Leslie Citrome, MD, MPH

In “Treating chronic insomnia: An alternating medication strategy” (Current Psychiatry, October 2023, p. 25-31, doi:10.12788/cp.0397), Dr. Kaplan correctly identified tolerance and tachyphylaxis as significant problems when prescribing traditional hypnotics, and proposed a solution of using 2 sleep medications, each having a different mechanism of action, on an alternating schedule. However, with the availability of the dual orexin receptor antagonists (DORAs) daridorexant, lemborexant, and suvorexant, this approach is unnecessary. Moreover, the mechanism of action of orexin receptor antagonism directly addresses extant hyperarousal by decreasing wake signaling, without any deleterious effect on sleep architecture.¹ Additionally, the DORAs are not associated with physiological dependence, withdrawal, or rebound. Their efficacy profile is as good as or better than other FDA-approved agents for insomnia disorder.¹ An obstacle to their use is that they are not yet available as generic products, but access is facilitated by the manufacturers’ patient assistance programs. Additional resources elaborate on indirect comparisons among agents using number needed to treat and number needed to harm, metrics that are helpful when clinically appraising new agents.^2-5

Leslie Citrome, MD, MPH
Valhalla, New York

In “Treating chronic insomnia: An alternating medication strategy” (Current Psychiatry, October 2023, p. 25-31, doi:10.12788/cp.0397), Dr. Kaplan correctly identified tolerance and tachyphylaxis as significant problems when prescribing traditional hypnotics, and proposed a solution of using 2 sleep medications, each having a different mechanism of action, on an alternating schedule. However, with the availability of the dual orexin receptor antagonists (DORAs) daridorexant, lemborexant, and suvorexant, this approach is unnecessary. Moreover, the mechanism of action of orexin receptor antagonism directly addresses extant hyperarousal by decreasing wake signaling, without any deleterious effect on sleep architecture.¹ Additionally, the DORAs are not associated with physiological dependence, withdrawal, or rebound. Their efficacy profile is as good as or better than other FDA-approved agents for insomnia disorder.¹ An obstacle to their use is that they are not yet available as generic products, but access is facilitated by the manufacturers’ patient assistance programs. Additional resources elaborate on indirect comparisons among agents using number needed to treat and number needed to harm, metrics that are helpful when clinically appraising new agents.^2-5

Leslie Citrome, MD, MPH
Valhalla, New York

In “Treating chronic insomnia: An alternating medication strategy” (Current Psychiatry, October 2023, p. 25-31, doi:10.12788/cp.0397), Dr. Kaplan correctly identified tolerance and tachyphylaxis as significant problems when prescribing traditional hypnotics, and proposed a solution of using 2 sleep medications, each having a different mechanism of action, on an alternating schedule. However, with the availability of the dual orexin receptor antagonists (DORAs) daridorexant, lemborexant, and suvorexant, this approach is unnecessary. Moreover, the mechanism of action of orexin receptor antagonism directly addresses extant hyperarousal by decreasing wake signaling, without any deleterious effect on sleep architecture.¹ Additionally, the DORAs are not associated with physiological dependence, withdrawal, or rebound. Their efficacy profile is as good as or better than other FDA-approved agents for insomnia disorder.¹ An obstacle to their use is that they are not yet available as generic products, but access is facilitated by the manufacturers’ patient assistance programs. Additional resources elaborate on indirect comparisons among agents using number needed to treat and number needed to harm, metrics that are helpful when clinically appraising new agents.^2-5

Leslie Citrome, MD, MPH
Valhalla, New York

Approved by the FDA on April 5, 2022, dexmedetomidine sublingual film (Igalmi, manufactured and distributed by BioXcel Therapeutics, Inc., New Haven, CT USA) is indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder (Table).^1,2 It is administered sublingually or buccally under the supervision of a health care provider. After administration, patients should have their vital signs and alertness assessed but there is no FDA Risk Evaluation and Mitigation Strategy (REMS) required for use. A limitation of use is that the safety and effectiveness of dexmedetomidine sublingual film has not been established beyond 24 hours from the first dose.² There are no contraindications for use.²

Dexmedetomidine is a well-known efficacious alpha-2 adrenergic receptor agonist available since 1999 in an IV formulation indicated for sedation of initially intubated and mechanically ventilated patients in an ICU setting, and sedation of nonintubated patients prior to and/or during surgical and other procedures.^3,4 The reformulation of dexmedetomidine as a sublingual film allows the broader use of this agent in psychiatric settings when managing agitation in patients with schizophrenia or bipolar disorder, and thus potentially avoiding the use of IM administration of antipsychotics and/or benzodiazepines. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.⁵

Dosing

Dexmedetomidine sublingual film is distributed commercially in the following strengths: 180 mcg and 120 mcg. It consists of a lightly mint-flavored, rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. Dosage strengths of 90 mcg and 60 mcg are available by cutting the 180 mcg or 120 mcg film in half between the 2 visible darker blue dots. The recommended dose depends on the severity of agitation, age, and the presence of hepatic impairment.² For severe agitation, the recommended dose is 180 mcg. For mild or moderate agitation, the recommended dose is 120 mcg. Dosage is reduced in patients with mild/moderate hepatic impairment (120 mcg for severe agitation and 90 mcg for mild or moderate agitation) or severe hepatic impairment (90 mcg and 60 mcg, for severe and mild/moderate agitation, respectively). The dose recommended for geriatric patients (defined as age ≥65 years) is 120 mcg for either mild, moderate, or severe agitation. Patients are advised not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration (defined as placement in the mouth directly behind the lower lip).

If agitation persists after the initial dose, up to 2 additional doses (90 mcg if the initial dose was 180 mcg, otherwise 60 mcg if the initial dose was 120, 90, or 60 mcg) may be given at least 2 hours apart. Assessment of vital signs, including orthostatic measurements, is required prior to the administration of any subsequent doses. Due to risk of hypotension, additional doses are not recommended in patients with systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, heart rate <60 beats per minute, or postural decrease in systolic blood pressure ≥20 mm Hg or in diastolic blood pressure ≥10 mm Hg.

Mechanism of action and pharmacodynamics

Dexmedetomidine is an alpha-2 adrenergic receptor agonist and the mechanism of action in the acute treatment of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.² Binding affinities (Ki values) are 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.²

Dexmedetomidine exhibits concentration-dependent QT prolongation, with mean QTc increases from baseline from 6 msec (120 mcg single dose) to 11 msec (180 mcg plus 2 additional doses of 90 mcg 2 hours apart for a total of 3 doses).² Placing the observation about QTc prolongation into clinical context, studies of IM administration of ziprasidone 20 mg and 30 mg and haloperidol 7.5 mg and 10 mg resulted in changes of the QTc interval of 4.6 msec and 6.0 msec, respectively, after 1 dose.⁶ After a second injection, these values were 12.8 msec and 14.7 msec, respectively.⁶

Clinical pharmacokinetics

The sublingual film formulation is absorbed orally, bypassing first-pass metabolism, and achieving higher dexmedetomidine bioavailability than ingested formulations.⁷ Exposure is dose-dependent, with dexmedetomidine being quantifiable in plasma after 5 to 20 minutes post dosing, and with a plasma half-life of 2 to 3 hours.^2,8 Mean time for the film to dissolve in the mouth was approximately 6 to 8 minutes following sublingual administration, and 18 minutes following buccal administration.² Absolute bioavailability was approximately 72% and 82% following sublingual and buccal administration, respectively.² Mean maximal plasma concentrations of dexmedetomidine were reached approximately 2 hours after sublingual or buccal administration.² Compared to drinking water at 2 hours post administration, early water intake (as early as 15 minutes post-dose) had minimal effects on the rate or extent of sublingual absorption but was not assessed after buccal administration.² The average protein binding was 94% and was constant across the different plasma concentrations evaluated and similar in males and females, but significantly decreased in participants with hepatic impairment compared to healthy individuals.² In contrast, the pharmacokinetic profile of dexmedetomidine is not significantly different in patients with creatinine clearance <30 mL/minute compared to those with normal renal function.² Dexmedetomidine undergoes almost complete biotransformation to inactive metabolites via direct glucuronidation as well as cytochrome P450 (CYP) (primarily CYP2A6)–mediated metabolism.² There is no evidence of any CYP–mediated drug interactions that are likely to be of clinical relevance.²

Continue to: Efficacy

The efficacy and tolerability of 120 mcg and 180 mcg doses of dexmedetomidine sublingual film was evaluated in 2 similarly designed, randomized, double-blind, placebo-controlled, Phase 3 trials in the treatment of acute agitation associated with schizophrenia, schizoaffective, or schizophreniform disorder⁹ and bipolar I or II disorder.¹⁰ These studies included a total of 758 adult patients age range 18 to 71 (mean age approximately 46.5), with about 59% male participants.² In contrast to other agents approved by the FDA for treatment of agitation associated with bipolar disorder, dexmedetomidine sublingual film was assessed in patients regardless of polarity (manic, mixed features, or depressed).⁵ The primary efficacy measure for the dexmedetomidine sublingual film studies was the investigator-administered Positive and Negative Syndrome Scale-Excited Component (PANSS-EC), consisting of the following 5 items: excitement, tension, hostility, uncooperativeness, and poor impulse control.¹¹ The items from the PANSS-EC are rated from 1 (not present) to 7 (extremely severe) and thus the total scores range from 5 to 35. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PANSS-EC score ≥14, with at least 1 individual item score ≥4.²

After study medication administration, the PANSS-EC was assessed from 10 minutes through 24 hours, with the primary endpoint being at 2 hours post-dose. Patients with schizophrenia or bipolar disorder who were treated with dexmedetomidine sublingual film 120 mcg or 180 mcg had superior symptomatic improvements from baseline to 2 hours post-dose compared to placebo, with treatment effects beginning as early as 20 to 30 minutes post-dose (for patients with schizophrenia, dexmedetomidine was statistically significantly superior to placebo beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose; for patients with bipolar disorder, differences from placebo were statistically significant beginning at 20 minutes after treatment with both the 120 mcg and 180 mcg doses).² Evaluation of effect size for dexmedetomidine vs placebo for PANSS-EC response at 2 hours (defined as ≥40% improvement from baseline) resulted in a number needed to treat (NNT) of 3 when combining both studies and both doses,¹² comparing favorably with the NNT values observed for IM formulations of aripiprazole, haloperidol, lorazepam, olanzapine, and ziprasidone,¹³ and inhaled loxapine.¹⁴

Overall tolerability and safety

The highlights of the prescribing information contain warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence.² Advice is provided to ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation, a concern commonly raised when assessing potential treatments for agitation.¹⁵ Dexmedetomidine sublingual film should be avoided in patients with risk factors for prolonged QT interval, a precaution that was evident for the use of ziprasidone¹⁶ and where an effect is also noted with haloperidol.⁶ As per the prescribing information, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Rates of adverse reactions of somnolence (including fatigue and sluggishness) with dexmedetomidine 120 mcg or 180 mcg are almost the same (22% and 23%, respectively), and higher than the 6% observed with placebo.² Other adverse reactions are substantially lower in frequency. These include oral paresthesia or oral hypoesthesia (6%, 7%, and 1%, for dexmedetomidine 120 mcg, 180 mcg, or placebo, respectively), dizziness (4%, 6%, 1%), hypotension (5%, 5%, 0%), orthostatic hypotension (3%, 5%, <1%), dry mouth (7%, 4%, 1%), nausea (2%, 3%, 2%), bradycardia (2%, 2%, 0%), and abdominal discomfort (0%, 2%, 1%).²

Regarding dose-dependent changes in blood pressure during the studies, 16%, 18%, and 9% of patients treated with 120 mcg, 180 mcg, and placebo, respectively, experienced orthostatic hypotension at 2 hours post dose. However, at 24 hours, none of the patients in the 180-mcg group experienced a systolic blood pressure ≤90 mm Hg with a decrease ≥20 mm Hg, compared with one patient (<1%) in the 120-mcg group and none in the placebo group.²

The prescribing information advises that concomitant use of dexmedetomidine sublingual film with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects, and that the prescriber should consider a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.²

Summary

Dexmedetomidine sublingual film is an oral medication indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. The recommended dose depends on severity of agitation, age, and the presence of hepatic impairment. A dose of 180 mcg is recommended for severe agitation and a dose of 120 mcg is recommended for mild or moderate agitation, with doses adjusted lower in the presence of hepatic impairment. There are no contraindications but there are warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence. Clinicians should monitor vital signs and alertness after administration to prevent falls and syncope; however, there is no FDA REMS required for use. The clinical trial evidence supporting the use of dexmedetomidine is robust, with evidence of a treatment effect as early as 20 minutes after administration. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.

Bottom Line

Dexmedetomidine sublingual film provides an opportunity to rethink the approach to the management of agitation and avoid the potentially unnecessary use of IM injections. Dexmedetomidine sublingual film acts rapidly and is simple to use.

Related Resources

• Dexmedetomidine sublingual film (Iglami) prescribing information. https://www.igalmihcp.com/igalmi-pi.pdf

Drug Brand Names

Aripiprazole • Abilify
Dexmedetomidine • Igalmi, Precedex
Haloperidol • Haldol
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Olanzapine • Zyprexa
Ziprasidone • Geodon

Approved by the FDA on April 5, 2022, dexmedetomidine sublingual film (Igalmi, manufactured and distributed by BioXcel Therapeutics, Inc., New Haven, CT USA) is indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder (Table).^1,2 It is administered sublingually or buccally under the supervision of a health care provider. After administration, patients should have their vital signs and alertness assessed but there is no FDA Risk Evaluation and Mitigation Strategy (REMS) required for use. A limitation of use is that the safety and effectiveness of dexmedetomidine sublingual film has not been established beyond 24 hours from the first dose.² There are no contraindications for use.²

Dexmedetomidine is a well-known efficacious alpha-2 adrenergic receptor agonist available since 1999 in an IV formulation indicated for sedation of initially intubated and mechanically ventilated patients in an ICU setting, and sedation of nonintubated patients prior to and/or during surgical and other procedures.^3,4 The reformulation of dexmedetomidine as a sublingual film allows the broader use of this agent in psychiatric settings when managing agitation in patients with schizophrenia or bipolar disorder, and thus potentially avoiding the use of IM administration of antipsychotics and/or benzodiazepines. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.⁵

Dosing

Dexmedetomidine sublingual film is distributed commercially in the following strengths: 180 mcg and 120 mcg. It consists of a lightly mint-flavored, rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. Dosage strengths of 90 mcg and 60 mcg are available by cutting the 180 mcg or 120 mcg film in half between the 2 visible darker blue dots. The recommended dose depends on the severity of agitation, age, and the presence of hepatic impairment.² For severe agitation, the recommended dose is 180 mcg. For mild or moderate agitation, the recommended dose is 120 mcg. Dosage is reduced in patients with mild/moderate hepatic impairment (120 mcg for severe agitation and 90 mcg for mild or moderate agitation) or severe hepatic impairment (90 mcg and 60 mcg, for severe and mild/moderate agitation, respectively). The dose recommended for geriatric patients (defined as age ≥65 years) is 120 mcg for either mild, moderate, or severe agitation. Patients are advised not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration (defined as placement in the mouth directly behind the lower lip).

If agitation persists after the initial dose, up to 2 additional doses (90 mcg if the initial dose was 180 mcg, otherwise 60 mcg if the initial dose was 120, 90, or 60 mcg) may be given at least 2 hours apart. Assessment of vital signs, including orthostatic measurements, is required prior to the administration of any subsequent doses. Due to risk of hypotension, additional doses are not recommended in patients with systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, heart rate <60 beats per minute, or postural decrease in systolic blood pressure ≥20 mm Hg or in diastolic blood pressure ≥10 mm Hg.

Mechanism of action and pharmacodynamics

Dexmedetomidine is an alpha-2 adrenergic receptor agonist and the mechanism of action in the acute treatment of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.² Binding affinities (Ki values) are 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.²

Dexmedetomidine exhibits concentration-dependent QT prolongation, with mean QTc increases from baseline from 6 msec (120 mcg single dose) to 11 msec (180 mcg plus 2 additional doses of 90 mcg 2 hours apart for a total of 3 doses).² Placing the observation about QTc prolongation into clinical context, studies of IM administration of ziprasidone 20 mg and 30 mg and haloperidol 7.5 mg and 10 mg resulted in changes of the QTc interval of 4.6 msec and 6.0 msec, respectively, after 1 dose.⁶ After a second injection, these values were 12.8 msec and 14.7 msec, respectively.⁶

Clinical pharmacokinetics

The sublingual film formulation is absorbed orally, bypassing first-pass metabolism, and achieving higher dexmedetomidine bioavailability than ingested formulations.⁷ Exposure is dose-dependent, with dexmedetomidine being quantifiable in plasma after 5 to 20 minutes post dosing, and with a plasma half-life of 2 to 3 hours.^2,8 Mean time for the film to dissolve in the mouth was approximately 6 to 8 minutes following sublingual administration, and 18 minutes following buccal administration.² Absolute bioavailability was approximately 72% and 82% following sublingual and buccal administration, respectively.² Mean maximal plasma concentrations of dexmedetomidine were reached approximately 2 hours after sublingual or buccal administration.² Compared to drinking water at 2 hours post administration, early water intake (as early as 15 minutes post-dose) had minimal effects on the rate or extent of sublingual absorption but was not assessed after buccal administration.² The average protein binding was 94% and was constant across the different plasma concentrations evaluated and similar in males and females, but significantly decreased in participants with hepatic impairment compared to healthy individuals.² In contrast, the pharmacokinetic profile of dexmedetomidine is not significantly different in patients with creatinine clearance <30 mL/minute compared to those with normal renal function.² Dexmedetomidine undergoes almost complete biotransformation to inactive metabolites via direct glucuronidation as well as cytochrome P450 (CYP) (primarily CYP2A6)–mediated metabolism.² There is no evidence of any CYP–mediated drug interactions that are likely to be of clinical relevance.²

Continue to: Efficacy

The efficacy and tolerability of 120 mcg and 180 mcg doses of dexmedetomidine sublingual film was evaluated in 2 similarly designed, randomized, double-blind, placebo-controlled, Phase 3 trials in the treatment of acute agitation associated with schizophrenia, schizoaffective, or schizophreniform disorder⁹ and bipolar I or II disorder.¹⁰ These studies included a total of 758 adult patients age range 18 to 71 (mean age approximately 46.5), with about 59% male participants.² In contrast to other agents approved by the FDA for treatment of agitation associated with bipolar disorder, dexmedetomidine sublingual film was assessed in patients regardless of polarity (manic, mixed features, or depressed).⁵ The primary efficacy measure for the dexmedetomidine sublingual film studies was the investigator-administered Positive and Negative Syndrome Scale-Excited Component (PANSS-EC), consisting of the following 5 items: excitement, tension, hostility, uncooperativeness, and poor impulse control.¹¹ The items from the PANSS-EC are rated from 1 (not present) to 7 (extremely severe) and thus the total scores range from 5 to 35. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PANSS-EC score ≥14, with at least 1 individual item score ≥4.²

After study medication administration, the PANSS-EC was assessed from 10 minutes through 24 hours, with the primary endpoint being at 2 hours post-dose. Patients with schizophrenia or bipolar disorder who were treated with dexmedetomidine sublingual film 120 mcg or 180 mcg had superior symptomatic improvements from baseline to 2 hours post-dose compared to placebo, with treatment effects beginning as early as 20 to 30 minutes post-dose (for patients with schizophrenia, dexmedetomidine was statistically significantly superior to placebo beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose; for patients with bipolar disorder, differences from placebo were statistically significant beginning at 20 minutes after treatment with both the 120 mcg and 180 mcg doses).² Evaluation of effect size for dexmedetomidine vs placebo for PANSS-EC response at 2 hours (defined as ≥40% improvement from baseline) resulted in a number needed to treat (NNT) of 3 when combining both studies and both doses,¹² comparing favorably with the NNT values observed for IM formulations of aripiprazole, haloperidol, lorazepam, olanzapine, and ziprasidone,¹³ and inhaled loxapine.¹⁴

Overall tolerability and safety

The highlights of the prescribing information contain warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence.² Advice is provided to ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation, a concern commonly raised when assessing potential treatments for agitation.¹⁵ Dexmedetomidine sublingual film should be avoided in patients with risk factors for prolonged QT interval, a precaution that was evident for the use of ziprasidone¹⁶ and where an effect is also noted with haloperidol.⁶ As per the prescribing information, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Rates of adverse reactions of somnolence (including fatigue and sluggishness) with dexmedetomidine 120 mcg or 180 mcg are almost the same (22% and 23%, respectively), and higher than the 6% observed with placebo.² Other adverse reactions are substantially lower in frequency. These include oral paresthesia or oral hypoesthesia (6%, 7%, and 1%, for dexmedetomidine 120 mcg, 180 mcg, or placebo, respectively), dizziness (4%, 6%, 1%), hypotension (5%, 5%, 0%), orthostatic hypotension (3%, 5%, <1%), dry mouth (7%, 4%, 1%), nausea (2%, 3%, 2%), bradycardia (2%, 2%, 0%), and abdominal discomfort (0%, 2%, 1%).²

Regarding dose-dependent changes in blood pressure during the studies, 16%, 18%, and 9% of patients treated with 120 mcg, 180 mcg, and placebo, respectively, experienced orthostatic hypotension at 2 hours post dose. However, at 24 hours, none of the patients in the 180-mcg group experienced a systolic blood pressure ≤90 mm Hg with a decrease ≥20 mm Hg, compared with one patient (<1%) in the 120-mcg group and none in the placebo group.²

The prescribing information advises that concomitant use of dexmedetomidine sublingual film with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects, and that the prescriber should consider a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.²

Summary

Dexmedetomidine sublingual film is an oral medication indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. The recommended dose depends on severity of agitation, age, and the presence of hepatic impairment. A dose of 180 mcg is recommended for severe agitation and a dose of 120 mcg is recommended for mild or moderate agitation, with doses adjusted lower in the presence of hepatic impairment. There are no contraindications but there are warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence. Clinicians should monitor vital signs and alertness after administration to prevent falls and syncope; however, there is no FDA REMS required for use. The clinical trial evidence supporting the use of dexmedetomidine is robust, with evidence of a treatment effect as early as 20 minutes after administration. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.

Bottom Line

Dexmedetomidine sublingual film provides an opportunity to rethink the approach to the management of agitation and avoid the potentially unnecessary use of IM injections. Dexmedetomidine sublingual film acts rapidly and is simple to use.

Related Resources

• Dexmedetomidine sublingual film (Iglami) prescribing information. https://www.igalmihcp.com/igalmi-pi.pdf

Drug Brand Names

Aripiprazole • Abilify
Dexmedetomidine • Igalmi, Precedex
Haloperidol • Haldol
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Olanzapine • Zyprexa
Ziprasidone • Geodon

Approved by the FDA on April 5, 2022, dexmedetomidine sublingual film (Igalmi, manufactured and distributed by BioXcel Therapeutics, Inc., New Haven, CT USA) is indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder (Table).^1,2 It is administered sublingually or buccally under the supervision of a health care provider. After administration, patients should have their vital signs and alertness assessed but there is no FDA Risk Evaluation and Mitigation Strategy (REMS) required for use. A limitation of use is that the safety and effectiveness of dexmedetomidine sublingual film has not been established beyond 24 hours from the first dose.² There are no contraindications for use.²

Dexmedetomidine is a well-known efficacious alpha-2 adrenergic receptor agonist available since 1999 in an IV formulation indicated for sedation of initially intubated and mechanically ventilated patients in an ICU setting, and sedation of nonintubated patients prior to and/or during surgical and other procedures.^3,4 The reformulation of dexmedetomidine as a sublingual film allows the broader use of this agent in psychiatric settings when managing agitation in patients with schizophrenia or bipolar disorder, and thus potentially avoiding the use of IM administration of antipsychotics and/or benzodiazepines. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.⁵

Dosing

Dexmedetomidine sublingual film is distributed commercially in the following strengths: 180 mcg and 120 mcg. It consists of a lightly mint-flavored, rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. Dosage strengths of 90 mcg and 60 mcg are available by cutting the 180 mcg or 120 mcg film in half between the 2 visible darker blue dots. The recommended dose depends on the severity of agitation, age, and the presence of hepatic impairment.² For severe agitation, the recommended dose is 180 mcg. For mild or moderate agitation, the recommended dose is 120 mcg. Dosage is reduced in patients with mild/moderate hepatic impairment (120 mcg for severe agitation and 90 mcg for mild or moderate agitation) or severe hepatic impairment (90 mcg and 60 mcg, for severe and mild/moderate agitation, respectively). The dose recommended for geriatric patients (defined as age ≥65 years) is 120 mcg for either mild, moderate, or severe agitation. Patients are advised not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration (defined as placement in the mouth directly behind the lower lip).

If agitation persists after the initial dose, up to 2 additional doses (90 mcg if the initial dose was 180 mcg, otherwise 60 mcg if the initial dose was 120, 90, or 60 mcg) may be given at least 2 hours apart. Assessment of vital signs, including orthostatic measurements, is required prior to the administration of any subsequent doses. Due to risk of hypotension, additional doses are not recommended in patients with systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, heart rate <60 beats per minute, or postural decrease in systolic blood pressure ≥20 mm Hg or in diastolic blood pressure ≥10 mm Hg.

Mechanism of action and pharmacodynamics

Dexmedetomidine is an alpha-2 adrenergic receptor agonist and the mechanism of action in the acute treatment of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.² Binding affinities (Ki values) are 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.²

Dexmedetomidine exhibits concentration-dependent QT prolongation, with mean QTc increases from baseline from 6 msec (120 mcg single dose) to 11 msec (180 mcg plus 2 additional doses of 90 mcg 2 hours apart for a total of 3 doses).² Placing the observation about QTc prolongation into clinical context, studies of IM administration of ziprasidone 20 mg and 30 mg and haloperidol 7.5 mg and 10 mg resulted in changes of the QTc interval of 4.6 msec and 6.0 msec, respectively, after 1 dose.⁶ After a second injection, these values were 12.8 msec and 14.7 msec, respectively.⁶

Clinical pharmacokinetics

The sublingual film formulation is absorbed orally, bypassing first-pass metabolism, and achieving higher dexmedetomidine bioavailability than ingested formulations.⁷ Exposure is dose-dependent, with dexmedetomidine being quantifiable in plasma after 5 to 20 minutes post dosing, and with a plasma half-life of 2 to 3 hours.^2,8 Mean time for the film to dissolve in the mouth was approximately 6 to 8 minutes following sublingual administration, and 18 minutes following buccal administration.² Absolute bioavailability was approximately 72% and 82% following sublingual and buccal administration, respectively.² Mean maximal plasma concentrations of dexmedetomidine were reached approximately 2 hours after sublingual or buccal administration.² Compared to drinking water at 2 hours post administration, early water intake (as early as 15 minutes post-dose) had minimal effects on the rate or extent of sublingual absorption but was not assessed after buccal administration.² The average protein binding was 94% and was constant across the different plasma concentrations evaluated and similar in males and females, but significantly decreased in participants with hepatic impairment compared to healthy individuals.² In contrast, the pharmacokinetic profile of dexmedetomidine is not significantly different in patients with creatinine clearance <30 mL/minute compared to those with normal renal function.² Dexmedetomidine undergoes almost complete biotransformation to inactive metabolites via direct glucuronidation as well as cytochrome P450 (CYP) (primarily CYP2A6)–mediated metabolism.² There is no evidence of any CYP–mediated drug interactions that are likely to be of clinical relevance.²

Continue to: Efficacy

The efficacy and tolerability of 120 mcg and 180 mcg doses of dexmedetomidine sublingual film was evaluated in 2 similarly designed, randomized, double-blind, placebo-controlled, Phase 3 trials in the treatment of acute agitation associated with schizophrenia, schizoaffective, or schizophreniform disorder⁹ and bipolar I or II disorder.¹⁰ These studies included a total of 758 adult patients age range 18 to 71 (mean age approximately 46.5), with about 59% male participants.² In contrast to other agents approved by the FDA for treatment of agitation associated with bipolar disorder, dexmedetomidine sublingual film was assessed in patients regardless of polarity (manic, mixed features, or depressed).⁵ The primary efficacy measure for the dexmedetomidine sublingual film studies was the investigator-administered Positive and Negative Syndrome Scale-Excited Component (PANSS-EC), consisting of the following 5 items: excitement, tension, hostility, uncooperativeness, and poor impulse control.¹¹ The items from the PANSS-EC are rated from 1 (not present) to 7 (extremely severe) and thus the total scores range from 5 to 35. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PANSS-EC score ≥14, with at least 1 individual item score ≥4.²

After study medication administration, the PANSS-EC was assessed from 10 minutes through 24 hours, with the primary endpoint being at 2 hours post-dose. Patients with schizophrenia or bipolar disorder who were treated with dexmedetomidine sublingual film 120 mcg or 180 mcg had superior symptomatic improvements from baseline to 2 hours post-dose compared to placebo, with treatment effects beginning as early as 20 to 30 minutes post-dose (for patients with schizophrenia, dexmedetomidine was statistically significantly superior to placebo beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose; for patients with bipolar disorder, differences from placebo were statistically significant beginning at 20 minutes after treatment with both the 120 mcg and 180 mcg doses).² Evaluation of effect size for dexmedetomidine vs placebo for PANSS-EC response at 2 hours (defined as ≥40% improvement from baseline) resulted in a number needed to treat (NNT) of 3 when combining both studies and both doses,¹² comparing favorably with the NNT values observed for IM formulations of aripiprazole, haloperidol, lorazepam, olanzapine, and ziprasidone,¹³ and inhaled loxapine.¹⁴

Overall tolerability and safety

The highlights of the prescribing information contain warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence.² Advice is provided to ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation, a concern commonly raised when assessing potential treatments for agitation.¹⁵ Dexmedetomidine sublingual film should be avoided in patients with risk factors for prolonged QT interval, a precaution that was evident for the use of ziprasidone¹⁶ and where an effect is also noted with haloperidol.⁶ As per the prescribing information, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Rates of adverse reactions of somnolence (including fatigue and sluggishness) with dexmedetomidine 120 mcg or 180 mcg are almost the same (22% and 23%, respectively), and higher than the 6% observed with placebo.² Other adverse reactions are substantially lower in frequency. These include oral paresthesia or oral hypoesthesia (6%, 7%, and 1%, for dexmedetomidine 120 mcg, 180 mcg, or placebo, respectively), dizziness (4%, 6%, 1%), hypotension (5%, 5%, 0%), orthostatic hypotension (3%, 5%, <1%), dry mouth (7%, 4%, 1%), nausea (2%, 3%, 2%), bradycardia (2%, 2%, 0%), and abdominal discomfort (0%, 2%, 1%).²

Regarding dose-dependent changes in blood pressure during the studies, 16%, 18%, and 9% of patients treated with 120 mcg, 180 mcg, and placebo, respectively, experienced orthostatic hypotension at 2 hours post dose. However, at 24 hours, none of the patients in the 180-mcg group experienced a systolic blood pressure ≤90 mm Hg with a decrease ≥20 mm Hg, compared with one patient (<1%) in the 120-mcg group and none in the placebo group.²

The prescribing information advises that concomitant use of dexmedetomidine sublingual film with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects, and that the prescriber should consider a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.²

Summary

Dexmedetomidine sublingual film is an oral medication indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. The recommended dose depends on severity of agitation, age, and the presence of hepatic impairment. A dose of 180 mcg is recommended for severe agitation and a dose of 120 mcg is recommended for mild or moderate agitation, with doses adjusted lower in the presence of hepatic impairment. There are no contraindications but there are warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence. Clinicians should monitor vital signs and alertness after administration to prevent falls and syncope; however, there is no FDA REMS required for use. The clinical trial evidence supporting the use of dexmedetomidine is robust, with evidence of a treatment effect as early as 20 minutes after administration. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.

Bottom Line

Dexmedetomidine sublingual film provides an opportunity to rethink the approach to the management of agitation and avoid the potentially unnecessary use of IM injections. Dexmedetomidine sublingual film acts rapidly and is simple to use.

Related Resources

• Dexmedetomidine sublingual film (Iglami) prescribing information. https://www.igalmihcp.com/igalmi-pi.pdf

Drug Brand Names

Aripiprazole • Abilify
Dexmedetomidine • Igalmi, Precedex
Haloperidol • Haldol
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Olanzapine • Zyprexa
Ziprasidone • Geodon

The term evidence-based medicine (EBM) has been derided by some as “cookbook medicine.” To others, EBM conjures up the efforts of describing interventions in terms of comparative effectiveness, drowning us in a deluge of “evidence-based” publications. The moniker has also been hijacked by companies to name their Health Economics and Outcomes research divisions. The spirit behind EBM is getting lost. EBM is not just about the evidence; it is about how we use it.¹

In this commentary, we describe the concept of EBM and discuss teaching EBM to medical students and residents, its role in continuing medical education, and how it may be applied to practice, using a case scenario as a guide.

What is evidence-based medicine?

Sackett et al² summed it best in an editorial published in the BMJ in 1996, where he emphasized decision-making in the care of individual patients. When making clinical decisions, using the best evidence available makes sense, but so does integrating individual clinical expertise and considering the individual patient’s preferences. Sackett et al² warns about practice becoming tyrannized by evidence: “even excellent external evidence may be inapplicable to or inappropriate for an individual patient.” Clearly, EBM is not cookbook medicine.

Figure 1³ illustrates EBM as the confluence of clinical judgment, relevant scientific evidence, and patients’ values and preferences. The results from a clinical trial are only one part of the equation. As practitioners, we have the advantage of detailed knowledge about the patient, and our decisions are not “one size fits all.” Prior information about the patient dictates how we apply the evidence that supports potential interventions.

The concept of EBM was born out of necessity to bring scientific principles into the heart of medicine. As outlined by Sackett,⁴ the practice of EBM is a process of lifelong, self-directed learning in which caring for our own patients creates the need for clinically important information about diagnosis, prognosis, therapy, and other clinical and health care issues. Through EBM, we:

• convert these information needs into answerable questions
• track down, with maximum efficiency, the best evidence with which to answer questions (whether from clinical examination, diagnostic laboratory results, research evidence, or other sources)
• critically appraise that evidence for its validity (closeness to the truth) and usefulness (clinical applicability)
• integrate this appraisal with our clinical expertise and apply it in practice
• evaluate our performance.

Over the years, the original aim of EBM as a self-directed method for clinicians to practice high-quality medicine was morphed by some into a tool of enforced standardization and a boilerplate approach to managing costs across systems of care. As a result, the term EBM has been criticized because of:

• its reliance on empiricism
• a narrow definition of evidence
• a lack of evidence of efficacy
• its limited usefulness for individual patients
• threats to the autonomy of the doctor-patient relationship.

These 5 categories are associated with severe drawbacks when used for individual patient care.⁵ In addition to problems with applying standardized population research to a specific patient with a specific set of symptoms, medications, genetic variations, and unique environment, it can take years for clinicians to change their practices to incorporate new information.⁶

Continue to: Evidence that is too narrow...

Evidence that is too narrow in scope may not be useful. Single-molecule pharmaceutical clinical trials have erroneously become a synonym of EBM. Such studies do not reflect complex, real-life situations. Based on such studies, FDA product labeling can be inadequate in its guidance, particularly when faced with complex comorbidities. The standard comparison of active treatment to placebo is also seen as EBM, narrowing its scope and deflecting from clinical medicine when physicians measure one treatment’s success against another vs measuring real treatments against shams. Real-life treatment choice is frequently based on considering adverse effects as important to consider as therapeutic efficacy; however, this concept is outside of the common (mis)understanding of EBM.

Conflicting and ever-changing data and the push to replace clinical thinking with general dogmas trivializes medical practice and endangers treatment outcomes. This would not happen to the extent we see now if EBM was again seen as a guide and general direction rather than a blanket, distorted requirement to follow rigid recommendations for specific patients.

Insurance companies have driven a change in the understanding of EBM by using the FDA label as an excuse to deny, delay, and/or refuse to pay for treatments that are not explicitly and narrowly on-label. Dependence on on-label treatments is even more challenging in specialty medicine because primary care clinicians generally have tried the conventional approaches before referring patients to a specialist. However, insurance denials rarely differentiate between practice settings.

Medicolegal issues have cemented the present situation when clinically valid “off-label” treatments may be a reasonable consideration for patients but can place health care practitioners in jeopardy. The distorted EBM doctrine has become a justification for legal actions against clinicians who practice individualized medicine.

Concision bias (selectively focusing on information, losing nuance) and selection bias (patients in clinical trials who do not reflect real-life patients) have become an impediment to progress and EBM as originally intended.

Continue to: Training medical students and residents

Although there is some variation in how EBM is taught to medical students and residents,^7,8 the expectation is that such education occurs. The Accreditation Council for Graduate Medical Education requirements for a residency program state that “the program must advance residents’ knowledge and practice of the scholarly approach to evidence-based patient care.”⁹ The topic has been part of the American Society of Clinical Psychopharmacology Model Psychopharmacology Curriculum, but only in an optional lecture.¹⁰ The formal teaching of EBM includes how to find relevant biomedical publications for the clinical issues at hand, understand the different hierarchies of evidence, interpret results in terms of effect size, and apply this knowledge in the care of patients. This 5-step process is illustrated in Figure 2⁸. See Related Resources for 3 books that provide a scholarly yet clinically relevant approach to EBM.

Continuing medical education

Most Current Psychiatry readers have been out of residency for some time and have not necessarily been exposed to the philosophy and tools of EBM. It may be easier to simply jump in and learn about effect sizes and then use information already curated and apply this knowledge. A good starting point is a recap^11,12 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia that answers the questions: “How large is the effect being measured?” “Is it clinically important?” and “How are we dealing with a result that may be statistically significant but irrelevant for day-to-day patient care?” Number needed to treat (NNT) and number needed to harm (NNH) can help explain this by allowing one to judge the clinical significance of a statistically significant result.¹³

Practical applications

There are common clinical scenarios where evidence is ignored, or where it is overvalued. For example, the treatment of bipolar depression can be made worse with the use of antidepressants.¹⁴ Does this mean that antidepressants should never be used? What about patient history and preference? What if the approved agents fail to relieve symptoms or are not well tolerated? Available FDA-approved choices may not always be suitable.¹⁵ The Table illustrates some of these scenarios.

The term evidence-based medicine (EBM) has been derided by some as “cookbook medicine.” To others, EBM conjures up the efforts of describing interventions in terms of comparative effectiveness, drowning us in a deluge of “evidence-based” publications. The moniker has also been hijacked by companies to name their Health Economics and Outcomes research divisions. The spirit behind EBM is getting lost. EBM is not just about the evidence; it is about how we use it.¹

In this commentary, we describe the concept of EBM and discuss teaching EBM to medical students and residents, its role in continuing medical education, and how it may be applied to practice, using a case scenario as a guide.

What is evidence-based medicine?

Sackett et al² summed it best in an editorial published in the BMJ in 1996, where he emphasized decision-making in the care of individual patients. When making clinical decisions, using the best evidence available makes sense, but so does integrating individual clinical expertise and considering the individual patient’s preferences. Sackett et al² warns about practice becoming tyrannized by evidence: “even excellent external evidence may be inapplicable to or inappropriate for an individual patient.” Clearly, EBM is not cookbook medicine.

Figure 1³ illustrates EBM as the confluence of clinical judgment, relevant scientific evidence, and patients’ values and preferences. The results from a clinical trial are only one part of the equation. As practitioners, we have the advantage of detailed knowledge about the patient, and our decisions are not “one size fits all.” Prior information about the patient dictates how we apply the evidence that supports potential interventions.

The concept of EBM was born out of necessity to bring scientific principles into the heart of medicine. As outlined by Sackett,⁴ the practice of EBM is a process of lifelong, self-directed learning in which caring for our own patients creates the need for clinically important information about diagnosis, prognosis, therapy, and other clinical and health care issues. Through EBM, we:

• convert these information needs into answerable questions
• track down, with maximum efficiency, the best evidence with which to answer questions (whether from clinical examination, diagnostic laboratory results, research evidence, or other sources)
• critically appraise that evidence for its validity (closeness to the truth) and usefulness (clinical applicability)
• integrate this appraisal with our clinical expertise and apply it in practice
• evaluate our performance.

Over the years, the original aim of EBM as a self-directed method for clinicians to practice high-quality medicine was morphed by some into a tool of enforced standardization and a boilerplate approach to managing costs across systems of care. As a result, the term EBM has been criticized because of:

• its reliance on empiricism
• a narrow definition of evidence
• a lack of evidence of efficacy
• its limited usefulness for individual patients
• threats to the autonomy of the doctor-patient relationship.

These 5 categories are associated with severe drawbacks when used for individual patient care.⁵ In addition to problems with applying standardized population research to a specific patient with a specific set of symptoms, medications, genetic variations, and unique environment, it can take years for clinicians to change their practices to incorporate new information.⁶

Continue to: Evidence that is too narrow...

Evidence that is too narrow in scope may not be useful. Single-molecule pharmaceutical clinical trials have erroneously become a synonym of EBM. Such studies do not reflect complex, real-life situations. Based on such studies, FDA product labeling can be inadequate in its guidance, particularly when faced with complex comorbidities. The standard comparison of active treatment to placebo is also seen as EBM, narrowing its scope and deflecting from clinical medicine when physicians measure one treatment’s success against another vs measuring real treatments against shams. Real-life treatment choice is frequently based on considering adverse effects as important to consider as therapeutic efficacy; however, this concept is outside of the common (mis)understanding of EBM.

Conflicting and ever-changing data and the push to replace clinical thinking with general dogmas trivializes medical practice and endangers treatment outcomes. This would not happen to the extent we see now if EBM was again seen as a guide and general direction rather than a blanket, distorted requirement to follow rigid recommendations for specific patients.

Insurance companies have driven a change in the understanding of EBM by using the FDA label as an excuse to deny, delay, and/or refuse to pay for treatments that are not explicitly and narrowly on-label. Dependence on on-label treatments is even more challenging in specialty medicine because primary care clinicians generally have tried the conventional approaches before referring patients to a specialist. However, insurance denials rarely differentiate between practice settings.

Medicolegal issues have cemented the present situation when clinically valid “off-label” treatments may be a reasonable consideration for patients but can place health care practitioners in jeopardy. The distorted EBM doctrine has become a justification for legal actions against clinicians who practice individualized medicine.

Concision bias (selectively focusing on information, losing nuance) and selection bias (patients in clinical trials who do not reflect real-life patients) have become an impediment to progress and EBM as originally intended.

Continue to: Training medical students and residents

Although there is some variation in how EBM is taught to medical students and residents,^7,8 the expectation is that such education occurs. The Accreditation Council for Graduate Medical Education requirements for a residency program state that “the program must advance residents’ knowledge and practice of the scholarly approach to evidence-based patient care.”⁹ The topic has been part of the American Society of Clinical Psychopharmacology Model Psychopharmacology Curriculum, but only in an optional lecture.¹⁰ The formal teaching of EBM includes how to find relevant biomedical publications for the clinical issues at hand, understand the different hierarchies of evidence, interpret results in terms of effect size, and apply this knowledge in the care of patients. This 5-step process is illustrated in Figure 2⁸. See Related Resources for 3 books that provide a scholarly yet clinically relevant approach to EBM.

Continuing medical education

Most Current Psychiatry readers have been out of residency for some time and have not necessarily been exposed to the philosophy and tools of EBM. It may be easier to simply jump in and learn about effect sizes and then use information already curated and apply this knowledge. A good starting point is a recap^11,12 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia that answers the questions: “How large is the effect being measured?” “Is it clinically important?” and “How are we dealing with a result that may be statistically significant but irrelevant for day-to-day patient care?” Number needed to treat (NNT) and number needed to harm (NNH) can help explain this by allowing one to judge the clinical significance of a statistically significant result.¹³

Practical applications

There are common clinical scenarios where evidence is ignored, or where it is overvalued. For example, the treatment of bipolar depression can be made worse with the use of antidepressants.¹⁴ Does this mean that antidepressants should never be used? What about patient history and preference? What if the approved agents fail to relieve symptoms or are not well tolerated? Available FDA-approved choices may not always be suitable.¹⁵ The Table illustrates some of these scenarios.

The term evidence-based medicine (EBM) has been derided by some as “cookbook medicine.” To others, EBM conjures up the efforts of describing interventions in terms of comparative effectiveness, drowning us in a deluge of “evidence-based” publications. The moniker has also been hijacked by companies to name their Health Economics and Outcomes research divisions. The spirit behind EBM is getting lost. EBM is not just about the evidence; it is about how we use it.¹

In this commentary, we describe the concept of EBM and discuss teaching EBM to medical students and residents, its role in continuing medical education, and how it may be applied to practice, using a case scenario as a guide.

What is evidence-based medicine?

Sackett et al² summed it best in an editorial published in the BMJ in 1996, where he emphasized decision-making in the care of individual patients. When making clinical decisions, using the best evidence available makes sense, but so does integrating individual clinical expertise and considering the individual patient’s preferences. Sackett et al² warns about practice becoming tyrannized by evidence: “even excellent external evidence may be inapplicable to or inappropriate for an individual patient.” Clearly, EBM is not cookbook medicine.

Figure 1³ illustrates EBM as the confluence of clinical judgment, relevant scientific evidence, and patients’ values and preferences. The results from a clinical trial are only one part of the equation. As practitioners, we have the advantage of detailed knowledge about the patient, and our decisions are not “one size fits all.” Prior information about the patient dictates how we apply the evidence that supports potential interventions.

The concept of EBM was born out of necessity to bring scientific principles into the heart of medicine. As outlined by Sackett,⁴ the practice of EBM is a process of lifelong, self-directed learning in which caring for our own patients creates the need for clinically important information about diagnosis, prognosis, therapy, and other clinical and health care issues. Through EBM, we:

• convert these information needs into answerable questions
• track down, with maximum efficiency, the best evidence with which to answer questions (whether from clinical examination, diagnostic laboratory results, research evidence, or other sources)
• critically appraise that evidence for its validity (closeness to the truth) and usefulness (clinical applicability)
• integrate this appraisal with our clinical expertise and apply it in practice
• evaluate our performance.

Over the years, the original aim of EBM as a self-directed method for clinicians to practice high-quality medicine was morphed by some into a tool of enforced standardization and a boilerplate approach to managing costs across systems of care. As a result, the term EBM has been criticized because of:

• its reliance on empiricism
• a narrow definition of evidence
• a lack of evidence of efficacy
• its limited usefulness for individual patients
• threats to the autonomy of the doctor-patient relationship.

These 5 categories are associated with severe drawbacks when used for individual patient care.⁵ In addition to problems with applying standardized population research to a specific patient with a specific set of symptoms, medications, genetic variations, and unique environment, it can take years for clinicians to change their practices to incorporate new information.⁶

Continue to: Evidence that is too narrow...

Evidence that is too narrow in scope may not be useful. Single-molecule pharmaceutical clinical trials have erroneously become a synonym of EBM. Such studies do not reflect complex, real-life situations. Based on such studies, FDA product labeling can be inadequate in its guidance, particularly when faced with complex comorbidities. The standard comparison of active treatment to placebo is also seen as EBM, narrowing its scope and deflecting from clinical medicine when physicians measure one treatment’s success against another vs measuring real treatments against shams. Real-life treatment choice is frequently based on considering adverse effects as important to consider as therapeutic efficacy; however, this concept is outside of the common (mis)understanding of EBM.

Conflicting and ever-changing data and the push to replace clinical thinking with general dogmas trivializes medical practice and endangers treatment outcomes. This would not happen to the extent we see now if EBM was again seen as a guide and general direction rather than a blanket, distorted requirement to follow rigid recommendations for specific patients.

Insurance companies have driven a change in the understanding of EBM by using the FDA label as an excuse to deny, delay, and/or refuse to pay for treatments that are not explicitly and narrowly on-label. Dependence on on-label treatments is even more challenging in specialty medicine because primary care clinicians generally have tried the conventional approaches before referring patients to a specialist. However, insurance denials rarely differentiate between practice settings.

Medicolegal issues have cemented the present situation when clinically valid “off-label” treatments may be a reasonable consideration for patients but can place health care practitioners in jeopardy. The distorted EBM doctrine has become a justification for legal actions against clinicians who practice individualized medicine.

Concision bias (selectively focusing on information, losing nuance) and selection bias (patients in clinical trials who do not reflect real-life patients) have become an impediment to progress and EBM as originally intended.

Continue to: Training medical students and residents

Although there is some variation in how EBM is taught to medical students and residents,^7,8 the expectation is that such education occurs. The Accreditation Council for Graduate Medical Education requirements for a residency program state that “the program must advance residents’ knowledge and practice of the scholarly approach to evidence-based patient care.”⁹ The topic has been part of the American Society of Clinical Psychopharmacology Model Psychopharmacology Curriculum, but only in an optional lecture.¹⁰ The formal teaching of EBM includes how to find relevant biomedical publications for the clinical issues at hand, understand the different hierarchies of evidence, interpret results in terms of effect size, and apply this knowledge in the care of patients. This 5-step process is illustrated in Figure 2⁸. See Related Resources for 3 books that provide a scholarly yet clinically relevant approach to EBM.

Continuing medical education

Most Current Psychiatry readers have been out of residency for some time and have not necessarily been exposed to the philosophy and tools of EBM. It may be easier to simply jump in and learn about effect sizes and then use information already curated and apply this knowledge. A good starting point is a recap^11,12 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia that answers the questions: “How large is the effect being measured?” “Is it clinically important?” and “How are we dealing with a result that may be statistically significant but irrelevant for day-to-day patient care?” Number needed to treat (NNT) and number needed to harm (NNH) can help explain this by allowing one to judge the clinical significance of a statistically significant result.¹³

Practical applications

There are common clinical scenarios where evidence is ignored, or where it is overvalued. For example, the treatment of bipolar depression can be made worse with the use of antidepressants.¹⁴ Does this mean that antidepressants should never be used? What about patient history and preference? What if the approved agents fail to relieve symptoms or are not well tolerated? Available FDA-approved choices may not always be suitable.¹⁵ The Table illustrates some of these scenarios.

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

Aripiprazole, brexpiprazole, and cariprazine are dopamine receptor partial agonists, and on the surface, they appear similar. However, there are key differences in terms of available indications, formulations, pharmacodynamics, pharmacokinetics, dosing, drug interactions, tolerability, and other factors related to successful use.¹ This review will cover the main points that the knowledgeable clinician will need to be mindful of when prescribing these agents.

Aripiprazole

Aripiprazole was launched in the United States in 2002² as the first dopamine receptor partial agonist approved for the treatment of schizophrenia; it later received additional indications for adults with manic or mixed episodes associated with bipolar I disorder and the maintenance treatment of bipolar I disorder, as well as for the adjunctive treatment of major depressive disorder (MDD). Pediatric indications include schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder, irritability associated with autistic disorder, and Tourette’s disorder.

Several formulations also became available, including a short-acting injection indicated for agitation associated with schizophrenia or bipolar mania, and oral disintegrating tablets and an oral solution that could substitute for the regular tablet. Presently the medication has gone “generic,” and not all formulations are being manufactured. The long-acting formulations of aripiprazole (aripiprazole monohydrate and aripiprazole lauroxil) are considered different products, each with its own product insert, with indications that are more limited in scope than for the oral forms.^3,4

Although dopamine D2 receptor partial agonism is a relevant mechanism of action, partial agonist activity at serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors also play a role.² Actions at receptors other than dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A may explain some of the other clinical effects of aripiprazole. In terms of binding, aripiprazole has very high binding affinities (Ki) to dopamine D2 (0.34 nM), dopamine D3 (0.8 nM), and serotonin 5-HT2B (0.36 nM) receptors, and high binding affinities to serotonin 5-HT1A (1.7 nM) and serotonin 5-HT2A (3.4 nM) receptors.

Dosage recommendations for adults with schizophrenia suggest a starting and maintenance dose of 10 to 15 mg/d.² Although the maximum dose is 30 mg/d, there is no evidence that doses >15 mg/d are superior to lower doses.⁵ In adolescents with schizophrenia, the product label recommends a starting dose of 2 mg/d, a maintenance dose of 10 mg/d, and a maximum dose of 30 mg/d. Recommendations for dosing in bipolar mania are similar. Dosing for the other indications is lower.

Efficacy in schizophrenia can be quantified using number needed to treat (NNT) for response vs placebo. The NNT answers the question “How many patients need to be randomized to aripiprazole vs placebo before expecting to encounter one additional responder?”⁶ From the 4 positive pivotal short-term acute schizophrenia trials for aripiprazole in adults,^7-10 using the definition of response as a ≥30% decrease in the Positive and Negative Syndrome Scale (PANSS) total score or a Clinical Global Impressions–Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved), and pooling the data for aripiprazole doses 10 to 30 mg/d, response rates were 38% for aripiprazole vs 24% for placebo, resulting in a NNT of 8 (95% confidence interval [CI] 6 to 13).

From the 4 positive pivotal short-term acute bipolar mania trials for aripiprazole monotherapy in adults^11-14 using the definition of response as a ≥50% decrease in the Young Mania Rating Scale (YMRS) total score, and pooling the data for aripiprazole doses 15 to 30 mg/d, response rates were 47% for aripiprazole vs 31% for placebo, resulting in a NNT of 7 (95% CI 5 to 11).¹ Similar results were observed in the adjunctive aripiprazole acute bipolar mania trial¹⁵ where the NNT for response was also 7.¹

Continue to: From the 2 positive pivotal short-term...

From the 2 positive pivotal short-term acute MDD trials for aripiprazole,^16,17 using the definition of response as a ≥50% decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and pooling the data (aripiprazole flexibly dosed 2 to 20 mg/d, with a median dose of 10 mg/d), response rates were 33% for aripiprazole vs 20% for placebo, resulting in a NNT of 8 (95% CI 6 to 17). After including a third trial not described in product labeling,¹⁸ the NNT became a more robust 7 (95% CI 5 to 11).¹

The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) in the pivotal trials were akathisia (schizophrenia); akathisia, sedation, restlessness, tremor, and extrapyramidal disorder (bipolar mania, monotherapy); akathisia, insomnia, and extrapyramidal disorder (bipolar mania, adjunctive therapy); akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision (MDD); and nausea (short-acting IM formulation). Table 1¹ summarizes the tolerability information regarding rate of discontinuation due to adverse events (an overall indicator of tolerability), and the incidence of the most common adverse event, together with the calculated number needed to harm (NNH). Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability; for the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability for these indications.

Brexpiprazole

Brexpiprazole was launched in the United States in 2015 for 2 indications: schizophrenia and the adjunctive treatment of MDD, both in adults.¹⁹ In terms of binding, brexpiprazole has very high binding affinities to serotonin 5-HT1A (0.12 nM), adrenergic α1B (0.17 nM), dopamine D2 (0.30 nM), serotonin 5-HT2A (0.47 nM), and adrenergic α2C (0.59 nM) receptors, and high binding affinities to dopamine D3 (1.1 nM), serotonin 5-HT2B (1.9 nM), adrenergic α1D (2.6 nM), serotonin 5-HT7 (3.7 nM), and adrenergic α1A (3.8 nM) receptors.

The 1-mg/d starting dose for brexpiprazole is lower than the recommended dose range of 2 to 4 mg/d for schizophrenia or the recommended dose of 2 mg/d for MDD.¹⁹ Thus brexpiprazole requires titration. The recommended rate of titration depends on the disease state being treated. For schizophrenia, the recommended titration schedule is to increase the dose to 2 mg/d on Day 5 through Day 7, then to 4 mg/d (the maximum recommended dose) on Day 8 based on the patient’s clinical response and tolerability. For MDD, there is the option of starting at 0.5 mg/d and the titration process is slower, with dosage increases occurring at weekly intervals, and with a maximum dose of 3 mg/d.

Using the identical definition of response in persons with schizophrenia as for the aripiprazole data described above, pooling together all the available data for the recommended target dose of brexpiprazole for schizophrenia (2 to 4 mg/d) from the 2 studies listed in the product label,^20,21 the percentage of responders was 46%, compared with 31% for the pooled placebo groups, yielding a NNT of 7 (95% CI 5 to 12).²²

Continue to: For MDD...

For MDD, using the definition of response as a ≥50% decrease in MADRS total score, and pooling the results for brexpiprazole 1, 2, and 3 mg/d from the 2 pivotal trials,^23,24 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI 8 to 26).²² Including the 1.5-mg/d dose arm and the placebo arm from the phase II study for which results are also available but not included in product labelling, the NNT becomes a slightly more robust 11 (95% CI 8 to 20).²² Although the magnitude of the NNT effect size is stronger for aripiprazole than for brexpiprazole, the 95% CIs do overlap.

The most commonly encountered adverse event in the short-term trials in schizophrenia (incidence ≥4% and at least twice the rate of placebo) was increased weight. The most commonly encountered adverse events in the short-term trials in MDD (incidence ≥5% and at least twice the rate of placebo) were increased weight and akathisia. Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability, and for MDD the NNH vs placebo on discontinuation because of an adverse event was 50, representing reasonable overall tolerability for this indication as well (Table 1¹).

Cariprazine

Cariprazine was launched in the United States in 2015 for 2 indications: schizophrenia, and the acute treatment of manic or mixed episodes associated with bipolar I disorder, both in adults.²⁵ In terms of binding, cariprazine has very high binding affinities to dopamine D3 (0.085 nM), dopamine D2L (0.49 nM), serotonin 5-HT2B (0.58 nM), and dopamine D2S (0.69 nM) receptors, and high binding affinity to serotonin 5-HT1A (2.6 nM) receptors. Cariprazine forms 2 major metabolites, desmethyl cariprazine and didesmethyl cariprazine, that have in vitro receptor binding profiles similar to the parent drug. This latter metabolite, didesmethyl cariprazine, has a half-life of 1 to 3 weeks, and is the active moiety responsible for the majority of cariprazine’s effect when in steady state. Thus, following discontinuation of cariprazine, the decline in plasma concentrations of active drug will be slow.

The starting dose for cariprazine for schizophrenia, 1.5 mg/d, can be therapeutic. The dosage can be increased to 3 mg/d on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3-mg increments to a maximum dose of 6 mg/d. For the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d; this can be done on Day 2. Cariprazine has been tested in clinical trials at higher doses; however, doses that exceed 6 mg/d did not confer significant additional benefit.²⁵

A more conservative definition of response was used in the reporting of the cariprazine acute schizophrenia studies. This was simply a ≥30% decrease in the PANSS total score, and did not include the option of including patients who scored a 1 or 2 on the CGI-I. For pooled doses of cariprazine 1.5 to 6 mg/d,^26-28 the percentage of responders was 31%, compared with 21% for the pooled placebo groups, yielding a NNT of 10 (95% CI 7 to 18).¹ Although the magnitude of the NNT effect size is weaker for cariprazine than the other dopamine receptor partial agonists, the 95% CI overlaps with that of aripiprazole and brexpiprazole. An appropriately designed head-to-head trial would be necessary to directly test noninferiority.

Continue to: Pooling the data...

Pooling the data from the 3 pivotal short-term acute bipolar mania trials for cariprazine monotherapy in adults^29-31 and using the definition of response as a ≥50% decrease in the YMRS total score for the recommended target dose of 3 to 6 mg/d, the percentage of responders was 57%, compared with 36% for the pooled placebo groups, yielding a NNT of 5 (95% CI 4 to 8).¹ The magnitude of the NNT effect size is stronger for cariprazine than for aripiprazole, but the 95% CIs overlap.

The most commonly encountered adverse events in the short-term trials (incidence ≥5% and at least twice the rate of placebo) were extrapyramidal symptoms and akathisia (schizophrenia); and extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness (bipolar mania). In the schizophrenia studies, rates of discontinuation because of an adverse event were not higher for active medication vs placebo, suggesting excellent overall tolerability, and for bipolar disorder the NNH vs placebo on discontinuation because of an adverse event was 20, representing reasonable overall tolerability for this indication as well (Table 1).

Differences to consider

Indications. Although all 3 medications are approved for the treatment of schizophrenia, both aripiprazole and brexpiprazole are also approved for adjunctive treatment of MDD, and both aripiprazole and cariprazine are also approved for acute treatment of manic or mixed episodes associated with bipolar I disorder. In addition, aripiprazole is approved for a number of different disease states in pediatric patients. Aripiprazole has also been approved in a number of different formulations (oral and IM), but brexpiprazole and cariprazine are presently available only as oral pills (tablets for brexpiprazole, capsules for cariprazine).

Contraindications. All 3 agents are contraindicated in patients with a known hypersensitivity reaction to the product. All 3 also have a “black-box” warning for increased mortality in geriatric patients with dementia-related psychosis, a warning that is found in all antipsychotic medication labels. Additional black-box warnings are included regarding suicidality in the product labels of aripiprazole and brexpiprazole by virtue of their approval for the treatment of MDD.

Pharmacodynamics. All 3 agents describe a similar mechanism of action in their respective product labels: “efficacy … could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.”^2,19,25

Continue to: However, binding affinities differ...

However, binding affinities differ substantially among the agents (for example, cariprazine has only moderate binding affinity at serotonin 5-HT2A receptors [18.8 nM]), and differences also exist in terms of intrinsic activity at the receptors where partial agonism is operative. Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the dopamine D2 receptor (and thus is expected to cause less akathisia), and has an approximately 10-fold higher affinity for serotonin 5-HT1A and 5-HT2A receptors, also potentially enhancing tolerability and perhaps anxiolytic activity.^32,33 When cariprazine was compared with aripiprazole in functional assays for dopamine D2 and D3 receptors, similar D2 and higher D3 antagonist-partial agonist affinity and a 3- to 10-fold greater D3 vs D2 selectivity was observed for cariprazine.³⁴ Whether specifically targeting the dopamine D3 receptor over the dopamine D2 receptor is clinically advantageous remains unknown, but in preclinical studies, dopamine D3–preferring agents may exert pro-cognitive effects.^35-37 All 3 agents have only moderate binding affinities to histamine H1 receptors, thus sedation should not be prominent for any of them. None of the 3 agents have appreciable binding at muscarinic receptors, thus adverse effects related to antimuscarinic activity should not be present as well.

Schizophrenia is a heterogenous disorder. We know from clinical practice that patients respond differently to specific antipsychotics. Having different pharmacodynamic “fingerprints” to choose from allows for flexibility in treatment. Moreover, dopamine receptor partial agonists provide an alternative to the array of dopamine receptor antagonists, such as the other second-generation antipsychotics and all first-generation antipsychotics.

Dosing. Although all 3 agents are dosed once daily, only for aripiprazole is the recommended starting dose the same as the recommended maintenance dose in adults with schizophrenia or bipolar mania. Although the starting dose for cariprazine for schizophrenia can be therapeutic (1.5 mg/d), for the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d.

Half-life. Aripiprazole and brexpiprazole share a similar elimination half-life: approximately 75 hours and 94 hours for aripiprazole and its active metabolite dehydro-aripiprazole, respectively, and 91 hours and 86 hours for brexpiprazole and its major metabolite, DM-3411 (inactive), respectively. Cariprazine is strikingly different, with an elimination half-life of 2 to 4 days, and approximately 1 to 3 weeks for its active metabolite didesmethyl cariprazine.

Drug interactions. Both aripiprazole and brexpiprazole are metabolized via cytochrome P450 (CYP) 2D6 and CYP3A4, and thus the dose may need to be adjusted in the presence of CYP2D6 inhibitors or CYP3A4 inhibitors/inducers; with inhibitors, the dose is decreased by half or more, and with inducers, the dose is doubled. In contrast, cariprazine is primarily metabolized by CYP3A4 and thus potential drug–drug interactions are primarily focused on CYP3A4 inhibitors (decrease cariprazine dose by half) and inducers (co-prescribing of cariprazine with a CYP3A4 inducer is not recommended).

Continue to: Tolerability

Tolerability. For all 3 agents, rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability.^2,19,25 For the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability. For the most commonly encountered adverse event for each medication, the NNH values ranged from 5 (akathisia for aripiprazole for adjunctive use in MDD) to 50 (increased weight for brexpiprazole for schizophrenia). Of special interest are the adverse events of weight gain ≥7% from baseline, somnolence adverse events, and akathisia adverse events; the NNH values vs placebo for these are listed in Table 2¹. Pragmatically, NNH values <10 are likely to be more clinically relevant. For aripiprazole, brexpiprazole, and cariprazine for the treatment of schizophrenia, none of the NNH values for weight gain, somnolence, or akathisia were <10; however, this was not the case for the mood disorders, where in general, akathisia was more frequently observed for each of the agents. For the indication of schizophrenia, the rank order for propensity for weight gain appears to be brexpiprazole > aripiprazole > cariprazine, the propensity for somnolence aripiprazole > brexpiprazole > cariprazine, and the propensity for akathisia cariprazine > aripiprazole > brexpiprazole; however, this is by indirect comparison, and appropriately designed head-to-head clinical trials will be necessary in order to accurately assess these potential differences.

Because of the partial agonist activity at the dopamine D2 receptor, aripiprazole, brexpiprazole, and cariprazine are less likely to cause hyperprolactinemia than other first-line first- or second-generation antipsychotics. Other differentiating features of the dopamine receptor partial agonists compared with other choices include a relative lack of effect on the QT interval.³⁸ In general, as predicted by their relatively lower binding affinities to histamine H1 receptors, the dopamine receptor partial agonists are not especially sedating.³⁹

Likelihood to be helped or harmed

The concept of likelihood to be helped or harmed (LHH) can be useful to assess benefit vs risk, provided you select a relevant harm to contrast with the expected benefit.⁴⁰ Table 3¹ provides the NNT for response, NNH for discontinuation because of an adverse event (where applicable), the NNHs for weight gain ≥7%, somnolence adverse events, and akathisia adverse events, together with the calculated LHH (where applicable). With the exception of aripiprazole for the treatment of MDD when comparing response vs akathisia, all LHH values are >1.0, and thus the benefit (response) would be encountered more often than the harm. When LHH values are ≥10, this can be interpreted that one would encounter a response at least 10 times more often than the adverse event of interest. This was observed for brexpiprazole for the treatment of schizophrenia when comparing response vs akathisia, for cariprazine for schizophrenia when comparing response vs somnolence, for aripiprazole for bipolar mania when comparing response vs discontinuation because of an adverse event, and for cariprazine for bipolar mania when comparing response vs somnolence.

Beyond acute studies

When treating patients with schizophrenia, delaying time to relapse is a main goal. In placebo-controlled randomized withdrawal studies of oral aripiprazole, brexpiprazole, and cariprazine in patients with schizophrenia, observed relapse rates vs placebo were reported, allowing the calculation of NNT vs placebo for the avoidance of relapse.^41-44 These NNT values were similar and ranged from 4 to 5. For aripiprazole, relapse rates vs placebo in the 26-week study were 34% vs 57%, resulting in a NNT of 5 (95% CI 3 to 9); brexpiprazole, 52-week study, 13.5% vs 38.5%, NNT of 4 (95% CI 3 to 8); and cariprazine, 72-week study, 25% vs 47.5%, NNT of 5 (95% CI 3 to 11). In addition, cariprazine, 4.5 mg/d, has been directly compared with risperidone, 4 mg/d, in a 26-week double-blind study in non-geriatric adult patients with schizophrenia and predominant negative symptoms for at least 6 months.⁴⁵ Cariprazine was superior to risperidone on the PANSS–Negative Factor Score, and response to treatment (decrease ≥20% in PANSS–Negative Factor Score) was achieved by more patients treated with cariprazine by 26 weeks than those treated with risperidone (69% vs 58%, NNT 9 [95% CI 5 to 44]).

Caveats

The harms discussed in this article are primarily from acute studies and do not reflect effects that can take time to develop, such as tardive dyskinesia, the long-term accumulation of body weight, and the development of insulin resistance/type 2 diabetes mellitus.⁴⁰ The data presented are from carefully conducted registration trials that enrolled subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ from those encountered in routine clinical practice. Keep in mind that adverse events may differ in terms of impact and may not be clinically relevant if the adverse event is mild, time-limited, or easily managed. Moreover, different patients carry different propensities to experience different adverse events or to achieve a therapeutic response.

Continue to: Bottom Line

Although aripiprazole, brexpiprazole, and cariprazine are all dopamine receptor partial agonists with demonstrated efficacy in psychiatric disorders, they differ in terms of available formulations, indications, pharmacodynamics, pharmacokinetics, titration requirements, and tolerability. Careful consideration of these factors can increase the likelihood of successful treatment.

Related Resources

• Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. 2013;27(11):879-911.
• Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013;67(5):407-411.
• U.S. Food & Drug Administration. Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf.

Drug Brand Names

Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Abilify Maintena
Brexpiprazole • Rexulti
Cariprazine • Vraylar

Aripiprazole, brexpiprazole, and cariprazine are dopamine receptor partial agonists, and on the surface, they appear similar. However, there are key differences in terms of available indications, formulations, pharmacodynamics, pharmacokinetics, dosing, drug interactions, tolerability, and other factors related to successful use.¹ This review will cover the main points that the knowledgeable clinician will need to be mindful of when prescribing these agents.

Aripiprazole

Aripiprazole was launched in the United States in 2002² as the first dopamine receptor partial agonist approved for the treatment of schizophrenia; it later received additional indications for adults with manic or mixed episodes associated with bipolar I disorder and the maintenance treatment of bipolar I disorder, as well as for the adjunctive treatment of major depressive disorder (MDD). Pediatric indications include schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder, irritability associated with autistic disorder, and Tourette’s disorder.

Several formulations also became available, including a short-acting injection indicated for agitation associated with schizophrenia or bipolar mania, and oral disintegrating tablets and an oral solution that could substitute for the regular tablet. Presently the medication has gone “generic,” and not all formulations are being manufactured. The long-acting formulations of aripiprazole (aripiprazole monohydrate and aripiprazole lauroxil) are considered different products, each with its own product insert, with indications that are more limited in scope than for the oral forms.^3,4

Although dopamine D2 receptor partial agonism is a relevant mechanism of action, partial agonist activity at serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors also play a role.² Actions at receptors other than dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A may explain some of the other clinical effects of aripiprazole. In terms of binding, aripiprazole has very high binding affinities (Ki) to dopamine D2 (0.34 nM), dopamine D3 (0.8 nM), and serotonin 5-HT2B (0.36 nM) receptors, and high binding affinities to serotonin 5-HT1A (1.7 nM) and serotonin 5-HT2A (3.4 nM) receptors.

Dosage recommendations for adults with schizophrenia suggest a starting and maintenance dose of 10 to 15 mg/d.² Although the maximum dose is 30 mg/d, there is no evidence that doses >15 mg/d are superior to lower doses.⁵ In adolescents with schizophrenia, the product label recommends a starting dose of 2 mg/d, a maintenance dose of 10 mg/d, and a maximum dose of 30 mg/d. Recommendations for dosing in bipolar mania are similar. Dosing for the other indications is lower.

Efficacy in schizophrenia can be quantified using number needed to treat (NNT) for response vs placebo. The NNT answers the question “How many patients need to be randomized to aripiprazole vs placebo before expecting to encounter one additional responder?”⁶ From the 4 positive pivotal short-term acute schizophrenia trials for aripiprazole in adults,^7-10 using the definition of response as a ≥30% decrease in the Positive and Negative Syndrome Scale (PANSS) total score or a Clinical Global Impressions–Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved), and pooling the data for aripiprazole doses 10 to 30 mg/d, response rates were 38% for aripiprazole vs 24% for placebo, resulting in a NNT of 8 (95% confidence interval [CI] 6 to 13).

From the 4 positive pivotal short-term acute bipolar mania trials for aripiprazole monotherapy in adults^11-14 using the definition of response as a ≥50% decrease in the Young Mania Rating Scale (YMRS) total score, and pooling the data for aripiprazole doses 15 to 30 mg/d, response rates were 47% for aripiprazole vs 31% for placebo, resulting in a NNT of 7 (95% CI 5 to 11).¹ Similar results were observed in the adjunctive aripiprazole acute bipolar mania trial¹⁵ where the NNT for response was also 7.¹

Continue to: From the 2 positive pivotal short-term...

From the 2 positive pivotal short-term acute MDD trials for aripiprazole,^16,17 using the definition of response as a ≥50% decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and pooling the data (aripiprazole flexibly dosed 2 to 20 mg/d, with a median dose of 10 mg/d), response rates were 33% for aripiprazole vs 20% for placebo, resulting in a NNT of 8 (95% CI 6 to 17). After including a third trial not described in product labeling,¹⁸ the NNT became a more robust 7 (95% CI 5 to 11).¹

The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) in the pivotal trials were akathisia (schizophrenia); akathisia, sedation, restlessness, tremor, and extrapyramidal disorder (bipolar mania, monotherapy); akathisia, insomnia, and extrapyramidal disorder (bipolar mania, adjunctive therapy); akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision (MDD); and nausea (short-acting IM formulation). Table 1¹ summarizes the tolerability information regarding rate of discontinuation due to adverse events (an overall indicator of tolerability), and the incidence of the most common adverse event, together with the calculated number needed to harm (NNH). Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability; for the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability for these indications.

Brexpiprazole

Brexpiprazole was launched in the United States in 2015 for 2 indications: schizophrenia and the adjunctive treatment of MDD, both in adults.¹⁹ In terms of binding, brexpiprazole has very high binding affinities to serotonin 5-HT1A (0.12 nM), adrenergic α1B (0.17 nM), dopamine D2 (0.30 nM), serotonin 5-HT2A (0.47 nM), and adrenergic α2C (0.59 nM) receptors, and high binding affinities to dopamine D3 (1.1 nM), serotonin 5-HT2B (1.9 nM), adrenergic α1D (2.6 nM), serotonin 5-HT7 (3.7 nM), and adrenergic α1A (3.8 nM) receptors.

The 1-mg/d starting dose for brexpiprazole is lower than the recommended dose range of 2 to 4 mg/d for schizophrenia or the recommended dose of 2 mg/d for MDD.¹⁹ Thus brexpiprazole requires titration. The recommended rate of titration depends on the disease state being treated. For schizophrenia, the recommended titration schedule is to increase the dose to 2 mg/d on Day 5 through Day 7, then to 4 mg/d (the maximum recommended dose) on Day 8 based on the patient’s clinical response and tolerability. For MDD, there is the option of starting at 0.5 mg/d and the titration process is slower, with dosage increases occurring at weekly intervals, and with a maximum dose of 3 mg/d.

Using the identical definition of response in persons with schizophrenia as for the aripiprazole data described above, pooling together all the available data for the recommended target dose of brexpiprazole for schizophrenia (2 to 4 mg/d) from the 2 studies listed in the product label,^20,21 the percentage of responders was 46%, compared with 31% for the pooled placebo groups, yielding a NNT of 7 (95% CI 5 to 12).²²

Continue to: For MDD...

For MDD, using the definition of response as a ≥50% decrease in MADRS total score, and pooling the results for brexpiprazole 1, 2, and 3 mg/d from the 2 pivotal trials,^23,24 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI 8 to 26).²² Including the 1.5-mg/d dose arm and the placebo arm from the phase II study for which results are also available but not included in product labelling, the NNT becomes a slightly more robust 11 (95% CI 8 to 20).²² Although the magnitude of the NNT effect size is stronger for aripiprazole than for brexpiprazole, the 95% CIs do overlap.

The most commonly encountered adverse event in the short-term trials in schizophrenia (incidence ≥4% and at least twice the rate of placebo) was increased weight. The most commonly encountered adverse events in the short-term trials in MDD (incidence ≥5% and at least twice the rate of placebo) were increased weight and akathisia. Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability, and for MDD the NNH vs placebo on discontinuation because of an adverse event was 50, representing reasonable overall tolerability for this indication as well (Table 1¹).

Cariprazine

Cariprazine was launched in the United States in 2015 for 2 indications: schizophrenia, and the acute treatment of manic or mixed episodes associated with bipolar I disorder, both in adults.²⁵ In terms of binding, cariprazine has very high binding affinities to dopamine D3 (0.085 nM), dopamine D2L (0.49 nM), serotonin 5-HT2B (0.58 nM), and dopamine D2S (0.69 nM) receptors, and high binding affinity to serotonin 5-HT1A (2.6 nM) receptors. Cariprazine forms 2 major metabolites, desmethyl cariprazine and didesmethyl cariprazine, that have in vitro receptor binding profiles similar to the parent drug. This latter metabolite, didesmethyl cariprazine, has a half-life of 1 to 3 weeks, and is the active moiety responsible for the majority of cariprazine’s effect when in steady state. Thus, following discontinuation of cariprazine, the decline in plasma concentrations of active drug will be slow.

The starting dose for cariprazine for schizophrenia, 1.5 mg/d, can be therapeutic. The dosage can be increased to 3 mg/d on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3-mg increments to a maximum dose of 6 mg/d. For the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d; this can be done on Day 2. Cariprazine has been tested in clinical trials at higher doses; however, doses that exceed 6 mg/d did not confer significant additional benefit.²⁵

A more conservative definition of response was used in the reporting of the cariprazine acute schizophrenia studies. This was simply a ≥30% decrease in the PANSS total score, and did not include the option of including patients who scored a 1 or 2 on the CGI-I. For pooled doses of cariprazine 1.5 to 6 mg/d,^26-28 the percentage of responders was 31%, compared with 21% for the pooled placebo groups, yielding a NNT of 10 (95% CI 7 to 18).¹ Although the magnitude of the NNT effect size is weaker for cariprazine than the other dopamine receptor partial agonists, the 95% CI overlaps with that of aripiprazole and brexpiprazole. An appropriately designed head-to-head trial would be necessary to directly test noninferiority.

Continue to: Pooling the data...

Pooling the data from the 3 pivotal short-term acute bipolar mania trials for cariprazine monotherapy in adults^29-31 and using the definition of response as a ≥50% decrease in the YMRS total score for the recommended target dose of 3 to 6 mg/d, the percentage of responders was 57%, compared with 36% for the pooled placebo groups, yielding a NNT of 5 (95% CI 4 to 8).¹ The magnitude of the NNT effect size is stronger for cariprazine than for aripiprazole, but the 95% CIs overlap.

The most commonly encountered adverse events in the short-term trials (incidence ≥5% and at least twice the rate of placebo) were extrapyramidal symptoms and akathisia (schizophrenia); and extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness (bipolar mania). In the schizophrenia studies, rates of discontinuation because of an adverse event were not higher for active medication vs placebo, suggesting excellent overall tolerability, and for bipolar disorder the NNH vs placebo on discontinuation because of an adverse event was 20, representing reasonable overall tolerability for this indication as well (Table 1).

Differences to consider

Indications. Although all 3 medications are approved for the treatment of schizophrenia, both aripiprazole and brexpiprazole are also approved for adjunctive treatment of MDD, and both aripiprazole and cariprazine are also approved for acute treatment of manic or mixed episodes associated with bipolar I disorder. In addition, aripiprazole is approved for a number of different disease states in pediatric patients. Aripiprazole has also been approved in a number of different formulations (oral and IM), but brexpiprazole and cariprazine are presently available only as oral pills (tablets for brexpiprazole, capsules for cariprazine).

Contraindications. All 3 agents are contraindicated in patients with a known hypersensitivity reaction to the product. All 3 also have a “black-box” warning for increased mortality in geriatric patients with dementia-related psychosis, a warning that is found in all antipsychotic medication labels. Additional black-box warnings are included regarding suicidality in the product labels of aripiprazole and brexpiprazole by virtue of their approval for the treatment of MDD.

Pharmacodynamics. All 3 agents describe a similar mechanism of action in their respective product labels: “efficacy … could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.”^2,19,25

Continue to: However, binding affinities differ...

However, binding affinities differ substantially among the agents (for example, cariprazine has only moderate binding affinity at serotonin 5-HT2A receptors [18.8 nM]), and differences also exist in terms of intrinsic activity at the receptors where partial agonism is operative. Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the dopamine D2 receptor (and thus is expected to cause less akathisia), and has an approximately 10-fold higher affinity for serotonin 5-HT1A and 5-HT2A receptors, also potentially enhancing tolerability and perhaps anxiolytic activity.^32,33 When cariprazine was compared with aripiprazole in functional assays for dopamine D2 and D3 receptors, similar D2 and higher D3 antagonist-partial agonist affinity and a 3- to 10-fold greater D3 vs D2 selectivity was observed for cariprazine.³⁴ Whether specifically targeting the dopamine D3 receptor over the dopamine D2 receptor is clinically advantageous remains unknown, but in preclinical studies, dopamine D3–preferring agents may exert pro-cognitive effects.^35-37 All 3 agents have only moderate binding affinities to histamine H1 receptors, thus sedation should not be prominent for any of them. None of the 3 agents have appreciable binding at muscarinic receptors, thus adverse effects related to antimuscarinic activity should not be present as well.

Schizophrenia is a heterogenous disorder. We know from clinical practice that patients respond differently to specific antipsychotics. Having different pharmacodynamic “fingerprints” to choose from allows for flexibility in treatment. Moreover, dopamine receptor partial agonists provide an alternative to the array of dopamine receptor antagonists, such as the other second-generation antipsychotics and all first-generation antipsychotics.

Dosing. Although all 3 agents are dosed once daily, only for aripiprazole is the recommended starting dose the same as the recommended maintenance dose in adults with schizophrenia or bipolar mania. Although the starting dose for cariprazine for schizophrenia can be therapeutic (1.5 mg/d), for the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d.

Half-life. Aripiprazole and brexpiprazole share a similar elimination half-life: approximately 75 hours and 94 hours for aripiprazole and its active metabolite dehydro-aripiprazole, respectively, and 91 hours and 86 hours for brexpiprazole and its major metabolite, DM-3411 (inactive), respectively. Cariprazine is strikingly different, with an elimination half-life of 2 to 4 days, and approximately 1 to 3 weeks for its active metabolite didesmethyl cariprazine.

Drug interactions. Both aripiprazole and brexpiprazole are metabolized via cytochrome P450 (CYP) 2D6 and CYP3A4, and thus the dose may need to be adjusted in the presence of CYP2D6 inhibitors or CYP3A4 inhibitors/inducers; with inhibitors, the dose is decreased by half or more, and with inducers, the dose is doubled. In contrast, cariprazine is primarily metabolized by CYP3A4 and thus potential drug–drug interactions are primarily focused on CYP3A4 inhibitors (decrease cariprazine dose by half) and inducers (co-prescribing of cariprazine with a CYP3A4 inducer is not recommended).

Continue to: Tolerability

Tolerability. For all 3 agents, rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability.^2,19,25 For the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability. For the most commonly encountered adverse event for each medication, the NNH values ranged from 5 (akathisia for aripiprazole for adjunctive use in MDD) to 50 (increased weight for brexpiprazole for schizophrenia). Of special interest are the adverse events of weight gain ≥7% from baseline, somnolence adverse events, and akathisia adverse events; the NNH values vs placebo for these are listed in Table 2¹. Pragmatically, NNH values <10 are likely to be more clinically relevant. For aripiprazole, brexpiprazole, and cariprazine for the treatment of schizophrenia, none of the NNH values for weight gain, somnolence, or akathisia were <10; however, this was not the case for the mood disorders, where in general, akathisia was more frequently observed for each of the agents. For the indication of schizophrenia, the rank order for propensity for weight gain appears to be brexpiprazole > aripiprazole > cariprazine, the propensity for somnolence aripiprazole > brexpiprazole > cariprazine, and the propensity for akathisia cariprazine > aripiprazole > brexpiprazole; however, this is by indirect comparison, and appropriately designed head-to-head clinical trials will be necessary in order to accurately assess these potential differences.

Because of the partial agonist activity at the dopamine D2 receptor, aripiprazole, brexpiprazole, and cariprazine are less likely to cause hyperprolactinemia than other first-line first- or second-generation antipsychotics. Other differentiating features of the dopamine receptor partial agonists compared with other choices include a relative lack of effect on the QT interval.³⁸ In general, as predicted by their relatively lower binding affinities to histamine H1 receptors, the dopamine receptor partial agonists are not especially sedating.³⁹

Likelihood to be helped or harmed

The concept of likelihood to be helped or harmed (LHH) can be useful to assess benefit vs risk, provided you select a relevant harm to contrast with the expected benefit.⁴⁰ Table 3¹ provides the NNT for response, NNH for discontinuation because of an adverse event (where applicable), the NNHs for weight gain ≥7%, somnolence adverse events, and akathisia adverse events, together with the calculated LHH (where applicable). With the exception of aripiprazole for the treatment of MDD when comparing response vs akathisia, all LHH values are >1.0, and thus the benefit (response) would be encountered more often than the harm. When LHH values are ≥10, this can be interpreted that one would encounter a response at least 10 times more often than the adverse event of interest. This was observed for brexpiprazole for the treatment of schizophrenia when comparing response vs akathisia, for cariprazine for schizophrenia when comparing response vs somnolence, for aripiprazole for bipolar mania when comparing response vs discontinuation because of an adverse event, and for cariprazine for bipolar mania when comparing response vs somnolence.

Beyond acute studies

When treating patients with schizophrenia, delaying time to relapse is a main goal. In placebo-controlled randomized withdrawal studies of oral aripiprazole, brexpiprazole, and cariprazine in patients with schizophrenia, observed relapse rates vs placebo were reported, allowing the calculation of NNT vs placebo for the avoidance of relapse.^41-44 These NNT values were similar and ranged from 4 to 5. For aripiprazole, relapse rates vs placebo in the 26-week study were 34% vs 57%, resulting in a NNT of 5 (95% CI 3 to 9); brexpiprazole, 52-week study, 13.5% vs 38.5%, NNT of 4 (95% CI 3 to 8); and cariprazine, 72-week study, 25% vs 47.5%, NNT of 5 (95% CI 3 to 11). In addition, cariprazine, 4.5 mg/d, has been directly compared with risperidone, 4 mg/d, in a 26-week double-blind study in non-geriatric adult patients with schizophrenia and predominant negative symptoms for at least 6 months.⁴⁵ Cariprazine was superior to risperidone on the PANSS–Negative Factor Score, and response to treatment (decrease ≥20% in PANSS–Negative Factor Score) was achieved by more patients treated with cariprazine by 26 weeks than those treated with risperidone (69% vs 58%, NNT 9 [95% CI 5 to 44]).

Caveats

The harms discussed in this article are primarily from acute studies and do not reflect effects that can take time to develop, such as tardive dyskinesia, the long-term accumulation of body weight, and the development of insulin resistance/type 2 diabetes mellitus.⁴⁰ The data presented are from carefully conducted registration trials that enrolled subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ from those encountered in routine clinical practice. Keep in mind that adverse events may differ in terms of impact and may not be clinically relevant if the adverse event is mild, time-limited, or easily managed. Moreover, different patients carry different propensities to experience different adverse events or to achieve a therapeutic response.

Continue to: Bottom Line

Although aripiprazole, brexpiprazole, and cariprazine are all dopamine receptor partial agonists with demonstrated efficacy in psychiatric disorders, they differ in terms of available formulations, indications, pharmacodynamics, pharmacokinetics, titration requirements, and tolerability. Careful consideration of these factors can increase the likelihood of successful treatment.

Related Resources

• Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. 2013;27(11):879-911.
• Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013;67(5):407-411.
• U.S. Food & Drug Administration. Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf.

Drug Brand Names

Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Abilify Maintena
Brexpiprazole • Rexulti
Cariprazine • Vraylar

Aripiprazole, brexpiprazole, and cariprazine are dopamine receptor partial agonists, and on the surface, they appear similar. However, there are key differences in terms of available indications, formulations, pharmacodynamics, pharmacokinetics, dosing, drug interactions, tolerability, and other factors related to successful use.¹ This review will cover the main points that the knowledgeable clinician will need to be mindful of when prescribing these agents.

Aripiprazole

Aripiprazole was launched in the United States in 2002² as the first dopamine receptor partial agonist approved for the treatment of schizophrenia; it later received additional indications for adults with manic or mixed episodes associated with bipolar I disorder and the maintenance treatment of bipolar I disorder, as well as for the adjunctive treatment of major depressive disorder (MDD). Pediatric indications include schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder, irritability associated with autistic disorder, and Tourette’s disorder.

Several formulations also became available, including a short-acting injection indicated for agitation associated with schizophrenia or bipolar mania, and oral disintegrating tablets and an oral solution that could substitute for the regular tablet. Presently the medication has gone “generic,” and not all formulations are being manufactured. The long-acting formulations of aripiprazole (aripiprazole monohydrate and aripiprazole lauroxil) are considered different products, each with its own product insert, with indications that are more limited in scope than for the oral forms.^3,4

Although dopamine D2 receptor partial agonism is a relevant mechanism of action, partial agonist activity at serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors also play a role.² Actions at receptors other than dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A may explain some of the other clinical effects of aripiprazole. In terms of binding, aripiprazole has very high binding affinities (Ki) to dopamine D2 (0.34 nM), dopamine D3 (0.8 nM), and serotonin 5-HT2B (0.36 nM) receptors, and high binding affinities to serotonin 5-HT1A (1.7 nM) and serotonin 5-HT2A (3.4 nM) receptors.

Dosage recommendations for adults with schizophrenia suggest a starting and maintenance dose of 10 to 15 mg/d.² Although the maximum dose is 30 mg/d, there is no evidence that doses >15 mg/d are superior to lower doses.⁵ In adolescents with schizophrenia, the product label recommends a starting dose of 2 mg/d, a maintenance dose of 10 mg/d, and a maximum dose of 30 mg/d. Recommendations for dosing in bipolar mania are similar. Dosing for the other indications is lower.

Efficacy in schizophrenia can be quantified using number needed to treat (NNT) for response vs placebo. The NNT answers the question “How many patients need to be randomized to aripiprazole vs placebo before expecting to encounter one additional responder?”⁶ From the 4 positive pivotal short-term acute schizophrenia trials for aripiprazole in adults,^7-10 using the definition of response as a ≥30% decrease in the Positive and Negative Syndrome Scale (PANSS) total score or a Clinical Global Impressions–Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved), and pooling the data for aripiprazole doses 10 to 30 mg/d, response rates were 38% for aripiprazole vs 24% for placebo, resulting in a NNT of 8 (95% confidence interval [CI] 6 to 13).

From the 4 positive pivotal short-term acute bipolar mania trials for aripiprazole monotherapy in adults^11-14 using the definition of response as a ≥50% decrease in the Young Mania Rating Scale (YMRS) total score, and pooling the data for aripiprazole doses 15 to 30 mg/d, response rates were 47% for aripiprazole vs 31% for placebo, resulting in a NNT of 7 (95% CI 5 to 11).¹ Similar results were observed in the adjunctive aripiprazole acute bipolar mania trial¹⁵ where the NNT for response was also 7.¹

Continue to: From the 2 positive pivotal short-term...

From the 2 positive pivotal short-term acute MDD trials for aripiprazole,^16,17 using the definition of response as a ≥50% decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and pooling the data (aripiprazole flexibly dosed 2 to 20 mg/d, with a median dose of 10 mg/d), response rates were 33% for aripiprazole vs 20% for placebo, resulting in a NNT of 8 (95% CI 6 to 17). After including a third trial not described in product labeling,¹⁸ the NNT became a more robust 7 (95% CI 5 to 11).¹

The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) in the pivotal trials were akathisia (schizophrenia); akathisia, sedation, restlessness, tremor, and extrapyramidal disorder (bipolar mania, monotherapy); akathisia, insomnia, and extrapyramidal disorder (bipolar mania, adjunctive therapy); akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision (MDD); and nausea (short-acting IM formulation). Table 1¹ summarizes the tolerability information regarding rate of discontinuation due to adverse events (an overall indicator of tolerability), and the incidence of the most common adverse event, together with the calculated number needed to harm (NNH). Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability; for the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability for these indications.

Brexpiprazole

Brexpiprazole was launched in the United States in 2015 for 2 indications: schizophrenia and the adjunctive treatment of MDD, both in adults.¹⁹ In terms of binding, brexpiprazole has very high binding affinities to serotonin 5-HT1A (0.12 nM), adrenergic α1B (0.17 nM), dopamine D2 (0.30 nM), serotonin 5-HT2A (0.47 nM), and adrenergic α2C (0.59 nM) receptors, and high binding affinities to dopamine D3 (1.1 nM), serotonin 5-HT2B (1.9 nM), adrenergic α1D (2.6 nM), serotonin 5-HT7 (3.7 nM), and adrenergic α1A (3.8 nM) receptors.

The 1-mg/d starting dose for brexpiprazole is lower than the recommended dose range of 2 to 4 mg/d for schizophrenia or the recommended dose of 2 mg/d for MDD.¹⁹ Thus brexpiprazole requires titration. The recommended rate of titration depends on the disease state being treated. For schizophrenia, the recommended titration schedule is to increase the dose to 2 mg/d on Day 5 through Day 7, then to 4 mg/d (the maximum recommended dose) on Day 8 based on the patient’s clinical response and tolerability. For MDD, there is the option of starting at 0.5 mg/d and the titration process is slower, with dosage increases occurring at weekly intervals, and with a maximum dose of 3 mg/d.

Using the identical definition of response in persons with schizophrenia as for the aripiprazole data described above, pooling together all the available data for the recommended target dose of brexpiprazole for schizophrenia (2 to 4 mg/d) from the 2 studies listed in the product label,^20,21 the percentage of responders was 46%, compared with 31% for the pooled placebo groups, yielding a NNT of 7 (95% CI 5 to 12).²²

Continue to: For MDD...

For MDD, using the definition of response as a ≥50% decrease in MADRS total score, and pooling the results for brexpiprazole 1, 2, and 3 mg/d from the 2 pivotal trials,^23,24 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI 8 to 26).²² Including the 1.5-mg/d dose arm and the placebo arm from the phase II study for which results are also available but not included in product labelling, the NNT becomes a slightly more robust 11 (95% CI 8 to 20).²² Although the magnitude of the NNT effect size is stronger for aripiprazole than for brexpiprazole, the 95% CIs do overlap.

The most commonly encountered adverse event in the short-term trials in schizophrenia (incidence ≥4% and at least twice the rate of placebo) was increased weight. The most commonly encountered adverse events in the short-term trials in MDD (incidence ≥5% and at least twice the rate of placebo) were increased weight and akathisia. Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability, and for MDD the NNH vs placebo on discontinuation because of an adverse event was 50, representing reasonable overall tolerability for this indication as well (Table 1¹).

Cariprazine

Cariprazine was launched in the United States in 2015 for 2 indications: schizophrenia, and the acute treatment of manic or mixed episodes associated with bipolar I disorder, both in adults.²⁵ In terms of binding, cariprazine has very high binding affinities to dopamine D3 (0.085 nM), dopamine D2L (0.49 nM), serotonin 5-HT2B (0.58 nM), and dopamine D2S (0.69 nM) receptors, and high binding affinity to serotonin 5-HT1A (2.6 nM) receptors. Cariprazine forms 2 major metabolites, desmethyl cariprazine and didesmethyl cariprazine, that have in vitro receptor binding profiles similar to the parent drug. This latter metabolite, didesmethyl cariprazine, has a half-life of 1 to 3 weeks, and is the active moiety responsible for the majority of cariprazine’s effect when in steady state. Thus, following discontinuation of cariprazine, the decline in plasma concentrations of active drug will be slow.

The starting dose for cariprazine for schizophrenia, 1.5 mg/d, can be therapeutic. The dosage can be increased to 3 mg/d on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3-mg increments to a maximum dose of 6 mg/d. For the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d; this can be done on Day 2. Cariprazine has been tested in clinical trials at higher doses; however, doses that exceed 6 mg/d did not confer significant additional benefit.²⁵

A more conservative definition of response was used in the reporting of the cariprazine acute schizophrenia studies. This was simply a ≥30% decrease in the PANSS total score, and did not include the option of including patients who scored a 1 or 2 on the CGI-I. For pooled doses of cariprazine 1.5 to 6 mg/d,^26-28 the percentage of responders was 31%, compared with 21% for the pooled placebo groups, yielding a NNT of 10 (95% CI 7 to 18).¹ Although the magnitude of the NNT effect size is weaker for cariprazine than the other dopamine receptor partial agonists, the 95% CI overlaps with that of aripiprazole and brexpiprazole. An appropriately designed head-to-head trial would be necessary to directly test noninferiority.

Continue to: Pooling the data...

Pooling the data from the 3 pivotal short-term acute bipolar mania trials for cariprazine monotherapy in adults^29-31 and using the definition of response as a ≥50% decrease in the YMRS total score for the recommended target dose of 3 to 6 mg/d, the percentage of responders was 57%, compared with 36% for the pooled placebo groups, yielding a NNT of 5 (95% CI 4 to 8).¹ The magnitude of the NNT effect size is stronger for cariprazine than for aripiprazole, but the 95% CIs overlap.

The most commonly encountered adverse events in the short-term trials (incidence ≥5% and at least twice the rate of placebo) were extrapyramidal symptoms and akathisia (schizophrenia); and extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness (bipolar mania). In the schizophrenia studies, rates of discontinuation because of an adverse event were not higher for active medication vs placebo, suggesting excellent overall tolerability, and for bipolar disorder the NNH vs placebo on discontinuation because of an adverse event was 20, representing reasonable overall tolerability for this indication as well (Table 1).

Differences to consider

Indications. Although all 3 medications are approved for the treatment of schizophrenia, both aripiprazole and brexpiprazole are also approved for adjunctive treatment of MDD, and both aripiprazole and cariprazine are also approved for acute treatment of manic or mixed episodes associated with bipolar I disorder. In addition, aripiprazole is approved for a number of different disease states in pediatric patients. Aripiprazole has also been approved in a number of different formulations (oral and IM), but brexpiprazole and cariprazine are presently available only as oral pills (tablets for brexpiprazole, capsules for cariprazine).

Contraindications. All 3 agents are contraindicated in patients with a known hypersensitivity reaction to the product. All 3 also have a “black-box” warning for increased mortality in geriatric patients with dementia-related psychosis, a warning that is found in all antipsychotic medication labels. Additional black-box warnings are included regarding suicidality in the product labels of aripiprazole and brexpiprazole by virtue of their approval for the treatment of MDD.

Pharmacodynamics. All 3 agents describe a similar mechanism of action in their respective product labels: “efficacy … could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.”^2,19,25

Continue to: However, binding affinities differ...

However, binding affinities differ substantially among the agents (for example, cariprazine has only moderate binding affinity at serotonin 5-HT2A receptors [18.8 nM]), and differences also exist in terms of intrinsic activity at the receptors where partial agonism is operative. Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the dopamine D2 receptor (and thus is expected to cause less akathisia), and has an approximately 10-fold higher affinity for serotonin 5-HT1A and 5-HT2A receptors, also potentially enhancing tolerability and perhaps anxiolytic activity.^32,33 When cariprazine was compared with aripiprazole in functional assays for dopamine D2 and D3 receptors, similar D2 and higher D3 antagonist-partial agonist affinity and a 3- to 10-fold greater D3 vs D2 selectivity was observed for cariprazine.³⁴ Whether specifically targeting the dopamine D3 receptor over the dopamine D2 receptor is clinically advantageous remains unknown, but in preclinical studies, dopamine D3–preferring agents may exert pro-cognitive effects.^35-37 All 3 agents have only moderate binding affinities to histamine H1 receptors, thus sedation should not be prominent for any of them. None of the 3 agents have appreciable binding at muscarinic receptors, thus adverse effects related to antimuscarinic activity should not be present as well.

Schizophrenia is a heterogenous disorder. We know from clinical practice that patients respond differently to specific antipsychotics. Having different pharmacodynamic “fingerprints” to choose from allows for flexibility in treatment. Moreover, dopamine receptor partial agonists provide an alternative to the array of dopamine receptor antagonists, such as the other second-generation antipsychotics and all first-generation antipsychotics.

Dosing. Although all 3 agents are dosed once daily, only for aripiprazole is the recommended starting dose the same as the recommended maintenance dose in adults with schizophrenia or bipolar mania. Although the starting dose for cariprazine for schizophrenia can be therapeutic (1.5 mg/d), for the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d.

Half-life. Aripiprazole and brexpiprazole share a similar elimination half-life: approximately 75 hours and 94 hours for aripiprazole and its active metabolite dehydro-aripiprazole, respectively, and 91 hours and 86 hours for brexpiprazole and its major metabolite, DM-3411 (inactive), respectively. Cariprazine is strikingly different, with an elimination half-life of 2 to 4 days, and approximately 1 to 3 weeks for its active metabolite didesmethyl cariprazine.

Drug interactions. Both aripiprazole and brexpiprazole are metabolized via cytochrome P450 (CYP) 2D6 and CYP3A4, and thus the dose may need to be adjusted in the presence of CYP2D6 inhibitors or CYP3A4 inhibitors/inducers; with inhibitors, the dose is decreased by half or more, and with inducers, the dose is doubled. In contrast, cariprazine is primarily metabolized by CYP3A4 and thus potential drug–drug interactions are primarily focused on CYP3A4 inhibitors (decrease cariprazine dose by half) and inducers (co-prescribing of cariprazine with a CYP3A4 inducer is not recommended).

Continue to: Tolerability

Tolerability. For all 3 agents, rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability.^2,19,25 For the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability. For the most commonly encountered adverse event for each medication, the NNH values ranged from 5 (akathisia for aripiprazole for adjunctive use in MDD) to 50 (increased weight for brexpiprazole for schizophrenia). Of special interest are the adverse events of weight gain ≥7% from baseline, somnolence adverse events, and akathisia adverse events; the NNH values vs placebo for these are listed in Table 2¹. Pragmatically, NNH values <10 are likely to be more clinically relevant. For aripiprazole, brexpiprazole, and cariprazine for the treatment of schizophrenia, none of the NNH values for weight gain, somnolence, or akathisia were <10; however, this was not the case for the mood disorders, where in general, akathisia was more frequently observed for each of the agents. For the indication of schizophrenia, the rank order for propensity for weight gain appears to be brexpiprazole > aripiprazole > cariprazine, the propensity for somnolence aripiprazole > brexpiprazole > cariprazine, and the propensity for akathisia cariprazine > aripiprazole > brexpiprazole; however, this is by indirect comparison, and appropriately designed head-to-head clinical trials will be necessary in order to accurately assess these potential differences.

Because of the partial agonist activity at the dopamine D2 receptor, aripiprazole, brexpiprazole, and cariprazine are less likely to cause hyperprolactinemia than other first-line first- or second-generation antipsychotics. Other differentiating features of the dopamine receptor partial agonists compared with other choices include a relative lack of effect on the QT interval.³⁸ In general, as predicted by their relatively lower binding affinities to histamine H1 receptors, the dopamine receptor partial agonists are not especially sedating.³⁹

Likelihood to be helped or harmed

The concept of likelihood to be helped or harmed (LHH) can be useful to assess benefit vs risk, provided you select a relevant harm to contrast with the expected benefit.⁴⁰ Table 3¹ provides the NNT for response, NNH for discontinuation because of an adverse event (where applicable), the NNHs for weight gain ≥7%, somnolence adverse events, and akathisia adverse events, together with the calculated LHH (where applicable). With the exception of aripiprazole for the treatment of MDD when comparing response vs akathisia, all LHH values are >1.0, and thus the benefit (response) would be encountered more often than the harm. When LHH values are ≥10, this can be interpreted that one would encounter a response at least 10 times more often than the adverse event of interest. This was observed for brexpiprazole for the treatment of schizophrenia when comparing response vs akathisia, for cariprazine for schizophrenia when comparing response vs somnolence, for aripiprazole for bipolar mania when comparing response vs discontinuation because of an adverse event, and for cariprazine for bipolar mania when comparing response vs somnolence.

Beyond acute studies

When treating patients with schizophrenia, delaying time to relapse is a main goal. In placebo-controlled randomized withdrawal studies of oral aripiprazole, brexpiprazole, and cariprazine in patients with schizophrenia, observed relapse rates vs placebo were reported, allowing the calculation of NNT vs placebo for the avoidance of relapse.^41-44 These NNT values were similar and ranged from 4 to 5. For aripiprazole, relapse rates vs placebo in the 26-week study were 34% vs 57%, resulting in a NNT of 5 (95% CI 3 to 9); brexpiprazole, 52-week study, 13.5% vs 38.5%, NNT of 4 (95% CI 3 to 8); and cariprazine, 72-week study, 25% vs 47.5%, NNT of 5 (95% CI 3 to 11). In addition, cariprazine, 4.5 mg/d, has been directly compared with risperidone, 4 mg/d, in a 26-week double-blind study in non-geriatric adult patients with schizophrenia and predominant negative symptoms for at least 6 months.⁴⁵ Cariprazine was superior to risperidone on the PANSS–Negative Factor Score, and response to treatment (decrease ≥20% in PANSS–Negative Factor Score) was achieved by more patients treated with cariprazine by 26 weeks than those treated with risperidone (69% vs 58%, NNT 9 [95% CI 5 to 44]).

Caveats

The harms discussed in this article are primarily from acute studies and do not reflect effects that can take time to develop, such as tardive dyskinesia, the long-term accumulation of body weight, and the development of insulin resistance/type 2 diabetes mellitus.⁴⁰ The data presented are from carefully conducted registration trials that enrolled subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ from those encountered in routine clinical practice. Keep in mind that adverse events may differ in terms of impact and may not be clinically relevant if the adverse event is mild, time-limited, or easily managed. Moreover, different patients carry different propensities to experience different adverse events or to achieve a therapeutic response.

Continue to: Bottom Line

Although aripiprazole, brexpiprazole, and cariprazine are all dopamine receptor partial agonists with demonstrated efficacy in psychiatric disorders, they differ in terms of available formulations, indications, pharmacodynamics, pharmacokinetics, titration requirements, and tolerability. Careful consideration of these factors can increase the likelihood of successful treatment.

Related Resources

• Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. 2013;27(11):879-911.
• Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013;67(5):407-411.
• U.S. Food & Drug Administration. Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf.

Drug Brand Names

Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Abilify Maintena
Brexpiprazole • Rexulti
Cariprazine • Vraylar

Brexpiprazole, FDA-approved in July 2015 to treat schizophrenia and as an adjunct for major depressive disorder (MDD) (Table 1), has shown effi­cacy in 2 phase-III acute trials for each indication.^1-6 Although brexpiprazole is a dopamine D2 partial agonist, it differs from aripiprazole, the other available D2 partial agonist, because it is more potent at serotonin 5-HT1A and 5-HT2A recep­tors and displays less intrinsic activity at D2 receptors,⁷ which could mean better tolerability.

Clinical implications
Schizophrenia is heterogeneous, and indi­vidual response and tolerability to anti­psychotics vary greatly⁸; therefore, new drug options are useful. For MDD, before the availability of brexpiprazole, only 3 antipsychotics were FDA-approved for adjunctive use with antidepressant ther­apy⁹; brexpiprazole represents another agent for patients whose depressive symp­toms persist after standard antidepressant treatment.

Variables that limit the use of antipsy­chotics include extrapyramidal symptoms (EPS), akathisia, sedation/somnolence, weight gain, metabolic abnormalities, and hyperprolactinemia. If post-marketing studies and clinical experience confirm that brexpiprazole has an overall favor­able side-effect profile regarding these tolerability obstacles, brexpiprazole would potentially have advantages over some other available agents, including aripiprazole.

How it works
In addition to a subnanomolar binding affin­ity (Ki < 1 nM) to dopamine D2 receptors as a partial agonist, brexpiprazole also exhib­its similar binding affinities for serotonin 5-HT1A (partial agonist), 5-HT2A (antago­nist), and adrenergic α1B (antagonist) and α2C (antagonist) receptors.⁷

Brexpiprazole also has high affinity (Ki < 5 nM) for dopamine D3 (partial ago­ nist), serotonin 5-HT2B (antagonist), and 5-HT7 (antagonist), and at adrenergic α1A (antagonist) and α1D (antagonist) recep­tors. Brexpiprazole has moderate affinity for histamine H1 receptors (Ki = 19 nM, antago­nist), and low affinity for muscarinic M1 receptors (Ki > 1000 nM, antagonist).

Brexpiprazole’s pharmacodynamic pro­file differs from other available antipsy­chotics, including aripiprazole. Whether this translates to meaningful differences in efficacy and tolerability will depend on the outcomes of specifically designed clinical trials as well as “real-world” experience. Animal models have suggested amelio­ration of schizophrenia-like behavior, depression-like behavior, and anxiety-like behavior with brexipiprazole.⁶

Pharmacokinetics
At 91 hours, brexpiprazole’s half-life is rel­atively long; a steady-state concentration therefore is attained in approximately 2 weeks.1 In the phase-III clinical trials, brex­piprazole was titrated to target dosages, and therefore the product label recommends the same. Brexpiprazole can be administered with or without food.

In a study of brexpiprazole excretion, after a single oral dose of [14C]-labeled brexpip­razole, approximately 25% and 46% of the administered radioactivity was recovered in urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged in the feces.

Exposure, as measured by maximum con­centration and area under the concentration curve, is dose proportional.

Metabolism of brexpiprazole is mediated principally by cytochrome P450 (CYP) 3A4 and CYP2D6. Based on in vitro data, brex­piprazole shows little or no inhibition of CYP450 isozymes.

Efficacy
FDA approval for brexpiprazole for schizo­phrenia and for adjunctive use in MDD was based on 4 phase-III pivotal acute clinical trials conducted in adults, 2 studies each for each disorder.^1-6 These studies are described in Table 2.^2-5

Although not described in product label­ing, a phase-III 52-week maintenance study demonstrated brexpiprazole’s efficacy in preventing exacerbation of psychotic symp­toms and impending relapse in patients with schizophrenia.10 Time from randomiza­tion to exacerbation of psychotic symptoms or impending relapse showed a beneficial effect with brexpiprazole compared with placebo (log-rank test: hazard ratio = 0.292, P < .0001). Significantly fewer patients in the brexpiprazole group relapsed compared with placebo (13.5% vs 38.5%, P < .0001), resulting in a NNT of 4 (95% CI, 3-8).

Major depressive disorder. The primary outcome measure for the acute MDD stud­ies was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to 6-week endpoint of the ran­domized treatment phase. All patients were required to have a history of inadequate response to 1 to 3 treatment trials of standard antidepressants for their current depressive episode. In addition, patients entered the randomized phase only if they had an inad­equate response to antidepressant therapy during an 8-week prospective treatment trial of standard antidepressant treatment plus single-blind placebo.

Participants who responded adequately to the antidepressant in the prospective single-blind phase were not randomized, but instead continued on antidepressant treat­ment plus single-blind placebo for 6 weeks.

The phase-III studies showed positive results for brexpiprazole, 2 mg/d and 3 mg/d, with change in MADRS from baseline to endpoint superior to that observed with placebo.^4,5

When examining treatment response, defined as a reduction of ≥50% in MADRS total score from baseline, NNT vs placebo for response were 12 at all dosages tested, however, NNT vs placebo for remission (defined as MADRS total score ≤10 and ≥50% improvement from baseline) ranged from 17 to 31 and were not statistically significant.⁶ When the results for brexpiprazole, 1 mg/d, 2 mg/d, and 3 mg/d, from the 2 phase-III tri­als are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI, 8-26); 14.4% of the brexpiprazole-treated patients met remission criteria, vs 9.6% for placebo, resulting in a NNT of 21 (95% CI, 12-138).⁶

Tolerability
Overall tolerability can be evaluated by examining the percentage of patients who discontinued the clinical trials because of an adverse event (AE). In the acute schizo­phrenia double-blind trials for the recom­mended dosage range of 2 to 4 mg, the discontinuation rates were lower overall for patients receiving brexpiprazole com­pared with placebo.^2,3 In the acute MDD trials, 32.6% of brexpiprazole-treated patients and 10.7% of placebo-treated patients discontinued because of AEs,^4,5 yielding a number needed to harm (NNH) of 53 (95% CI, 30-235).⁶

The most commonly encountered AEs for MDD (incidence ≥5% and at least twice the rate for placebo) were akathisia (8.6% vs 1.7% for brexpiprazole vs placebo, and dose-related) and weight gain (6.7% vs 1.9%),¹ with NNH values of 15 (95% CI, 11-23), and 22 (95% CI, 15-42), respectively.⁶ The most commonly encountered AE for schizophre­nia (incidence ≥4% and at least twice the rate for placebo) was weight gain (4% vs 2%),¹ with a NNH of 50 (95% CI, 26-1773).⁶

Of note, rates of akathisia in the schizo­phrenia trials were 5.5% for brexpiprazole and 4.6% for placebo,¹ yielding a non-statistically significant NNH of 112.6 In a 6-week exploratory study,¹¹ the incidence of EPS-related AEs including akathisia was lower for brexpiprazole-treated patients (14.1%) compared with those receiving aripiprazole (30.3%), for a NNT advan­tage for brexpiprazole of 7 (not statistically significant).

Short-term weight gain appears modest; however, outliers with an increase of ≥7% of body weight were evident in open-label long-term safety studies.^1,6 Effects on glucose and lipids were small. Minimal effects on prolac­tin were observed, and no clinically relevant effects on the QT interval were evident.

Contraindications
The only absolute contraindication for brexpiprazole is known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swell­ing, urticaria, and anaphylaxis.¹

As with all antipsychotics and antipsy­chotics with an indication for a depressive disorder:
   • there is a bolded boxed warning in the product label regarding increased mortality in geriatric patients with dementia-related psychosis. Brexpiprazole is not approved for treating patients with dementia-related psychosis
   • there is a bolded boxed warning in the product label about suicidal thoughts and behaviors in patients age ≤24. The safety and efficacy of brexpiprazole have not been estab­lished in pediatric patients.
 

Dosing
Schizophrenia. The recommended starting dosage for brexpiprazole for schizophrenia is 1 mg/d on Days 1 to 4. Brexpiprazole can be titrated to 2 mg/d on Day 5 through Day 7, then to 4 mg/d on Day 8 based on the patient’s response and ability to tolerate the medication. The recommended target dos­age is 2 to 4 mg/d with a maximum recom­mended daily dosage of 4 mg.

Major depressive disorder. The recom­mended starting dosage for brexpiprazole as adjunctive treatment for MDD is 0.5 mg or 1 mg/d. Brexpiprazole can be titrated to 1 mg/d, then up to the target dosage of 2 mg/d, with dosage increases occurring at weekly intervals based on the patient’s clinical response and ability to tolerate the agent, with a maximum recommended dos­age of 3 mg/d.

Other considerations. For patients with moderate to severe hepatic impairment, or moderate, severe, or end-stage renal impair­ment, the maximum recommended dosage is 3 mg/d for patients with schizophrenia, and 2 mg/d for patients with MDD.

In general, dosage adjustments are rec­ommended in patients who are known CYP2D6 poor metabolizers and in those taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers¹:
   • for strong CYP2D6 or CYP3A4 inhibi­tors, administer one-half the usual dosage
   • for strong/moderate CYP2D6 with strong/moderate CYP3A4 inhibitors, administer a one-quarter of the usual dosage
   • for known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors, also administer a one-quarter of the usual dosage
   • for strong CYP3A4 inducers, double the usual dosage and further adjust based on clinical response.

In clinical trials for MDD, brexpiprazole dosage was not adjusted for strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine). Therefore, CYP considerations are already factored into general dosing recommenda­tions and brexpiprazole could be adminis­tered without dosage adjustment in patients with MDD; however, under these circum­stances, it would be prudent to start brexpip­razole at 0.5 mg, which, although “on-label,” represents a low starting dosage. (Whenever 2 drugs are co-administered and 1 agent has the ability to disturb the metabolism of the other, using smaller increments to the target dosage and possibly waiting longer between dosage adjustments could help avoid poten­tial drug–drug interactions.)

No dosage adjustment for brexpiprazole is required on the basis of sex, race or eth­nicity, or smoking status. Although clinical studies did not include patients age ≥65, the product label recommends that in general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.
 

Bottom Line
Brexpiprazole, an atypical antipsychotic, is FDA-approved for schizophrenia and as an adjunct to antidepressants in major depressive disorder. For both indications, brexpiprazole demonstrated positive results compared with placebo in phase-III trials. Brexpiprazole is more potent at serotonin 5-HT1A and 5-HT2A receptors and displays less intrinsic activity at D2 receptors than aripiprazole, which could mean that the drug may be better-tolerated.

Related Resources
• Citrome L. Brexpiprazole: a new dopamine D2 receptor par­tial agonist for the treatment of schizophrenia and major de­pressive disorder. Drugs Today (Barc). 2015;51(7):397-414.
• Citrome L, Stensbøl TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treat­ment of psychiatric disorders? Expert Rev Neurother. In press.

Drug Brand Names
Aripiprazole • Abilify
Brexpiprazole • Rexulti
Fluoxetine • Prozac
Paroxetine • Paxil

Disclosure
Dr. Citrome is a consultant to Alexza Pharmaceuticals, Alkermes, Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Forum Pharmaceuticals, Genentech, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant Pharmaceuticals; and is a speaker for Allergan, AstraZeneca, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva.

Brexpiprazole, FDA-approved in July 2015 to treat schizophrenia and as an adjunct for major depressive disorder (MDD) (Table 1), has shown effi­cacy in 2 phase-III acute trials for each indication.^1-6 Although brexpiprazole is a dopamine D2 partial agonist, it differs from aripiprazole, the other available D2 partial agonist, because it is more potent at serotonin 5-HT1A and 5-HT2A recep­tors and displays less intrinsic activity at D2 receptors,⁷ which could mean better tolerability.

Clinical implications
Schizophrenia is heterogeneous, and indi­vidual response and tolerability to anti­psychotics vary greatly⁸; therefore, new drug options are useful. For MDD, before the availability of brexpiprazole, only 3 antipsychotics were FDA-approved for adjunctive use with antidepressant ther­apy⁹; brexpiprazole represents another agent for patients whose depressive symp­toms persist after standard antidepressant treatment.

Variables that limit the use of antipsy­chotics include extrapyramidal symptoms (EPS), akathisia, sedation/somnolence, weight gain, metabolic abnormalities, and hyperprolactinemia. If post-marketing studies and clinical experience confirm that brexpiprazole has an overall favor­able side-effect profile regarding these tolerability obstacles, brexpiprazole would potentially have advantages over some other available agents, including aripiprazole.

How it works
In addition to a subnanomolar binding affin­ity (Ki < 1 nM) to dopamine D2 receptors as a partial agonist, brexpiprazole also exhib­its similar binding affinities for serotonin 5-HT1A (partial agonist), 5-HT2A (antago­nist), and adrenergic α1B (antagonist) and α2C (antagonist) receptors.⁷

Brexpiprazole also has high affinity (Ki < 5 nM) for dopamine D3 (partial ago­ nist), serotonin 5-HT2B (antagonist), and 5-HT7 (antagonist), and at adrenergic α1A (antagonist) and α1D (antagonist) recep­tors. Brexpiprazole has moderate affinity for histamine H1 receptors (Ki = 19 nM, antago­nist), and low affinity for muscarinic M1 receptors (Ki > 1000 nM, antagonist).

Brexpiprazole’s pharmacodynamic pro­file differs from other available antipsy­chotics, including aripiprazole. Whether this translates to meaningful differences in efficacy and tolerability will depend on the outcomes of specifically designed clinical trials as well as “real-world” experience. Animal models have suggested amelio­ration of schizophrenia-like behavior, depression-like behavior, and anxiety-like behavior with brexipiprazole.⁶

Pharmacokinetics
At 91 hours, brexpiprazole’s half-life is rel­atively long; a steady-state concentration therefore is attained in approximately 2 weeks.1 In the phase-III clinical trials, brex­piprazole was titrated to target dosages, and therefore the product label recommends the same. Brexpiprazole can be administered with or without food.

In a study of brexpiprazole excretion, after a single oral dose of [14C]-labeled brexpip­razole, approximately 25% and 46% of the administered radioactivity was recovered in urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged in the feces.

Exposure, as measured by maximum con­centration and area under the concentration curve, is dose proportional.

Metabolism of brexpiprazole is mediated principally by cytochrome P450 (CYP) 3A4 and CYP2D6. Based on in vitro data, brex­piprazole shows little or no inhibition of CYP450 isozymes.

Efficacy
FDA approval for brexpiprazole for schizo­phrenia and for adjunctive use in MDD was based on 4 phase-III pivotal acute clinical trials conducted in adults, 2 studies each for each disorder.^1-6 These studies are described in Table 2.^2-5

Although not described in product label­ing, a phase-III 52-week maintenance study demonstrated brexpiprazole’s efficacy in preventing exacerbation of psychotic symp­toms and impending relapse in patients with schizophrenia.10 Time from randomiza­tion to exacerbation of psychotic symptoms or impending relapse showed a beneficial effect with brexpiprazole compared with placebo (log-rank test: hazard ratio = 0.292, P < .0001). Significantly fewer patients in the brexpiprazole group relapsed compared with placebo (13.5% vs 38.5%, P < .0001), resulting in a NNT of 4 (95% CI, 3-8).

Major depressive disorder. The primary outcome measure for the acute MDD stud­ies was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to 6-week endpoint of the ran­domized treatment phase. All patients were required to have a history of inadequate response to 1 to 3 treatment trials of standard antidepressants for their current depressive episode. In addition, patients entered the randomized phase only if they had an inad­equate response to antidepressant therapy during an 8-week prospective treatment trial of standard antidepressant treatment plus single-blind placebo.

Participants who responded adequately to the antidepressant in the prospective single-blind phase were not randomized, but instead continued on antidepressant treat­ment plus single-blind placebo for 6 weeks.

The phase-III studies showed positive results for brexpiprazole, 2 mg/d and 3 mg/d, with change in MADRS from baseline to endpoint superior to that observed with placebo.^4,5

When examining treatment response, defined as a reduction of ≥50% in MADRS total score from baseline, NNT vs placebo for response were 12 at all dosages tested, however, NNT vs placebo for remission (defined as MADRS total score ≤10 and ≥50% improvement from baseline) ranged from 17 to 31 and were not statistically significant.⁶ When the results for brexpiprazole, 1 mg/d, 2 mg/d, and 3 mg/d, from the 2 phase-III tri­als are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI, 8-26); 14.4% of the brexpiprazole-treated patients met remission criteria, vs 9.6% for placebo, resulting in a NNT of 21 (95% CI, 12-138).⁶

Tolerability
Overall tolerability can be evaluated by examining the percentage of patients who discontinued the clinical trials because of an adverse event (AE). In the acute schizo­phrenia double-blind trials for the recom­mended dosage range of 2 to 4 mg, the discontinuation rates were lower overall for patients receiving brexpiprazole com­pared with placebo.^2,3 In the acute MDD trials, 32.6% of brexpiprazole-treated patients and 10.7% of placebo-treated patients discontinued because of AEs,^4,5 yielding a number needed to harm (NNH) of 53 (95% CI, 30-235).⁶

The most commonly encountered AEs for MDD (incidence ≥5% and at least twice the rate for placebo) were akathisia (8.6% vs 1.7% for brexpiprazole vs placebo, and dose-related) and weight gain (6.7% vs 1.9%),¹ with NNH values of 15 (95% CI, 11-23), and 22 (95% CI, 15-42), respectively.⁶ The most commonly encountered AE for schizophre­nia (incidence ≥4% and at least twice the rate for placebo) was weight gain (4% vs 2%),¹ with a NNH of 50 (95% CI, 26-1773).⁶

Of note, rates of akathisia in the schizo­phrenia trials were 5.5% for brexpiprazole and 4.6% for placebo,¹ yielding a non-statistically significant NNH of 112.6 In a 6-week exploratory study,¹¹ the incidence of EPS-related AEs including akathisia was lower for brexpiprazole-treated patients (14.1%) compared with those receiving aripiprazole (30.3%), for a NNT advan­tage for brexpiprazole of 7 (not statistically significant).

Short-term weight gain appears modest; however, outliers with an increase of ≥7% of body weight were evident in open-label long-term safety studies.^1,6 Effects on glucose and lipids were small. Minimal effects on prolac­tin were observed, and no clinically relevant effects on the QT interval were evident.

Contraindications
The only absolute contraindication for brexpiprazole is known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swell­ing, urticaria, and anaphylaxis.¹

As with all antipsychotics and antipsy­chotics with an indication for a depressive disorder:
   • there is a bolded boxed warning in the product label regarding increased mortality in geriatric patients with dementia-related psychosis. Brexpiprazole is not approved for treating patients with dementia-related psychosis
   • there is a bolded boxed warning in the product label about suicidal thoughts and behaviors in patients age ≤24. The safety and efficacy of brexpiprazole have not been estab­lished in pediatric patients.
 

Dosing
Schizophrenia. The recommended starting dosage for brexpiprazole for schizophrenia is 1 mg/d on Days 1 to 4. Brexpiprazole can be titrated to 2 mg/d on Day 5 through Day 7, then to 4 mg/d on Day 8 based on the patient’s response and ability to tolerate the medication. The recommended target dos­age is 2 to 4 mg/d with a maximum recom­mended daily dosage of 4 mg.

Major depressive disorder. The recom­mended starting dosage for brexpiprazole as adjunctive treatment for MDD is 0.5 mg or 1 mg/d. Brexpiprazole can be titrated to 1 mg/d, then up to the target dosage of 2 mg/d, with dosage increases occurring at weekly intervals based on the patient’s clinical response and ability to tolerate the agent, with a maximum recommended dos­age of 3 mg/d.

Other considerations. For patients with moderate to severe hepatic impairment, or moderate, severe, or end-stage renal impair­ment, the maximum recommended dosage is 3 mg/d for patients with schizophrenia, and 2 mg/d for patients with MDD.

In general, dosage adjustments are rec­ommended in patients who are known CYP2D6 poor metabolizers and in those taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers¹:
   • for strong CYP2D6 or CYP3A4 inhibi­tors, administer one-half the usual dosage
   • for strong/moderate CYP2D6 with strong/moderate CYP3A4 inhibitors, administer a one-quarter of the usual dosage
   • for known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors, also administer a one-quarter of the usual dosage
   • for strong CYP3A4 inducers, double the usual dosage and further adjust based on clinical response.

In clinical trials for MDD, brexpiprazole dosage was not adjusted for strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine). Therefore, CYP considerations are already factored into general dosing recommenda­tions and brexpiprazole could be adminis­tered without dosage adjustment in patients with MDD; however, under these circum­stances, it would be prudent to start brexpip­razole at 0.5 mg, which, although “on-label,” represents a low starting dosage. (Whenever 2 drugs are co-administered and 1 agent has the ability to disturb the metabolism of the other, using smaller increments to the target dosage and possibly waiting longer between dosage adjustments could help avoid poten­tial drug–drug interactions.)

No dosage adjustment for brexpiprazole is required on the basis of sex, race or eth­nicity, or smoking status. Although clinical studies did not include patients age ≥65, the product label recommends that in general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.
 

Bottom Line
Brexpiprazole, an atypical antipsychotic, is FDA-approved for schizophrenia and as an adjunct to antidepressants in major depressive disorder. For both indications, brexpiprazole demonstrated positive results compared with placebo in phase-III trials. Brexpiprazole is more potent at serotonin 5-HT1A and 5-HT2A receptors and displays less intrinsic activity at D2 receptors than aripiprazole, which could mean that the drug may be better-tolerated.

Related Resources
• Citrome L. Brexpiprazole: a new dopamine D2 receptor par­tial agonist for the treatment of schizophrenia and major de­pressive disorder. Drugs Today (Barc). 2015;51(7):397-414.
• Citrome L, Stensbøl TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treat­ment of psychiatric disorders? Expert Rev Neurother. In press.

Drug Brand Names
Aripiprazole • Abilify
Brexpiprazole • Rexulti
Fluoxetine • Prozac
Paroxetine • Paxil

Disclosure
Dr. Citrome is a consultant to Alexza Pharmaceuticals, Alkermes, Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Forum Pharmaceuticals, Genentech, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant Pharmaceuticals; and is a speaker for Allergan, AstraZeneca, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva.

Brexpiprazole, FDA-approved in July 2015 to treat schizophrenia and as an adjunct for major depressive disorder (MDD) (Table 1), has shown effi­cacy in 2 phase-III acute trials for each indication.^1-6 Although brexpiprazole is a dopamine D2 partial agonist, it differs from aripiprazole, the other available D2 partial agonist, because it is more potent at serotonin 5-HT1A and 5-HT2A recep­tors and displays less intrinsic activity at D2 receptors,⁷ which could mean better tolerability.

Clinical implications
Schizophrenia is heterogeneous, and indi­vidual response and tolerability to anti­psychotics vary greatly⁸; therefore, new drug options are useful. For MDD, before the availability of brexpiprazole, only 3 antipsychotics were FDA-approved for adjunctive use with antidepressant ther­apy⁹; brexpiprazole represents another agent for patients whose depressive symp­toms persist after standard antidepressant treatment.

Variables that limit the use of antipsy­chotics include extrapyramidal symptoms (EPS), akathisia, sedation/somnolence, weight gain, metabolic abnormalities, and hyperprolactinemia. If post-marketing studies and clinical experience confirm that brexpiprazole has an overall favor­able side-effect profile regarding these tolerability obstacles, brexpiprazole would potentially have advantages over some other available agents, including aripiprazole.

How it works
In addition to a subnanomolar binding affin­ity (Ki < 1 nM) to dopamine D2 receptors as a partial agonist, brexpiprazole also exhib­its similar binding affinities for serotonin 5-HT1A (partial agonist), 5-HT2A (antago­nist), and adrenergic α1B (antagonist) and α2C (antagonist) receptors.⁷

Brexpiprazole also has high affinity (Ki < 5 nM) for dopamine D3 (partial ago­ nist), serotonin 5-HT2B (antagonist), and 5-HT7 (antagonist), and at adrenergic α1A (antagonist) and α1D (antagonist) recep­tors. Brexpiprazole has moderate affinity for histamine H1 receptors (Ki = 19 nM, antago­nist), and low affinity for muscarinic M1 receptors (Ki > 1000 nM, antagonist).

Brexpiprazole’s pharmacodynamic pro­file differs from other available antipsy­chotics, including aripiprazole. Whether this translates to meaningful differences in efficacy and tolerability will depend on the outcomes of specifically designed clinical trials as well as “real-world” experience. Animal models have suggested amelio­ration of schizophrenia-like behavior, depression-like behavior, and anxiety-like behavior with brexipiprazole.⁶

Pharmacokinetics
At 91 hours, brexpiprazole’s half-life is rel­atively long; a steady-state concentration therefore is attained in approximately 2 weeks.1 In the phase-III clinical trials, brex­piprazole was titrated to target dosages, and therefore the product label recommends the same. Brexpiprazole can be administered with or without food.

In a study of brexpiprazole excretion, after a single oral dose of [14C]-labeled brexpip­razole, approximately 25% and 46% of the administered radioactivity was recovered in urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged in the feces.

Exposure, as measured by maximum con­centration and area under the concentration curve, is dose proportional.

Metabolism of brexpiprazole is mediated principally by cytochrome P450 (CYP) 3A4 and CYP2D6. Based on in vitro data, brex­piprazole shows little or no inhibition of CYP450 isozymes.

Efficacy
FDA approval for brexpiprazole for schizo­phrenia and for adjunctive use in MDD was based on 4 phase-III pivotal acute clinical trials conducted in adults, 2 studies each for each disorder.^1-6 These studies are described in Table 2.^2-5

Although not described in product label­ing, a phase-III 52-week maintenance study demonstrated brexpiprazole’s efficacy in preventing exacerbation of psychotic symp­toms and impending relapse in patients with schizophrenia.10 Time from randomiza­tion to exacerbation of psychotic symptoms or impending relapse showed a beneficial effect with brexpiprazole compared with placebo (log-rank test: hazard ratio = 0.292, P < .0001). Significantly fewer patients in the brexpiprazole group relapsed compared with placebo (13.5% vs 38.5%, P < .0001), resulting in a NNT of 4 (95% CI, 3-8).

Major depressive disorder. The primary outcome measure for the acute MDD stud­ies was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to 6-week endpoint of the ran­domized treatment phase. All patients were required to have a history of inadequate response to 1 to 3 treatment trials of standard antidepressants for their current depressive episode. In addition, patients entered the randomized phase only if they had an inad­equate response to antidepressant therapy during an 8-week prospective treatment trial of standard antidepressant treatment plus single-blind placebo.

Participants who responded adequately to the antidepressant in the prospective single-blind phase were not randomized, but instead continued on antidepressant treat­ment plus single-blind placebo for 6 weeks.

The phase-III studies showed positive results for brexpiprazole, 2 mg/d and 3 mg/d, with change in MADRS from baseline to endpoint superior to that observed with placebo.^4,5

When examining treatment response, defined as a reduction of ≥50% in MADRS total score from baseline, NNT vs placebo for response were 12 at all dosages tested, however, NNT vs placebo for remission (defined as MADRS total score ≤10 and ≥50% improvement from baseline) ranged from 17 to 31 and were not statistically significant.⁶ When the results for brexpiprazole, 1 mg/d, 2 mg/d, and 3 mg/d, from the 2 phase-III tri­als are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI, 8-26); 14.4% of the brexpiprazole-treated patients met remission criteria, vs 9.6% for placebo, resulting in a NNT of 21 (95% CI, 12-138).⁶

Tolerability
Overall tolerability can be evaluated by examining the percentage of patients who discontinued the clinical trials because of an adverse event (AE). In the acute schizo­phrenia double-blind trials for the recom­mended dosage range of 2 to 4 mg, the discontinuation rates were lower overall for patients receiving brexpiprazole com­pared with placebo.^2,3 In the acute MDD trials, 32.6% of brexpiprazole-treated patients and 10.7% of placebo-treated patients discontinued because of AEs,^4,5 yielding a number needed to harm (NNH) of 53 (95% CI, 30-235).⁶

The most commonly encountered AEs for MDD (incidence ≥5% and at least twice the rate for placebo) were akathisia (8.6% vs 1.7% for brexpiprazole vs placebo, and dose-related) and weight gain (6.7% vs 1.9%),¹ with NNH values of 15 (95% CI, 11-23), and 22 (95% CI, 15-42), respectively.⁶ The most commonly encountered AE for schizophre­nia (incidence ≥4% and at least twice the rate for placebo) was weight gain (4% vs 2%),¹ with a NNH of 50 (95% CI, 26-1773).⁶

Of note, rates of akathisia in the schizo­phrenia trials were 5.5% for brexpiprazole and 4.6% for placebo,¹ yielding a non-statistically significant NNH of 112.6 In a 6-week exploratory study,¹¹ the incidence of EPS-related AEs including akathisia was lower for brexpiprazole-treated patients (14.1%) compared with those receiving aripiprazole (30.3%), for a NNT advan­tage for brexpiprazole of 7 (not statistically significant).

Short-term weight gain appears modest; however, outliers with an increase of ≥7% of body weight were evident in open-label long-term safety studies.^1,6 Effects on glucose and lipids were small. Minimal effects on prolac­tin were observed, and no clinically relevant effects on the QT interval were evident.

Contraindications
The only absolute contraindication for brexpiprazole is known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swell­ing, urticaria, and anaphylaxis.¹

As with all antipsychotics and antipsy­chotics with an indication for a depressive disorder:
   • there is a bolded boxed warning in the product label regarding increased mortality in geriatric patients with dementia-related psychosis. Brexpiprazole is not approved for treating patients with dementia-related psychosis
   • there is a bolded boxed warning in the product label about suicidal thoughts and behaviors in patients age ≤24. The safety and efficacy of brexpiprazole have not been estab­lished in pediatric patients.
 

Dosing
Schizophrenia. The recommended starting dosage for brexpiprazole for schizophrenia is 1 mg/d on Days 1 to 4. Brexpiprazole can be titrated to 2 mg/d on Day 5 through Day 7, then to 4 mg/d on Day 8 based on the patient’s response and ability to tolerate the medication. The recommended target dos­age is 2 to 4 mg/d with a maximum recom­mended daily dosage of 4 mg.

Major depressive disorder. The recom­mended starting dosage for brexpiprazole as adjunctive treatment for MDD is 0.5 mg or 1 mg/d. Brexpiprazole can be titrated to 1 mg/d, then up to the target dosage of 2 mg/d, with dosage increases occurring at weekly intervals based on the patient’s clinical response and ability to tolerate the agent, with a maximum recommended dos­age of 3 mg/d.

Other considerations. For patients with moderate to severe hepatic impairment, or moderate, severe, or end-stage renal impair­ment, the maximum recommended dosage is 3 mg/d for patients with schizophrenia, and 2 mg/d for patients with MDD.

In general, dosage adjustments are rec­ommended in patients who are known CYP2D6 poor metabolizers and in those taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers¹:
   • for strong CYP2D6 or CYP3A4 inhibi­tors, administer one-half the usual dosage
   • for strong/moderate CYP2D6 with strong/moderate CYP3A4 inhibitors, administer a one-quarter of the usual dosage
   • for known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors, also administer a one-quarter of the usual dosage
   • for strong CYP3A4 inducers, double the usual dosage and further adjust based on clinical response.

In clinical trials for MDD, brexpiprazole dosage was not adjusted for strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine). Therefore, CYP considerations are already factored into general dosing recommenda­tions and brexpiprazole could be adminis­tered without dosage adjustment in patients with MDD; however, under these circum­stances, it would be prudent to start brexpip­razole at 0.5 mg, which, although “on-label,” represents a low starting dosage. (Whenever 2 drugs are co-administered and 1 agent has the ability to disturb the metabolism of the other, using smaller increments to the target dosage and possibly waiting longer between dosage adjustments could help avoid poten­tial drug–drug interactions.)

No dosage adjustment for brexpiprazole is required on the basis of sex, race or eth­nicity, or smoking status. Although clinical studies did not include patients age ≥65, the product label recommends that in general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.
 

Bottom Line
Brexpiprazole, an atypical antipsychotic, is FDA-approved for schizophrenia and as an adjunct to antidepressants in major depressive disorder. For both indications, brexpiprazole demonstrated positive results compared with placebo in phase-III trials. Brexpiprazole is more potent at serotonin 5-HT1A and 5-HT2A receptors and displays less intrinsic activity at D2 receptors than aripiprazole, which could mean that the drug may be better-tolerated.

Related Resources
• Citrome L. Brexpiprazole: a new dopamine D2 receptor par­tial agonist for the treatment of schizophrenia and major de­pressive disorder. Drugs Today (Barc). 2015;51(7):397-414.
• Citrome L, Stensbøl TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treat­ment of psychiatric disorders? Expert Rev Neurother. In press.

Drug Brand Names
Aripiprazole • Abilify
Brexpiprazole • Rexulti
Fluoxetine • Prozac
Paroxetine • Paxil

Disclosure
Dr. Citrome is a consultant to Alexza Pharmaceuticals, Alkermes, Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Forum Pharmaceuticals, Genentech, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant Pharmaceuticals; and is a speaker for Allergan, AstraZeneca, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva.