the Aid to Capacity Evaluation⁸ may be the best instrument for performing capacity assessments.

Patients with anorexia nervosa often differ substantially from healthy people in how they assign values to life and death,⁹ which can make it difficult to evaluate their capacity to refuse life-saving treatment. Malnutrition can alter patients’ ability to think clearly, a phenomenon that some patients with anorexia mention as a reason they are grateful (in retrospect) for the compulsory treatment they received.¹⁰ Yet, if an evaluation shows that the patient has the decision-making capacity to refuse care, then her (his) caregivers should carefully document this conclusion and the basis for it. Although caregivers might encourage her to accept the treatment they believe she needs, they should not provide treatment that conflicts with their patient’s wishes.

If evaluation shows that the patient lacks capacity, however, the findings that support this conclusion should be documented clearly. The team then should consult the hospital attorney to determine how to best proceed. The attorney might recommend that a physician on the primary treatment team initiate a “medical hold”—an order that the patient may not leave against medical advice (AMA)—and then seek an emergency guardianship to permit medical treatment, such as refeeding.

To treat or not to treat?
What are the legal risks of allowing Ms. Q to leave AMA before she reaches medical stability?

Powers and Cloak¹¹ describe a case of a 26-year-old woman with anorexia nervosa who came to the hospital with dizziness, weakness, and a very low blood glucose level. She was discharged after 6 days without having received any feeding, only to return to the emergency department 2 days later. This time, she had a letter from her physician stating that she needed medical supervision to start refeeding, yet she was discharged from the emergency department within a few hours. She was re-admitted to the hospital the next day.

Powers and Cloak¹¹ do not report this woman’s medical outcome. But what if she had suffered a fatal cardiac arrhythmia before her third presentation to the emergency department or suffered another injury attributable to her nutritional state: Could her physicians be found at fault?

On Cohen & Associates’ Web site, they essentially answer, “Yes.” They describe a case of “Miss McIntosh,” who had anorexia nervosa and was discharged home from a hospital despite “chronic metabolic problems and not eating properly.” She went into a “hypoglycemic encephalopathic coma” and “suffered irreversible brain damage.” A subsequent lawsuit against the hospital resulted in a 7-figure settlement,¹² illustrating the potential for adverse medicolegal consequences if failure to treat a patient with anorexia nervosa could be linked to subsequent physical harm. On the other hand, could a patient with anorexia who is being force-fed take legal action against her providers? At least 3 recent British cases suggest that this is possible.^13-15 A British medical student with anorexia, E, made an emergency application to the Court of Protection in London, claiming that being fed against her will was akin to reliving her past experience of sexual abuse. In E’s case, the judge ruled “that the balance tips slowly but unmistakably in the direction of life preserving treatment” and authorized feeding over her objection.⁶ In 2 other cases, however, British courts have ruled that force-feeding anorexic patients would be futile and disallowed the practice.^14,15

Faced with possible legal action, no matter what course you take, how should you respond? Getting legal and ethical consultation is prudent if time allows. In many cases, hospital attorneys might prefer that physicians err on the side of preserving life(D. Vanderpool, MBA, JD, personal communication, February 3, 2016)—even if that means detaining a patient without clear legal authorization to do so—because attorneys would prefer to defend a doctor who acted to save someone’s life than to defend a doctor who knowingly allowed a patient to die.

When might persons with an eating disorder be civilly committed?
Suppose that Ms. Q does not need urgent nonpsychiatric medical care, or that her life-threatening physical problems now have been addressed. Her physicians strongly recommend that she undergo inpatient psychiatric treatment for her eating disorder, but she wants to leave. Would it now be appropriate to fill out paperwork to initiate a psychiatric hold?

All U.S. jurisdictions authorize “civil commitment” proceedings that can lead to involuntary psychiatric hospitalization of people who have a mental disorder and pose a risk to themselves or others because of the disorder.¹⁶

In general, to be subject to civil commitment, a person must have a substantial disorder of thought, mood, perception, orientation, or memory. In addition, that disorder must grossly impair her (his) judgment, behavior, reality testing, or ability to meet the demands of everyday life.¹⁷

People with psychosis, a severe mood disorder, or dementia often meet these criteria. However, psychiatrists do not usually consider anorexia nervosa to be a thought disorder, mood disorder, or memory disorder. Does this mean that people with anorexia nervosa cannot meet the “substantial” mental disorder criterion?

It does not. Courts interpret the words in statutes based on their “ordinary and natural meaning.”¹⁸ If Ms. Q perceived herself as fat, despite having a BMI that was far below the healthy range, most people would regard her thinking to be disordered. If, in addition, her mental disorder impaired her “judgment, behavior, and capacity to meet the ordinary demands of sustaining existence,” then her anorexia nervosa “would qualify as a mental disorder for commitment purposes.”¹⁹

To be subject to civil commitment, a person with a substantial mental disorder also must pose a risk of harm to herself or others because of the disorder. That risk can be evidenced via an action, attempt, or threat to do direct physical harm, or it might inhere in the potential for developing grave disability through neglect of one’s basic needs, such as failing to eat adequately. In Ms. Q’s case, if the evidence shows her eating-disordered behavior has placed her at imminent risk of permanent injury or death, she has satisfied the legal criteria that justify court-ordered psychiatric hospitalization.

Bottom Line
When a severely malnourished patient with anorexia nervosa does not agree to allow recommended care, an appropriate clinical response should include judgment about the urgency of the proposed treatment, what treatment setting is best suited to the patient’s condition, and whether the patient has the mental capacity to refuse potentially life-saving care.

Non-drug treatment options, such as behavioral techniques and environment adjustment, should be considered before initiating pharmacotherapy in older patients with behavioral deregulation caused by a neurocognitive disorder. Before considering any interventions, including medical therapy, an evaluation and development of a profile of behavioral symptoms is warranted.

The purpose of such a profile is to:

• guide a patient-specific treatment plan
• measure treatment response (whether medication-related or otherwise).

Developing a profile for a patient can lead to a more tailored treatment plan. Such a plan includes identification of mitigating factors for the patient’s behavior and use of specific interventions, with a preference for non-medication interventions.

Profile assessment can guide treatment
The disruptive-behavior profile that I created (Table) can be used as an initial screening device; the score (1 through 4) in each domain indicates the intensity of intervention required. The profile also can be used to evaluate treatment response.

For example, when caring for a person with a neurocognitive disorder with agitation and disruptive behavior, this profile can be used by the caregiver as a reporting tool for the behavioral heath professional providing consultation. Based on this report, the behavioral health professional can evaluate the predisposing, precipitating, and perpetuating factors of the behavioral disturbance, and a treatment plan can be implemented. After interventions are applied, follow-up assessment with the tool can assess the response to the intervention.

The scale can aid in averting overuse of non-specific medication therapy and, if required, can guide pharmacotherapy. This assessment tool can be useful for clinicians providing care for patients with a neurocognitive disorder, not only in choosing treatment, but also to justify clinical rationale.

How does this scale compare with others?
The Neuropsychiatric Inventory (NPI), Behavioral Pathology in Alzheimer’s Disease (Behave-AD), Cohen-Mansfield Agitation Inventory, and Brief Agitation Rating Scale provide valuable information for clinical care. However:

• Use of the NPI in everyday practice is limited; time spent completing the NPI scale remains a significant impediment for the busy clinician.
• Behave-AD requires a higher level of skill for some caregivers to estimate behavioral symptoms and answer questions about severity.
• Cohen-Mansfeld and Brief Agitation Rating Scale provide a limited description of the intensity of behavioral disturbance.

Developing a treatment plan and justifying pharmacotherapy in patients with a neurocognitive disorder is a challenge for clinicians. The scale that I developed aims to (1) assist the busy clinician who must construct a targeted treatment plan and (2) avoid pharmacotherapy when it is unnecessary. If pharmacotherapy is warranted on the basis of any of the domain scores in the profile, it should be documented with a judicious rationale.

Non-drug treatment options, such as behavioral techniques and environment adjustment, should be considered before initiating pharmacotherapy in older patients with behavioral deregulation caused by a neurocognitive disorder. Before considering any interventions, including medical therapy, an evaluation and development of a profile of behavioral symptoms is warranted.

The purpose of such a profile is to:

• guide a patient-specific treatment plan
• measure treatment response (whether medication-related or otherwise).

Developing a profile for a patient can lead to a more tailored treatment plan. Such a plan includes identification of mitigating factors for the patient’s behavior and use of specific interventions, with a preference for non-medication interventions.

Profile assessment can guide treatment
The disruptive-behavior profile that I created (Table) can be used as an initial screening device; the score (1 through 4) in each domain indicates the intensity of intervention required. The profile also can be used to evaluate treatment response.

For example, when caring for a person with a neurocognitive disorder with agitation and disruptive behavior, this profile can be used by the caregiver as a reporting tool for the behavioral heath professional providing consultation. Based on this report, the behavioral health professional can evaluate the predisposing, precipitating, and perpetuating factors of the behavioral disturbance, and a treatment plan can be implemented. After interventions are applied, follow-up assessment with the tool can assess the response to the intervention.

The scale can aid in averting overuse of non-specific medication therapy and, if required, can guide pharmacotherapy. This assessment tool can be useful for clinicians providing care for patients with a neurocognitive disorder, not only in choosing treatment, but also to justify clinical rationale.

How does this scale compare with others?
The Neuropsychiatric Inventory (NPI), Behavioral Pathology in Alzheimer’s Disease (Behave-AD), Cohen-Mansfield Agitation Inventory, and Brief Agitation Rating Scale provide valuable information for clinical care. However:

• Use of the NPI in everyday practice is limited; time spent completing the NPI scale remains a significant impediment for the busy clinician.
• Behave-AD requires a higher level of skill for some caregivers to estimate behavioral symptoms and answer questions about severity.
• Cohen-Mansfeld and Brief Agitation Rating Scale provide a limited description of the intensity of behavioral disturbance.

Developing a treatment plan and justifying pharmacotherapy in patients with a neurocognitive disorder is a challenge for clinicians. The scale that I developed aims to (1) assist the busy clinician who must construct a targeted treatment plan and (2) avoid pharmacotherapy when it is unnecessary. If pharmacotherapy is warranted on the basis of any of the domain scores in the profile, it should be documented with a judicious rationale.

Non-drug treatment options, such as behavioral techniques and environment adjustment, should be considered before initiating pharmacotherapy in older patients with behavioral deregulation caused by a neurocognitive disorder. Before considering any interventions, including medical therapy, an evaluation and development of a profile of behavioral symptoms is warranted.

The purpose of such a profile is to:

• guide a patient-specific treatment plan
• measure treatment response (whether medication-related or otherwise).

Developing a profile for a patient can lead to a more tailored treatment plan. Such a plan includes identification of mitigating factors for the patient’s behavior and use of specific interventions, with a preference for non-medication interventions.

Profile assessment can guide treatment
The disruptive-behavior profile that I created (Table) can be used as an initial screening device; the score (1 through 4) in each domain indicates the intensity of intervention required. The profile also can be used to evaluate treatment response.

For example, when caring for a person with a neurocognitive disorder with agitation and disruptive behavior, this profile can be used by the caregiver as a reporting tool for the behavioral heath professional providing consultation. Based on this report, the behavioral health professional can evaluate the predisposing, precipitating, and perpetuating factors of the behavioral disturbance, and a treatment plan can be implemented. After interventions are applied, follow-up assessment with the tool can assess the response to the intervention.

The scale can aid in averting overuse of non-specific medication therapy and, if required, can guide pharmacotherapy. This assessment tool can be useful for clinicians providing care for patients with a neurocognitive disorder, not only in choosing treatment, but also to justify clinical rationale.

How does this scale compare with others?
The Neuropsychiatric Inventory (NPI), Behavioral Pathology in Alzheimer’s Disease (Behave-AD), Cohen-Mansfield Agitation Inventory, and Brief Agitation Rating Scale provide valuable information for clinical care. However:

• Use of the NPI in everyday practice is limited; time spent completing the NPI scale remains a significant impediment for the busy clinician.
• Behave-AD requires a higher level of skill for some caregivers to estimate behavioral symptoms and answer questions about severity.
• Cohen-Mansfeld and Brief Agitation Rating Scale provide a limited description of the intensity of behavioral disturbance.

Developing a treatment plan and justifying pharmacotherapy in patients with a neurocognitive disorder is a challenge for clinicians. The scale that I developed aims to (1) assist the busy clinician who must construct a targeted treatment plan and (2) avoid pharmacotherapy when it is unnecessary. If pharmacotherapy is warranted on the basis of any of the domain scores in the profile, it should be documented with a judicious rationale.

An amphetamine-based, extended-release, orally disintegrating tablet for patients age ≥6 diagnosed with attention-deficit/hyperactivity disorder (ADHD) won FDA approval on January 28, 2016 (Table).¹

Adzenys XR-ODT is the first extended-release, orally disintegrating tablet for ADHD, Neos Therapeutics, Inc. the drug’s manufacturer, said in a statement.² The newly approved agent is bioequivalent to Adderall XR (the capsule form of extended-release mixed amphetamine salts), and patients taking Adderall XR can be switched to the new drug. Equivalent dosages of the 2 drugs are outlined on the prescribing information.¹

“The novel features of an extended-release orally disintegrating tablet ... make Adzenys XR-ODT attractive for use in both children (6 and older) and adults,” Alice R. Mao, MD, Medical Director, Memorial Park Psychiatry, Houston, Texas, said in the statement.²

As a condition of the approval, Neos must annually report the status of 3 post-marketing studies of children diagnosed with ADHD taking Adzenys XR-ODT, according to the approval letter.² One is a single-dose, open-label study of children ages 4 and 5; the second is a randomized, double-blind, placebo-controlled titration study of children ages 4 and 5; and the third is a 1-year, open-label safety study of patients ages 4 and 5.

For patients age 6 to 17, the starting dosage is 6.3 mg once daily in the morning; for adults, it is 12.5 mg once daily in the morning, according to the label.¹ The medication will be available in 4 other dose strengths: 3.1 mg, 9.4 mg, 15.7 mg, and 18.8 mg.

The most common adverse reactions to the drug among pediatric patients include loss of appetite, insomnia, and abdominal pain. Among adult patients, adverse reactions include dry mouth, loss of appetite, and insomnia.

An amphetamine-based, extended-release, orally disintegrating tablet for patients age ≥6 diagnosed with attention-deficit/hyperactivity disorder (ADHD) won FDA approval on January 28, 2016 (Table).¹

Adzenys XR-ODT is the first extended-release, orally disintegrating tablet for ADHD, Neos Therapeutics, Inc. the drug’s manufacturer, said in a statement.² The newly approved agent is bioequivalent to Adderall XR (the capsule form of extended-release mixed amphetamine salts), and patients taking Adderall XR can be switched to the new drug. Equivalent dosages of the 2 drugs are outlined on the prescribing information.¹

“The novel features of an extended-release orally disintegrating tablet ... make Adzenys XR-ODT attractive for use in both children (6 and older) and adults,” Alice R. Mao, MD, Medical Director, Memorial Park Psychiatry, Houston, Texas, said in the statement.²

As a condition of the approval, Neos must annually report the status of 3 post-marketing studies of children diagnosed with ADHD taking Adzenys XR-ODT, according to the approval letter.² One is a single-dose, open-label study of children ages 4 and 5; the second is a randomized, double-blind, placebo-controlled titration study of children ages 4 and 5; and the third is a 1-year, open-label safety study of patients ages 4 and 5.

For patients age 6 to 17, the starting dosage is 6.3 mg once daily in the morning; for adults, it is 12.5 mg once daily in the morning, according to the label.¹ The medication will be available in 4 other dose strengths: 3.1 mg, 9.4 mg, 15.7 mg, and 18.8 mg.

The most common adverse reactions to the drug among pediatric patients include loss of appetite, insomnia, and abdominal pain. Among adult patients, adverse reactions include dry mouth, loss of appetite, and insomnia.

An amphetamine-based, extended-release, orally disintegrating tablet for patients age ≥6 diagnosed with attention-deficit/hyperactivity disorder (ADHD) won FDA approval on January 28, 2016 (Table).¹

Adzenys XR-ODT is the first extended-release, orally disintegrating tablet for ADHD, Neos Therapeutics, Inc. the drug’s manufacturer, said in a statement.² The newly approved agent is bioequivalent to Adderall XR (the capsule form of extended-release mixed amphetamine salts), and patients taking Adderall XR can be switched to the new drug. Equivalent dosages of the 2 drugs are outlined on the prescribing information.¹

“The novel features of an extended-release orally disintegrating tablet ... make Adzenys XR-ODT attractive for use in both children (6 and older) and adults,” Alice R. Mao, MD, Medical Director, Memorial Park Psychiatry, Houston, Texas, said in the statement.²

As a condition of the approval, Neos must annually report the status of 3 post-marketing studies of children diagnosed with ADHD taking Adzenys XR-ODT, according to the approval letter.² One is a single-dose, open-label study of children ages 4 and 5; the second is a randomized, double-blind, placebo-controlled titration study of children ages 4 and 5; and the third is a 1-year, open-label safety study of patients ages 4 and 5.

For patients age 6 to 17, the starting dosage is 6.3 mg once daily in the morning; for adults, it is 12.5 mg once daily in the morning, according to the label.¹ The medication will be available in 4 other dose strengths: 3.1 mg, 9.4 mg, 15.7 mg, and 18.8 mg.

The most common adverse reactions to the drug among pediatric patients include loss of appetite, insomnia, and abdominal pain. Among adult patients, adverse reactions include dry mouth, loss of appetite, and insomnia.

Flibanserin, FDA-approved in August 2015, is the first medication approved to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women (Table 1). In clinical trials,^1-4 the drug has shown modest efficacy in improving symptoms of low sexual desire (number of satisfying sexual events [SSEs], sexual desire, and overall sexual function). Flibanserin is not indicated to enhance sexual performance, for HSDD in postmenopausal women, or in men.
 

Clinical implications
Flibanserin could help premenopausal women who have distressing low sexual desire, which must be acquired and generalized:

• “Acquired low sexual desire” means that a patient had an adequate sexual desire that decreased or ceased for an unknown reason.
• “Generalized low sexual desire” means that lack of sexual desire occurs all the time and in all situations, not only with a certain partner or in some situations.

Women taking flibanserin could experience gradually increased sexual desire, increase in SSEs, and decrease of sexual distress. Flibanserin is indicated for long-term use; however, it should be discontinued after 8 weeks if the patient does not report any improvement in symptoms.

The number needed to treat with flibanserin likely would be rather large, but it is not available because of complex outcome measures in clinical trials. Flibanserin was not approved at 2 previous FDA committee hearings—mainly because of safety issues but also because of concerns about efficacy. For example, during the 2013 FDA hearing, the results presented showed statistically significant, but numerically small, treatment differences at 24 weeks compared with placebo. In an FDA responder analysis of the Phase-III trials, after accounting for the placebo effect, approximately 8% to 13% women were at least “much improved” on at least 1 of the primary outcomes.⁵

Flibanserin is not indicated for women whose sexual desire is due to (1) coexisting medical or psychiatric condition, (2) effects of medication or substance abuse, or (3) a relationship problem. It is unknown whether supplemental treatment would help these patients; however, it seems reasonable that combining flibanserin with psychosocial treatment, such as sex therapy or individual therapy, could be beneficial because it may be difficult to disentangle sexual dysfunction and relationship issues—2 problems that often are interwoven.

How it works
Flibanserin is a serotonin 1A receptor agonist and serotonin 2A receptor antagonist. In vitro, flibanserin demonstrated high affinity for the following 5-HT receptors:

• agonist activity at 5-HT1A
• antagonist activity at 5-HT2A, mostly in the prefrontal cortex.

Flibanserin also has moderate antagonist activities at the 5-HT2B, 5-HT2C, and dopamine D4 receptors. Flibanserin presumably acts centrally in the CNS; it has been suggested that flibanserin could rebalance neural circuitry involved in processing sexual desire by reducing serotonin activity and enhancing dopamine and epinephrine activity. The exact mechanism of how flibanserin improves sexual desire in women is unknown.

Pharmacokinetics
Flibanserin has a mean termination half-life of approximately 11 hours. It is administered once a day (50 to 100 mg) at bedtime. Steady state in healthy women was achieved after 3 days. Based on clinical observations, onset of action seems to be gradual and reaches maximum efficacy in approximately 8 weeks. Patients should discontinue the drug if no improvement is reported after 8 weeks. Flibanserin is readily absorbed from the gastrointestinal tract; however, food slows its absorption. The drug is 98% protein (mostly albumin)-bound.

Flibanserin is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Co-administration of moderate (diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil) or strong (eg, ketoconazole, clarithromycin, nefazodone, ritonavir) CYP3A4 inhibitors increases the concentration of flibanserin. This could lead to severe hypotension and syncope; therefore, co-administering flibanserin with a strong CYP3A4 inhibitor is contraindicated. Grapefruit juice is a moderate inhibitor of CYP3A4, and in a study of 26 healthy females, 240 mL of grapefruit juice increased flibanserin concentration 1.4-fold. Flibanserin is excreted though urine and feces. Flibanserin should be taken once a day at bedtime because of sedation, somnolence, and possible syncope.

Efficacy
The efficacy of flibanserin for treating HSDD was established in three 24-week, randomized, double-blind, placebo-controlled studies (Table 2). The target population in these studies was premenopausal women (mean age 36, range 19 to 55) with acquired HSDD lasting at least 6 months (mean duration, approximately 5 years). The 3 studies included 1,187 women who received flibanserin, 100 mg at bedtime, and 1,188 women who received placebo. Participants were mostly white (88.6%), and included black (9.6%) and Asian (1.5%) women. The completion rates were 69% for flibanserin and 78% for placebo. Some of the trials included arms with a lower dosage of flibanserin (25 mg and 50 mg), which are not included in this analysis.
 

As noted in the package insert, these trials each had 2 co-primary efficacy endpoints, SSEs and sexual desire:

• change from baseline to Week 24 in the number of monthly SSEs (ie, sexual intercourse, oral sex, masturbation, or genital stimulation by the partner)
• change in sexual desire from baseline to 24-week endpoint.

In Study 1 and 2, change in sexual desire from baseline to Week 24 was measured daily by using an electronic diary. Every day, patients rated their sexual desire level by answering the question, “Indicate your most intense level of sexual desire” from 0 (no desire) to 3 (strong desire). These responses were totaled over a 28-day period to yield the monthly sexual desire score, which ranged from 0 to 84. These 2 studies also used the Female Sexual Function Index (FSFI) Desire domain as a secondary endpoint.

Study 3 used the FSFI Desire domain, comprising 2 questions, as the sexual desire co-primary endpoint:

• “Over the past 4 weeks, how often did you feel sexual desire or interest?” Responses ranged from 1 (almost never or never) to 5 (almost always or always).
• “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?” Responses ranged from 1 (very low or none at all) to 5 (very high).

In all 3 trials, flibanserin was associated with a small, yet statistically significant, improvement in change in monthly SSEs from baseline to Week 24 compared with placebo. In Study 1 and 2, there were no statistically significant differences between flibanserin and placebo for the electronic diary sexual desire endpoint. In the third study, there was statistically significant improvement in the change in sexual desire using the FSFI Desire domain with flibanserin compared with placebo. The FSFI Desire domain findings were consistent across all 3 trials. Flibanserin was associated with a decrease in sexual distress compared with placebo in all 3 studies.

Tolerability
Flibanserin was well tolerated in the 3 clinical trials. As the FDA noted, clinical trials are conducted under widely varying conditions and therefore adverse reaction rates observed in trials of flibanserin cannot be directly compared with those reported in clinical trials of another drug and might not reflect rates observed in clinical practice.

The discontinuation rate due to adverse reactions was 13% among patients treated with flibanserin, 100 mg at bedtime, and 6% among those taking placebo. The most common side effects were somnolence, dizziness, fatigue, nausea, insomnia, and dry mouth, which appear dose-dependent. Onset of most of these adverse events was within 14 days after the start of treatment.

Although hypotension and syncope rarely were seen with flibanserin alone in clinical trials, these adverse events occurred more frequently in the morning and when taken with alcohol and with some drugs (moderate or strong CYP3A4 inhibitors), and in patients with hepatic impairment. Therefore, women who drink alcohol or take a moderate or strong inhibitor of CYP3A4—both of which are contraindicated—and those with hepatic impairment should not take flibanserin.

Flibanserin should be taken at bedtime, because the risk of hypotension and syncope is higher when flibanserin is taken in the morning and because of associated sedation and somnolence.

Unique clinical issues
Flibanserin is the first FDA-approved medication for treating HSDD. It is important to note that the drug originally was developed as an antidepressant, but failed to show efficacy. Researchers noted that the drug was more effective than placebo when patients were asked, “How strong is your sexual desire?” The focus of development then shifted to a potential treatment of HSDD.

Flibanserin was not approved at 2 previous FDA hearings, mainly because of safety concerns. For the second hearing, the manufacturer, Boehringer Ingelheim, which sold the rights to the drug to Sprout Pharmaceuticals in 2011,⁶ did not present any new efficacy data, but provided additional safety data, such as research suggesting the absence of next-day driving impairment and data related to alcohol use (the study confirming hypotension associated with alcohol abuse used a small sample, and only 2 of 25 participants were women).

Contraindications
Flibanserin is contraindicated in patients using alcohol because of an increased risk of hypotension and syncope. A patient’s alcohol use should be evaluated before administering flibanserin, and patients should be counseled about the importance of abstaining from alcohol.

Similarly, concomitant use of flibanserin with a moderate or strong inhibitor of CYP3A4 increases the concentration of flibanserin and raises the risk of hypotension and syncope. Therefore, the use of a moderate or strong inhibitor of CYP3A4 in patients taking flibanserin is contraindicated. Similarly, patients with liver impairment should not take this drug.

Strong CYP2C19 inhibitors (proton-pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals) could increase flibanserin exposure, which may increase risk of hypotension, syncope, and CNS depression. Discuss these risks with your patients; doing so is particularly important when treating women of Chinese heritage, and some other Asian women, because 20% of these populations are genotypic CYP2C19 poor metabolizers.

Because of the increased risk of hypotension and syncope with alcohol use, flibanserin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Addyi REMS Program. Flibanserin can be prescribed or dispensed only by physicians and pharmacists who watch this program’s online slide presentation and passed a comprehension test.^a

Pregnant women should not take flibanserin because the effect on the fetus is unknown. Also, because the interaction with some oral contraceptives is unknown, patients should be cautioned about unwanted pregnancy. Women who are breastfeeding also should avoid using flibanserin because it is not known whether the drug is excreted in breast milk.

Women taking flibanserin also should avoid grapefruit juice, which increases flibanserin levels, and avoid using herbal products, resveratrol, and some over-the-counter drugs such as cimetidine. Women who have a depressive disorder also should avoid using flibanserin because their low sexual desire is more likely due to depression, which is not a therapeutic target for the drug.

Dosing
Flibanserin is provided in 100-mg film-coated tablets. It should be taken once a day at bedtime; titration is unnecessary. Length of treatment has not been determined, but it is recommended that patients stop flibanserin if they do not experience any benefit after 8 weeks. Although there is no guidance in the prescribing information, the medication probably could be stopped without tapering because withdrawal effects have not been observed.

Bottom Line
Flibanserin is FDA-approved for treating generalized, acquired hypoactive sexual desire disorder in premenopausal women. In clinical trials, the drug increased the number of satisfying sexual events and sexual desire, as measured by a diary and rating scales. Alcohol use and use of any moderate or strong inhibitor of cytochrome P450 3A4 are contraindicated in patients taking flibanserin because of an increased risk of hypotension and syncope.

Flibanserin, FDA-approved in August 2015, is the first medication approved to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women (Table 1). In clinical trials,^1-4 the drug has shown modest efficacy in improving symptoms of low sexual desire (number of satisfying sexual events [SSEs], sexual desire, and overall sexual function). Flibanserin is not indicated to enhance sexual performance, for HSDD in postmenopausal women, or in men.
 

Clinical implications
Flibanserin could help premenopausal women who have distressing low sexual desire, which must be acquired and generalized:

• “Acquired low sexual desire” means that a patient had an adequate sexual desire that decreased or ceased for an unknown reason.
• “Generalized low sexual desire” means that lack of sexual desire occurs all the time and in all situations, not only with a certain partner or in some situations.

Women taking flibanserin could experience gradually increased sexual desire, increase in SSEs, and decrease of sexual distress. Flibanserin is indicated for long-term use; however, it should be discontinued after 8 weeks if the patient does not report any improvement in symptoms.

The number needed to treat with flibanserin likely would be rather large, but it is not available because of complex outcome measures in clinical trials. Flibanserin was not approved at 2 previous FDA committee hearings—mainly because of safety issues but also because of concerns about efficacy. For example, during the 2013 FDA hearing, the results presented showed statistically significant, but numerically small, treatment differences at 24 weeks compared with placebo. In an FDA responder analysis of the Phase-III trials, after accounting for the placebo effect, approximately 8% to 13% women were at least “much improved” on at least 1 of the primary outcomes.⁵

Flibanserin is not indicated for women whose sexual desire is due to (1) coexisting medical or psychiatric condition, (2) effects of medication or substance abuse, or (3) a relationship problem. It is unknown whether supplemental treatment would help these patients; however, it seems reasonable that combining flibanserin with psychosocial treatment, such as sex therapy or individual therapy, could be beneficial because it may be difficult to disentangle sexual dysfunction and relationship issues—2 problems that often are interwoven.

How it works
Flibanserin is a serotonin 1A receptor agonist and serotonin 2A receptor antagonist. In vitro, flibanserin demonstrated high affinity for the following 5-HT receptors:

• agonist activity at 5-HT1A
• antagonist activity at 5-HT2A, mostly in the prefrontal cortex.

Flibanserin also has moderate antagonist activities at the 5-HT2B, 5-HT2C, and dopamine D4 receptors. Flibanserin presumably acts centrally in the CNS; it has been suggested that flibanserin could rebalance neural circuitry involved in processing sexual desire by reducing serotonin activity and enhancing dopamine and epinephrine activity. The exact mechanism of how flibanserin improves sexual desire in women is unknown.

Pharmacokinetics
Flibanserin has a mean termination half-life of approximately 11 hours. It is administered once a day (50 to 100 mg) at bedtime. Steady state in healthy women was achieved after 3 days. Based on clinical observations, onset of action seems to be gradual and reaches maximum efficacy in approximately 8 weeks. Patients should discontinue the drug if no improvement is reported after 8 weeks. Flibanserin is readily absorbed from the gastrointestinal tract; however, food slows its absorption. The drug is 98% protein (mostly albumin)-bound.

Flibanserin is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Co-administration of moderate (diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil) or strong (eg, ketoconazole, clarithromycin, nefazodone, ritonavir) CYP3A4 inhibitors increases the concentration of flibanserin. This could lead to severe hypotension and syncope; therefore, co-administering flibanserin with a strong CYP3A4 inhibitor is contraindicated. Grapefruit juice is a moderate inhibitor of CYP3A4, and in a study of 26 healthy females, 240 mL of grapefruit juice increased flibanserin concentration 1.4-fold. Flibanserin is excreted though urine and feces. Flibanserin should be taken once a day at bedtime because of sedation, somnolence, and possible syncope.

Efficacy
The efficacy of flibanserin for treating HSDD was established in three 24-week, randomized, double-blind, placebo-controlled studies (Table 2). The target population in these studies was premenopausal women (mean age 36, range 19 to 55) with acquired HSDD lasting at least 6 months (mean duration, approximately 5 years). The 3 studies included 1,187 women who received flibanserin, 100 mg at bedtime, and 1,188 women who received placebo. Participants were mostly white (88.6%), and included black (9.6%) and Asian (1.5%) women. The completion rates were 69% for flibanserin and 78% for placebo. Some of the trials included arms with a lower dosage of flibanserin (25 mg and 50 mg), which are not included in this analysis.
 

As noted in the package insert, these trials each had 2 co-primary efficacy endpoints, SSEs and sexual desire:

• change from baseline to Week 24 in the number of monthly SSEs (ie, sexual intercourse, oral sex, masturbation, or genital stimulation by the partner)
• change in sexual desire from baseline to 24-week endpoint.

In Study 1 and 2, change in sexual desire from baseline to Week 24 was measured daily by using an electronic diary. Every day, patients rated their sexual desire level by answering the question, “Indicate your most intense level of sexual desire” from 0 (no desire) to 3 (strong desire). These responses were totaled over a 28-day period to yield the monthly sexual desire score, which ranged from 0 to 84. These 2 studies also used the Female Sexual Function Index (FSFI) Desire domain as a secondary endpoint.

Study 3 used the FSFI Desire domain, comprising 2 questions, as the sexual desire co-primary endpoint:

• “Over the past 4 weeks, how often did you feel sexual desire or interest?” Responses ranged from 1 (almost never or never) to 5 (almost always or always).
• “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?” Responses ranged from 1 (very low or none at all) to 5 (very high).

In all 3 trials, flibanserin was associated with a small, yet statistically significant, improvement in change in monthly SSEs from baseline to Week 24 compared with placebo. In Study 1 and 2, there were no statistically significant differences between flibanserin and placebo for the electronic diary sexual desire endpoint. In the third study, there was statistically significant improvement in the change in sexual desire using the FSFI Desire domain with flibanserin compared with placebo. The FSFI Desire domain findings were consistent across all 3 trials. Flibanserin was associated with a decrease in sexual distress compared with placebo in all 3 studies.

Tolerability
Flibanserin was well tolerated in the 3 clinical trials. As the FDA noted, clinical trials are conducted under widely varying conditions and therefore adverse reaction rates observed in trials of flibanserin cannot be directly compared with those reported in clinical trials of another drug and might not reflect rates observed in clinical practice.

The discontinuation rate due to adverse reactions was 13% among patients treated with flibanserin, 100 mg at bedtime, and 6% among those taking placebo. The most common side effects were somnolence, dizziness, fatigue, nausea, insomnia, and dry mouth, which appear dose-dependent. Onset of most of these adverse events was within 14 days after the start of treatment.

Although hypotension and syncope rarely were seen with flibanserin alone in clinical trials, these adverse events occurred more frequently in the morning and when taken with alcohol and with some drugs (moderate or strong CYP3A4 inhibitors), and in patients with hepatic impairment. Therefore, women who drink alcohol or take a moderate or strong inhibitor of CYP3A4—both of which are contraindicated—and those with hepatic impairment should not take flibanserin.

Flibanserin should be taken at bedtime, because the risk of hypotension and syncope is higher when flibanserin is taken in the morning and because of associated sedation and somnolence.

Unique clinical issues
Flibanserin is the first FDA-approved medication for treating HSDD. It is important to note that the drug originally was developed as an antidepressant, but failed to show efficacy. Researchers noted that the drug was more effective than placebo when patients were asked, “How strong is your sexual desire?” The focus of development then shifted to a potential treatment of HSDD.

Flibanserin was not approved at 2 previous FDA hearings, mainly because of safety concerns. For the second hearing, the manufacturer, Boehringer Ingelheim, which sold the rights to the drug to Sprout Pharmaceuticals in 2011,⁶ did not present any new efficacy data, but provided additional safety data, such as research suggesting the absence of next-day driving impairment and data related to alcohol use (the study confirming hypotension associated with alcohol abuse used a small sample, and only 2 of 25 participants were women).

Contraindications
Flibanserin is contraindicated in patients using alcohol because of an increased risk of hypotension and syncope. A patient’s alcohol use should be evaluated before administering flibanserin, and patients should be counseled about the importance of abstaining from alcohol.

Similarly, concomitant use of flibanserin with a moderate or strong inhibitor of CYP3A4 increases the concentration of flibanserin and raises the risk of hypotension and syncope. Therefore, the use of a moderate or strong inhibitor of CYP3A4 in patients taking flibanserin is contraindicated. Similarly, patients with liver impairment should not take this drug.

Strong CYP2C19 inhibitors (proton-pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals) could increase flibanserin exposure, which may increase risk of hypotension, syncope, and CNS depression. Discuss these risks with your patients; doing so is particularly important when treating women of Chinese heritage, and some other Asian women, because 20% of these populations are genotypic CYP2C19 poor metabolizers.

Because of the increased risk of hypotension and syncope with alcohol use, flibanserin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Addyi REMS Program. Flibanserin can be prescribed or dispensed only by physicians and pharmacists who watch this program’s online slide presentation and passed a comprehension test.^a

Pregnant women should not take flibanserin because the effect on the fetus is unknown. Also, because the interaction with some oral contraceptives is unknown, patients should be cautioned about unwanted pregnancy. Women who are breastfeeding also should avoid using flibanserin because it is not known whether the drug is excreted in breast milk.

Women taking flibanserin also should avoid grapefruit juice, which increases flibanserin levels, and avoid using herbal products, resveratrol, and some over-the-counter drugs such as cimetidine. Women who have a depressive disorder also should avoid using flibanserin because their low sexual desire is more likely due to depression, which is not a therapeutic target for the drug.

Dosing
Flibanserin is provided in 100-mg film-coated tablets. It should be taken once a day at bedtime; titration is unnecessary. Length of treatment has not been determined, but it is recommended that patients stop flibanserin if they do not experience any benefit after 8 weeks. Although there is no guidance in the prescribing information, the medication probably could be stopped without tapering because withdrawal effects have not been observed.

Bottom Line
Flibanserin is FDA-approved for treating generalized, acquired hypoactive sexual desire disorder in premenopausal women. In clinical trials, the drug increased the number of satisfying sexual events and sexual desire, as measured by a diary and rating scales. Alcohol use and use of any moderate or strong inhibitor of cytochrome P450 3A4 are contraindicated in patients taking flibanserin because of an increased risk of hypotension and syncope.

Flibanserin, FDA-approved in August 2015, is the first medication approved to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women (Table 1). In clinical trials,^1-4 the drug has shown modest efficacy in improving symptoms of low sexual desire (number of satisfying sexual events [SSEs], sexual desire, and overall sexual function). Flibanserin is not indicated to enhance sexual performance, for HSDD in postmenopausal women, or in men.
 

Clinical implications
Flibanserin could help premenopausal women who have distressing low sexual desire, which must be acquired and generalized:

• “Acquired low sexual desire” means that a patient had an adequate sexual desire that decreased or ceased for an unknown reason.
• “Generalized low sexual desire” means that lack of sexual desire occurs all the time and in all situations, not only with a certain partner or in some situations.

Women taking flibanserin could experience gradually increased sexual desire, increase in SSEs, and decrease of sexual distress. Flibanserin is indicated for long-term use; however, it should be discontinued after 8 weeks if the patient does not report any improvement in symptoms.

The number needed to treat with flibanserin likely would be rather large, but it is not available because of complex outcome measures in clinical trials. Flibanserin was not approved at 2 previous FDA committee hearings—mainly because of safety issues but also because of concerns about efficacy. For example, during the 2013 FDA hearing, the results presented showed statistically significant, but numerically small, treatment differences at 24 weeks compared with placebo. In an FDA responder analysis of the Phase-III trials, after accounting for the placebo effect, approximately 8% to 13% women were at least “much improved” on at least 1 of the primary outcomes.⁵

Flibanserin is not indicated for women whose sexual desire is due to (1) coexisting medical or psychiatric condition, (2) effects of medication or substance abuse, or (3) a relationship problem. It is unknown whether supplemental treatment would help these patients; however, it seems reasonable that combining flibanserin with psychosocial treatment, such as sex therapy or individual therapy, could be beneficial because it may be difficult to disentangle sexual dysfunction and relationship issues—2 problems that often are interwoven.

How it works
Flibanserin is a serotonin 1A receptor agonist and serotonin 2A receptor antagonist. In vitro, flibanserin demonstrated high affinity for the following 5-HT receptors:

• agonist activity at 5-HT1A
• antagonist activity at 5-HT2A, mostly in the prefrontal cortex.

Flibanserin also has moderate antagonist activities at the 5-HT2B, 5-HT2C, and dopamine D4 receptors. Flibanserin presumably acts centrally in the CNS; it has been suggested that flibanserin could rebalance neural circuitry involved in processing sexual desire by reducing serotonin activity and enhancing dopamine and epinephrine activity. The exact mechanism of how flibanserin improves sexual desire in women is unknown.

Pharmacokinetics
Flibanserin has a mean termination half-life of approximately 11 hours. It is administered once a day (50 to 100 mg) at bedtime. Steady state in healthy women was achieved after 3 days. Based on clinical observations, onset of action seems to be gradual and reaches maximum efficacy in approximately 8 weeks. Patients should discontinue the drug if no improvement is reported after 8 weeks. Flibanserin is readily absorbed from the gastrointestinal tract; however, food slows its absorption. The drug is 98% protein (mostly albumin)-bound.

Flibanserin is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Co-administration of moderate (diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil) or strong (eg, ketoconazole, clarithromycin, nefazodone, ritonavir) CYP3A4 inhibitors increases the concentration of flibanserin. This could lead to severe hypotension and syncope; therefore, co-administering flibanserin with a strong CYP3A4 inhibitor is contraindicated. Grapefruit juice is a moderate inhibitor of CYP3A4, and in a study of 26 healthy females, 240 mL of grapefruit juice increased flibanserin concentration 1.4-fold. Flibanserin is excreted though urine and feces. Flibanserin should be taken once a day at bedtime because of sedation, somnolence, and possible syncope.

Efficacy
The efficacy of flibanserin for treating HSDD was established in three 24-week, randomized, double-blind, placebo-controlled studies (Table 2). The target population in these studies was premenopausal women (mean age 36, range 19 to 55) with acquired HSDD lasting at least 6 months (mean duration, approximately 5 years). The 3 studies included 1,187 women who received flibanserin, 100 mg at bedtime, and 1,188 women who received placebo. Participants were mostly white (88.6%), and included black (9.6%) and Asian (1.5%) women. The completion rates were 69% for flibanserin and 78% for placebo. Some of the trials included arms with a lower dosage of flibanserin (25 mg and 50 mg), which are not included in this analysis.
 

As noted in the package insert, these trials each had 2 co-primary efficacy endpoints, SSEs and sexual desire:

• change from baseline to Week 24 in the number of monthly SSEs (ie, sexual intercourse, oral sex, masturbation, or genital stimulation by the partner)
• change in sexual desire from baseline to 24-week endpoint.

In Study 1 and 2, change in sexual desire from baseline to Week 24 was measured daily by using an electronic diary. Every day, patients rated their sexual desire level by answering the question, “Indicate your most intense level of sexual desire” from 0 (no desire) to 3 (strong desire). These responses were totaled over a 28-day period to yield the monthly sexual desire score, which ranged from 0 to 84. These 2 studies also used the Female Sexual Function Index (FSFI) Desire domain as a secondary endpoint.

Study 3 used the FSFI Desire domain, comprising 2 questions, as the sexual desire co-primary endpoint:

• “Over the past 4 weeks, how often did you feel sexual desire or interest?” Responses ranged from 1 (almost never or never) to 5 (almost always or always).
• “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?” Responses ranged from 1 (very low or none at all) to 5 (very high).

In all 3 trials, flibanserin was associated with a small, yet statistically significant, improvement in change in monthly SSEs from baseline to Week 24 compared with placebo. In Study 1 and 2, there were no statistically significant differences between flibanserin and placebo for the electronic diary sexual desire endpoint. In the third study, there was statistically significant improvement in the change in sexual desire using the FSFI Desire domain with flibanserin compared with placebo. The FSFI Desire domain findings were consistent across all 3 trials. Flibanserin was associated with a decrease in sexual distress compared with placebo in all 3 studies.

Tolerability
Flibanserin was well tolerated in the 3 clinical trials. As the FDA noted, clinical trials are conducted under widely varying conditions and therefore adverse reaction rates observed in trials of flibanserin cannot be directly compared with those reported in clinical trials of another drug and might not reflect rates observed in clinical practice.

The discontinuation rate due to adverse reactions was 13% among patients treated with flibanserin, 100 mg at bedtime, and 6% among those taking placebo. The most common side effects were somnolence, dizziness, fatigue, nausea, insomnia, and dry mouth, which appear dose-dependent. Onset of most of these adverse events was within 14 days after the start of treatment.

Although hypotension and syncope rarely were seen with flibanserin alone in clinical trials, these adverse events occurred more frequently in the morning and when taken with alcohol and with some drugs (moderate or strong CYP3A4 inhibitors), and in patients with hepatic impairment. Therefore, women who drink alcohol or take a moderate or strong inhibitor of CYP3A4—both of which are contraindicated—and those with hepatic impairment should not take flibanserin.

Flibanserin should be taken at bedtime, because the risk of hypotension and syncope is higher when flibanserin is taken in the morning and because of associated sedation and somnolence.

Unique clinical issues
Flibanserin is the first FDA-approved medication for treating HSDD. It is important to note that the drug originally was developed as an antidepressant, but failed to show efficacy. Researchers noted that the drug was more effective than placebo when patients were asked, “How strong is your sexual desire?” The focus of development then shifted to a potential treatment of HSDD.

Flibanserin was not approved at 2 previous FDA hearings, mainly because of safety concerns. For the second hearing, the manufacturer, Boehringer Ingelheim, which sold the rights to the drug to Sprout Pharmaceuticals in 2011,⁶ did not present any new efficacy data, but provided additional safety data, such as research suggesting the absence of next-day driving impairment and data related to alcohol use (the study confirming hypotension associated with alcohol abuse used a small sample, and only 2 of 25 participants were women).

Contraindications
Flibanserin is contraindicated in patients using alcohol because of an increased risk of hypotension and syncope. A patient’s alcohol use should be evaluated before administering flibanserin, and patients should be counseled about the importance of abstaining from alcohol.

Similarly, concomitant use of flibanserin with a moderate or strong inhibitor of CYP3A4 increases the concentration of flibanserin and raises the risk of hypotension and syncope. Therefore, the use of a moderate or strong inhibitor of CYP3A4 in patients taking flibanserin is contraindicated. Similarly, patients with liver impairment should not take this drug.

Strong CYP2C19 inhibitors (proton-pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals) could increase flibanserin exposure, which may increase risk of hypotension, syncope, and CNS depression. Discuss these risks with your patients; doing so is particularly important when treating women of Chinese heritage, and some other Asian women, because 20% of these populations are genotypic CYP2C19 poor metabolizers.

Because of the increased risk of hypotension and syncope with alcohol use, flibanserin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Addyi REMS Program. Flibanserin can be prescribed or dispensed only by physicians and pharmacists who watch this program’s online slide presentation and passed a comprehension test.^a

Pregnant women should not take flibanserin because the effect on the fetus is unknown. Also, because the interaction with some oral contraceptives is unknown, patients should be cautioned about unwanted pregnancy. Women who are breastfeeding also should avoid using flibanserin because it is not known whether the drug is excreted in breast milk.

Women taking flibanserin also should avoid grapefruit juice, which increases flibanserin levels, and avoid using herbal products, resveratrol, and some over-the-counter drugs such as cimetidine. Women who have a depressive disorder also should avoid using flibanserin because their low sexual desire is more likely due to depression, which is not a therapeutic target for the drug.

Dosing
Flibanserin is provided in 100-mg film-coated tablets. It should be taken once a day at bedtime; titration is unnecessary. Length of treatment has not been determined, but it is recommended that patients stop flibanserin if they do not experience any benefit after 8 weeks. Although there is no guidance in the prescribing information, the medication probably could be stopped without tapering because withdrawal effects have not been observed.

Bottom Line
Flibanserin is FDA-approved for treating generalized, acquired hypoactive sexual desire disorder in premenopausal women. In clinical trials, the drug increased the number of satisfying sexual events and sexual desire, as measured by a diary and rating scales. Alcohol use and use of any moderate or strong inhibitor of cytochrome P450 3A4 are contraindicated in patients taking flibanserin because of an increased risk of hypotension and syncope.