Out Of The Pipeline

In October 2010, the FDA approved a combination of dextromethorphan (DM) and quinidine for the treatment of pseudobulbar affect (PBA)—also called pathological laughing and crying, affective lability, emotional dyscontrol, emotional incontinence, and involuntary emotional expression disorder—in patients with neurologic disorders and brain injuries (Table). Despite receiving an approvable letter in 2006, the compound was not approved at that time because of concerns about the arrhythmogenic potential of quinidine, which prolongs the QT interval. The manufacturer conducted another study using one-third of the previous quinidine dose, which ameliorated this concern and led to approval.

Clinical implications

PBA is manifested by involuntary labile, shallow affect with sudden and unpredictable laughing, crying, or other emotional displays that are not appropriate to the social setting and may not be congruent with the patient’s prevailing mood.¹ Episodes are often paroxysmal and cannot be interrupted voluntarily.² PBA seems to be caused by a loss of descending cortical control of brainstem motor nuclei and possibly the cerebellum, disrupting inhibitory mechanisms and resulting in inappropriate and involuntary emotional display.³ Several studies have demonstrated involvement of subcortical areas, particularly the anterior limb of the internal capsule and the bulbar area. The patho-physiology of PBA may involve excessive release of glutamate by injured neurons, disrupting systems for motor control of emotional expression.^4,5

Table

Dextromethorphan/quinidine: Fast facts

PBA is most common in diseases that interfere bilaterally with the corticohypothalamic and corticobulbar tracts that control voluntary and involuntary faciorespiratory mechanisms. However, PBA occurs in unilateral disease as well. The reported prevalence of PBA is:

• 49% in amyotrophic lateral sclerosis (ALS)
• 18% to 39% in Alzheimer’s disease
• 11% to 34% in stroke
• 10% to 11% in multiple sclerosis (MS) and traumatic brain injury.^6,7

PBA also has been reported in patients with Parkinson’s disease, brain tumors, Wilson’s disease, syphilitic pseudobulbar palsy, and various encephalitides.¹ An estimated 880,000 U.S. patients exhibit PBA.⁸

Previously, there was no FDA-approved treatment for PBA. However, small controlled trials suggest that selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs)— usually in doses lower than those used to treat depression—may effectively reduce symptoms within 2 to 3 days.¹ Although dopaminergic agents such as levodopa and amantadine have shown benefit in open trials, results of controlled studies using objective measurements have not been positive.

How it works

DM is a serotonergic substance that also is an agonist of 1-sigma receptors and a low-affinity, uncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors, which are important in glutamate signaling, through binding at the phencyclidine site on the NMDA complex.^7,9 The 1-sigma receptor was thought to be an opioid receptor subtype, but unlike opioid receptors it is not blocked by narcotic antagonists and does not have an endogenous ligand. However, the 1-sigma receptor does modulate activity of opioid mu receptors in addition to altering dopamine release and possibly reducing glutamate release.⁹ Sigma receptors are densely distributed in the limbic system and in systems related to motor control of affective expression and seem to be involved in learning, responses to stress, mood regulation, and drug dependence.¹ Because DM preferentially binds to brain regions that regulate emotional expression,¹⁰ it could normalize glutaminergic neurotransmission and other relevant systems in these regions.¹ However, DM’s exact mechanism of action is unknown.

Quinidine is a sodium channel antagonist usually used as a type Ia antiarrhythmic.⁵ DM is subject to extensive first-pass metabolism by cytochrome P (CYP) 450 2D6 to dextrorphan, which after being glucuronidated cannot cross the blood-brain barrier. In doses 10 to 25 times lower than those used to treat cardiac arrhythmias, quinidine inhibits 2D6 and increases DM bioavailability.¹⁰ DM blood levels increase linearly with dose following coadministration with quinidine but are undetectable in most patients given DM alone.^7,9

Efficacy and tolerability

A combination of DM and quinidine (DMQ) reduced Center for Neurologic Study-Lability Scale (CNC-LS) scores and the number of daily PBA episodes in 3 randomized trials.^5,7,10 Visit this article at CurrentPsychiatry.com for a table summarizing these studies.

An 85-day randomized, double-blind, placebo-controlled study of 150 patients with PBA associated with MS found that DM, 30 mg, plus quinidine, 30 mg, (DMQ 30-30) was twice as effective as placebo within a week in reducing CNC-LS scores.¹⁰ DMQ 30-30 patients also had approximately half as many episodes of inappropriate laughing, crying, or combined laughing and crying and a 2-fold greater decrease in pain intensity.¹⁰ Twenty-one percent of DMQ 30-30 patients experienced complete remission—no PBA episodes—compared with 7% of placebo patients. There were no significant differences in QT prolongation between DMQ 30-30 and placebo.

A 3-arm, double-blind, 28-day, phase III multicenter trial of 140 ALS patients with PBA compared DM monotherapy, quinidine monotherapy, and DMQ 30-30.⁵ Compared with either drug alone, DMQ 30-30 showed greater reduction of CNC-LS scores, as well as improved quality of life and quality of relationships scores, with equal benefit in poor and extensive DM metabolizers. However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.

In a manufacturer-sponsored, multicenter, 12-week randomized trial, 326 patients with ALS or MS and clinically significant PBA were randomly assigned to DM, 30 mg, plus quinidine, 10 mg (DMQ 30-10), DM, 20 mg, plus quinidine, 10 mg (DMQ 20-10), or placebo, each administered twice daily.⁷ Patients with comorbid psychiatric disorders or significant depressive symptoms were excluded. Although daily PBA episodes decreased in all groups, the daily rate of PBA episodes was 47% lower for patients taking DMQ 30-10, and 49% lower with DMQ 20-10 compared with placebo (both P < .001). The mean decrease in the number of daily PBA episodes was 3.9 to 4.1 with active treatment and 3.0 with placebo. Side effects were more common with active drug than placebo and included dizziness, nausea, diarrhea, and urinary tract infection. There were no serious adverse cardiac events and no active drug recipients showed a QTc interval >480 msec or a change from baseline >60 msec.¹¹ Discontinuation rates in this study were lower than in studies of DMQ 30-30. In an open-label extension of 253 patients who completed the double-blind phase and were assigned to DMQ 30-10 for 12 weeks, the incidence of treatment-related adverse events was 28%, with a 5.5% rate of serious adverse events.¹²

Safety

Because the 10 mg dose of quinidine in the approved formulation of DMQ is 10 times lower than the antiarrhythmic dose, substantial ECG changes and adverse cardiac effects with DMQ have not been reported. The most common side effects of DM are nausea, somnolence, dizziness, and headache. Thrombocytopenia, QT prolongation, hepatotoxicity, allergic reactions, and anticholinergic side effects can occur.

In high doses and combined with other substances, DM has been used as a recreational drug. When taken in high doses, adverse effects include nausea, vomiting, malaise, dilated pupils, difficulty urinating, increased urination frequency, fever, tachycardia, loss of appetite, shakiness, seizures, and potentially coma and death. DMQ may have a greater potential for serious adverse effects than DM alone because quinidine increases DM bioavailability and blood levels. The abuse potential of DMQ is not clear.

Psychosis has been reported with higher DM doses. The psychotomimetic effects of phencyclidine (PCP) are related to binding to the PCP site on the NMDA receptor complex—to which DM also binds—with reduced glutamate signaling in information processing systems. Therefore, caution is indicated when prescribing DM to patients with psychosis.

Because DM, a CYP2D6 substrate, is combined with quinidine, a 2D6 inhibitor, administering DMQ with other 2D6 inhibitors could lead to toxicity. When DMQ is combined with SSRIs and similar agents, the serotonergic properties of DM could result in serotonin syndrome, which could be fatal if DM is combined with monoamine oxidase inhibitors.¹⁰ Combinations of DM and acetaminophen and antihistamines can be dangerous at higher doses.¹⁰ Because quinidine is metabolized by CYP3A, inhibitors of this enzyme such as ketoconazole, nefazodone, and grapefruit juice should be avoided. Similarly, inhibition of CYP2D6 by quinidine could raise levels of coadministered 2D6 substrates.

Contraindications. DMQ is contraindicated in patients with:

• heart failure
• prolonged QT interval
• congenital long QT interval
• history of torsades de pointes
• complete atrioventricular (AV) block without implanted pacemakers.¹³

DMQ also is contraindicated in patients at high risk for complete AV block.¹³

Dosing

DMQ is available as a capsule containing DM, 20 mg, and quinidine, 10 mg. The recommended starting dose is 1 capsule by mouth for 7 days, then 1 capsule every 12 hours.

Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a non-serotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated. In view of the unknown potential for abuse and toxicity as well as the cost of the proprietary drug ($3,000 to $5,000 a year), it would seem prudent to consider using an SSRI or a TCA first.⁸ These medications also act on 1-sigma receptors,^14,15 which may account in part for their reported benefit.

Related Resource

• Neudexta [package insert]. Aliso Viejo, CA: Avanir Pharmaceuticals; 2010.

Drug Brand Names

• Amantadine • Symmetrel
• Dextromethorphan/quinidine •Nefazodone
• Ketoconazole • Nizoral
• Levodopa • Sinemet
• Neudexta • Serzone
• Quinidine • Quinidex

Disclosures

Dr. Dubovsky receives research support from Biogen Idec, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Otsuka, the Peter and Elizabeth C. Tower Foundation, and Pfizer, Inc.

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

Table 2

Dextromethorphan/quinidine for PBA: Evidence shows efficacy

In October 2010, the FDA approved a combination of dextromethorphan (DM) and quinidine for the treatment of pseudobulbar affect (PBA)—also called pathological laughing and crying, affective lability, emotional dyscontrol, emotional incontinence, and involuntary emotional expression disorder—in patients with neurologic disorders and brain injuries (Table). Despite receiving an approvable letter in 2006, the compound was not approved at that time because of concerns about the arrhythmogenic potential of quinidine, which prolongs the QT interval. The manufacturer conducted another study using one-third of the previous quinidine dose, which ameliorated this concern and led to approval.

Clinical implications

PBA is manifested by involuntary labile, shallow affect with sudden and unpredictable laughing, crying, or other emotional displays that are not appropriate to the social setting and may not be congruent with the patient’s prevailing mood.¹ Episodes are often paroxysmal and cannot be interrupted voluntarily.² PBA seems to be caused by a loss of descending cortical control of brainstem motor nuclei and possibly the cerebellum, disrupting inhibitory mechanisms and resulting in inappropriate and involuntary emotional display.³ Several studies have demonstrated involvement of subcortical areas, particularly the anterior limb of the internal capsule and the bulbar area. The patho-physiology of PBA may involve excessive release of glutamate by injured neurons, disrupting systems for motor control of emotional expression.^4,5

Table

Dextromethorphan/quinidine: Fast facts

PBA is most common in diseases that interfere bilaterally with the corticohypothalamic and corticobulbar tracts that control voluntary and involuntary faciorespiratory mechanisms. However, PBA occurs in unilateral disease as well. The reported prevalence of PBA is:

• 49% in amyotrophic lateral sclerosis (ALS)
• 18% to 39% in Alzheimer’s disease
• 11% to 34% in stroke
• 10% to 11% in multiple sclerosis (MS) and traumatic brain injury.^6,7

PBA also has been reported in patients with Parkinson’s disease, brain tumors, Wilson’s disease, syphilitic pseudobulbar palsy, and various encephalitides.¹ An estimated 880,000 U.S. patients exhibit PBA.⁸

Previously, there was no FDA-approved treatment for PBA. However, small controlled trials suggest that selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs)— usually in doses lower than those used to treat depression—may effectively reduce symptoms within 2 to 3 days.¹ Although dopaminergic agents such as levodopa and amantadine have shown benefit in open trials, results of controlled studies using objective measurements have not been positive.

How it works

DM is a serotonergic substance that also is an agonist of 1-sigma receptors and a low-affinity, uncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors, which are important in glutamate signaling, through binding at the phencyclidine site on the NMDA complex.^7,9 The 1-sigma receptor was thought to be an opioid receptor subtype, but unlike opioid receptors it is not blocked by narcotic antagonists and does not have an endogenous ligand. However, the 1-sigma receptor does modulate activity of opioid mu receptors in addition to altering dopamine release and possibly reducing glutamate release.⁹ Sigma receptors are densely distributed in the limbic system and in systems related to motor control of affective expression and seem to be involved in learning, responses to stress, mood regulation, and drug dependence.¹ Because DM preferentially binds to brain regions that regulate emotional expression,¹⁰ it could normalize glutaminergic neurotransmission and other relevant systems in these regions.¹ However, DM’s exact mechanism of action is unknown.

Quinidine is a sodium channel antagonist usually used as a type Ia antiarrhythmic.⁵ DM is subject to extensive first-pass metabolism by cytochrome P (CYP) 450 2D6 to dextrorphan, which after being glucuronidated cannot cross the blood-brain barrier. In doses 10 to 25 times lower than those used to treat cardiac arrhythmias, quinidine inhibits 2D6 and increases DM bioavailability.¹⁰ DM blood levels increase linearly with dose following coadministration with quinidine but are undetectable in most patients given DM alone.^7,9

Efficacy and tolerability

A combination of DM and quinidine (DMQ) reduced Center for Neurologic Study-Lability Scale (CNC-LS) scores and the number of daily PBA episodes in 3 randomized trials.^5,7,10 Visit this article at CurrentPsychiatry.com for a table summarizing these studies.

An 85-day randomized, double-blind, placebo-controlled study of 150 patients with PBA associated with MS found that DM, 30 mg, plus quinidine, 30 mg, (DMQ 30-30) was twice as effective as placebo within a week in reducing CNC-LS scores.¹⁰ DMQ 30-30 patients also had approximately half as many episodes of inappropriate laughing, crying, or combined laughing and crying and a 2-fold greater decrease in pain intensity.¹⁰ Twenty-one percent of DMQ 30-30 patients experienced complete remission—no PBA episodes—compared with 7% of placebo patients. There were no significant differences in QT prolongation between DMQ 30-30 and placebo.

A 3-arm, double-blind, 28-day, phase III multicenter trial of 140 ALS patients with PBA compared DM monotherapy, quinidine monotherapy, and DMQ 30-30.⁵ Compared with either drug alone, DMQ 30-30 showed greater reduction of CNC-LS scores, as well as improved quality of life and quality of relationships scores, with equal benefit in poor and extensive DM metabolizers. However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.

In a manufacturer-sponsored, multicenter, 12-week randomized trial, 326 patients with ALS or MS and clinically significant PBA were randomly assigned to DM, 30 mg, plus quinidine, 10 mg (DMQ 30-10), DM, 20 mg, plus quinidine, 10 mg (DMQ 20-10), or placebo, each administered twice daily.⁷ Patients with comorbid psychiatric disorders or significant depressive symptoms were excluded. Although daily PBA episodes decreased in all groups, the daily rate of PBA episodes was 47% lower for patients taking DMQ 30-10, and 49% lower with DMQ 20-10 compared with placebo (both P < .001). The mean decrease in the number of daily PBA episodes was 3.9 to 4.1 with active treatment and 3.0 with placebo. Side effects were more common with active drug than placebo and included dizziness, nausea, diarrhea, and urinary tract infection. There were no serious adverse cardiac events and no active drug recipients showed a QTc interval >480 msec or a change from baseline >60 msec.¹¹ Discontinuation rates in this study were lower than in studies of DMQ 30-30. In an open-label extension of 253 patients who completed the double-blind phase and were assigned to DMQ 30-10 for 12 weeks, the incidence of treatment-related adverse events was 28%, with a 5.5% rate of serious adverse events.¹²

Safety

Because the 10 mg dose of quinidine in the approved formulation of DMQ is 10 times lower than the antiarrhythmic dose, substantial ECG changes and adverse cardiac effects with DMQ have not been reported. The most common side effects of DM are nausea, somnolence, dizziness, and headache. Thrombocytopenia, QT prolongation, hepatotoxicity, allergic reactions, and anticholinergic side effects can occur.

In high doses and combined with other substances, DM has been used as a recreational drug. When taken in high doses, adverse effects include nausea, vomiting, malaise, dilated pupils, difficulty urinating, increased urination frequency, fever, tachycardia, loss of appetite, shakiness, seizures, and potentially coma and death. DMQ may have a greater potential for serious adverse effects than DM alone because quinidine increases DM bioavailability and blood levels. The abuse potential of DMQ is not clear.

Psychosis has been reported with higher DM doses. The psychotomimetic effects of phencyclidine (PCP) are related to binding to the PCP site on the NMDA receptor complex—to which DM also binds—with reduced glutamate signaling in information processing systems. Therefore, caution is indicated when prescribing DM to patients with psychosis.

Because DM, a CYP2D6 substrate, is combined with quinidine, a 2D6 inhibitor, administering DMQ with other 2D6 inhibitors could lead to toxicity. When DMQ is combined with SSRIs and similar agents, the serotonergic properties of DM could result in serotonin syndrome, which could be fatal if DM is combined with monoamine oxidase inhibitors.¹⁰ Combinations of DM and acetaminophen and antihistamines can be dangerous at higher doses.¹⁰ Because quinidine is metabolized by CYP3A, inhibitors of this enzyme such as ketoconazole, nefazodone, and grapefruit juice should be avoided. Similarly, inhibition of CYP2D6 by quinidine could raise levels of coadministered 2D6 substrates.

Contraindications. DMQ is contraindicated in patients with:

• heart failure
• prolonged QT interval
• congenital long QT interval
• history of torsades de pointes
• complete atrioventricular (AV) block without implanted pacemakers.¹³

DMQ also is contraindicated in patients at high risk for complete AV block.¹³

Dosing

DMQ is available as a capsule containing DM, 20 mg, and quinidine, 10 mg. The recommended starting dose is 1 capsule by mouth for 7 days, then 1 capsule every 12 hours.

Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a non-serotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated. In view of the unknown potential for abuse and toxicity as well as the cost of the proprietary drug ($3,000 to $5,000 a year), it would seem prudent to consider using an SSRI or a TCA first.⁸ These medications also act on 1-sigma receptors,^14,15 which may account in part for their reported benefit.

Related Resource

• Neudexta [package insert]. Aliso Viejo, CA: Avanir Pharmaceuticals; 2010.

Drug Brand Names

• Amantadine • Symmetrel
• Dextromethorphan/quinidine •Nefazodone
• Ketoconazole • Nizoral
• Levodopa • Sinemet
• Neudexta • Serzone
• Quinidine • Quinidex

Disclosures

Dr. Dubovsky receives research support from Biogen Idec, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Otsuka, the Peter and Elizabeth C. Tower Foundation, and Pfizer, Inc.

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

Table 2

Dextromethorphan/quinidine for PBA: Evidence shows efficacy

In October 2010, the FDA approved a combination of dextromethorphan (DM) and quinidine for the treatment of pseudobulbar affect (PBA)—also called pathological laughing and crying, affective lability, emotional dyscontrol, emotional incontinence, and involuntary emotional expression disorder—in patients with neurologic disorders and brain injuries (Table). Despite receiving an approvable letter in 2006, the compound was not approved at that time because of concerns about the arrhythmogenic potential of quinidine, which prolongs the QT interval. The manufacturer conducted another study using one-third of the previous quinidine dose, which ameliorated this concern and led to approval.

Clinical implications

PBA is manifested by involuntary labile, shallow affect with sudden and unpredictable laughing, crying, or other emotional displays that are not appropriate to the social setting and may not be congruent with the patient’s prevailing mood.¹ Episodes are often paroxysmal and cannot be interrupted voluntarily.² PBA seems to be caused by a loss of descending cortical control of brainstem motor nuclei and possibly the cerebellum, disrupting inhibitory mechanisms and resulting in inappropriate and involuntary emotional display.³ Several studies have demonstrated involvement of subcortical areas, particularly the anterior limb of the internal capsule and the bulbar area. The patho-physiology of PBA may involve excessive release of glutamate by injured neurons, disrupting systems for motor control of emotional expression.^4,5

Table

Dextromethorphan/quinidine: Fast facts

PBA is most common in diseases that interfere bilaterally with the corticohypothalamic and corticobulbar tracts that control voluntary and involuntary faciorespiratory mechanisms. However, PBA occurs in unilateral disease as well. The reported prevalence of PBA is:

• 49% in amyotrophic lateral sclerosis (ALS)
• 18% to 39% in Alzheimer’s disease
• 11% to 34% in stroke
• 10% to 11% in multiple sclerosis (MS) and traumatic brain injury.^6,7

PBA also has been reported in patients with Parkinson’s disease, brain tumors, Wilson’s disease, syphilitic pseudobulbar palsy, and various encephalitides.¹ An estimated 880,000 U.S. patients exhibit PBA.⁸

Previously, there was no FDA-approved treatment for PBA. However, small controlled trials suggest that selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs)— usually in doses lower than those used to treat depression—may effectively reduce symptoms within 2 to 3 days.¹ Although dopaminergic agents such as levodopa and amantadine have shown benefit in open trials, results of controlled studies using objective measurements have not been positive.

How it works

DM is a serotonergic substance that also is an agonist of 1-sigma receptors and a low-affinity, uncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors, which are important in glutamate signaling, through binding at the phencyclidine site on the NMDA complex.^7,9 The 1-sigma receptor was thought to be an opioid receptor subtype, but unlike opioid receptors it is not blocked by narcotic antagonists and does not have an endogenous ligand. However, the 1-sigma receptor does modulate activity of opioid mu receptors in addition to altering dopamine release and possibly reducing glutamate release.⁹ Sigma receptors are densely distributed in the limbic system and in systems related to motor control of affective expression and seem to be involved in learning, responses to stress, mood regulation, and drug dependence.¹ Because DM preferentially binds to brain regions that regulate emotional expression,¹⁰ it could normalize glutaminergic neurotransmission and other relevant systems in these regions.¹ However, DM’s exact mechanism of action is unknown.

Quinidine is a sodium channel antagonist usually used as a type Ia antiarrhythmic.⁵ DM is subject to extensive first-pass metabolism by cytochrome P (CYP) 450 2D6 to dextrorphan, which after being glucuronidated cannot cross the blood-brain barrier. In doses 10 to 25 times lower than those used to treat cardiac arrhythmias, quinidine inhibits 2D6 and increases DM bioavailability.¹⁰ DM blood levels increase linearly with dose following coadministration with quinidine but are undetectable in most patients given DM alone.^7,9

Efficacy and tolerability

A combination of DM and quinidine (DMQ) reduced Center for Neurologic Study-Lability Scale (CNC-LS) scores and the number of daily PBA episodes in 3 randomized trials.^5,7,10 Visit this article at CurrentPsychiatry.com for a table summarizing these studies.

An 85-day randomized, double-blind, placebo-controlled study of 150 patients with PBA associated with MS found that DM, 30 mg, plus quinidine, 30 mg, (DMQ 30-30) was twice as effective as placebo within a week in reducing CNC-LS scores.¹⁰ DMQ 30-30 patients also had approximately half as many episodes of inappropriate laughing, crying, or combined laughing and crying and a 2-fold greater decrease in pain intensity.¹⁰ Twenty-one percent of DMQ 30-30 patients experienced complete remission—no PBA episodes—compared with 7% of placebo patients. There were no significant differences in QT prolongation between DMQ 30-30 and placebo.

A 3-arm, double-blind, 28-day, phase III multicenter trial of 140 ALS patients with PBA compared DM monotherapy, quinidine monotherapy, and DMQ 30-30.⁵ Compared with either drug alone, DMQ 30-30 showed greater reduction of CNC-LS scores, as well as improved quality of life and quality of relationships scores, with equal benefit in poor and extensive DM metabolizers. However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.

In a manufacturer-sponsored, multicenter, 12-week randomized trial, 326 patients with ALS or MS and clinically significant PBA were randomly assigned to DM, 30 mg, plus quinidine, 10 mg (DMQ 30-10), DM, 20 mg, plus quinidine, 10 mg (DMQ 20-10), or placebo, each administered twice daily.⁷ Patients with comorbid psychiatric disorders or significant depressive symptoms were excluded. Although daily PBA episodes decreased in all groups, the daily rate of PBA episodes was 47% lower for patients taking DMQ 30-10, and 49% lower with DMQ 20-10 compared with placebo (both P < .001). The mean decrease in the number of daily PBA episodes was 3.9 to 4.1 with active treatment and 3.0 with placebo. Side effects were more common with active drug than placebo and included dizziness, nausea, diarrhea, and urinary tract infection. There were no serious adverse cardiac events and no active drug recipients showed a QTc interval >480 msec or a change from baseline >60 msec.¹¹ Discontinuation rates in this study were lower than in studies of DMQ 30-30. In an open-label extension of 253 patients who completed the double-blind phase and were assigned to DMQ 30-10 for 12 weeks, the incidence of treatment-related adverse events was 28%, with a 5.5% rate of serious adverse events.¹²

Safety

Because the 10 mg dose of quinidine in the approved formulation of DMQ is 10 times lower than the antiarrhythmic dose, substantial ECG changes and adverse cardiac effects with DMQ have not been reported. The most common side effects of DM are nausea, somnolence, dizziness, and headache. Thrombocytopenia, QT prolongation, hepatotoxicity, allergic reactions, and anticholinergic side effects can occur.

In high doses and combined with other substances, DM has been used as a recreational drug. When taken in high doses, adverse effects include nausea, vomiting, malaise, dilated pupils, difficulty urinating, increased urination frequency, fever, tachycardia, loss of appetite, shakiness, seizures, and potentially coma and death. DMQ may have a greater potential for serious adverse effects than DM alone because quinidine increases DM bioavailability and blood levels. The abuse potential of DMQ is not clear.

Psychosis has been reported with higher DM doses. The psychotomimetic effects of phencyclidine (PCP) are related to binding to the PCP site on the NMDA receptor complex—to which DM also binds—with reduced glutamate signaling in information processing systems. Therefore, caution is indicated when prescribing DM to patients with psychosis.

Because DM, a CYP2D6 substrate, is combined with quinidine, a 2D6 inhibitor, administering DMQ with other 2D6 inhibitors could lead to toxicity. When DMQ is combined with SSRIs and similar agents, the serotonergic properties of DM could result in serotonin syndrome, which could be fatal if DM is combined with monoamine oxidase inhibitors.¹⁰ Combinations of DM and acetaminophen and antihistamines can be dangerous at higher doses.¹⁰ Because quinidine is metabolized by CYP3A, inhibitors of this enzyme such as ketoconazole, nefazodone, and grapefruit juice should be avoided. Similarly, inhibition of CYP2D6 by quinidine could raise levels of coadministered 2D6 substrates.

Contraindications. DMQ is contraindicated in patients with:

• heart failure
• prolonged QT interval
• congenital long QT interval
• history of torsades de pointes
• complete atrioventricular (AV) block without implanted pacemakers.¹³

DMQ also is contraindicated in patients at high risk for complete AV block.¹³

Dosing

DMQ is available as a capsule containing DM, 20 mg, and quinidine, 10 mg. The recommended starting dose is 1 capsule by mouth for 7 days, then 1 capsule every 12 hours.

Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a non-serotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated. In view of the unknown potential for abuse and toxicity as well as the cost of the proprietary drug ($3,000 to $5,000 a year), it would seem prudent to consider using an SSRI or a TCA first.⁸ These medications also act on 1-sigma receptors,^14,15 which may account in part for their reported benefit.

Related Resource

• Neudexta [package insert]. Aliso Viejo, CA: Avanir Pharmaceuticals; 2010.

Drug Brand Names

• Amantadine • Symmetrel
• Dextromethorphan/quinidine •Nefazodone
• Ketoconazole • Nizoral
• Levodopa • Sinemet
• Neudexta • Serzone
• Quinidine • Quinidex

Disclosures

Dr. Dubovsky receives research support from Biogen Idec, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Otsuka, the Peter and Elizabeth C. Tower Foundation, and Pfizer, Inc.

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

Table 2

Dextromethorphan/quinidine for PBA: Evidence shows efficacy

In October 2010, the FDA approved lurasidone for the acute treatment of schizophrenia at a dose of 40 or 80 mg/d administered once daily with food (Table 1).

Table 1

Lurasidone: Fast facts

How it works

Although the drug’s exact mechanism of action is not known, it is thought that lurasidone’s antipsychotic properties are related to its antagonism at serotonin 2A (5-HT2A) and dopamine D2 receptors.¹

Similar to most other atypical antipsychotics, lurasidone has high binding affinity for 5-HT2A and D2. Lurasidone has also high binding affinity for 5-HT7, 5-HT1A, and α2C-adrenergic receptors, low affinity for α-1 receptors, and virtually no affinity for H1 and M1 receptors (Table 2). Activity on 5-HT7, 5-HT1A, and α2C-adrenergic receptors is believed to enhance cognition, and 5-HT7 is being studied for a potential role in mood regulation and sensory processing.^2,3 Lurasidone’s low activity on α-1, H1, and M1 receptors suggests a low risk of orthostatic hypotension, H1-mediated sedation and weight gain, and H1- and M1-mediated cognitive blunting.

Pharmacokinetics

Lurasidone is absorbed in the gastrointestinal tract. It reaches maximum concentration (Cmax) in 1 to 3 hours. Cmax doubles when lurasidone is administered with food (≥350 calories), but absorption is independent of the meal’s fat content.⁴ After absorption, the drug is highly bound (99%) to serum proteins (albumin and α-1-glycoprotein). The elimination half-life is 18 hours and steady-state concentration is reached within 7 days.¹ Lurasidone is eliminated predominantly through cytochrome P450 (CYP) 3A4 metabolism in the liver.

Efficacy

Lurasidone’s efficacy for treatment of acute schizophrenia was established in four 6-week, randomized placebo-controlled clinical trials.¹ The patients were adults (mean age: 38.8; range: 18 to 72) who met DSM-IVTR criteria for schizophrenia, didn’t abuse drugs or alcohol, and had not taken any investigational drug for ≥1 month. Symptoms were measured on the Positive and Negative Syndrome Scale (PANSS); Brief Psychiatric Rating Scale as derived from the PANSS (BPRSd); and the Clinical Global Impressions-Severity scale (CGI-S).

In the first clinical trial, 145 patients were randomized to lurasidone, 40 mg/d or 120 mg/d, or placebo. Treatment with either dose of lurasidone was superior to treatment with placebo on the BPRSd (Least Squares Mean [LSM] difference from placebo in change from baseline: -5.6 on lurasidone 40 mg/d, -6.7 on lurasidone 120 mg/d) and CGI-S.^1,5

The second trial randomized 180 patients to lurasidone, 80 mg/d, or placebo. Lurasidone, 80 mg/d, was superior to placebo as measured on the BPRSd (LSM difference from placebo in change from baseline: -4.7 on lurasidone 80 mg/d) and CGI-S.^1,6

The third trial randomized 489 patients to lurasidone, 40 mg/d, 80 mg/d, 120 mg/d, or placebo. All lurasidone arms were superior to placebo on PANSS (LSM difference from placebo in change from baseline: -2.1 on 40 mg/d, -6.4 on 80 mg/d, and -3.5 on 120 mg/d) and CGI-S scores. This study also showed that lurasidone appears to have a rapid onset of action (day 3 to 4) and provides sustained improvement of symptoms.¹

In the fourth trial, 473 individuals were randomized to lurasidone, 40 mg/d or 120 mg/d, olanzapine, 15 mg/d, or placebo. Olanzapine and both dosages of lurasidone were superior to placebo in improving PANSS scores (LSM difference from placebo in change from baseline: -9.7 on lurasidone 40 mg/d, -7.5 on lurasidone 120 mg/d, and -12.6 on olanzapine 15 mg/d) and CGI-S.^1,7 Both doses of lurasidone were not superior to olanzapine but had less negative impact on lipid profile, weight gain, and glycemia.

Tolerability

Tolerability information is extracted from a clinical study database consisting of 2,096 patients with schizophrenia who participated in premarketing clinical trials and were exposed to single or multiple doses of lurasidone, 20 mg, 40 mg, 80 mg, or 120 mg.¹ Overall, lurasidone was well tolerated. The rate of discontinuation from clinical trials because of adverse effects was 9.4% for lurasidone vs 5.9% for placebo. Somnolence, akathisia, nausea, parkinsonism, and agitation were the most commonly reported adverse reactions; somnolence and akathisia appear dose-related. Other adverse effects associated with lurasidone were nausea, vomiting, dyspepsia, dystonia, dizziness, insomnia, agitation, and anxiety (Table 2).

Metabolic changes (hyperlipidemia, hyperglycemia, and increased body weight) associated with cardiovascular risk in patients treated with atypical antipsychotics were studied in short-term placebo-controlled trials. Lurasidone is considered to be weight-neutral and does not have significant effects on serum lipids or glucose.² As is the case with other D2 antagonists, lurasidone is associated with increased prolactin, which appears to be greater in females and is dose-dependent. Lurasidone is not associated with significant QTc prolongation, seizures, transaminases increase, or changes in serum chemistry, hematology, or urinalysis.

Table 2

Lurasidone receptor binding profile and receptor-related effects

Contraindications

Lurasidone is contraindicated in patients with known sensitivity to lurasidone hydrochloride. Because of the risk for pharmacokinetic drug-drug interactions, lurasidone is contraindicated for patients who are taking strong CYP3A4 inhibitors (eg, ketoconazole) or inducers (eg, rifampin).

Similar to other medications in its class, lurasidone carries a “black-box” warning of increased mortality in elderly patients with dementia-related psychosis and it is not FDA-approved for treating this condition. Animal teratogenicity studies using lurasidone, 25 mg/kg/d and 50 mg/kg/d, did not show adverse effects during organogenesis, and lurasidone is classified as pregnancy category B (animal studies failed to demonstrate risk to the fetus and there are no adequate and well-controlled studies in pregnant women, or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester). The use of lurasidone in geriatric and pediatric populations was not studied.¹

Dosing

Lurasidone is manufactured as 40 mg and 80 mg tablets. The recommended starting dose is 40 mg/d and the maximum recommended dose is 80 mg/d.¹ In clinical trials, lurasidone, 120 mg/d, was associated with increased incidence of adverse effects without added benefit.

Lurasidone doesn’t require initial dose titration and should be given with food that provides ≥350 calories to improve medication absorption. Dose adjustment is recommended for use in patients with moderate or severe renal or hepatic impairment and when coadministered with CYP3A4 moderate inhibitors; the dose in these patients should not exceed 40 mg/d.

Related Resource

• Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract. 2010 Epub ahead of print.

Drug Brand Names

• Ketoconazole • Nizoral
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Rifampin • Rifadin

Disclosure

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

In October 2010, the FDA approved lurasidone for the acute treatment of schizophrenia at a dose of 40 or 80 mg/d administered once daily with food (Table 1).

Table 1

Lurasidone: Fast facts

How it works

Although the drug’s exact mechanism of action is not known, it is thought that lurasidone’s antipsychotic properties are related to its antagonism at serotonin 2A (5-HT2A) and dopamine D2 receptors.¹

Similar to most other atypical antipsychotics, lurasidone has high binding affinity for 5-HT2A and D2. Lurasidone has also high binding affinity for 5-HT7, 5-HT1A, and α2C-adrenergic receptors, low affinity for α-1 receptors, and virtually no affinity for H1 and M1 receptors (Table 2). Activity on 5-HT7, 5-HT1A, and α2C-adrenergic receptors is believed to enhance cognition, and 5-HT7 is being studied for a potential role in mood regulation and sensory processing.^2,3 Lurasidone’s low activity on α-1, H1, and M1 receptors suggests a low risk of orthostatic hypotension, H1-mediated sedation and weight gain, and H1- and M1-mediated cognitive blunting.

Pharmacokinetics

Lurasidone is absorbed in the gastrointestinal tract. It reaches maximum concentration (Cmax) in 1 to 3 hours. Cmax doubles when lurasidone is administered with food (≥350 calories), but absorption is independent of the meal’s fat content.⁴ After absorption, the drug is highly bound (99%) to serum proteins (albumin and α-1-glycoprotein). The elimination half-life is 18 hours and steady-state concentration is reached within 7 days.¹ Lurasidone is eliminated predominantly through cytochrome P450 (CYP) 3A4 metabolism in the liver.

Efficacy

Lurasidone’s efficacy for treatment of acute schizophrenia was established in four 6-week, randomized placebo-controlled clinical trials.¹ The patients were adults (mean age: 38.8; range: 18 to 72) who met DSM-IVTR criteria for schizophrenia, didn’t abuse drugs or alcohol, and had not taken any investigational drug for ≥1 month. Symptoms were measured on the Positive and Negative Syndrome Scale (PANSS); Brief Psychiatric Rating Scale as derived from the PANSS (BPRSd); and the Clinical Global Impressions-Severity scale (CGI-S).

In the first clinical trial, 145 patients were randomized to lurasidone, 40 mg/d or 120 mg/d, or placebo. Treatment with either dose of lurasidone was superior to treatment with placebo on the BPRSd (Least Squares Mean [LSM] difference from placebo in change from baseline: -5.6 on lurasidone 40 mg/d, -6.7 on lurasidone 120 mg/d) and CGI-S.^1,5

The second trial randomized 180 patients to lurasidone, 80 mg/d, or placebo. Lurasidone, 80 mg/d, was superior to placebo as measured on the BPRSd (LSM difference from placebo in change from baseline: -4.7 on lurasidone 80 mg/d) and CGI-S.^1,6

The third trial randomized 489 patients to lurasidone, 40 mg/d, 80 mg/d, 120 mg/d, or placebo. All lurasidone arms were superior to placebo on PANSS (LSM difference from placebo in change from baseline: -2.1 on 40 mg/d, -6.4 on 80 mg/d, and -3.5 on 120 mg/d) and CGI-S scores. This study also showed that lurasidone appears to have a rapid onset of action (day 3 to 4) and provides sustained improvement of symptoms.¹

In the fourth trial, 473 individuals were randomized to lurasidone, 40 mg/d or 120 mg/d, olanzapine, 15 mg/d, or placebo. Olanzapine and both dosages of lurasidone were superior to placebo in improving PANSS scores (LSM difference from placebo in change from baseline: -9.7 on lurasidone 40 mg/d, -7.5 on lurasidone 120 mg/d, and -12.6 on olanzapine 15 mg/d) and CGI-S.^1,7 Both doses of lurasidone were not superior to olanzapine but had less negative impact on lipid profile, weight gain, and glycemia.

Tolerability

Tolerability information is extracted from a clinical study database consisting of 2,096 patients with schizophrenia who participated in premarketing clinical trials and were exposed to single or multiple doses of lurasidone, 20 mg, 40 mg, 80 mg, or 120 mg.¹ Overall, lurasidone was well tolerated. The rate of discontinuation from clinical trials because of adverse effects was 9.4% for lurasidone vs 5.9% for placebo. Somnolence, akathisia, nausea, parkinsonism, and agitation were the most commonly reported adverse reactions; somnolence and akathisia appear dose-related. Other adverse effects associated with lurasidone were nausea, vomiting, dyspepsia, dystonia, dizziness, insomnia, agitation, and anxiety (Table 2).

Metabolic changes (hyperlipidemia, hyperglycemia, and increased body weight) associated with cardiovascular risk in patients treated with atypical antipsychotics were studied in short-term placebo-controlled trials. Lurasidone is considered to be weight-neutral and does not have significant effects on serum lipids or glucose.² As is the case with other D2 antagonists, lurasidone is associated with increased prolactin, which appears to be greater in females and is dose-dependent. Lurasidone is not associated with significant QTc prolongation, seizures, transaminases increase, or changes in serum chemistry, hematology, or urinalysis.

Table 2

Lurasidone receptor binding profile and receptor-related effects

Contraindications

Lurasidone is contraindicated in patients with known sensitivity to lurasidone hydrochloride. Because of the risk for pharmacokinetic drug-drug interactions, lurasidone is contraindicated for patients who are taking strong CYP3A4 inhibitors (eg, ketoconazole) or inducers (eg, rifampin).

Similar to other medications in its class, lurasidone carries a “black-box” warning of increased mortality in elderly patients with dementia-related psychosis and it is not FDA-approved for treating this condition. Animal teratogenicity studies using lurasidone, 25 mg/kg/d and 50 mg/kg/d, did not show adverse effects during organogenesis, and lurasidone is classified as pregnancy category B (animal studies failed to demonstrate risk to the fetus and there are no adequate and well-controlled studies in pregnant women, or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester). The use of lurasidone in geriatric and pediatric populations was not studied.¹

Dosing

Lurasidone is manufactured as 40 mg and 80 mg tablets. The recommended starting dose is 40 mg/d and the maximum recommended dose is 80 mg/d.¹ In clinical trials, lurasidone, 120 mg/d, was associated with increased incidence of adverse effects without added benefit.

Lurasidone doesn’t require initial dose titration and should be given with food that provides ≥350 calories to improve medication absorption. Dose adjustment is recommended for use in patients with moderate or severe renal or hepatic impairment and when coadministered with CYP3A4 moderate inhibitors; the dose in these patients should not exceed 40 mg/d.

Related Resource

• Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract. 2010 Epub ahead of print.

Drug Brand Names

• Ketoconazole • Nizoral
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Rifampin • Rifadin

Disclosure

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

In October 2010, the FDA approved lurasidone for the acute treatment of schizophrenia at a dose of 40 or 80 mg/d administered once daily with food (Table 1).

Table 1

Lurasidone: Fast facts

How it works

Although the drug’s exact mechanism of action is not known, it is thought that lurasidone’s antipsychotic properties are related to its antagonism at serotonin 2A (5-HT2A) and dopamine D2 receptors.¹

Similar to most other atypical antipsychotics, lurasidone has high binding affinity for 5-HT2A and D2. Lurasidone has also high binding affinity for 5-HT7, 5-HT1A, and α2C-adrenergic receptors, low affinity for α-1 receptors, and virtually no affinity for H1 and M1 receptors (Table 2). Activity on 5-HT7, 5-HT1A, and α2C-adrenergic receptors is believed to enhance cognition, and 5-HT7 is being studied for a potential role in mood regulation and sensory processing.^2,3 Lurasidone’s low activity on α-1, H1, and M1 receptors suggests a low risk of orthostatic hypotension, H1-mediated sedation and weight gain, and H1- and M1-mediated cognitive blunting.

Pharmacokinetics

Lurasidone is absorbed in the gastrointestinal tract. It reaches maximum concentration (Cmax) in 1 to 3 hours. Cmax doubles when lurasidone is administered with food (≥350 calories), but absorption is independent of the meal’s fat content.⁴ After absorption, the drug is highly bound (99%) to serum proteins (albumin and α-1-glycoprotein). The elimination half-life is 18 hours and steady-state concentration is reached within 7 days.¹ Lurasidone is eliminated predominantly through cytochrome P450 (CYP) 3A4 metabolism in the liver.

Efficacy

Lurasidone’s efficacy for treatment of acute schizophrenia was established in four 6-week, randomized placebo-controlled clinical trials.¹ The patients were adults (mean age: 38.8; range: 18 to 72) who met DSM-IVTR criteria for schizophrenia, didn’t abuse drugs or alcohol, and had not taken any investigational drug for ≥1 month. Symptoms were measured on the Positive and Negative Syndrome Scale (PANSS); Brief Psychiatric Rating Scale as derived from the PANSS (BPRSd); and the Clinical Global Impressions-Severity scale (CGI-S).

In the first clinical trial, 145 patients were randomized to lurasidone, 40 mg/d or 120 mg/d, or placebo. Treatment with either dose of lurasidone was superior to treatment with placebo on the BPRSd (Least Squares Mean [LSM] difference from placebo in change from baseline: -5.6 on lurasidone 40 mg/d, -6.7 on lurasidone 120 mg/d) and CGI-S.^1,5

The second trial randomized 180 patients to lurasidone, 80 mg/d, or placebo. Lurasidone, 80 mg/d, was superior to placebo as measured on the BPRSd (LSM difference from placebo in change from baseline: -4.7 on lurasidone 80 mg/d) and CGI-S.^1,6

The third trial randomized 489 patients to lurasidone, 40 mg/d, 80 mg/d, 120 mg/d, or placebo. All lurasidone arms were superior to placebo on PANSS (LSM difference from placebo in change from baseline: -2.1 on 40 mg/d, -6.4 on 80 mg/d, and -3.5 on 120 mg/d) and CGI-S scores. This study also showed that lurasidone appears to have a rapid onset of action (day 3 to 4) and provides sustained improvement of symptoms.¹

In the fourth trial, 473 individuals were randomized to lurasidone, 40 mg/d or 120 mg/d, olanzapine, 15 mg/d, or placebo. Olanzapine and both dosages of lurasidone were superior to placebo in improving PANSS scores (LSM difference from placebo in change from baseline: -9.7 on lurasidone 40 mg/d, -7.5 on lurasidone 120 mg/d, and -12.6 on olanzapine 15 mg/d) and CGI-S.^1,7 Both doses of lurasidone were not superior to olanzapine but had less negative impact on lipid profile, weight gain, and glycemia.

Tolerability

Tolerability information is extracted from a clinical study database consisting of 2,096 patients with schizophrenia who participated in premarketing clinical trials and were exposed to single or multiple doses of lurasidone, 20 mg, 40 mg, 80 mg, or 120 mg.¹ Overall, lurasidone was well tolerated. The rate of discontinuation from clinical trials because of adverse effects was 9.4% for lurasidone vs 5.9% for placebo. Somnolence, akathisia, nausea, parkinsonism, and agitation were the most commonly reported adverse reactions; somnolence and akathisia appear dose-related. Other adverse effects associated with lurasidone were nausea, vomiting, dyspepsia, dystonia, dizziness, insomnia, agitation, and anxiety (Table 2).

Metabolic changes (hyperlipidemia, hyperglycemia, and increased body weight) associated with cardiovascular risk in patients treated with atypical antipsychotics were studied in short-term placebo-controlled trials. Lurasidone is considered to be weight-neutral and does not have significant effects on serum lipids or glucose.² As is the case with other D2 antagonists, lurasidone is associated with increased prolactin, which appears to be greater in females and is dose-dependent. Lurasidone is not associated with significant QTc prolongation, seizures, transaminases increase, or changes in serum chemistry, hematology, or urinalysis.

Table 2

Lurasidone receptor binding profile and receptor-related effects

Contraindications

Lurasidone is contraindicated in patients with known sensitivity to lurasidone hydrochloride. Because of the risk for pharmacokinetic drug-drug interactions, lurasidone is contraindicated for patients who are taking strong CYP3A4 inhibitors (eg, ketoconazole) or inducers (eg, rifampin).

Similar to other medications in its class, lurasidone carries a “black-box” warning of increased mortality in elderly patients with dementia-related psychosis and it is not FDA-approved for treating this condition. Animal teratogenicity studies using lurasidone, 25 mg/kg/d and 50 mg/kg/d, did not show adverse effects during organogenesis, and lurasidone is classified as pregnancy category B (animal studies failed to demonstrate risk to the fetus and there are no adequate and well-controlled studies in pregnant women, or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester). The use of lurasidone in geriatric and pediatric populations was not studied.¹

Dosing

Lurasidone is manufactured as 40 mg and 80 mg tablets. The recommended starting dose is 40 mg/d and the maximum recommended dose is 80 mg/d.¹ In clinical trials, lurasidone, 120 mg/d, was associated with increased incidence of adverse effects without added benefit.

Lurasidone doesn’t require initial dose titration and should be given with food that provides ≥350 calories to improve medication absorption. Dose adjustment is recommended for use in patients with moderate or severe renal or hepatic impairment and when coadministered with CYP3A4 moderate inhibitors; the dose in these patients should not exceed 40 mg/d.

Related Resource

• Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract. 2010 Epub ahead of print.

Drug Brand Names

• Ketoconazole • Nizoral
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Rifampin • Rifadin

Disclosure

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

Extended-release (ER) trazodone—FDA-approved in February 2010—improves symptoms of major depressive disorder (MDD) and allows once-daily dosing (Table 1). Trazodone immediate release (IR) was developed in 1960 and approved by the FDA for treatment of MDD in December 1981. Trazodone IR is now mainly prescribed off-label as a hypnotic at lower-than-antidepressant doses, such as 50 to 100 mg/d at bedtime. The dose needed to achieve antidepressant effect is believed to be ≥300 mg/d. Use of the IR formulation for treating depression has been limited by the need for 3-times-a-day dosing and daytime sedation associated with peaks in serum concentration.

Table 1

Trazodone extended release: Fast facts

Clinical implications

Trazodone ER was designed to eliminate the peaks and troughs in serum concentration seen with trazodone IR. It was hypothesized that by reducing the maximum concentration (Cmax) peaks, trazodone ER would permit higher doses to be better tolerated and help patients to more easily reach target antidepressant doses (≥300 mg/d). Trazodone ER’s once-daily dosing also may increase patient adherence.

How it works

The exact mechanism of action through which trazodone treats depression is not completely understood, but is likely related to enhancing serotonergic activity in the CNS. Trazodone is a triazolopyridine antidepressant, inhibits the serotonin transporter, and is a 5-HT2A and 5-HT2C antagonist. This is why it is sometimes referred as a serotonin antagonist/reuptake inhibitor, but regulatory agencies do not accept this class name. Trazodone is an antagonist at both histamine (H1) and α1-adrenergic receptors, which may mediate trazodone’s sedating properties (H1) and hypotensive (α1-adrenergic) effects.

The ER formulation employs a cross-linked, high-amylose starch excipient that provides controlled release of trazodone over an extended period.

Pharmacokinetics

Trazodone ER has linear pharmacokinetics in doses from 75 to 375 mg. Trazodone ER, 300 mg/d, provides a steady-state exposure equivalent to 100 mg of trazodone IR given 3 times daily, while having a lower Cmax. A high-fat meal can increase Cmax of trazodone ER by 1.9-fold. Trazodone is extensively biotransformed in the liver via the cytochrome P450 (CYP) 3A4 pathway and its metabolites are eliminated within 72 hours. Elimination is predominantly renal, with 70% to 75% of an oral dose being recovered in the urine within 72 hours.¹ This formulation maintains its controlled-release properties if bisected.

Because trazodone is a substrate of the CYP3A4 enzyme, its metabolism can be inhibited by CYP3A4 inhibitors. Exercise caution when coadministering medications that cause CYP3A4 inhibition with trazodone ER. The effect of short-term administration of ritonavir (4 doses of 200 mg) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects.² The Cmax of trazodone increased by 34%, area under the curve increased 2.4-fold, half-life increased by 2.2-fold, and clearance decreased by 52%. There is no difference in the half-life between the IR and ER formulations because the ER formulation influences only the release kinetics of the drug, not the half-life of the medication.

Efficacy

Efficacy of trazodone for MDD initially was established in trials conducted with trazodone IR.^3-10 The efficacy of the ER formulation was established in a multi-center randomized, double-blind, placebo-controlled trial with 412 patients (age 18 to 80). Patients who met DSM-IV criteria for MDD were randomly assigned to trazodone ER (n=206) or placebo (n=206) for 8 weeks.¹¹ This study showed a statistically significant difference between trazodone ER and placebo after 8 weeks of treatment on the primary outcome measure, which was a change in score on the 17-item Hamilton Depression Rating scale (HAMD-17). HAM-D-17 scores decreased 11.4 points in the trazodone ER group and 9.3 points in the placebo group (P=.012 in the modified intent to treat [ITT] population; P=.009 in the completer analysis). This difference was seen from week 1 and throughout the study. Efficacy of trazodone ER was further supported by statistically significant differences between the drug and placebo in 7 of 13 secondary efficacy endpoints in both the modified ITT and per protocol (PP) populations (HAM-D-17 mood item, mean Montgomery-Åsberg Depression Rating Scale [MADRS] total score, mean Clinical Global Impressions Severity of Illness [CGI-S] score, percentage of HAM-D-17 responders, and 3 quality of sleep items [overall quality of sleep, trouble falling asleep, and awakening during the night]). Overall effect sizes for the HAM-D-17 were -0.26 (modified ITT-last observation carried forward [LOCF] dataset) and -0.33 (PP/observed cases [OC] dataset). The effect sizes in MADRS scores were -0.22 and -0.29 for the modified ITT-LOCF and the PP/OC analyses, respectively.¹²

Sleep measures. In the study sample >90% of patients had insomnia at baseline (defined as a score ≥2 in any HAM-D-17 sleep item or sum of all 3 sleep items of ≥4). Patients receiving trazodone ER had significant improvement in all 3 HAM-D-17 sleep items. Subjects reported improvement in the overall quality of sleep and awakening during the night after the first week of treatment. Investigators found no significant interaction between improvements in core symptoms of depression and baseline MADRS reduced sleep item or early changes in the HAM-D-17 sleep items. This suggests that the antidepressant effect of trazodone ER was independent of severity of sleep difficulties at baseline and of improvement in insomnia during the study.¹²

Researchers observed improvement in suicidal ideation on MADRS (item 10) and HAM-D-17 (item 3) after 8 weeks of treatment (effect size -0.2 favoring trazodone ER over placebo).¹²

In 2 European comparative, randomized, double-blind trials, trazodone prolonged release showed similar antidepressant efficacy as paroxetine⁴ and setraline⁵ as measured by HAM-D, MADRS, and CGI-S. This prolonged release formulation made in Europe is not the same technology as the ER formulation recently approved by the FDA.

Tolerability

In the pivotal registration study, trazodone ER was well tolerated at a mean dose of 310 mg/d.¹¹ Twenty-five patients (12.4%) in the trazodone ER group discontinued the drug because of side effects. The most common side effects leading to discontinuation in the active treatment group were dizziness (n=7), sedation (n=5), and somnolence (n=3).¹¹ The most frequent adverse events reported at any study time point were headache (33%), somnolence (31%), dry mouth (25%), dizziness (25%), nausea (21%), sedation (17%), and fatigue (15%) (Table 2).¹¹ In general, these adverse events were mild to moderate and short-lived; most side effects resolved within the first 2 to 3 weeks of treatment with trazodone ER.¹¹

Sexual side effects—delayed ejaculation, delayed time to orgasm, or orgasmic blockade—are common with many anti-depressants. In the pivotal registration study, the incidence of sexual side effects was low (4.9% with trazodone ER vs 2.5% with placebo).¹¹ This is much lower than the rates typically found with selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, which range from 17% to 41%.^13,14 This benefit is thought to be mediated through 5-HT2A and 5-HT2C antagonism. Priapism has been reported in trazodone IR at rates ranging from 1 in 1,000 to 1 in 10,000 and does not appear to be dose-related.¹⁵ The rate of priapism in persons using agents for erectile dysfunction ranges from .05% to 6%.¹⁵ No case of priapism was seen in the trazodone ER study; however, with its sample size of 412 patients this study was not powered to adequately detect this adverse event.¹¹

There was no significant weight gain difference between the active drug and placebo groups over 8 weeks of treatment.

Safety. Trazodone ER should not be used within 14 days of taking a monoamine oxidase inhibitor.¹ Trazodone carries a pregnancy category C, meaning that it should be used only if the potential benefit justifies potential risk to the fetus. In animal studies, trazodone has been shown to cause increased fetal resorption and congenital anomalities with doses up to 50 times the maximum human dose (375 mg/d). Trazo-done may be secreted in breast milk. The drug is best avoided in patients with recent myocardial infarction.

Table 2

Trazodone extended release treatment-emergent adverse events*

Dosing

The recommended starting dose is 150 mg/d at bedtime. The dose may be increased by 75 mg/d every 3 days, but the maximum dose should not exceed 375 mg/d.¹ Trazodone ER is available in 150 mg or 300 mg bisectable tablets. Breaking the tablets in half does not affect the controlled release, but they should not be chewed or crushed.

Related Resource

• Extended-release trazodone (Oleptro) prescribing information. www.oleptro.com/images/9379.pdf.

Drug Brand Names

• Paroxetine • Paxil
• Ritonavir • Norvir
• Sertraline • Zoloft
• Trazodone • Desyrel
• Trazodone extended-release • Oleptro

Disclosures

Dr. Hidalgo receives grant/research support from AstraZeneca, CeNeRx Biopharma, Centers for Disease Control and Prevention, Dainippon Sumitomo Pharma America, Inc., Eli Lilly and Company, Forest Laboratories, Indevus Pharmaceuticals, Janssen Pharmaceuticals, Labopharm, Otsuka, Pfizer, Inc., Repligen Corp., Sanofi-Synthelabo, Sepracor, and the University of South Florida, and is consultant to the MAPI Institute.

Dr. Sheehan has received grant funding support from, been affiliated with, or received honoraria and travel expenses related to lectures/presentations or consultant activities from the following organizations: Abbott Laboratories,^1,2,3 Ad Hoc Committee, Treatment Drug and Assessment Research Review,¹ Alexza,¹ Alza Pharmaceuticals, Palo Alto, CA,¹ the American Medical Association,² American Psychiatric Association Task Force on Benzodiazepine Dependency,¹ American Psychiatric Association Task Force on Treatments of Psychiatric Disorders,¹ American Psychiatric Association Working Group to Revise DSM III Anxiety Disorders Section,¹ Anclote Foundation,² Anxiety Disorders Resource Center,¹ Anxiety Drug Efficacy Case, the FDA,¹ Applied Health Outcomes/Xcenda,¹ AstraZeneca,^1,2,3 Avera Pharmaceuticals,^1,2 Boehringer Ingelheim,³ Boots Pharmaceuticals,³ Bristol-Myers Squibb,^1,2,3 Burroughs Wellcome,^2,3 Cephalon,¹ Charter Hospitals,³ Ciba Geigy,³ Committee (RRC) of the National Institute for Mental Health on Anxiety and Phobic Disorder Projects,¹ Connecticut and Ohio Academies of Family Physicians,¹ Cortex Pharmaceutical,¹ Council on Anxiety Disorders,¹ CPC Coliseum Medical Center,¹ Cypress Bioscience,¹ Dista Products Company,³ Division of Drugs and Technology, American Medical Association,¹ Eisai,^1,2 Eli Lilly and Company,^2,3 Excerpta Medica Asia,³ Faxmed, Inc.,¹ Forest Laboratories,^1,2 Glaxo Pharmaceuticals,³ GlaxoSmithKline,^1,2,3 Glaxo-Wellcome,² Hospital Corporation of America,³ Humana,³ ICI,³ INC Research,¹ International Clinical Research (ICR),² International Society for CNS Drug Development (ISCDD),¹ Janssen Pharmaceuticals,^1,2,3 Jazz Pharmaceuticals,^1,2 Kali-Duphar,^2,3 Labopharm,¹ Layton Bioscience,¹ Lilly Research Laboratories,¹ Lundbeck, Denmark,¹ Marion Merrell Dow,³ McNeil Pharmaceuticals,³ Mead Johnson,^2,3 Medical Outcome Systems,⁴ MediciNova,^1,2 Merck Sharp & Dohme,^2,3 National Anxiety Awareness Program,¹ National Anxiety Foundation,¹ National Depressive and Manic Depressive Association,¹ National Institute on Drug Abuse,² National Institute of Health,² Neuronetics,¹ Novartis Pharmaceuticals Corp.,² Novo Nordisk,³ Organon,^1,3 Orion Pharma,¹ Parexel International Corporation,¹ Parke-Davis,^2,3 Pfizer, Inc.,^1,2,3 Pharmacia,¹ Pharmacia and Upjohn,^1,3 Philadelphia College of Pharmacy and Science,¹ Pierre Fabre, France,¹ Quintiles,² Rhone Laboratories,³ Rhone-Poulenc Rorer Pharmaceuticals,³ Roche,¹ Roerig,³ Sandoz Pharmaceuticals,^2,3 sanofi-aventis,^1,2,3 Sanofi-Synthelabo Recherche,^1,2 Schering Corporation,³ Sepracor,¹ Shire Laboratories, Inc.,¹ SmithKline Beecham,^1,2,3 Solvay Pharmaceuticals,^1,3 Takeda Pharmaceuticals,¹ Tampa General Hospital,¹ University of South Florida Psychiatry Center,² University of South Florida College of Medicine, TAP Pharmaceuticals,^2,3 Targacept,¹ Tampa General Hospital-University Psychiatry Center,³ Tikvah Therapeutics,¹ Titan Pharmaceuticals,¹ United Bioscience,² The Upjohn Company,^1,2,3 U.S. Congress-House of Representatives Committee,¹ University of South Florida Friends of Research in Psychiatry, Board of Trustees,¹ Warner Chilcott,^2,3 World Health Organization,¹ Worldwide Clinical Trials,² Wyeth-Ayerst,^1,2,3 ZARS,¹ and Zeneca Pharmaceuticals.1

1: Consultant; 2: Grant/Research Support; 3: Lectures/ Presentations; 4: Stock Holder

Extended-release (ER) trazodone—FDA-approved in February 2010—improves symptoms of major depressive disorder (MDD) and allows once-daily dosing (Table 1). Trazodone immediate release (IR) was developed in 1960 and approved by the FDA for treatment of MDD in December 1981. Trazodone IR is now mainly prescribed off-label as a hypnotic at lower-than-antidepressant doses, such as 50 to 100 mg/d at bedtime. The dose needed to achieve antidepressant effect is believed to be ≥300 mg/d. Use of the IR formulation for treating depression has been limited by the need for 3-times-a-day dosing and daytime sedation associated with peaks in serum concentration.

Table 1

Trazodone extended release: Fast facts

Clinical implications

Trazodone ER was designed to eliminate the peaks and troughs in serum concentration seen with trazodone IR. It was hypothesized that by reducing the maximum concentration (Cmax) peaks, trazodone ER would permit higher doses to be better tolerated and help patients to more easily reach target antidepressant doses (≥300 mg/d). Trazodone ER’s once-daily dosing also may increase patient adherence.

How it works

The exact mechanism of action through which trazodone treats depression is not completely understood, but is likely related to enhancing serotonergic activity in the CNS. Trazodone is a triazolopyridine antidepressant, inhibits the serotonin transporter, and is a 5-HT2A and 5-HT2C antagonist. This is why it is sometimes referred as a serotonin antagonist/reuptake inhibitor, but regulatory agencies do not accept this class name. Trazodone is an antagonist at both histamine (H1) and α1-adrenergic receptors, which may mediate trazodone’s sedating properties (H1) and hypotensive (α1-adrenergic) effects.

The ER formulation employs a cross-linked, high-amylose starch excipient that provides controlled release of trazodone over an extended period.

Pharmacokinetics

Trazodone ER has linear pharmacokinetics in doses from 75 to 375 mg. Trazodone ER, 300 mg/d, provides a steady-state exposure equivalent to 100 mg of trazodone IR given 3 times daily, while having a lower Cmax. A high-fat meal can increase Cmax of trazodone ER by 1.9-fold. Trazodone is extensively biotransformed in the liver via the cytochrome P450 (CYP) 3A4 pathway and its metabolites are eliminated within 72 hours. Elimination is predominantly renal, with 70% to 75% of an oral dose being recovered in the urine within 72 hours.¹ This formulation maintains its controlled-release properties if bisected.

Because trazodone is a substrate of the CYP3A4 enzyme, its metabolism can be inhibited by CYP3A4 inhibitors. Exercise caution when coadministering medications that cause CYP3A4 inhibition with trazodone ER. The effect of short-term administration of ritonavir (4 doses of 200 mg) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects.² The Cmax of trazodone increased by 34%, area under the curve increased 2.4-fold, half-life increased by 2.2-fold, and clearance decreased by 52%. There is no difference in the half-life between the IR and ER formulations because the ER formulation influences only the release kinetics of the drug, not the half-life of the medication.

Efficacy

Efficacy of trazodone for MDD initially was established in trials conducted with trazodone IR.^3-10 The efficacy of the ER formulation was established in a multi-center randomized, double-blind, placebo-controlled trial with 412 patients (age 18 to 80). Patients who met DSM-IV criteria for MDD were randomly assigned to trazodone ER (n=206) or placebo (n=206) for 8 weeks.¹¹ This study showed a statistically significant difference between trazodone ER and placebo after 8 weeks of treatment on the primary outcome measure, which was a change in score on the 17-item Hamilton Depression Rating scale (HAMD-17). HAM-D-17 scores decreased 11.4 points in the trazodone ER group and 9.3 points in the placebo group (P=.012 in the modified intent to treat [ITT] population; P=.009 in the completer analysis). This difference was seen from week 1 and throughout the study. Efficacy of trazodone ER was further supported by statistically significant differences between the drug and placebo in 7 of 13 secondary efficacy endpoints in both the modified ITT and per protocol (PP) populations (HAM-D-17 mood item, mean Montgomery-Åsberg Depression Rating Scale [MADRS] total score, mean Clinical Global Impressions Severity of Illness [CGI-S] score, percentage of HAM-D-17 responders, and 3 quality of sleep items [overall quality of sleep, trouble falling asleep, and awakening during the night]). Overall effect sizes for the HAM-D-17 were -0.26 (modified ITT-last observation carried forward [LOCF] dataset) and -0.33 (PP/observed cases [OC] dataset). The effect sizes in MADRS scores were -0.22 and -0.29 for the modified ITT-LOCF and the PP/OC analyses, respectively.¹²

Sleep measures. In the study sample >90% of patients had insomnia at baseline (defined as a score ≥2 in any HAM-D-17 sleep item or sum of all 3 sleep items of ≥4). Patients receiving trazodone ER had significant improvement in all 3 HAM-D-17 sleep items. Subjects reported improvement in the overall quality of sleep and awakening during the night after the first week of treatment. Investigators found no significant interaction between improvements in core symptoms of depression and baseline MADRS reduced sleep item or early changes in the HAM-D-17 sleep items. This suggests that the antidepressant effect of trazodone ER was independent of severity of sleep difficulties at baseline and of improvement in insomnia during the study.¹²

Researchers observed improvement in suicidal ideation on MADRS (item 10) and HAM-D-17 (item 3) after 8 weeks of treatment (effect size -0.2 favoring trazodone ER over placebo).¹²

In 2 European comparative, randomized, double-blind trials, trazodone prolonged release showed similar antidepressant efficacy as paroxetine⁴ and setraline⁵ as measured by HAM-D, MADRS, and CGI-S. This prolonged release formulation made in Europe is not the same technology as the ER formulation recently approved by the FDA.

Tolerability

In the pivotal registration study, trazodone ER was well tolerated at a mean dose of 310 mg/d.¹¹ Twenty-five patients (12.4%) in the trazodone ER group discontinued the drug because of side effects. The most common side effects leading to discontinuation in the active treatment group were dizziness (n=7), sedation (n=5), and somnolence (n=3).¹¹ The most frequent adverse events reported at any study time point were headache (33%), somnolence (31%), dry mouth (25%), dizziness (25%), nausea (21%), sedation (17%), and fatigue (15%) (Table 2).¹¹ In general, these adverse events were mild to moderate and short-lived; most side effects resolved within the first 2 to 3 weeks of treatment with trazodone ER.¹¹

Sexual side effects—delayed ejaculation, delayed time to orgasm, or orgasmic blockade—are common with many anti-depressants. In the pivotal registration study, the incidence of sexual side effects was low (4.9% with trazodone ER vs 2.5% with placebo).¹¹ This is much lower than the rates typically found with selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, which range from 17% to 41%.^13,14 This benefit is thought to be mediated through 5-HT2A and 5-HT2C antagonism. Priapism has been reported in trazodone IR at rates ranging from 1 in 1,000 to 1 in 10,000 and does not appear to be dose-related.¹⁵ The rate of priapism in persons using agents for erectile dysfunction ranges from .05% to 6%.¹⁵ No case of priapism was seen in the trazodone ER study; however, with its sample size of 412 patients this study was not powered to adequately detect this adverse event.¹¹

There was no significant weight gain difference between the active drug and placebo groups over 8 weeks of treatment.

Safety. Trazodone ER should not be used within 14 days of taking a monoamine oxidase inhibitor.¹ Trazodone carries a pregnancy category C, meaning that it should be used only if the potential benefit justifies potential risk to the fetus. In animal studies, trazodone has been shown to cause increased fetal resorption and congenital anomalities with doses up to 50 times the maximum human dose (375 mg/d). Trazo-done may be secreted in breast milk. The drug is best avoided in patients with recent myocardial infarction.

Table 2

Trazodone extended release treatment-emergent adverse events*

Dosing

The recommended starting dose is 150 mg/d at bedtime. The dose may be increased by 75 mg/d every 3 days, but the maximum dose should not exceed 375 mg/d.¹ Trazodone ER is available in 150 mg or 300 mg bisectable tablets. Breaking the tablets in half does not affect the controlled release, but they should not be chewed or crushed.

Related Resource

• Extended-release trazodone (Oleptro) prescribing information. www.oleptro.com/images/9379.pdf.

Drug Brand Names

• Paroxetine • Paxil
• Ritonavir • Norvir
• Sertraline • Zoloft
• Trazodone • Desyrel
• Trazodone extended-release • Oleptro

Disclosures

Dr. Hidalgo receives grant/research support from AstraZeneca, CeNeRx Biopharma, Centers for Disease Control and Prevention, Dainippon Sumitomo Pharma America, Inc., Eli Lilly and Company, Forest Laboratories, Indevus Pharmaceuticals, Janssen Pharmaceuticals, Labopharm, Otsuka, Pfizer, Inc., Repligen Corp., Sanofi-Synthelabo, Sepracor, and the University of South Florida, and is consultant to the MAPI Institute.

Dr. Sheehan has received grant funding support from, been affiliated with, or received honoraria and travel expenses related to lectures/presentations or consultant activities from the following organizations: Abbott Laboratories,^1,2,3 Ad Hoc Committee, Treatment Drug and Assessment Research Review,¹ Alexza,¹ Alza Pharmaceuticals, Palo Alto, CA,¹ the American Medical Association,² American Psychiatric Association Task Force on Benzodiazepine Dependency,¹ American Psychiatric Association Task Force on Treatments of Psychiatric Disorders,¹ American Psychiatric Association Working Group to Revise DSM III Anxiety Disorders Section,¹ Anclote Foundation,² Anxiety Disorders Resource Center,¹ Anxiety Drug Efficacy Case, the FDA,¹ Applied Health Outcomes/Xcenda,¹ AstraZeneca,^1,2,3 Avera Pharmaceuticals,^1,2 Boehringer Ingelheim,³ Boots Pharmaceuticals,³ Bristol-Myers Squibb,^1,2,3 Burroughs Wellcome,^2,3 Cephalon,¹ Charter Hospitals,³ Ciba Geigy,³ Committee (RRC) of the National Institute for Mental Health on Anxiety and Phobic Disorder Projects,¹ Connecticut and Ohio Academies of Family Physicians,¹ Cortex Pharmaceutical,¹ Council on Anxiety Disorders,¹ CPC Coliseum Medical Center,¹ Cypress Bioscience,¹ Dista Products Company,³ Division of Drugs and Technology, American Medical Association,¹ Eisai,^1,2 Eli Lilly and Company,^2,3 Excerpta Medica Asia,³ Faxmed, Inc.,¹ Forest Laboratories,^1,2 Glaxo Pharmaceuticals,³ GlaxoSmithKline,^1,2,3 Glaxo-Wellcome,² Hospital Corporation of America,³ Humana,³ ICI,³ INC Research,¹ International Clinical Research (ICR),² International Society for CNS Drug Development (ISCDD),¹ Janssen Pharmaceuticals,^1,2,3 Jazz Pharmaceuticals,^1,2 Kali-Duphar,^2,3 Labopharm,¹ Layton Bioscience,¹ Lilly Research Laboratories,¹ Lundbeck, Denmark,¹ Marion Merrell Dow,³ McNeil Pharmaceuticals,³ Mead Johnson,^2,3 Medical Outcome Systems,⁴ MediciNova,^1,2 Merck Sharp & Dohme,^2,3 National Anxiety Awareness Program,¹ National Anxiety Foundation,¹ National Depressive and Manic Depressive Association,¹ National Institute on Drug Abuse,² National Institute of Health,² Neuronetics,¹ Novartis Pharmaceuticals Corp.,² Novo Nordisk,³ Organon,^1,3 Orion Pharma,¹ Parexel International Corporation,¹ Parke-Davis,^2,3 Pfizer, Inc.,^1,2,3 Pharmacia,¹ Pharmacia and Upjohn,^1,3 Philadelphia College of Pharmacy and Science,¹ Pierre Fabre, France,¹ Quintiles,² Rhone Laboratories,³ Rhone-Poulenc Rorer Pharmaceuticals,³ Roche,¹ Roerig,³ Sandoz Pharmaceuticals,^2,3 sanofi-aventis,^1,2,3 Sanofi-Synthelabo Recherche,^1,2 Schering Corporation,³ Sepracor,¹ Shire Laboratories, Inc.,¹ SmithKline Beecham,^1,2,3 Solvay Pharmaceuticals,^1,3 Takeda Pharmaceuticals,¹ Tampa General Hospital,¹ University of South Florida Psychiatry Center,² University of South Florida College of Medicine, TAP Pharmaceuticals,^2,3 Targacept,¹ Tampa General Hospital-University Psychiatry Center,³ Tikvah Therapeutics,¹ Titan Pharmaceuticals,¹ United Bioscience,² The Upjohn Company,^1,2,3 U.S. Congress-House of Representatives Committee,¹ University of South Florida Friends of Research in Psychiatry, Board of Trustees,¹ Warner Chilcott,^2,3 World Health Organization,¹ Worldwide Clinical Trials,² Wyeth-Ayerst,^1,2,3 ZARS,¹ and Zeneca Pharmaceuticals.1

1: Consultant; 2: Grant/Research Support; 3: Lectures/ Presentations; 4: Stock Holder

Extended-release (ER) trazodone—FDA-approved in February 2010—improves symptoms of major depressive disorder (MDD) and allows once-daily dosing (Table 1). Trazodone immediate release (IR) was developed in 1960 and approved by the FDA for treatment of MDD in December 1981. Trazodone IR is now mainly prescribed off-label as a hypnotic at lower-than-antidepressant doses, such as 50 to 100 mg/d at bedtime. The dose needed to achieve antidepressant effect is believed to be ≥300 mg/d. Use of the IR formulation for treating depression has been limited by the need for 3-times-a-day dosing and daytime sedation associated with peaks in serum concentration.

Table 1

Trazodone extended release: Fast facts

Clinical implications

Trazodone ER was designed to eliminate the peaks and troughs in serum concentration seen with trazodone IR. It was hypothesized that by reducing the maximum concentration (Cmax) peaks, trazodone ER would permit higher doses to be better tolerated and help patients to more easily reach target antidepressant doses (≥300 mg/d). Trazodone ER’s once-daily dosing also may increase patient adherence.

How it works

The exact mechanism of action through which trazodone treats depression is not completely understood, but is likely related to enhancing serotonergic activity in the CNS. Trazodone is a triazolopyridine antidepressant, inhibits the serotonin transporter, and is a 5-HT2A and 5-HT2C antagonist. This is why it is sometimes referred as a serotonin antagonist/reuptake inhibitor, but regulatory agencies do not accept this class name. Trazodone is an antagonist at both histamine (H1) and α1-adrenergic receptors, which may mediate trazodone’s sedating properties (H1) and hypotensive (α1-adrenergic) effects.

The ER formulation employs a cross-linked, high-amylose starch excipient that provides controlled release of trazodone over an extended period.

Pharmacokinetics

Trazodone ER has linear pharmacokinetics in doses from 75 to 375 mg. Trazodone ER, 300 mg/d, provides a steady-state exposure equivalent to 100 mg of trazodone IR given 3 times daily, while having a lower Cmax. A high-fat meal can increase Cmax of trazodone ER by 1.9-fold. Trazodone is extensively biotransformed in the liver via the cytochrome P450 (CYP) 3A4 pathway and its metabolites are eliminated within 72 hours. Elimination is predominantly renal, with 70% to 75% of an oral dose being recovered in the urine within 72 hours.¹ This formulation maintains its controlled-release properties if bisected.

Because trazodone is a substrate of the CYP3A4 enzyme, its metabolism can be inhibited by CYP3A4 inhibitors. Exercise caution when coadministering medications that cause CYP3A4 inhibition with trazodone ER. The effect of short-term administration of ritonavir (4 doses of 200 mg) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects.² The Cmax of trazodone increased by 34%, area under the curve increased 2.4-fold, half-life increased by 2.2-fold, and clearance decreased by 52%. There is no difference in the half-life between the IR and ER formulations because the ER formulation influences only the release kinetics of the drug, not the half-life of the medication.

Efficacy

Efficacy of trazodone for MDD initially was established in trials conducted with trazodone IR.^3-10 The efficacy of the ER formulation was established in a multi-center randomized, double-blind, placebo-controlled trial with 412 patients (age 18 to 80). Patients who met DSM-IV criteria for MDD were randomly assigned to trazodone ER (n=206) or placebo (n=206) for 8 weeks.¹¹ This study showed a statistically significant difference between trazodone ER and placebo after 8 weeks of treatment on the primary outcome measure, which was a change in score on the 17-item Hamilton Depression Rating scale (HAMD-17). HAM-D-17 scores decreased 11.4 points in the trazodone ER group and 9.3 points in the placebo group (P=.012 in the modified intent to treat [ITT] population; P=.009 in the completer analysis). This difference was seen from week 1 and throughout the study. Efficacy of trazodone ER was further supported by statistically significant differences between the drug and placebo in 7 of 13 secondary efficacy endpoints in both the modified ITT and per protocol (PP) populations (HAM-D-17 mood item, mean Montgomery-Åsberg Depression Rating Scale [MADRS] total score, mean Clinical Global Impressions Severity of Illness [CGI-S] score, percentage of HAM-D-17 responders, and 3 quality of sleep items [overall quality of sleep, trouble falling asleep, and awakening during the night]). Overall effect sizes for the HAM-D-17 were -0.26 (modified ITT-last observation carried forward [LOCF] dataset) and -0.33 (PP/observed cases [OC] dataset). The effect sizes in MADRS scores were -0.22 and -0.29 for the modified ITT-LOCF and the PP/OC analyses, respectively.¹²

Sleep measures. In the study sample >90% of patients had insomnia at baseline (defined as a score ≥2 in any HAM-D-17 sleep item or sum of all 3 sleep items of ≥4). Patients receiving trazodone ER had significant improvement in all 3 HAM-D-17 sleep items. Subjects reported improvement in the overall quality of sleep and awakening during the night after the first week of treatment. Investigators found no significant interaction between improvements in core symptoms of depression and baseline MADRS reduced sleep item or early changes in the HAM-D-17 sleep items. This suggests that the antidepressant effect of trazodone ER was independent of severity of sleep difficulties at baseline and of improvement in insomnia during the study.¹²

Researchers observed improvement in suicidal ideation on MADRS (item 10) and HAM-D-17 (item 3) after 8 weeks of treatment (effect size -0.2 favoring trazodone ER over placebo).¹²

In 2 European comparative, randomized, double-blind trials, trazodone prolonged release showed similar antidepressant efficacy as paroxetine⁴ and setraline⁵ as measured by HAM-D, MADRS, and CGI-S. This prolonged release formulation made in Europe is not the same technology as the ER formulation recently approved by the FDA.

Tolerability

In the pivotal registration study, trazodone ER was well tolerated at a mean dose of 310 mg/d.¹¹ Twenty-five patients (12.4%) in the trazodone ER group discontinued the drug because of side effects. The most common side effects leading to discontinuation in the active treatment group were dizziness (n=7), sedation (n=5), and somnolence (n=3).¹¹ The most frequent adverse events reported at any study time point were headache (33%), somnolence (31%), dry mouth (25%), dizziness (25%), nausea (21%), sedation (17%), and fatigue (15%) (Table 2).¹¹ In general, these adverse events were mild to moderate and short-lived; most side effects resolved within the first 2 to 3 weeks of treatment with trazodone ER.¹¹

Sexual side effects—delayed ejaculation, delayed time to orgasm, or orgasmic blockade—are common with many anti-depressants. In the pivotal registration study, the incidence of sexual side effects was low (4.9% with trazodone ER vs 2.5% with placebo).¹¹ This is much lower than the rates typically found with selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, which range from 17% to 41%.^13,14 This benefit is thought to be mediated through 5-HT2A and 5-HT2C antagonism. Priapism has been reported in trazodone IR at rates ranging from 1 in 1,000 to 1 in 10,000 and does not appear to be dose-related.¹⁵ The rate of priapism in persons using agents for erectile dysfunction ranges from .05% to 6%.¹⁵ No case of priapism was seen in the trazodone ER study; however, with its sample size of 412 patients this study was not powered to adequately detect this adverse event.¹¹

There was no significant weight gain difference between the active drug and placebo groups over 8 weeks of treatment.

Safety. Trazodone ER should not be used within 14 days of taking a monoamine oxidase inhibitor.¹ Trazodone carries a pregnancy category C, meaning that it should be used only if the potential benefit justifies potential risk to the fetus. In animal studies, trazodone has been shown to cause increased fetal resorption and congenital anomalities with doses up to 50 times the maximum human dose (375 mg/d). Trazo-done may be secreted in breast milk. The drug is best avoided in patients with recent myocardial infarction.

Table 2

Trazodone extended release treatment-emergent adverse events*

Dosing

The recommended starting dose is 150 mg/d at bedtime. The dose may be increased by 75 mg/d every 3 days, but the maximum dose should not exceed 375 mg/d.¹ Trazodone ER is available in 150 mg or 300 mg bisectable tablets. Breaking the tablets in half does not affect the controlled release, but they should not be chewed or crushed.

Related Resource

• Extended-release trazodone (Oleptro) prescribing information. www.oleptro.com/images/9379.pdf.

Drug Brand Names

• Paroxetine • Paxil
• Ritonavir • Norvir
• Sertraline • Zoloft
• Trazodone • Desyrel
• Trazodone extended-release • Oleptro

Disclosures

Dr. Hidalgo receives grant/research support from AstraZeneca, CeNeRx Biopharma, Centers for Disease Control and Prevention, Dainippon Sumitomo Pharma America, Inc., Eli Lilly and Company, Forest Laboratories, Indevus Pharmaceuticals, Janssen Pharmaceuticals, Labopharm, Otsuka, Pfizer, Inc., Repligen Corp., Sanofi-Synthelabo, Sepracor, and the University of South Florida, and is consultant to the MAPI Institute.

Dr. Sheehan has received grant funding support from, been affiliated with, or received honoraria and travel expenses related to lectures/presentations or consultant activities from the following organizations: Abbott Laboratories,^1,2,3 Ad Hoc Committee, Treatment Drug and Assessment Research Review,¹ Alexza,¹ Alza Pharmaceuticals, Palo Alto, CA,¹ the American Medical Association,² American Psychiatric Association Task Force on Benzodiazepine Dependency,¹ American Psychiatric Association Task Force on Treatments of Psychiatric Disorders,¹ American Psychiatric Association Working Group to Revise DSM III Anxiety Disorders Section,¹ Anclote Foundation,² Anxiety Disorders Resource Center,¹ Anxiety Drug Efficacy Case, the FDA,¹ Applied Health Outcomes/Xcenda,¹ AstraZeneca,^1,2,3 Avera Pharmaceuticals,^1,2 Boehringer Ingelheim,³ Boots Pharmaceuticals,³ Bristol-Myers Squibb,^1,2,3 Burroughs Wellcome,^2,3 Cephalon,¹ Charter Hospitals,³ Ciba Geigy,³ Committee (RRC) of the National Institute for Mental Health on Anxiety and Phobic Disorder Projects,¹ Connecticut and Ohio Academies of Family Physicians,¹ Cortex Pharmaceutical,¹ Council on Anxiety Disorders,¹ CPC Coliseum Medical Center,¹ Cypress Bioscience,¹ Dista Products Company,³ Division of Drugs and Technology, American Medical Association,¹ Eisai,^1,2 Eli Lilly and Company,^2,3 Excerpta Medica Asia,³ Faxmed, Inc.,¹ Forest Laboratories,^1,2 Glaxo Pharmaceuticals,³ GlaxoSmithKline,^1,2,3 Glaxo-Wellcome,² Hospital Corporation of America,³ Humana,³ ICI,³ INC Research,¹ International Clinical Research (ICR),² International Society for CNS Drug Development (ISCDD),¹ Janssen Pharmaceuticals,^1,2,3 Jazz Pharmaceuticals,^1,2 Kali-Duphar,^2,3 Labopharm,¹ Layton Bioscience,¹ Lilly Research Laboratories,¹ Lundbeck, Denmark,¹ Marion Merrell Dow,³ McNeil Pharmaceuticals,³ Mead Johnson,^2,3 Medical Outcome Systems,⁴ MediciNova,^1,2 Merck Sharp & Dohme,^2,3 National Anxiety Awareness Program,¹ National Anxiety Foundation,¹ National Depressive and Manic Depressive Association,¹ National Institute on Drug Abuse,² National Institute of Health,² Neuronetics,¹ Novartis Pharmaceuticals Corp.,² Novo Nordisk,³ Organon,^1,3 Orion Pharma,¹ Parexel International Corporation,¹ Parke-Davis,^2,3 Pfizer, Inc.,^1,2,3 Pharmacia,¹ Pharmacia and Upjohn,^1,3 Philadelphia College of Pharmacy and Science,¹ Pierre Fabre, France,¹ Quintiles,² Rhone Laboratories,³ Rhone-Poulenc Rorer Pharmaceuticals,³ Roche,¹ Roerig,³ Sandoz Pharmaceuticals,^2,3 sanofi-aventis,^1,2,3 Sanofi-Synthelabo Recherche,^1,2 Schering Corporation,³ Sepracor,¹ Shire Laboratories, Inc.,¹ SmithKline Beecham,^1,2,3 Solvay Pharmaceuticals,^1,3 Takeda Pharmaceuticals,¹ Tampa General Hospital,¹ University of South Florida Psychiatry Center,² University of South Florida College of Medicine, TAP Pharmaceuticals,^2,3 Targacept,¹ Tampa General Hospital-University Psychiatry Center,³ Tikvah Therapeutics,¹ Titan Pharmaceuticals,¹ United Bioscience,² The Upjohn Company,^1,2,3 U.S. Congress-House of Representatives Committee,¹ University of South Florida Friends of Research in Psychiatry, Board of Trustees,¹ Warner Chilcott,^2,3 World Health Organization,¹ Worldwide Clinical Trials,² Wyeth-Ayerst,^1,2,3 ZARS,¹ and Zeneca Pharmaceuticals.1

1: Consultant; 2: Grant/Research Support; 3: Lectures/ Presentations; 4: Stock Holder

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

• dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
• dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),¹ which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.¹

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.²

Table 2

Asenapine’s binding affinity for receptor subtypes*

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.³

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.^3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.^3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.^3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.^3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.

Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.^3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.

In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.

Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.¹⁰

Tolerability in clinical trials

Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:¹¹

• 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
• 486 subjects were treated for at least 24 weeks
• 293 subjects were treated for at least 52 weeks.

Overall, asenapine was well tolerated (Table 3).¹¹ The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.

Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.

Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.

In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.³ Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.

In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.³ In both groups, the greatest weight increase occurred in subjects with body mass index <23.

There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.

Table 3

Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo

Contraindications

There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:

• women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
• breast-feeding mothers
• patients with severe hepatic impairment (Child-Pugh C).

Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.

Because asenapine is associated with QT prolongation, do not administer it with other QT-prolonging agents, such as procainamide, sotalol, quinidine, erythromycin, clarithromycin, methadone, or other antipsychotics.

Dosing

Asenapine is manufactured as 5-mg and 10-mg sublingual tablets. Advise patients to avoid eating or drinking for 10 minutes after taking asenapine.

The recommended starting and target dosage for patients with schizophrenia is 5 mg twice daily. The recommended starting dosage for patients with an acute mixed or manic episode of bipolar I disorder is 10 mg twice daily; however, this can be reduced to 5 mg twice daily if the patient experiences intolerable side effects.

Related resource

• Asenapine (Saphris) prescribing information. www.spfiles.com/pisaphrisv1.pdf.

Drug brand names

• Asenapine • Saphris
• Clarithromycin • Biaxin
• Clozapine • Clozaril
• Erythromycin • ERY-C, Ery-Tab
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Procainamide • Procanbid
• Quinidine • Quinidine
• Risperidone • Risperdal
• Sotalol • Betapace, Sorine

Disclosures

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

Dr. Preskorn receives grant/research support from AstraZeneca, Biovail, Boehringer-Ingleheim, Cyberonics, Eli Lilly and Company, EnVivo, GlaxoSmithKline, UNC Chapel Hill, and Wyeth. He is a consultant to Allergan, Covidien, Eli Lilly and Company, Evotec, Lundbeck/Takeda, Transcept, and Wyeth.

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

• dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
• dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),¹ which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.¹

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.²

Table 2

Asenapine’s binding affinity for receptor subtypes*

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.³

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.^3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.^3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.^3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.^3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.

Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.^3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.

In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.

Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.¹⁰

Tolerability in clinical trials

Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:¹¹

• 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
• 486 subjects were treated for at least 24 weeks
• 293 subjects were treated for at least 52 weeks.

Overall, asenapine was well tolerated (Table 3).¹¹ The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.

Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.

Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.

In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.³ Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.

In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.³ In both groups, the greatest weight increase occurred in subjects with body mass index <23.

There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.

Table 3

Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo

Contraindications

There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:

• women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
• breast-feeding mothers
• patients with severe hepatic impairment (Child-Pugh C).

Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.

Because asenapine is associated with QT prolongation, do not administer it with other QT-prolonging agents, such as procainamide, sotalol, quinidine, erythromycin, clarithromycin, methadone, or other antipsychotics.

Dosing

Asenapine is manufactured as 5-mg and 10-mg sublingual tablets. Advise patients to avoid eating or drinking for 10 minutes after taking asenapine.

The recommended starting and target dosage for patients with schizophrenia is 5 mg twice daily. The recommended starting dosage for patients with an acute mixed or manic episode of bipolar I disorder is 10 mg twice daily; however, this can be reduced to 5 mg twice daily if the patient experiences intolerable side effects.

Related resource

• Asenapine (Saphris) prescribing information. www.spfiles.com/pisaphrisv1.pdf.

Drug brand names

• Asenapine • Saphris
• Clarithromycin • Biaxin
• Clozapine • Clozaril
• Erythromycin • ERY-C, Ery-Tab
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Procainamide • Procanbid
• Quinidine • Quinidine
• Risperidone • Risperdal
• Sotalol • Betapace, Sorine

Disclosures

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

Dr. Preskorn receives grant/research support from AstraZeneca, Biovail, Boehringer-Ingleheim, Cyberonics, Eli Lilly and Company, EnVivo, GlaxoSmithKline, UNC Chapel Hill, and Wyeth. He is a consultant to Allergan, Covidien, Eli Lilly and Company, Evotec, Lundbeck/Takeda, Transcept, and Wyeth.

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

• dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
• dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),¹ which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.¹

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.²

Table 2

Asenapine’s binding affinity for receptor subtypes*

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.³

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.^3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.^3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.^3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.^3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.

Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.^3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.

In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.

Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.¹⁰

Tolerability in clinical trials

Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:¹¹

• 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
• 486 subjects were treated for at least 24 weeks
• 293 subjects were treated for at least 52 weeks.

Overall, asenapine was well tolerated (Table 3).¹¹ The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.

Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.

Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.

In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.³ Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.

In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.³ In both groups, the greatest weight increase occurred in subjects with body mass index <23.

There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.

Table 3

Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo

Contraindications

There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:

• women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
• breast-feeding mothers
• patients with severe hepatic impairment (Child-Pugh C).

Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.

Because asenapine is associated with QT prolongation, do not administer it with other QT-prolonging agents, such as procainamide, sotalol, quinidine, erythromycin, clarithromycin, methadone, or other antipsychotics.

Dosing

Asenapine is manufactured as 5-mg and 10-mg sublingual tablets. Advise patients to avoid eating or drinking for 10 minutes after taking asenapine.

The recommended starting and target dosage for patients with schizophrenia is 5 mg twice daily. The recommended starting dosage for patients with an acute mixed or manic episode of bipolar I disorder is 10 mg twice daily; however, this can be reduced to 5 mg twice daily if the patient experiences intolerable side effects.

Related resource

• Asenapine (Saphris) prescribing information. www.spfiles.com/pisaphrisv1.pdf.

Drug brand names

• Asenapine • Saphris
• Clarithromycin • Biaxin
• Clozapine • Clozaril
• Erythromycin • ERY-C, Ery-Tab
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Procainamide • Procanbid
• Quinidine • Quinidine
• Risperidone • Risperdal
• Sotalol • Betapace, Sorine

Disclosures

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

Dr. Preskorn receives grant/research support from AstraZeneca, Biovail, Boehringer-Ingleheim, Cyberonics, Eli Lilly and Company, EnVivo, GlaxoSmithKline, UNC Chapel Hill, and Wyeth. He is a consultant to Allergan, Covidien, Eli Lilly and Company, Evotec, Lundbeck/Takeda, Transcept, and Wyeth.

Iloperidone is a second-generation (atypical) antipsychotic the FDA approved in May 2009 for treating acute schizophrenia in adults (Table 1). Iloperidone is not a derivative (metabolite, isomer, or different formulation) of any other antipsychotic. Clinical trials have shown that iloperidone is efficacious and suggest that for some patients its side-effect profile may be more favorable than that of other antipsychotics.

Table 1

Iloperidone: Fast facts

Clinical implications

Iloperidone’s binding profile is similar to that of other antipsychotics with relatively stronger affinity for serotonin (5-HT2A) than dopamine (D2) receptors, and its efficacy is roughly comparable to that of other non-clozapine antipsychotics.

Individual patients may respond differently to specific antipsychotics, even when those agents have shown equivalent efficacy in clinical trials. Therefore, a key therapeutic question is the degree of differential efficacy—differences in response at an individual level—among iloperidone and other antipsychotics.

The differential efficacy among iloperidone and other antipsychotics is unknown. Our clinical experience and iloperidone’s unique structure suggest, however, that this agent might be helpful for certain patients who do not fully respond to or are unable to tolerate other antipsychotics.

How iloperidone works

Like other antipsychotics, iloperidone’s efficacy presumably is based on its ability to block [antagonize] dopamine D2 receptors. Its chemical structure is most similar to risperidone, paliperidone, and ziprasidone, but its receptor binding profile is distinguished by a relatively lower affinity for serotonin receptors 5-HT1A and 5-HT2C than ziprasidone, and a relative lack of muscarinic and histaminic antagonist properties (Table 2).

The relatively higher affinity of iloperidone (and its metabolite P95) for the NEα1 receptor correlates with the drug’s propensity to cause orthostatic hypotension during initial up-titration.¹ Differences in iloperidone’s receptor binding profile compared with other antipsychotics likely are responsible for its different side-effect profile.^2,3

Table 2

Relative receptor binding affinities of 3 atypical antipsychotics*

Pharmacokinetics

Iloperidone is administered twice daily and can be taken with or without food. The bioavailability of iloperidone tablets is 96%, and peak plasma concentrations are achieved 2 to 4 hours after ingestion.

Like all antipsychotics except paliperidone, iloperidone is metabolized by the liver’s cytochrome P450 (CYP) system. The enzyme pathways CYP3A4 and CYP2D6 transform iloperidone into 2 metabolites: one with CNS activity (P88) and one that does not cross the blood-brain barrier and is not active in the CNS (P95) but likely has peripheral effects.

Genetic variations in CYP2D6 activity can substantially alter how individual patients metabolize iloperidone. The half-life of iloperidone and its active metabolites differs depending on whether someone is a poor metabolizer (no functional CYP2D6 activity), intermediate metabolizer (reduced CYP2D6 activity), or extensive metabolizer (“normal” CYP2D6 activity). The usual half-life of iloperidone (approximately 18 hours in extensive metabolizers) can be almost 50% longer (>24 hours) in CYP2D6 poor metabolizers.

There are no recommendations to test patients for genetic variants that result in poor metabolism from CYP2D6. Rather, clinicians simply need to be aware that this could be the source of interindividual differences they see in iloperidone tolerability, just as it is for any other medication that is a substrate for the CYP2D6 enzyme system.

Interactions. Medications that inhibit the CYP3A4 or CYP2D6 systems can increase iloperidone plasma level when taken concurrently with iloperidone, even if intrinsic liver metabolism activity is normal. Fluoxetine and paroxetine are potent CYP2D6 inhibitors. Concurrent treatment with either of these selective serotonin reuptake inhibitors could increase iloperidone plasma concentration by 100% or more.⁴

Similarly, cotreatment with a potent CYP3A4 inhibitor such as ketoconazole (or drinking grapefruit juice) will decrease metabolism and increase plasma concentrations of iloperidone and its active metabolites by about 50%. Smoking status should not influence iloperidone plasma concentration because this drug is not a primary substrate for CYP1A2, the enzyme induced by cigarette smoking.

The bottom line: reduce iloperidone dosage by 50% for patients who are taking a strong CYP2D6 and/or CYP3A4 inhibitor (see Dosing below).

Efficacy

In clinical trials, iloperidone was shown to be efficacious in treating positive and negative symptoms and general psychopathology in acute episodes of schizophrenia. It is important to consider the efficacy studies of iloperidone within the context of the history of its development plan.

Early clinical trials. Most of iloperidone’s phase II and III studies were conducted by Novartis between 1998 and 2002. Initial phase III studies included three 6-week, double-blind, placebo-controlled acute trials comparing a range of iloperidone doses with placebo and an active comparator:^5,6

• The first trial compared iloperidone, 4, 8, or 12 mg/d, with placebo or haloperidol, 15 mg/d.
• The second compared iloperidone, 4 to 8 mg/d or 10 to 16 mg/d, with placebo and risperidone, 4 to 8 mg/d.
• The third compared iloperidone, 12 to 16 mg/d or 20 to 24 mg/d, with placebo or risperidone, 6 to 8 mg/d.

These studies totaled 1,066 patients in the iloperidone treatment arms, with target dosages for iloperidone ranging from 4 to 24 mg/d. Iloperidone was more efficacious than placebo for positive, negative, and overall total symptoms on the Positive and Negative Syndrome Scale (PANSS), albeit 4 mg/d and 8 mg/d dosages narrowly missed the .05 significance level.

The haloperidol and risperidone active controls appeared more effective than iloperidone in the original analyses, but these studies were not designed for analysis of comparative efficacy. The protocols for all of these studies used an up-titration schedule for the iloperidone groups that took 1 week to reach steady-state levels, whereas the haloperidol and risperidone groups had a briefer up-titration to target dose.

The interpretation of these studies is complex and a detailed discussion is beyond the scope of this article. However, a post-hoc analysis that included subjects who remained in the study after 2 weeks of double-blind medication showed that iloperidone performed comparably to risperidone⁷ and haloperidol.⁸

A new phase III trial. The question remained whether iloperidone was as efficacious as other first-line antipsychotics but had been “penalized” by its slower up-titration schedule and clinical trial design flaws. After acquiring the development rights to iloperidone from Novartis and reviewing prior study designs and results, Vanda Pharmaceuticals designed another phase III study comparing iloperidone with placebo and ziprasidone. Its purpose was to correct for possible design flaws in the previous studies.

Ziprasidone was selected as the active control because of its established efficacy, safety, and twice-daily dosing. In this trial, researchers attempted to match the 2 drugs’ up-titration schedules. Twice-daily doses were given with food as follows:

• iloperidone, 1, 2, 4, 6, 8, 10, and 12 mg (days 1 to 7, respectively)
• ziprasidone, 20 mg (days 1 to 2), 40 mg (days 3 to 4), 60 mg (days 5 to 6), and 80 mg (day 7).

By day 7, target dosages were reached: iloperidone, 24 mg/d, and ziprasidone, 160 mg/d.⁹

Patients receiving iloperidone showed significantly greater improvement in PANSS total scores at 4 weeks vs those receiving placebo (–12.0, iloperidone; –7.1, placebo; P < .01).⁹ Patients receiving ziprasidone also achieved significantly greater improvement vs those receiving placebo (–12.3; P < .05 vs placebo).

The iloperidone and ziprasidone groups showed significantly greater improvement from baseline vs placebo in PANSS positive (P) and negative (N) subscale scores. Significantly more patients receiving iloperidone (72%) than placebo (52%) experienced improvement (≥20% reduction from baseline) in PANSS-P scores (P = .005).

Patients receiving iloperidone had a significantly greater reduction in Clinical Global Impression-Severity scale score vs placebo (–0.65 and –0.39, respectively; P = .007), as did patients receiving ziprasidone (–0.67; P = .013).

Iloperidone met all predefined protocol criteria for efficacy vs placebo and had efficacy equal to the highest approved dose of ziprasidone. These results demonstrated that iloperidone has comparable efficacy to ziprasidone and support the validity of the re-analysis of earlier studies showing comparable efficacy between iloperidone and risperidone⁷ or haloperidol.⁸ In July 2008 the FDA issued a not approvable letter for iloperidone, requesting further clinical trials because of concerns about the drug’s efficacy compared with risperidone. The FDA approved iloperidone in May 2009 after the manufacturer provided additional data from existing trials that demonstrated comparable efficacy to risperidone.

Long-term efficacy. A double-blind extension study compared patients remaining on blinded iloperidone (4 to 16 mg/d) or haloperidol (5 to 20 mg/d) after completing a 6-week efficacy study.¹⁰ The drugs showed equivalent efficacy in preventing relapse over 46 weeks follow-up. Because this study included no placebo group, the FDA does not consider it to be an interpretable relapse prevention study.

Tolerability

Clinicians might consider iloperidone when seeking to switch a patient to an antipsychotic with a potentially lower side-effect burden.^6,11 Compared with risperidone, iloperidone has a lower liability for extrapyramidal symptoms (EPS) and does not cause clinically significant prolactin elevation (Table 3).^5,7-9 Compared with ziprasidone, iloperidone has a lower EPS and akathisia liability. Somewhat greater weight gain was seen with iloperidone when compared with ziprasidone in a 4-week study (iloperidone, +2.8 kg; ziprasidone, +1.1 kg; placebo, +0.5 kg) but the 2 drugs’ effects on triglycerides and cholesterol were comparable.⁹

Iloperidone has a similar degree of QTc prolongation as ziprasidone (mean 9 msec at the highest dosage of 12 mg bid). Safety studies including administration of maximal doses of iloperidone with CYP3A4 and CYP2D6 inhibitors showed a mean QTc prolongation of 19 msec without clinically significant problems, and iloperidone has not been associated with serious arrhythmia.⁴ Iloperidone should not be prescribed to patients with significant cardiac problems or electrolyte disturbances, however, or those taking drugs known to have clinically significant QTc/proarrhythmic properties, such as thioridazine, droperidol, pimozide, or methadone.⁴

Iloperidone has the same safety concerns associated with other atypical antipsychotics, including tardive dyskinesia and neuroleptic malignant syndrome. Like other atypical antipsychotics, iloperidone carries a warning of increased mortality risk in elderly patients with dementia-related psychosis.

Dose-related side effects include dizziness, orthostatic hypotension, and tachycardia. Dizziness occurred more often at higher doses (20% at 20 to 24 mg/d vs 10% at 10 to 16 mg/d vs 7% in placebo groups). Presumably these side effects are related to NEα1 antagonism and are the basis for the recommended dose-titration schedule described below. Clinical trials do not seem to demonstrate a dose-response relationship for acute EPS or akathisia.

Table 3

Common side effects: Iloperidone vs other antipsychotics*

Dosing

The approved dosage range for iloperidone is 12 to 24 mg/d, given as 6 to 12 mg bid. Some trials suggest a dose-response relationship, with 24 mg being more effective than lower target doses.⁵ Reduce the target dosage of iloperidone by one-half when administering it concomitantly with medications that are strong CYP2D6 or CYP3A4 inhibitors.

Titration schedule. Because iloperidone’s relatively strong NEα1 antagonism creates risk for initial orthostatic hypotension, the drug needs to be titrated to the target dose over 4 to 7 days:

• 1 mg bid at day 1
• 2 mg bid at day 2
• 4 mg bid at day 3
• 6 mg bid at day 4 (for a target dosage of 12 mg/d)
• 8 mg bid at day 5
• 10 mg bid at day 6
• 12 mg bid at day 7 (for a target dosage of 24 mg/d).

Monitor patients for dose adjustments based on clinical status, concomitant use of other medications (including antipsychotics), and tolerability of up-titration.

The need to titrate iloperidone slowly to reach efficacious acute antipsychotic doses may lead to delayed effectiveness compared with antipsychotics that can be started at therapeutic doses. This problem also may be seen with up-titration of other agents with strong NEα1 properties, including chlorpromazine, clozapine, quetiapine, and risperidone, and should be considered when treating patients who need rapid dose escalation.

Related resource

• Iloperidone (Fanapt) prescribing information. www.fanapt.com/fanapt-pi-may09.pdf.

Drug brand names

• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Droperidol • Inapsine
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Ketoconazole • Nizoral
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Paroxetine • Paxil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone • Geodon

Disclosures

Dr. Weiden receives research support from the National Institute of Mental Health and Ortho-McNeil Janssen. He is a consultant to AstraZeneca, Bristol-Myers Squibb/Otsuka America Pharmaceutical, Eli Lilly and Company, Forest, Ortho-McNeil Janssen, Pfizer Inc., Schering-Plough, Vanda, and Wyeth, and a speaker for Ortho-McNeil Janssen and Pfizer Inc.

Dr. Bishop receives research/grant support from the National Institute of Mental Health, NARSAD, and Ortho-McNeil Janssen.

Iloperidone is a second-generation (atypical) antipsychotic the FDA approved in May 2009 for treating acute schizophrenia in adults (Table 1). Iloperidone is not a derivative (metabolite, isomer, or different formulation) of any other antipsychotic. Clinical trials have shown that iloperidone is efficacious and suggest that for some patients its side-effect profile may be more favorable than that of other antipsychotics.

Table 1

Iloperidone: Fast facts

Clinical implications

Iloperidone’s binding profile is similar to that of other antipsychotics with relatively stronger affinity for serotonin (5-HT2A) than dopamine (D2) receptors, and its efficacy is roughly comparable to that of other non-clozapine antipsychotics.

Individual patients may respond differently to specific antipsychotics, even when those agents have shown equivalent efficacy in clinical trials. Therefore, a key therapeutic question is the degree of differential efficacy—differences in response at an individual level—among iloperidone and other antipsychotics.

The differential efficacy among iloperidone and other antipsychotics is unknown. Our clinical experience and iloperidone’s unique structure suggest, however, that this agent might be helpful for certain patients who do not fully respond to or are unable to tolerate other antipsychotics.

How iloperidone works

Like other antipsychotics, iloperidone’s efficacy presumably is based on its ability to block [antagonize] dopamine D2 receptors. Its chemical structure is most similar to risperidone, paliperidone, and ziprasidone, but its receptor binding profile is distinguished by a relatively lower affinity for serotonin receptors 5-HT1A and 5-HT2C than ziprasidone, and a relative lack of muscarinic and histaminic antagonist properties (Table 2).

The relatively higher affinity of iloperidone (and its metabolite P95) for the NEα1 receptor correlates with the drug’s propensity to cause orthostatic hypotension during initial up-titration.¹ Differences in iloperidone’s receptor binding profile compared with other antipsychotics likely are responsible for its different side-effect profile.^2,3

Table 2

Relative receptor binding affinities of 3 atypical antipsychotics*

Pharmacokinetics

Iloperidone is administered twice daily and can be taken with or without food. The bioavailability of iloperidone tablets is 96%, and peak plasma concentrations are achieved 2 to 4 hours after ingestion.

Like all antipsychotics except paliperidone, iloperidone is metabolized by the liver’s cytochrome P450 (CYP) system. The enzyme pathways CYP3A4 and CYP2D6 transform iloperidone into 2 metabolites: one with CNS activity (P88) and one that does not cross the blood-brain barrier and is not active in the CNS (P95) but likely has peripheral effects.

Genetic variations in CYP2D6 activity can substantially alter how individual patients metabolize iloperidone. The half-life of iloperidone and its active metabolites differs depending on whether someone is a poor metabolizer (no functional CYP2D6 activity), intermediate metabolizer (reduced CYP2D6 activity), or extensive metabolizer (“normal” CYP2D6 activity). The usual half-life of iloperidone (approximately 18 hours in extensive metabolizers) can be almost 50% longer (>24 hours) in CYP2D6 poor metabolizers.

There are no recommendations to test patients for genetic variants that result in poor metabolism from CYP2D6. Rather, clinicians simply need to be aware that this could be the source of interindividual differences they see in iloperidone tolerability, just as it is for any other medication that is a substrate for the CYP2D6 enzyme system.

Interactions. Medications that inhibit the CYP3A4 or CYP2D6 systems can increase iloperidone plasma level when taken concurrently with iloperidone, even if intrinsic liver metabolism activity is normal. Fluoxetine and paroxetine are potent CYP2D6 inhibitors. Concurrent treatment with either of these selective serotonin reuptake inhibitors could increase iloperidone plasma concentration by 100% or more.⁴

Similarly, cotreatment with a potent CYP3A4 inhibitor such as ketoconazole (or drinking grapefruit juice) will decrease metabolism and increase plasma concentrations of iloperidone and its active metabolites by about 50%. Smoking status should not influence iloperidone plasma concentration because this drug is not a primary substrate for CYP1A2, the enzyme induced by cigarette smoking.

The bottom line: reduce iloperidone dosage by 50% for patients who are taking a strong CYP2D6 and/or CYP3A4 inhibitor (see Dosing below).

Efficacy

In clinical trials, iloperidone was shown to be efficacious in treating positive and negative symptoms and general psychopathology in acute episodes of schizophrenia. It is important to consider the efficacy studies of iloperidone within the context of the history of its development plan.

Early clinical trials. Most of iloperidone’s phase II and III studies were conducted by Novartis between 1998 and 2002. Initial phase III studies included three 6-week, double-blind, placebo-controlled acute trials comparing a range of iloperidone doses with placebo and an active comparator:^5,6

• The first trial compared iloperidone, 4, 8, or 12 mg/d, with placebo or haloperidol, 15 mg/d.
• The second compared iloperidone, 4 to 8 mg/d or 10 to 16 mg/d, with placebo and risperidone, 4 to 8 mg/d.
• The third compared iloperidone, 12 to 16 mg/d or 20 to 24 mg/d, with placebo or risperidone, 6 to 8 mg/d.

These studies totaled 1,066 patients in the iloperidone treatment arms, with target dosages for iloperidone ranging from 4 to 24 mg/d. Iloperidone was more efficacious than placebo for positive, negative, and overall total symptoms on the Positive and Negative Syndrome Scale (PANSS), albeit 4 mg/d and 8 mg/d dosages narrowly missed the .05 significance level.

The haloperidol and risperidone active controls appeared more effective than iloperidone in the original analyses, but these studies were not designed for analysis of comparative efficacy. The protocols for all of these studies used an up-titration schedule for the iloperidone groups that took 1 week to reach steady-state levels, whereas the haloperidol and risperidone groups had a briefer up-titration to target dose.

The interpretation of these studies is complex and a detailed discussion is beyond the scope of this article. However, a post-hoc analysis that included subjects who remained in the study after 2 weeks of double-blind medication showed that iloperidone performed comparably to risperidone⁷ and haloperidol.⁸

A new phase III trial. The question remained whether iloperidone was as efficacious as other first-line antipsychotics but had been “penalized” by its slower up-titration schedule and clinical trial design flaws. After acquiring the development rights to iloperidone from Novartis and reviewing prior study designs and results, Vanda Pharmaceuticals designed another phase III study comparing iloperidone with placebo and ziprasidone. Its purpose was to correct for possible design flaws in the previous studies.

Ziprasidone was selected as the active control because of its established efficacy, safety, and twice-daily dosing. In this trial, researchers attempted to match the 2 drugs’ up-titration schedules. Twice-daily doses were given with food as follows:

• iloperidone, 1, 2, 4, 6, 8, 10, and 12 mg (days 1 to 7, respectively)
• ziprasidone, 20 mg (days 1 to 2), 40 mg (days 3 to 4), 60 mg (days 5 to 6), and 80 mg (day 7).

By day 7, target dosages were reached: iloperidone, 24 mg/d, and ziprasidone, 160 mg/d.⁹

Patients receiving iloperidone showed significantly greater improvement in PANSS total scores at 4 weeks vs those receiving placebo (–12.0, iloperidone; –7.1, placebo; P < .01).⁹ Patients receiving ziprasidone also achieved significantly greater improvement vs those receiving placebo (–12.3; P < .05 vs placebo).

The iloperidone and ziprasidone groups showed significantly greater improvement from baseline vs placebo in PANSS positive (P) and negative (N) subscale scores. Significantly more patients receiving iloperidone (72%) than placebo (52%) experienced improvement (≥20% reduction from baseline) in PANSS-P scores (P = .005).

Patients receiving iloperidone had a significantly greater reduction in Clinical Global Impression-Severity scale score vs placebo (–0.65 and –0.39, respectively; P = .007), as did patients receiving ziprasidone (–0.67; P = .013).

Iloperidone met all predefined protocol criteria for efficacy vs placebo and had efficacy equal to the highest approved dose of ziprasidone. These results demonstrated that iloperidone has comparable efficacy to ziprasidone and support the validity of the re-analysis of earlier studies showing comparable efficacy between iloperidone and risperidone⁷ or haloperidol.⁸ In July 2008 the FDA issued a not approvable letter for iloperidone, requesting further clinical trials because of concerns about the drug’s efficacy compared with risperidone. The FDA approved iloperidone in May 2009 after the manufacturer provided additional data from existing trials that demonstrated comparable efficacy to risperidone.

Long-term efficacy. A double-blind extension study compared patients remaining on blinded iloperidone (4 to 16 mg/d) or haloperidol (5 to 20 mg/d) after completing a 6-week efficacy study.¹⁰ The drugs showed equivalent efficacy in preventing relapse over 46 weeks follow-up. Because this study included no placebo group, the FDA does not consider it to be an interpretable relapse prevention study.

Tolerability

Clinicians might consider iloperidone when seeking to switch a patient to an antipsychotic with a potentially lower side-effect burden.^6,11 Compared with risperidone, iloperidone has a lower liability for extrapyramidal symptoms (EPS) and does not cause clinically significant prolactin elevation (Table 3).^5,7-9 Compared with ziprasidone, iloperidone has a lower EPS and akathisia liability. Somewhat greater weight gain was seen with iloperidone when compared with ziprasidone in a 4-week study (iloperidone, +2.8 kg; ziprasidone, +1.1 kg; placebo, +0.5 kg) but the 2 drugs’ effects on triglycerides and cholesterol were comparable.⁹

Iloperidone has a similar degree of QTc prolongation as ziprasidone (mean 9 msec at the highest dosage of 12 mg bid). Safety studies including administration of maximal doses of iloperidone with CYP3A4 and CYP2D6 inhibitors showed a mean QTc prolongation of 19 msec without clinically significant problems, and iloperidone has not been associated with serious arrhythmia.⁴ Iloperidone should not be prescribed to patients with significant cardiac problems or electrolyte disturbances, however, or those taking drugs known to have clinically significant QTc/proarrhythmic properties, such as thioridazine, droperidol, pimozide, or methadone.⁴

Iloperidone has the same safety concerns associated with other atypical antipsychotics, including tardive dyskinesia and neuroleptic malignant syndrome. Like other atypical antipsychotics, iloperidone carries a warning of increased mortality risk in elderly patients with dementia-related psychosis.

Dose-related side effects include dizziness, orthostatic hypotension, and tachycardia. Dizziness occurred more often at higher doses (20% at 20 to 24 mg/d vs 10% at 10 to 16 mg/d vs 7% in placebo groups). Presumably these side effects are related to NEα1 antagonism and are the basis for the recommended dose-titration schedule described below. Clinical trials do not seem to demonstrate a dose-response relationship for acute EPS or akathisia.

Table 3

Common side effects: Iloperidone vs other antipsychotics*

Dosing

The approved dosage range for iloperidone is 12 to 24 mg/d, given as 6 to 12 mg bid. Some trials suggest a dose-response relationship, with 24 mg being more effective than lower target doses.⁵ Reduce the target dosage of iloperidone by one-half when administering it concomitantly with medications that are strong CYP2D6 or CYP3A4 inhibitors.

Titration schedule. Because iloperidone’s relatively strong NEα1 antagonism creates risk for initial orthostatic hypotension, the drug needs to be titrated to the target dose over 4 to 7 days:

• 1 mg bid at day 1
• 2 mg bid at day 2
• 4 mg bid at day 3
• 6 mg bid at day 4 (for a target dosage of 12 mg/d)
• 8 mg bid at day 5
• 10 mg bid at day 6
• 12 mg bid at day 7 (for a target dosage of 24 mg/d).

Monitor patients for dose adjustments based on clinical status, concomitant use of other medications (including antipsychotics), and tolerability of up-titration.

The need to titrate iloperidone slowly to reach efficacious acute antipsychotic doses may lead to delayed effectiveness compared with antipsychotics that can be started at therapeutic doses. This problem also may be seen with up-titration of other agents with strong NEα1 properties, including chlorpromazine, clozapine, quetiapine, and risperidone, and should be considered when treating patients who need rapid dose escalation.

Related resource

• Iloperidone (Fanapt) prescribing information. www.fanapt.com/fanapt-pi-may09.pdf.

Drug brand names

• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Droperidol • Inapsine
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Ketoconazole • Nizoral
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Paroxetine • Paxil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone • Geodon

Disclosures

Dr. Weiden receives research support from the National Institute of Mental Health and Ortho-McNeil Janssen. He is a consultant to AstraZeneca, Bristol-Myers Squibb/Otsuka America Pharmaceutical, Eli Lilly and Company, Forest, Ortho-McNeil Janssen, Pfizer Inc., Schering-Plough, Vanda, and Wyeth, and a speaker for Ortho-McNeil Janssen and Pfizer Inc.

Dr. Bishop receives research/grant support from the National Institute of Mental Health, NARSAD, and Ortho-McNeil Janssen.

Iloperidone is a second-generation (atypical) antipsychotic the FDA approved in May 2009 for treating acute schizophrenia in adults (Table 1). Iloperidone is not a derivative (metabolite, isomer, or different formulation) of any other antipsychotic. Clinical trials have shown that iloperidone is efficacious and suggest that for some patients its side-effect profile may be more favorable than that of other antipsychotics.

Table 1

Iloperidone: Fast facts

Clinical implications

Iloperidone’s binding profile is similar to that of other antipsychotics with relatively stronger affinity for serotonin (5-HT2A) than dopamine (D2) receptors, and its efficacy is roughly comparable to that of other non-clozapine antipsychotics.

Individual patients may respond differently to specific antipsychotics, even when those agents have shown equivalent efficacy in clinical trials. Therefore, a key therapeutic question is the degree of differential efficacy—differences in response at an individual level—among iloperidone and other antipsychotics.

The differential efficacy among iloperidone and other antipsychotics is unknown. Our clinical experience and iloperidone’s unique structure suggest, however, that this agent might be helpful for certain patients who do not fully respond to or are unable to tolerate other antipsychotics.

How iloperidone works

Like other antipsychotics, iloperidone’s efficacy presumably is based on its ability to block [antagonize] dopamine D2 receptors. Its chemical structure is most similar to risperidone, paliperidone, and ziprasidone, but its receptor binding profile is distinguished by a relatively lower affinity for serotonin receptors 5-HT1A and 5-HT2C than ziprasidone, and a relative lack of muscarinic and histaminic antagonist properties (Table 2).

The relatively higher affinity of iloperidone (and its metabolite P95) for the NEα1 receptor correlates with the drug’s propensity to cause orthostatic hypotension during initial up-titration.¹ Differences in iloperidone’s receptor binding profile compared with other antipsychotics likely are responsible for its different side-effect profile.^2,3

Table 2

Relative receptor binding affinities of 3 atypical antipsychotics*

Pharmacokinetics

Iloperidone is administered twice daily and can be taken with or without food. The bioavailability of iloperidone tablets is 96%, and peak plasma concentrations are achieved 2 to 4 hours after ingestion.

Like all antipsychotics except paliperidone, iloperidone is metabolized by the liver’s cytochrome P450 (CYP) system. The enzyme pathways CYP3A4 and CYP2D6 transform iloperidone into 2 metabolites: one with CNS activity (P88) and one that does not cross the blood-brain barrier and is not active in the CNS (P95) but likely has peripheral effects.

Genetic variations in CYP2D6 activity can substantially alter how individual patients metabolize iloperidone. The half-life of iloperidone and its active metabolites differs depending on whether someone is a poor metabolizer (no functional CYP2D6 activity), intermediate metabolizer (reduced CYP2D6 activity), or extensive metabolizer (“normal” CYP2D6 activity). The usual half-life of iloperidone (approximately 18 hours in extensive metabolizers) can be almost 50% longer (>24 hours) in CYP2D6 poor metabolizers.

There are no recommendations to test patients for genetic variants that result in poor metabolism from CYP2D6. Rather, clinicians simply need to be aware that this could be the source of interindividual differences they see in iloperidone tolerability, just as it is for any other medication that is a substrate for the CYP2D6 enzyme system.

Interactions. Medications that inhibit the CYP3A4 or CYP2D6 systems can increase iloperidone plasma level when taken concurrently with iloperidone, even if intrinsic liver metabolism activity is normal. Fluoxetine and paroxetine are potent CYP2D6 inhibitors. Concurrent treatment with either of these selective serotonin reuptake inhibitors could increase iloperidone plasma concentration by 100% or more.⁴

Similarly, cotreatment with a potent CYP3A4 inhibitor such as ketoconazole (or drinking grapefruit juice) will decrease metabolism and increase plasma concentrations of iloperidone and its active metabolites by about 50%. Smoking status should not influence iloperidone plasma concentration because this drug is not a primary substrate for CYP1A2, the enzyme induced by cigarette smoking.

The bottom line: reduce iloperidone dosage by 50% for patients who are taking a strong CYP2D6 and/or CYP3A4 inhibitor (see Dosing below).

Efficacy

In clinical trials, iloperidone was shown to be efficacious in treating positive and negative symptoms and general psychopathology in acute episodes of schizophrenia. It is important to consider the efficacy studies of iloperidone within the context of the history of its development plan.

Early clinical trials. Most of iloperidone’s phase II and III studies were conducted by Novartis between 1998 and 2002. Initial phase III studies included three 6-week, double-blind, placebo-controlled acute trials comparing a range of iloperidone doses with placebo and an active comparator:^5,6

• The first trial compared iloperidone, 4, 8, or 12 mg/d, with placebo or haloperidol, 15 mg/d.
• The second compared iloperidone, 4 to 8 mg/d or 10 to 16 mg/d, with placebo and risperidone, 4 to 8 mg/d.
• The third compared iloperidone, 12 to 16 mg/d or 20 to 24 mg/d, with placebo or risperidone, 6 to 8 mg/d.

These studies totaled 1,066 patients in the iloperidone treatment arms, with target dosages for iloperidone ranging from 4 to 24 mg/d. Iloperidone was more efficacious than placebo for positive, negative, and overall total symptoms on the Positive and Negative Syndrome Scale (PANSS), albeit 4 mg/d and 8 mg/d dosages narrowly missed the .05 significance level.

The haloperidol and risperidone active controls appeared more effective than iloperidone in the original analyses, but these studies were not designed for analysis of comparative efficacy. The protocols for all of these studies used an up-titration schedule for the iloperidone groups that took 1 week to reach steady-state levels, whereas the haloperidol and risperidone groups had a briefer up-titration to target dose.

The interpretation of these studies is complex and a detailed discussion is beyond the scope of this article. However, a post-hoc analysis that included subjects who remained in the study after 2 weeks of double-blind medication showed that iloperidone performed comparably to risperidone⁷ and haloperidol.⁸

A new phase III trial. The question remained whether iloperidone was as efficacious as other first-line antipsychotics but had been “penalized” by its slower up-titration schedule and clinical trial design flaws. After acquiring the development rights to iloperidone from Novartis and reviewing prior study designs and results, Vanda Pharmaceuticals designed another phase III study comparing iloperidone with placebo and ziprasidone. Its purpose was to correct for possible design flaws in the previous studies.

Ziprasidone was selected as the active control because of its established efficacy, safety, and twice-daily dosing. In this trial, researchers attempted to match the 2 drugs’ up-titration schedules. Twice-daily doses were given with food as follows:

• iloperidone, 1, 2, 4, 6, 8, 10, and 12 mg (days 1 to 7, respectively)
• ziprasidone, 20 mg (days 1 to 2), 40 mg (days 3 to 4), 60 mg (days 5 to 6), and 80 mg (day 7).

By day 7, target dosages were reached: iloperidone, 24 mg/d, and ziprasidone, 160 mg/d.⁹

Patients receiving iloperidone showed significantly greater improvement in PANSS total scores at 4 weeks vs those receiving placebo (–12.0, iloperidone; –7.1, placebo; P < .01).⁹ Patients receiving ziprasidone also achieved significantly greater improvement vs those receiving placebo (–12.3; P < .05 vs placebo).

The iloperidone and ziprasidone groups showed significantly greater improvement from baseline vs placebo in PANSS positive (P) and negative (N) subscale scores. Significantly more patients receiving iloperidone (72%) than placebo (52%) experienced improvement (≥20% reduction from baseline) in PANSS-P scores (P = .005).

Patients receiving iloperidone had a significantly greater reduction in Clinical Global Impression-Severity scale score vs placebo (–0.65 and –0.39, respectively; P = .007), as did patients receiving ziprasidone (–0.67; P = .013).

Iloperidone met all predefined protocol criteria for efficacy vs placebo and had efficacy equal to the highest approved dose of ziprasidone. These results demonstrated that iloperidone has comparable efficacy to ziprasidone and support the validity of the re-analysis of earlier studies showing comparable efficacy between iloperidone and risperidone⁷ or haloperidol.⁸ In July 2008 the FDA issued a not approvable letter for iloperidone, requesting further clinical trials because of concerns about the drug’s efficacy compared with risperidone. The FDA approved iloperidone in May 2009 after the manufacturer provided additional data from existing trials that demonstrated comparable efficacy to risperidone.

Long-term efficacy. A double-blind extension study compared patients remaining on blinded iloperidone (4 to 16 mg/d) or haloperidol (5 to 20 mg/d) after completing a 6-week efficacy study.¹⁰ The drugs showed equivalent efficacy in preventing relapse over 46 weeks follow-up. Because this study included no placebo group, the FDA does not consider it to be an interpretable relapse prevention study.

Tolerability

Clinicians might consider iloperidone when seeking to switch a patient to an antipsychotic with a potentially lower side-effect burden.^6,11 Compared with risperidone, iloperidone has a lower liability for extrapyramidal symptoms (EPS) and does not cause clinically significant prolactin elevation (Table 3).^5,7-9 Compared with ziprasidone, iloperidone has a lower EPS and akathisia liability. Somewhat greater weight gain was seen with iloperidone when compared with ziprasidone in a 4-week study (iloperidone, +2.8 kg; ziprasidone, +1.1 kg; placebo, +0.5 kg) but the 2 drugs’ effects on triglycerides and cholesterol were comparable.⁹

Iloperidone has a similar degree of QTc prolongation as ziprasidone (mean 9 msec at the highest dosage of 12 mg bid). Safety studies including administration of maximal doses of iloperidone with CYP3A4 and CYP2D6 inhibitors showed a mean QTc prolongation of 19 msec without clinically significant problems, and iloperidone has not been associated with serious arrhythmia.⁴ Iloperidone should not be prescribed to patients with significant cardiac problems or electrolyte disturbances, however, or those taking drugs known to have clinically significant QTc/proarrhythmic properties, such as thioridazine, droperidol, pimozide, or methadone.⁴

Iloperidone has the same safety concerns associated with other atypical antipsychotics, including tardive dyskinesia and neuroleptic malignant syndrome. Like other atypical antipsychotics, iloperidone carries a warning of increased mortality risk in elderly patients with dementia-related psychosis.

Dose-related side effects include dizziness, orthostatic hypotension, and tachycardia. Dizziness occurred more often at higher doses (20% at 20 to 24 mg/d vs 10% at 10 to 16 mg/d vs 7% in placebo groups). Presumably these side effects are related to NEα1 antagonism and are the basis for the recommended dose-titration schedule described below. Clinical trials do not seem to demonstrate a dose-response relationship for acute EPS or akathisia.

Table 3

Common side effects: Iloperidone vs other antipsychotics*

Dosing

The approved dosage range for iloperidone is 12 to 24 mg/d, given as 6 to 12 mg bid. Some trials suggest a dose-response relationship, with 24 mg being more effective than lower target doses.⁵ Reduce the target dosage of iloperidone by one-half when administering it concomitantly with medications that are strong CYP2D6 or CYP3A4 inhibitors.

Titration schedule. Because iloperidone’s relatively strong NEα1 antagonism creates risk for initial orthostatic hypotension, the drug needs to be titrated to the target dose over 4 to 7 days:

• 1 mg bid at day 1
• 2 mg bid at day 2
• 4 mg bid at day 3
• 6 mg bid at day 4 (for a target dosage of 12 mg/d)
• 8 mg bid at day 5
• 10 mg bid at day 6
• 12 mg bid at day 7 (for a target dosage of 24 mg/d).

Monitor patients for dose adjustments based on clinical status, concomitant use of other medications (including antipsychotics), and tolerability of up-titration.

The need to titrate iloperidone slowly to reach efficacious acute antipsychotic doses may lead to delayed effectiveness compared with antipsychotics that can be started at therapeutic doses. This problem also may be seen with up-titration of other agents with strong NEα1 properties, including chlorpromazine, clozapine, quetiapine, and risperidone, and should be considered when treating patients who need rapid dose escalation.

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