Savvy Psychopharmacology

Mr. S, a 45-year-old veteran, was diagnosed with posttraumatic stress disorder (PTSD) 18 years ago after a tour of duty in the Persian Gulf. He had combat-related flashbacks triggered by the smell of gasoline or smoke from a fire, was easily startled, and began to isolate himself socially. However, his symptoms improved when he started volunteering at his local Veterans Affairs Medical Center. After he lost his job 3 years ago, Mr. S started experiencing flashbacks. He was irritable, easily startled, and avoided things that reminded him of his time in the Persian Gulf. His psychiatrist prescribed sertraline, titrated to 200 mg/d. The drug reduced the severity of his avoidance and hyperarousal symptoms and improved his mood.

During a clinic visit, Mr. S says he is doing well and can fall asleep at night but is having recurring nightmares about traumatic events that occurred during combat. These nightmares wake him up and have become more frequent, occurring once per night for the past month. Mr. S says he has been watching more news programs about conflicts in Afghanistan and Iraq since the nightmares began. His psychiatrist starts quetiapine, 50 mg at bedtime for 7 nights then 100 mg at bedtime, but after 6 weeks Mr. S says his nightmares continue.

PTSD occurs in approximately 19% of Vietnam war combat veterans¹ and 14% of service members returning from Iraq and Afghanistan.² PTSD symptoms are classified into clusters: intrusive/re-experiencing; avoidant/numbing; and hyperarousal.³ Nightmares are part of the intrusive/re-experiencing cluster, which is Criterion B in DSM-IV-TR. See Table 1 for a description of DSM-IV-TR PTSD criteria. Among PTSD patients, 50% to 70% report PTSD-associated nightmares.⁴ Despite adequate treatment targeted to improve PTSD’s core symptoms, symptoms such as sleep disturbances or nightmares often persist.

Table 1

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Nightmares and other sleep disturbances are associated with significant distress and daytime impairment and can interfere with PTSD recovery^4-8 by disrupting sleep-dependent processing of emotional experiences and causing repeated resensitization to trauma cues (Table 2).⁸

Table 2

Psychosocial consequences of sleep disruption in PTSD

Few randomized controlled medication trials specifically address PTSD-related nightmares. Most PTSD studies do not examine sleep outcomes as a primary measure, and comprehensive literature reviews could not offer evidence-based recommendations.^9,10 The American Academy of Sleep Medicine (AASM) also noted a paucity of PTSD studies that identified nightmares as a primary outcome measure.¹¹ See Table 3 for a list of recommended medication options for PTSD-associated nightmares.

Table 3

Recommended medication treatments for PTSD-associated nightmares

CASE CONTINUED: Medication change, improvement

After reviewing AASM’s treatment recommendations, we prescribe prazosin, 1 mg at bedtime for 7 nights, then increase by 1 mg at bedtime each week until Mr. S’s nightmares improve. He reports a substantial improvement in nightmare severity and frequency after a few weeks of treatment with prazosin, 5 mg at bedtime.

Prazosin

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented.^12,13 In open-label trials,^14-18 a chart review,¹⁹ and placebo-controlled trials,^20-22prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo (Table 4). In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.¹¹

Table 4

RCTs of prazosin for trauma-related nightmares

Atypical antipsychotics

Atypical antipsychotics have been used to reduce nightmares in PTSD; however, most of the evidence from studies evaluated in the AASM’s Best Practice Guide were considered to be low quality.¹¹ Quetiapine and ziprasidone were not included in the AASM review. See (Table 5) for a review of the evidence for atypical antipsychotics for treating PTSD nightmares.

Table 5

Combat-related nightmares: Evidence for atypical antipsychotics

Comparing prazosin and quetiapine. A historical prospective cohort study of 237 veterans with PTSD receiving prazosin or quetiapine for nighttime PTSD symptoms demonstrated that although the 2 drugs have similar efficacy (defined as symptomatic improvement) for short-term, 6-month treatment (61% vs 62%; P=.54), a higher percentage of patients continued prazosin long-term (3 to 6 years) than those taking quetiapine (48% vs 24%; P < .001).²³ Twenty-five percent of patients taking quetiapine switched to prazosin during the study, and approximately one-half of these patients remained on prazosin until the study’s end. Only 8% of prazosin patients switched to quetiapine, and none continued this therapy until study end.²³ Patients in the quetiapine group were more likely to discontinue the drug because of lack of efficacy (13% vs 3%; P=.03) and adverse effects (35% vs 18%; P=.008), specifically sedation (21% vs 2%; P < .001) and metabolic effects (9% vs 0%; P=.014), compared with prazosin. Although this trial may be the only published comparison study of prazosin and quetiapine, its methodological quality has been questioned, which makes it difficult to draw definitive conclusions.

Metabolic syndrome—elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol—is common among PTSD patients treated with antipsychotics.²⁴ This syndrome may be caused by medications, lifestyle factors, or long-term overactivation of stress-response pathways. A retrospective chart review at a community mental health center revealed that patients taking even low doses of quetiapine for insomnia gained an average of 5 lbs (P=.037).²⁵ Another retrospective chart review at 2 military hospitals reported that patients receiving low-dose quetiapine (≤100 mg/d) gained an average of slightly less than 1 lb per month, which adds up to approximately 10 lbs per year (P < .001).²⁶ The benefit of using atypical antipsychotics may be outweighed by metabolic risks such as obesity, new-onset diabetes, and dyslipidemia.²⁷

Prazosin is considered a first-line treatment for sleep disturbances and nightmares in PTSD because of its superior long-term efficacy and decreased adverse effects compared with quetiapine.

Related Resources

• American Psychiatric Association. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2004.
• Veterans Affairs/Department of Defense clinical practice guidelines. Management of traumatic stress disorder and acute stress reaction. www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp.

Drug Brand Names

• Prazosin • Minipress
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

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

Mr. S, a 45-year-old veteran, was diagnosed with posttraumatic stress disorder (PTSD) 18 years ago after a tour of duty in the Persian Gulf. He had combat-related flashbacks triggered by the smell of gasoline or smoke from a fire, was easily startled, and began to isolate himself socially. However, his symptoms improved when he started volunteering at his local Veterans Affairs Medical Center. After he lost his job 3 years ago, Mr. S started experiencing flashbacks. He was irritable, easily startled, and avoided things that reminded him of his time in the Persian Gulf. His psychiatrist prescribed sertraline, titrated to 200 mg/d. The drug reduced the severity of his avoidance and hyperarousal symptoms and improved his mood.

During a clinic visit, Mr. S says he is doing well and can fall asleep at night but is having recurring nightmares about traumatic events that occurred during combat. These nightmares wake him up and have become more frequent, occurring once per night for the past month. Mr. S says he has been watching more news programs about conflicts in Afghanistan and Iraq since the nightmares began. His psychiatrist starts quetiapine, 50 mg at bedtime for 7 nights then 100 mg at bedtime, but after 6 weeks Mr. S says his nightmares continue.

PTSD occurs in approximately 19% of Vietnam war combat veterans¹ and 14% of service members returning from Iraq and Afghanistan.² PTSD symptoms are classified into clusters: intrusive/re-experiencing; avoidant/numbing; and hyperarousal.³ Nightmares are part of the intrusive/re-experiencing cluster, which is Criterion B in DSM-IV-TR. See Table 1 for a description of DSM-IV-TR PTSD criteria. Among PTSD patients, 50% to 70% report PTSD-associated nightmares.⁴ Despite adequate treatment targeted to improve PTSD’s core symptoms, symptoms such as sleep disturbances or nightmares often persist.

Table 1

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Nightmares and other sleep disturbances are associated with significant distress and daytime impairment and can interfere with PTSD recovery^4-8 by disrupting sleep-dependent processing of emotional experiences and causing repeated resensitization to trauma cues (Table 2).⁸

Table 2

Psychosocial consequences of sleep disruption in PTSD

Few randomized controlled medication trials specifically address PTSD-related nightmares. Most PTSD studies do not examine sleep outcomes as a primary measure, and comprehensive literature reviews could not offer evidence-based recommendations.^9,10 The American Academy of Sleep Medicine (AASM) also noted a paucity of PTSD studies that identified nightmares as a primary outcome measure.¹¹ See Table 3 for a list of recommended medication options for PTSD-associated nightmares.

Table 3

Recommended medication treatments for PTSD-associated nightmares

CASE CONTINUED: Medication change, improvement

After reviewing AASM’s treatment recommendations, we prescribe prazosin, 1 mg at bedtime for 7 nights, then increase by 1 mg at bedtime each week until Mr. S’s nightmares improve. He reports a substantial improvement in nightmare severity and frequency after a few weeks of treatment with prazosin, 5 mg at bedtime.

Prazosin

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented.^12,13 In open-label trials,^14-18 a chart review,¹⁹ and placebo-controlled trials,^20-22prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo (Table 4). In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.¹¹

Table 4

RCTs of prazosin for trauma-related nightmares

Atypical antipsychotics

Atypical antipsychotics have been used to reduce nightmares in PTSD; however, most of the evidence from studies evaluated in the AASM’s Best Practice Guide were considered to be low quality.¹¹ Quetiapine and ziprasidone were not included in the AASM review. See (Table 5) for a review of the evidence for atypical antipsychotics for treating PTSD nightmares.

Table 5

Combat-related nightmares: Evidence for atypical antipsychotics

Comparing prazosin and quetiapine. A historical prospective cohort study of 237 veterans with PTSD receiving prazosin or quetiapine for nighttime PTSD symptoms demonstrated that although the 2 drugs have similar efficacy (defined as symptomatic improvement) for short-term, 6-month treatment (61% vs 62%; P=.54), a higher percentage of patients continued prazosin long-term (3 to 6 years) than those taking quetiapine (48% vs 24%; P < .001).²³ Twenty-five percent of patients taking quetiapine switched to prazosin during the study, and approximately one-half of these patients remained on prazosin until the study’s end. Only 8% of prazosin patients switched to quetiapine, and none continued this therapy until study end.²³ Patients in the quetiapine group were more likely to discontinue the drug because of lack of efficacy (13% vs 3%; P=.03) and adverse effects (35% vs 18%; P=.008), specifically sedation (21% vs 2%; P < .001) and metabolic effects (9% vs 0%; P=.014), compared with prazosin. Although this trial may be the only published comparison study of prazosin and quetiapine, its methodological quality has been questioned, which makes it difficult to draw definitive conclusions.

Metabolic syndrome—elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol—is common among PTSD patients treated with antipsychotics.²⁴ This syndrome may be caused by medications, lifestyle factors, or long-term overactivation of stress-response pathways. A retrospective chart review at a community mental health center revealed that patients taking even low doses of quetiapine for insomnia gained an average of 5 lbs (P=.037).²⁵ Another retrospective chart review at 2 military hospitals reported that patients receiving low-dose quetiapine (≤100 mg/d) gained an average of slightly less than 1 lb per month, which adds up to approximately 10 lbs per year (P < .001).²⁶ The benefit of using atypical antipsychotics may be outweighed by metabolic risks such as obesity, new-onset diabetes, and dyslipidemia.²⁷

Prazosin is considered a first-line treatment for sleep disturbances and nightmares in PTSD because of its superior long-term efficacy and decreased adverse effects compared with quetiapine.

Related Resources

• American Psychiatric Association. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2004.
• Veterans Affairs/Department of Defense clinical practice guidelines. Management of traumatic stress disorder and acute stress reaction. www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp.

Drug Brand Names

• Prazosin • Minipress
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

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

Mr. S, a 45-year-old veteran, was diagnosed with posttraumatic stress disorder (PTSD) 18 years ago after a tour of duty in the Persian Gulf. He had combat-related flashbacks triggered by the smell of gasoline or smoke from a fire, was easily startled, and began to isolate himself socially. However, his symptoms improved when he started volunteering at his local Veterans Affairs Medical Center. After he lost his job 3 years ago, Mr. S started experiencing flashbacks. He was irritable, easily startled, and avoided things that reminded him of his time in the Persian Gulf. His psychiatrist prescribed sertraline, titrated to 200 mg/d. The drug reduced the severity of his avoidance and hyperarousal symptoms and improved his mood.

During a clinic visit, Mr. S says he is doing well and can fall asleep at night but is having recurring nightmares about traumatic events that occurred during combat. These nightmares wake him up and have become more frequent, occurring once per night for the past month. Mr. S says he has been watching more news programs about conflicts in Afghanistan and Iraq since the nightmares began. His psychiatrist starts quetiapine, 50 mg at bedtime for 7 nights then 100 mg at bedtime, but after 6 weeks Mr. S says his nightmares continue.

PTSD occurs in approximately 19% of Vietnam war combat veterans¹ and 14% of service members returning from Iraq and Afghanistan.² PTSD symptoms are classified into clusters: intrusive/re-experiencing; avoidant/numbing; and hyperarousal.³ Nightmares are part of the intrusive/re-experiencing cluster, which is Criterion B in DSM-IV-TR. See Table 1 for a description of DSM-IV-TR PTSD criteria. Among PTSD patients, 50% to 70% report PTSD-associated nightmares.⁴ Despite adequate treatment targeted to improve PTSD’s core symptoms, symptoms such as sleep disturbances or nightmares often persist.

Table 1

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Nightmares and other sleep disturbances are associated with significant distress and daytime impairment and can interfere with PTSD recovery^4-8 by disrupting sleep-dependent processing of emotional experiences and causing repeated resensitization to trauma cues (Table 2).⁸

Table 2

Psychosocial consequences of sleep disruption in PTSD

Few randomized controlled medication trials specifically address PTSD-related nightmares. Most PTSD studies do not examine sleep outcomes as a primary measure, and comprehensive literature reviews could not offer evidence-based recommendations.^9,10 The American Academy of Sleep Medicine (AASM) also noted a paucity of PTSD studies that identified nightmares as a primary outcome measure.¹¹ See Table 3 for a list of recommended medication options for PTSD-associated nightmares.

Table 3

Recommended medication treatments for PTSD-associated nightmares

CASE CONTINUED: Medication change, improvement

After reviewing AASM’s treatment recommendations, we prescribe prazosin, 1 mg at bedtime for 7 nights, then increase by 1 mg at bedtime each week until Mr. S’s nightmares improve. He reports a substantial improvement in nightmare severity and frequency after a few weeks of treatment with prazosin, 5 mg at bedtime.

Prazosin

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented.^12,13 In open-label trials,^14-18 a chart review,¹⁹ and placebo-controlled trials,^20-22prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo (Table 4). In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.¹¹

Table 4

RCTs of prazosin for trauma-related nightmares

Atypical antipsychotics

Atypical antipsychotics have been used to reduce nightmares in PTSD; however, most of the evidence from studies evaluated in the AASM’s Best Practice Guide were considered to be low quality.¹¹ Quetiapine and ziprasidone were not included in the AASM review. See (Table 5) for a review of the evidence for atypical antipsychotics for treating PTSD nightmares.

Table 5

Combat-related nightmares: Evidence for atypical antipsychotics

Comparing prazosin and quetiapine. A historical prospective cohort study of 237 veterans with PTSD receiving prazosin or quetiapine for nighttime PTSD symptoms demonstrated that although the 2 drugs have similar efficacy (defined as symptomatic improvement) for short-term, 6-month treatment (61% vs 62%; P=.54), a higher percentage of patients continued prazosin long-term (3 to 6 years) than those taking quetiapine (48% vs 24%; P < .001).²³ Twenty-five percent of patients taking quetiapine switched to prazosin during the study, and approximately one-half of these patients remained on prazosin until the study’s end. Only 8% of prazosin patients switched to quetiapine, and none continued this therapy until study end.²³ Patients in the quetiapine group were more likely to discontinue the drug because of lack of efficacy (13% vs 3%; P=.03) and adverse effects (35% vs 18%; P=.008), specifically sedation (21% vs 2%; P < .001) and metabolic effects (9% vs 0%; P=.014), compared with prazosin. Although this trial may be the only published comparison study of prazosin and quetiapine, its methodological quality has been questioned, which makes it difficult to draw definitive conclusions.

Metabolic syndrome—elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol—is common among PTSD patients treated with antipsychotics.²⁴ This syndrome may be caused by medications, lifestyle factors, or long-term overactivation of stress-response pathways. A retrospective chart review at a community mental health center revealed that patients taking even low doses of quetiapine for insomnia gained an average of 5 lbs (P=.037).²⁵ Another retrospective chart review at 2 military hospitals reported that patients receiving low-dose quetiapine (≤100 mg/d) gained an average of slightly less than 1 lb per month, which adds up to approximately 10 lbs per year (P < .001).²⁶ The benefit of using atypical antipsychotics may be outweighed by metabolic risks such as obesity, new-onset diabetes, and dyslipidemia.²⁷

Prazosin is considered a first-line treatment for sleep disturbances and nightmares in PTSD because of its superior long-term efficacy and decreased adverse effects compared with quetiapine.

Related Resources

• American Psychiatric Association. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2004.
• Veterans Affairs/Department of Defense clinical practice guidelines. Management of traumatic stress disorder and acute stress reaction. www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp.

Drug Brand Names

• Prazosin • Minipress
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

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

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Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

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

As prescribed by his internist, Mr. G, age 44, takes 10 mg of methadone every 4 hours for chronic back pain secondary to a work-related injury 3 years ago. He experiences minimal sedation. Mr. G presents for psychiatric evaluation with complaints of increasing irritability, poor focus, low energy, and lack of interest in usual activities. The psychiatrist diagnoses him with depressive disorder not otherwise specified, and prescribes fluoxetine, 20 mg/d. Three weeks later, Mr. G’s wife contacts the psychiatrist reporting that her husband seems “overmedicated” and describes excess drowsiness and slowed thought processing.

After discussion with Mr. G’s internist and pharmacist, the psychiatrist decides that this oversedation may represent a drug-drug interaction between methadone and fluoxetine resulting in higher-than-expected methadone serum levels. Mr. G is instructed to stop fluoxetine with no taper, and his methadone dose is lowered with good results. Over the next 2 weeks Mr. G is titrated back to his original methadone dose and is re-evaluated by the psychiatrist to discuss medication options to address his depression.

Psychiatrists commonly encounter patients who receive opiate medications for chronic pain. Being aware of potential drug-drug interactions between opiate medications and psychotropics can help avoid adverse effects and combinations that may affect the efficacy of either drug. Pharmacokinetic interactions may affect your choice of psychiatric medication and should be taken into account when addressing adverse effects in any patient who takes opiates and psychotropics.

Metabolic pathways

The primary metabolic pathways for opiate metabolism are the cytochrome P450 (CYP) 2D6 and 3A4 isoenzymes. Depending on the agent used, prescribers may need to consider interactions for both pathways (Table 1^1,2 and Table 2¹). For example, oxycodone is metabolized via 2D6 and 3A4 isoenzymes and is a potent analgesic with oxymorphone and noroxycodone as its active metabolites. These metabolites, however, make a negligible contribution to oxycodone’s analgesic effect.^3,4 Metabolism by the 3A4 isoenzyme is the principal oxidative pathway and the 2D6 site accounts for approximately 10% of oxycodone metabolism. A randomized, placebo-controlled, crossover study showed that 2D6 inhibition by paroxetine had no significant effect on oxycodone levels; however, a combination of paroxetine and itraconazole, a potent 3A4 inhibitor, resulted in substantial increases in oxycodone plasma levels.⁵ Remain vigilant for possible opiate toxicity when administering oxycodone with 3A4 inhibitors.

Methadone and meperidine also involve dual pathways. Methadone is metabolized primarily by 3A4 and 2B6, with 2D6 playing a smaller role.⁶ CYP2D6 seems to play an important part in metabolizing the R-enantiomer of methadone, which is largely responsible for the drug’s opiate effects, such as analgesia and respiratory depression.^7,8 Induction of the 3A4 isoenzyme may result in methadone withdrawal, and inhibition may cause methadone toxicity.⁹ Inducers of 3A4, such as carbamazepine, and inhibitors, such as fluoxetine and fluvoxamine, should be avoided or used very cautiously in patients taking methadone. The 2B6 and 2D6 isoenzymes also may increase or decrease methadone levels and should be treated similarly. In Mr. G’s case, fluoxetine inhibited all 3 isoenzymes that are primarily responsible for methadone metabolism. A better antidepressant choice for Mr. G may have been venlafaxine, which is known to only mildly inhibit 2D6, or mirtazapine, which does not seem to inhibit the major CYP isoforms to an appreciable degree.¹⁰

Although the full scope of meperidine metabolism has not been identified,⁹ an in vitro test demonstrated that 2B6 and 3A4 play important roles in metabolizing meperidine to normeperidine, its major metabolite.¹¹ Normeperidine does not provide analgesia and is associated with neurotoxicity, including anxiety, tremor, muscle twitching, and seizure.¹² Agents that induce 3A4—such as carbamazepine or St. John’s wort—may contribute to neurotoxicity.⁹ Inhibition of these isoenzymes may increase meperidine levels and lead to anticholinergic toxicity or respiratory and central nervous system depression.^13,14

Opiates metabolized by the 2D6 isoenzyme include codeine, hydrocodone, and tramadol. The analgesic effect of codeine seems dependent on 2D6 metabolism. Via this pathway, codeine is converted into morphine, which has a 300-times stronger affinity for the μ opioid receptor compared with codeine. 2D6 poor metabolizers have shown codeine intolerance and toxicity.³ Psychotropics known to strongly inhibit 2D6 isoenzyme processes—such as paroxetine, fluoxetine, and bupropion—should be avoided in patients taking codeine to prevent adverse effects and potential loss of efficacy. Better antidepressant choices include citalopram or venlafaxine, which inhibit 2D6 to a lesser degree.

Hydrocodone may be a viable option for patients taking 2D6 inhibitors. Hydrocodone is metabolized by 2D6 into hydromorphone, which is 7 to 33 times more potent than hydrocodone.¹⁵ Unlike codeine, 2D6 inhibition may have little effect on hydrocodone’s analgesic properties. Animal studies have shown that inhibition of the CYP analog to 2D6 does not affect analgesic response. In humans, 2D6 inhibition does not seem to affect hydrocodone’s abuse liability.¹⁶ Two case reports describe known 2D6 poor metabolizers who showed at least a partial response to hydrocodone.^15,16

Tramadol’s analgesic properties may be related to serotonin and norepinephrine reuptake inhibition. It is less potent than codeine but is metabolized via the 2D6 isoenzyme into 0-desmethyltramadol, which is up to 200 times stronger than its parent compound.¹⁷ Clinicians should be aware that tramadol’s efficacy may be decreased when coadministered with 2D6 inhibitors. In a randomized, placebo-controlled trial, paroxetine, a potent 2D6 inhibitor, was shown to lessen the analgesic effect of tramadol.¹⁸

The 3A4 site is the primary pathway for fentanyl metabolism. Agents that inhibit 3A4 could increase fentanyl plasma concentration, leading to respiratory depression.¹⁹ Examples of 3A4 inhibitors include fluoxetine and fluvoxamine.

Psychotropics may inhibit or induce P450 isoenzymes to varying degrees. For example, paroxetine and citalopram are known to inhibit 2D6 but paroxetine is a stronger inhibitor; therefore, a significant drug-drug interaction is more likely with paroxetine and a 2D6 substrate than the same substrate administered with citalopram.

Table 1

Cytochrome P450 isoenzymes inhibited and induced by psychotropics

Table 2

Cytochrome P450 isoenzymes inhibiting and inducing opiate metabolism

Other considerations

In addition to pharmacokinetic interactions, it is important to consider synergistic effects of some opiates and psychotropics. Examples include:

• additive effect on respiratory depression by benzodiazepines and opiates
• increased risk of serotonin syndrome and seizure when using tramadol with selective serotonin reuptake inhibitors or tricyclic antidepressants
• additive prolongation of the QTc interval by methadone when used with psychotropics known to prolong the QTc, such as ziprasidone.^9,17,20

Careful attention to these interactions and collaboration among providers can ensure the best outcome for our patients. In Mr. G’s case, collaboration with his internist would be in order, particularly if antidepressant choices are limited. In consultation with the psychiatrist, the internist might choose another opiate to treat Mr. G’s pain that would not interact with fluoxetine. If Mr. G and his physician have struggled to manage his pain and if he is stable on the current regimen, selecting a different antidepressant may be warranted.

Related Resources

• Indiana University School of Medicine drug interactions: cytochrome P450 drug interaction table. http://medicine.iupui.edu/clinpharm/ddis/table.asp.
• Ferrando SJ, Levenson JL, Owen JA, eds. Clinical manual of psychopharmacology in the medically ill. Arlington, VA: American Psychiatric Publishing, Inc; 2010.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fentanyl • Duragesic, Actiq
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Hydrocodone • Lortab, Vicodin, others
• Itraconazole • Sporanox
• Meperidine • Demerol
• Methadone • Dolophine, Methadose
• Mirtazapine • Remeron
• Morphine • Avinza, Duramorph, others
• Oxycodone • OxyContin, Roxicodone
• Paroxetine • Paxil
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tramadol • Ultram
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

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

As prescribed by his internist, Mr. G, age 44, takes 10 mg of methadone every 4 hours for chronic back pain secondary to a work-related injury 3 years ago. He experiences minimal sedation. Mr. G presents for psychiatric evaluation with complaints of increasing irritability, poor focus, low energy, and lack of interest in usual activities. The psychiatrist diagnoses him with depressive disorder not otherwise specified, and prescribes fluoxetine, 20 mg/d. Three weeks later, Mr. G’s wife contacts the psychiatrist reporting that her husband seems “overmedicated” and describes excess drowsiness and slowed thought processing.

After discussion with Mr. G’s internist and pharmacist, the psychiatrist decides that this oversedation may represent a drug-drug interaction between methadone and fluoxetine resulting in higher-than-expected methadone serum levels. Mr. G is instructed to stop fluoxetine with no taper, and his methadone dose is lowered with good results. Over the next 2 weeks Mr. G is titrated back to his original methadone dose and is re-evaluated by the psychiatrist to discuss medication options to address his depression.

Psychiatrists commonly encounter patients who receive opiate medications for chronic pain. Being aware of potential drug-drug interactions between opiate medications and psychotropics can help avoid adverse effects and combinations that may affect the efficacy of either drug. Pharmacokinetic interactions may affect your choice of psychiatric medication and should be taken into account when addressing adverse effects in any patient who takes opiates and psychotropics.

Metabolic pathways

The primary metabolic pathways for opiate metabolism are the cytochrome P450 (CYP) 2D6 and 3A4 isoenzymes. Depending on the agent used, prescribers may need to consider interactions for both pathways (Table 1^1,2 and Table 2¹). For example, oxycodone is metabolized via 2D6 and 3A4 isoenzymes and is a potent analgesic with oxymorphone and noroxycodone as its active metabolites. These metabolites, however, make a negligible contribution to oxycodone’s analgesic effect.^3,4 Metabolism by the 3A4 isoenzyme is the principal oxidative pathway and the 2D6 site accounts for approximately 10% of oxycodone metabolism. A randomized, placebo-controlled, crossover study showed that 2D6 inhibition by paroxetine had no significant effect on oxycodone levels; however, a combination of paroxetine and itraconazole, a potent 3A4 inhibitor, resulted in substantial increases in oxycodone plasma levels.⁵ Remain vigilant for possible opiate toxicity when administering oxycodone with 3A4 inhibitors.

Methadone and meperidine also involve dual pathways. Methadone is metabolized primarily by 3A4 and 2B6, with 2D6 playing a smaller role.⁶ CYP2D6 seems to play an important part in metabolizing the R-enantiomer of methadone, which is largely responsible for the drug’s opiate effects, such as analgesia and respiratory depression.^7,8 Induction of the 3A4 isoenzyme may result in methadone withdrawal, and inhibition may cause methadone toxicity.⁹ Inducers of 3A4, such as carbamazepine, and inhibitors, such as fluoxetine and fluvoxamine, should be avoided or used very cautiously in patients taking methadone. The 2B6 and 2D6 isoenzymes also may increase or decrease methadone levels and should be treated similarly. In Mr. G’s case, fluoxetine inhibited all 3 isoenzymes that are primarily responsible for methadone metabolism. A better antidepressant choice for Mr. G may have been venlafaxine, which is known to only mildly inhibit 2D6, or mirtazapine, which does not seem to inhibit the major CYP isoforms to an appreciable degree.¹⁰

Although the full scope of meperidine metabolism has not been identified,⁹ an in vitro test demonstrated that 2B6 and 3A4 play important roles in metabolizing meperidine to normeperidine, its major metabolite.¹¹ Normeperidine does not provide analgesia and is associated with neurotoxicity, including anxiety, tremor, muscle twitching, and seizure.¹² Agents that induce 3A4—such as carbamazepine or St. John’s wort—may contribute to neurotoxicity.⁹ Inhibition of these isoenzymes may increase meperidine levels and lead to anticholinergic toxicity or respiratory and central nervous system depression.^13,14

Opiates metabolized by the 2D6 isoenzyme include codeine, hydrocodone, and tramadol. The analgesic effect of codeine seems dependent on 2D6 metabolism. Via this pathway, codeine is converted into morphine, which has a 300-times stronger affinity for the μ opioid receptor compared with codeine. 2D6 poor metabolizers have shown codeine intolerance and toxicity.³ Psychotropics known to strongly inhibit 2D6 isoenzyme processes—such as paroxetine, fluoxetine, and bupropion—should be avoided in patients taking codeine to prevent adverse effects and potential loss of efficacy. Better antidepressant choices include citalopram or venlafaxine, which inhibit 2D6 to a lesser degree.

Hydrocodone may be a viable option for patients taking 2D6 inhibitors. Hydrocodone is metabolized by 2D6 into hydromorphone, which is 7 to 33 times more potent than hydrocodone.¹⁵ Unlike codeine, 2D6 inhibition may have little effect on hydrocodone’s analgesic properties. Animal studies have shown that inhibition of the CYP analog to 2D6 does not affect analgesic response. In humans, 2D6 inhibition does not seem to affect hydrocodone’s abuse liability.¹⁶ Two case reports describe known 2D6 poor metabolizers who showed at least a partial response to hydrocodone.^15,16

Tramadol’s analgesic properties may be related to serotonin and norepinephrine reuptake inhibition. It is less potent than codeine but is metabolized via the 2D6 isoenzyme into 0-desmethyltramadol, which is up to 200 times stronger than its parent compound.¹⁷ Clinicians should be aware that tramadol’s efficacy may be decreased when coadministered with 2D6 inhibitors. In a randomized, placebo-controlled trial, paroxetine, a potent 2D6 inhibitor, was shown to lessen the analgesic effect of tramadol.¹⁸

The 3A4 site is the primary pathway for fentanyl metabolism. Agents that inhibit 3A4 could increase fentanyl plasma concentration, leading to respiratory depression.¹⁹ Examples of 3A4 inhibitors include fluoxetine and fluvoxamine.

Psychotropics may inhibit or induce P450 isoenzymes to varying degrees. For example, paroxetine and citalopram are known to inhibit 2D6 but paroxetine is a stronger inhibitor; therefore, a significant drug-drug interaction is more likely with paroxetine and a 2D6 substrate than the same substrate administered with citalopram.

Table 1

Cytochrome P450 isoenzymes inhibited and induced by psychotropics

Table 2

Cytochrome P450 isoenzymes inhibiting and inducing opiate metabolism

Other considerations

In addition to pharmacokinetic interactions, it is important to consider synergistic effects of some opiates and psychotropics. Examples include:

• additive effect on respiratory depression by benzodiazepines and opiates
• increased risk of serotonin syndrome and seizure when using tramadol with selective serotonin reuptake inhibitors or tricyclic antidepressants
• additive prolongation of the QTc interval by methadone when used with psychotropics known to prolong the QTc, such as ziprasidone.^9,17,20

Careful attention to these interactions and collaboration among providers can ensure the best outcome for our patients. In Mr. G’s case, collaboration with his internist would be in order, particularly if antidepressant choices are limited. In consultation with the psychiatrist, the internist might choose another opiate to treat Mr. G’s pain that would not interact with fluoxetine. If Mr. G and his physician have struggled to manage his pain and if he is stable on the current regimen, selecting a different antidepressant may be warranted.

Related Resources

• Indiana University School of Medicine drug interactions: cytochrome P450 drug interaction table. http://medicine.iupui.edu/clinpharm/ddis/table.asp.
• Ferrando SJ, Levenson JL, Owen JA, eds. Clinical manual of psychopharmacology in the medically ill. Arlington, VA: American Psychiatric Publishing, Inc; 2010.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fentanyl • Duragesic, Actiq
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Hydrocodone • Lortab, Vicodin, others
• Itraconazole • Sporanox
• Meperidine • Demerol
• Methadone • Dolophine, Methadose
• Mirtazapine • Remeron
• Morphine • Avinza, Duramorph, others
• Oxycodone • OxyContin, Roxicodone
• Paroxetine • Paxil
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tramadol • Ultram
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

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

As prescribed by his internist, Mr. G, age 44, takes 10 mg of methadone every 4 hours for chronic back pain secondary to a work-related injury 3 years ago. He experiences minimal sedation. Mr. G presents for psychiatric evaluation with complaints of increasing irritability, poor focus, low energy, and lack of interest in usual activities. The psychiatrist diagnoses him with depressive disorder not otherwise specified, and prescribes fluoxetine, 20 mg/d. Three weeks later, Mr. G’s wife contacts the psychiatrist reporting that her husband seems “overmedicated” and describes excess drowsiness and slowed thought processing.

After discussion with Mr. G’s internist and pharmacist, the psychiatrist decides that this oversedation may represent a drug-drug interaction between methadone and fluoxetine resulting in higher-than-expected methadone serum levels. Mr. G is instructed to stop fluoxetine with no taper, and his methadone dose is lowered with good results. Over the next 2 weeks Mr. G is titrated back to his original methadone dose and is re-evaluated by the psychiatrist to discuss medication options to address his depression.

Psychiatrists commonly encounter patients who receive opiate medications for chronic pain. Being aware of potential drug-drug interactions between opiate medications and psychotropics can help avoid adverse effects and combinations that may affect the efficacy of either drug. Pharmacokinetic interactions may affect your choice of psychiatric medication and should be taken into account when addressing adverse effects in any patient who takes opiates and psychotropics.

Metabolic pathways

The primary metabolic pathways for opiate metabolism are the cytochrome P450 (CYP) 2D6 and 3A4 isoenzymes. Depending on the agent used, prescribers may need to consider interactions for both pathways (Table 1^1,2 and Table 2¹). For example, oxycodone is metabolized via 2D6 and 3A4 isoenzymes and is a potent analgesic with oxymorphone and noroxycodone as its active metabolites. These metabolites, however, make a negligible contribution to oxycodone’s analgesic effect.^3,4 Metabolism by the 3A4 isoenzyme is the principal oxidative pathway and the 2D6 site accounts for approximately 10% of oxycodone metabolism. A randomized, placebo-controlled, crossover study showed that 2D6 inhibition by paroxetine had no significant effect on oxycodone levels; however, a combination of paroxetine and itraconazole, a potent 3A4 inhibitor, resulted in substantial increases in oxycodone plasma levels.⁵ Remain vigilant for possible opiate toxicity when administering oxycodone with 3A4 inhibitors.

Methadone and meperidine also involve dual pathways. Methadone is metabolized primarily by 3A4 and 2B6, with 2D6 playing a smaller role.⁶ CYP2D6 seems to play an important part in metabolizing the R-enantiomer of methadone, which is largely responsible for the drug’s opiate effects, such as analgesia and respiratory depression.^7,8 Induction of the 3A4 isoenzyme may result in methadone withdrawal, and inhibition may cause methadone toxicity.⁹ Inducers of 3A4, such as carbamazepine, and inhibitors, such as fluoxetine and fluvoxamine, should be avoided or used very cautiously in patients taking methadone. The 2B6 and 2D6 isoenzymes also may increase or decrease methadone levels and should be treated similarly. In Mr. G’s case, fluoxetine inhibited all 3 isoenzymes that are primarily responsible for methadone metabolism. A better antidepressant choice for Mr. G may have been venlafaxine, which is known to only mildly inhibit 2D6, or mirtazapine, which does not seem to inhibit the major CYP isoforms to an appreciable degree.¹⁰

Although the full scope of meperidine metabolism has not been identified,⁹ an in vitro test demonstrated that 2B6 and 3A4 play important roles in metabolizing meperidine to normeperidine, its major metabolite.¹¹ Normeperidine does not provide analgesia and is associated with neurotoxicity, including anxiety, tremor, muscle twitching, and seizure.¹² Agents that induce 3A4—such as carbamazepine or St. John’s wort—may contribute to neurotoxicity.⁹ Inhibition of these isoenzymes may increase meperidine levels and lead to anticholinergic toxicity or respiratory and central nervous system depression.^13,14

Opiates metabolized by the 2D6 isoenzyme include codeine, hydrocodone, and tramadol. The analgesic effect of codeine seems dependent on 2D6 metabolism. Via this pathway, codeine is converted into morphine, which has a 300-times stronger affinity for the μ opioid receptor compared with codeine. 2D6 poor metabolizers have shown codeine intolerance and toxicity.³ Psychotropics known to strongly inhibit 2D6 isoenzyme processes—such as paroxetine, fluoxetine, and bupropion—should be avoided in patients taking codeine to prevent adverse effects and potential loss of efficacy. Better antidepressant choices include citalopram or venlafaxine, which inhibit 2D6 to a lesser degree.