Current Psychiatry

In February 2013, the FDA approved a long-acting IM aripiprazole formulation for treating adult schizophrenia (Table 1).¹ It is the fourth second-generation antipsychotic (SGA) depot formulation approved for treating schizophrenia, and the sixth depot antipsychotic if haloperidol and fluphenazine decanoate are considered.

Table 1

Depot aripiprazole: Fast facts

Clinical implications

Depot medications can improve treatment adherence²; however, long-term antipsychotic use can lead to irreversible adverse effects (dyskinesias), which in some cases were reduced by using newer antipsychotics.³

How it works

Similar to other SGAs, aripiprazole’s mechanism of action is unknown. Aripiprazole was developed based on the dopamine theory, in which dopamine hyperactivity in mesolimbic pathways of the brain leads to hallucinations, delusions, disorganization, and catatonia, and dopamine hypoactivity in mesocortical pathways and the prefrontal cortex causes alogia, anhedonia, autism, avolition, and problems with attention and abstract thinking.

Aripiprazole’s proposed mechanism of action on dopamine receptors is that of partial agonism,¹ rather than antagonism, as is the case for other SGAs. In theory, aripiprazole antagonizes postsynaptic D2 receptors and activates presynaptic D2 autoreceptors, with subsequently decreased dopamine production and further stabilization of the dopamine system.⁴ Its antagonism of 5-HT2A is similar to other SGAs.⁵

Pharmacokinetics

After depot aripiprazole is injected into the gluteal muscle, the active moiety slowly is released into circulation. The effectiveness of depot aripiprazole is attributable to its active parent drug, aripiprazole monohydrate, and its active metabolite, dehydro-aripiprazole, which is the same as oral aripiprazole. Depot aripiprazole reaches maximum concentration in 5 to 7 days. The elimination half-life of depot aripiprazole is 29.9 days for a 300-mg dose and 46.5 days for a 400-mg dose if administered monthly.¹

Aripiprazole does not undergo direct glucuronidation. It is metabolized predominantly through cytochrome P450 (CYP) 2D6 and 3A4 enzymes, which predisposes it to significant drug-drug interactions and may require dose adjustment (Table 2).¹

Table 2

Dose adjustments of depot aripiprazole

Efficacy

The ability of depot aripiprazole to sustain long-term symptom control in adult patients with schizophrenia was demonstrated in a randomized-withdrawal, double-blind, placebo-controlled trial.¹ Adults included had a DSM-IV-TR diagnosis of schizophrenia, had ≥3-year history of the illness, had undergone treatment with ≥1 antipsychotic, and had a history of relapse or symptom exacerbation when not receiving antipsychotics. Psychopathology was measured by the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity scale, the Clinical Global Impression-Improvement (CGI-I) scale, and the Clinical Global Impression-Severity of Suicide (CGI-SS) scale.¹

The trial lasted 52 weeks, was divided into 4 phases, and concluded early because of demonstrated efficacy.

Phase I: Conversion phase switched patients from a different antipsychotic to oral aripiprazole. This phase lasted 4 to 6 weeks and included 633 patients. An additional 210 patients already receiving aripiprazole were entered directly into Phase II.

Phase II: Open-label, oral stabilization phase included 710 patients (60% males) age 18 to 60 who had a mean PANSS score 66. Patients received 10 to 20 mg/d of oral aripiprazole until they achieved stabilization, defined as PANSS score

Phase III: IM depot stabilization (uncontrolled single blind) included 576 patients. Patients were started on depot aripiprazole, 400 mg monthly, and continued to take 10 to 20 mg/d of oral aripiprazole for 14 consecutive days. Depot aripiprazole was decreased to 300 mg monthly if a patient developed adverse effects. Patients continued to the double-blind phase when stabilization was achieved, as evidenced by PANSS score

Phase IV: Maintenance (double-blind, randomized, placebo-controlled) included 403 patients. Two-thirds of patients continued to take the same dose of depot aripiprazole they took in Phase III. One-third of patients were switched to placebo. The primary efficacy endpoint was time to impending relapse, defined as the first occurrence of ≥1 criteria: hospitalization due to psychosis; violence toward self, others, or property; CGI-SS score ≥4 on part I or ≥7 on part II; or CGI-I score ≥5 and any individual PANSS score >4 for disorganization, hallucinations, suspiciousness, or abnormal thought content.¹

Patients randomized to continue depot aripiprazole took longer to relapse or worsening of symptoms compared with the placebo group. Of 403 patients, 10% taking an active drug and 39.6% taking placebo relapsed within 360 days of randomization. This difference was statistically significant (P 1

Tolerability

One possible problem with any long-acting medication is increased duration of adverse effects (AEs), if they develop. Therefore, assessment of safety and tolerability is more important in depot formulations than in oral drugs. During the clinical trial, depot aripiprazole was well tolerated.⁶

During clinical trials, the most common AEs—insomnia (>5%), anxiety, and tremors—were mild to moderate and occurred within the first 4 weeks. Discontinuation of the medication because of AEs was low, and pain at the injection site was minimal.⁶ There were 2 deaths during the trial, which were unrelated to depot aripiprazole.⁶

Aripiprazole’s activity on the D2 receptor can cause extrapyramidal AEs. In head-to-head trials, patients taking aripiprazole had fewer extrapyramidal AEs than those taking risperidone or ziprasidone, but more than patients receiving olanzapine.⁷ Its moderate antagonism on α-adrenergic and histamine 1 (H1) receptors translates to low orthostatic hypotension, H1-mediated weight gain, and sedation. In clinical trials, weight gain and metabolic changes were comparable with placebo. In head-to-head trials, aripiprazole caused less weight gain and a higher incidence of increased cholesterol than olanzapine and risperidone, and less increase in blood glucose than olanzapine, but more than risperidone.⁸ Muscarinic 1-mediated cognitive impairment, dry mouth, constipation, urinary retention, and increased intraocular pressure were low.⁸ See Table 3 for aripiprazole's receptor binding profile.

Table 3

Aripiprazole’s receptor binding profile

Unique clinical issues

Clinical features for depot aripiprazole can be partially deduced based on data on oral aripiprazole. Advantages over other depot SGAs might include aripiprazole’s more favorable weight and metabolic profile.

Contraindications

Depot aripiprazole is contraindicated in patients with known sensitivity to aripiprazole or other components of the formulation. Because of pharmacokinetic drug-drug interactions, using depot aripiprazole should be avoided in patients taking strong CYP3A4 inducers (eg, rifampin and carbamazepine). Dose adjustment is recommended in patients who are taking moderate CYP2D6 and 3A4 inhibitors, such as paroxetine, fluoxetine, ketoconazole, or erythromycin.¹ A “black-box” warning of increased mortality in older patients with dementia-related psychosis applies for depot aripiprazole as well as for other atypical antipsychotics.¹

Depot aripiprazole is pregnancy category C and should be used in pregnant or breastfeeding mothers only when benefits outweigh the risks. Use of depot aripiprazole in geriatric and pediatric populations has not been studied; however, patients age ≥65 who received oral aripiprazole, 15 mg/d, showed decreased clearance by 20%.¹

Dosing

Depot aripiprazole is available as a lyophilized powder that needs to be reconstituted in sterile water. The drug can be stored at room temperature. The kit includes two 21-gauge needles, a 1.5-inch needle for non-obese patients and a 2-inch needle for obese patients. Depot aripiprazole should be given to patients who demonstrate tolerability to oral aripiprazole. The starting and maintenance dose of depot aripiprazole is 400 mg injected into the gluteal muscle, once a month. If a patient develops an AE, decrease the monthly dose to 300 mg. Rotate the injection site between gluteal muscles to reduce AEs from injection.

Because of the potential for significant pharmacokinetic drug-drug interactions, dose adjustment is recommended for patients who are CYP2D6 poor metabolizers and those taking certain other medications (Table 4).¹ See Table 4 for the recommended dosage adjustment in the case of missed doses.

Table 4

Adjusting depot aripiprazole after missed doses

After depot aripiprazole is injected into the gluteal muscle, the patient receives 10 to 20 mg/d of oral aripiprazole for 14 consecutive days to avoid a drop in plasma concentrations into subtherapeutic levels.

Related Resource

• Abilify Maintena [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Company; 2013.

Drug Brand Names

• Aripiprazole • Abilify
• Aripiprazole depot • Maintena
• Carbamazepine • Tegretol
• Desvenlafaxine • Pristiq
• Dextromethorphan • Delsym
• Erythromycin • E-Mycin
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Itraconazole • Sporanox
• Ketoconazole • Nizoral
• Lithium • Eskalith, Lithobid
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Paliperidone • Invega
• Paroxetine • Paxil
• Quinidine • Quinidex
• Rifampin • Rifadin
• Risperidone • Risperdal
• Valproate • Depakote
• Venlafaxine • Effexor
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosure

Dr. Lincoln receives grant or research support from the Wichita Center for Graduate Medical Education.

In February 2013, the FDA approved a long-acting IM aripiprazole formulation for treating adult schizophrenia (Table 1).¹ It is the fourth second-generation antipsychotic (SGA) depot formulation approved for treating schizophrenia, and the sixth depot antipsychotic if haloperidol and fluphenazine decanoate are considered.

Table 1

Depot aripiprazole: Fast facts

Clinical implications

Depot medications can improve treatment adherence²; however, long-term antipsychotic use can lead to irreversible adverse effects (dyskinesias), which in some cases were reduced by using newer antipsychotics.³

How it works

Similar to other SGAs, aripiprazole’s mechanism of action is unknown. Aripiprazole was developed based on the dopamine theory, in which dopamine hyperactivity in mesolimbic pathways of the brain leads to hallucinations, delusions, disorganization, and catatonia, and dopamine hypoactivity in mesocortical pathways and the prefrontal cortex causes alogia, anhedonia, autism, avolition, and problems with attention and abstract thinking.

Aripiprazole’s proposed mechanism of action on dopamine receptors is that of partial agonism,¹ rather than antagonism, as is the case for other SGAs. In theory, aripiprazole antagonizes postsynaptic D2 receptors and activates presynaptic D2 autoreceptors, with subsequently decreased dopamine production and further stabilization of the dopamine system.⁴ Its antagonism of 5-HT2A is similar to other SGAs.⁵

Pharmacokinetics

After depot aripiprazole is injected into the gluteal muscle, the active moiety slowly is released into circulation. The effectiveness of depot aripiprazole is attributable to its active parent drug, aripiprazole monohydrate, and its active metabolite, dehydro-aripiprazole, which is the same as oral aripiprazole. Depot aripiprazole reaches maximum concentration in 5 to 7 days. The elimination half-life of depot aripiprazole is 29.9 days for a 300-mg dose and 46.5 days for a 400-mg dose if administered monthly.¹

Aripiprazole does not undergo direct glucuronidation. It is metabolized predominantly through cytochrome P450 (CYP) 2D6 and 3A4 enzymes, which predisposes it to significant drug-drug interactions and may require dose adjustment (Table 2).¹

Table 2

Dose adjustments of depot aripiprazole

Efficacy

The ability of depot aripiprazole to sustain long-term symptom control in adult patients with schizophrenia was demonstrated in a randomized-withdrawal, double-blind, placebo-controlled trial.¹ Adults included had a DSM-IV-TR diagnosis of schizophrenia, had ≥3-year history of the illness, had undergone treatment with ≥1 antipsychotic, and had a history of relapse or symptom exacerbation when not receiving antipsychotics. Psychopathology was measured by the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity scale, the Clinical Global Impression-Improvement (CGI-I) scale, and the Clinical Global Impression-Severity of Suicide (CGI-SS) scale.¹

The trial lasted 52 weeks, was divided into 4 phases, and concluded early because of demonstrated efficacy.

Phase I: Conversion phase switched patients from a different antipsychotic to oral aripiprazole. This phase lasted 4 to 6 weeks and included 633 patients. An additional 210 patients already receiving aripiprazole were entered directly into Phase II.

Phase II: Open-label, oral stabilization phase included 710 patients (60% males) age 18 to 60 who had a mean PANSS score 66. Patients received 10 to 20 mg/d of oral aripiprazole until they achieved stabilization, defined as PANSS score

Phase III: IM depot stabilization (uncontrolled single blind) included 576 patients. Patients were started on depot aripiprazole, 400 mg monthly, and continued to take 10 to 20 mg/d of oral aripiprazole for 14 consecutive days. Depot aripiprazole was decreased to 300 mg monthly if a patient developed adverse effects. Patients continued to the double-blind phase when stabilization was achieved, as evidenced by PANSS score

Phase IV: Maintenance (double-blind, randomized, placebo-controlled) included 403 patients. Two-thirds of patients continued to take the same dose of depot aripiprazole they took in Phase III. One-third of patients were switched to placebo. The primary efficacy endpoint was time to impending relapse, defined as the first occurrence of ≥1 criteria: hospitalization due to psychosis; violence toward self, others, or property; CGI-SS score ≥4 on part I or ≥7 on part II; or CGI-I score ≥5 and any individual PANSS score >4 for disorganization, hallucinations, suspiciousness, or abnormal thought content.¹

Patients randomized to continue depot aripiprazole took longer to relapse or worsening of symptoms compared with the placebo group. Of 403 patients, 10% taking an active drug and 39.6% taking placebo relapsed within 360 days of randomization. This difference was statistically significant (P 1

Tolerability

One possible problem with any long-acting medication is increased duration of adverse effects (AEs), if they develop. Therefore, assessment of safety and tolerability is more important in depot formulations than in oral drugs. During the clinical trial, depot aripiprazole was well tolerated.⁶

During clinical trials, the most common AEs—insomnia (>5%), anxiety, and tremors—were mild to moderate and occurred within the first 4 weeks. Discontinuation of the medication because of AEs was low, and pain at the injection site was minimal.⁶ There were 2 deaths during the trial, which were unrelated to depot aripiprazole.⁶

Aripiprazole’s activity on the D2 receptor can cause extrapyramidal AEs. In head-to-head trials, patients taking aripiprazole had fewer extrapyramidal AEs than those taking risperidone or ziprasidone, but more than patients receiving olanzapine.⁷ Its moderate antagonism on α-adrenergic and histamine 1 (H1) receptors translates to low orthostatic hypotension, H1-mediated weight gain, and sedation. In clinical trials, weight gain and metabolic changes were comparable with placebo. In head-to-head trials, aripiprazole caused less weight gain and a higher incidence of increased cholesterol than olanzapine and risperidone, and less increase in blood glucose than olanzapine, but more than risperidone.⁸ Muscarinic 1-mediated cognitive impairment, dry mouth, constipation, urinary retention, and increased intraocular pressure were low.⁸ See Table 3 for aripiprazole's receptor binding profile.

Table 3

Aripiprazole’s receptor binding profile

Unique clinical issues

Clinical features for depot aripiprazole can be partially deduced based on data on oral aripiprazole. Advantages over other depot SGAs might include aripiprazole’s more favorable weight and metabolic profile.

Contraindications

Depot aripiprazole is contraindicated in patients with known sensitivity to aripiprazole or other components of the formulation. Because of pharmacokinetic drug-drug interactions, using depot aripiprazole should be avoided in patients taking strong CYP3A4 inducers (eg, rifampin and carbamazepine). Dose adjustment is recommended in patients who are taking moderate CYP2D6 and 3A4 inhibitors, such as paroxetine, fluoxetine, ketoconazole, or erythromycin.¹ A “black-box” warning of increased mortality in older patients with dementia-related psychosis applies for depot aripiprazole as well as for other atypical antipsychotics.¹

Depot aripiprazole is pregnancy category C and should be used in pregnant or breastfeeding mothers only when benefits outweigh the risks. Use of depot aripiprazole in geriatric and pediatric populations has not been studied; however, patients age ≥65 who received oral aripiprazole, 15 mg/d, showed decreased clearance by 20%.¹

Dosing

Depot aripiprazole is available as a lyophilized powder that needs to be reconstituted in sterile water. The drug can be stored at room temperature. The kit includes two 21-gauge needles, a 1.5-inch needle for non-obese patients and a 2-inch needle for obese patients. Depot aripiprazole should be given to patients who demonstrate tolerability to oral aripiprazole. The starting and maintenance dose of depot aripiprazole is 400 mg injected into the gluteal muscle, once a month. If a patient develops an AE, decrease the monthly dose to 300 mg. Rotate the injection site between gluteal muscles to reduce AEs from injection.

Because of the potential for significant pharmacokinetic drug-drug interactions, dose adjustment is recommended for patients who are CYP2D6 poor metabolizers and those taking certain other medications (Table 4).¹ See Table 4 for the recommended dosage adjustment in the case of missed doses.

Table 4

Adjusting depot aripiprazole after missed doses

After depot aripiprazole is injected into the gluteal muscle, the patient receives 10 to 20 mg/d of oral aripiprazole for 14 consecutive days to avoid a drop in plasma concentrations into subtherapeutic levels.

Related Resource

• Abilify Maintena [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Company; 2013.

Drug Brand Names

• Aripiprazole • Abilify
• Aripiprazole depot • Maintena
• Carbamazepine • Tegretol
• Desvenlafaxine • Pristiq
• Dextromethorphan • Delsym
• Erythromycin • E-Mycin
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Itraconazole • Sporanox
• Ketoconazole • Nizoral
• Lithium • Eskalith, Lithobid
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Paliperidone • Invega
• Paroxetine • Paxil
• Quinidine • Quinidex
• Rifampin • Rifadin
• Risperidone • Risperdal
• Valproate • Depakote
• Venlafaxine • Effexor
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosure

Dr. Lincoln receives grant or research support from the Wichita Center for Graduate Medical Education.

In February 2013, the FDA approved a long-acting IM aripiprazole formulation for treating adult schizophrenia (Table 1).¹ It is the fourth second-generation antipsychotic (SGA) depot formulation approved for treating schizophrenia, and the sixth depot antipsychotic if haloperidol and fluphenazine decanoate are considered.

Table 1

Depot aripiprazole: Fast facts

Clinical implications

Depot medications can improve treatment adherence²; however, long-term antipsychotic use can lead to irreversible adverse effects (dyskinesias), which in some cases were reduced by using newer antipsychotics.³

How it works

Similar to other SGAs, aripiprazole’s mechanism of action is unknown. Aripiprazole was developed based on the dopamine theory, in which dopamine hyperactivity in mesolimbic pathways of the brain leads to hallucinations, delusions, disorganization, and catatonia, and dopamine hypoactivity in mesocortical pathways and the prefrontal cortex causes alogia, anhedonia, autism, avolition, and problems with attention and abstract thinking.

Aripiprazole’s proposed mechanism of action on dopamine receptors is that of partial agonism,¹ rather than antagonism, as is the case for other SGAs. In theory, aripiprazole antagonizes postsynaptic D2 receptors and activates presynaptic D2 autoreceptors, with subsequently decreased dopamine production and further stabilization of the dopamine system.⁴ Its antagonism of 5-HT2A is similar to other SGAs.⁵

Pharmacokinetics

After depot aripiprazole is injected into the gluteal muscle, the active moiety slowly is released into circulation. The effectiveness of depot aripiprazole is attributable to its active parent drug, aripiprazole monohydrate, and its active metabolite, dehydro-aripiprazole, which is the same as oral aripiprazole. Depot aripiprazole reaches maximum concentration in 5 to 7 days. The elimination half-life of depot aripiprazole is 29.9 days for a 300-mg dose and 46.5 days for a 400-mg dose if administered monthly.¹

Aripiprazole does not undergo direct glucuronidation. It is metabolized predominantly through cytochrome P450 (CYP) 2D6 and 3A4 enzymes, which predisposes it to significant drug-drug interactions and may require dose adjustment (Table 2).¹

Table 2

Dose adjustments of depot aripiprazole

Efficacy

The ability of depot aripiprazole to sustain long-term symptom control in adult patients with schizophrenia was demonstrated in a randomized-withdrawal, double-blind, placebo-controlled trial.¹ Adults included had a DSM-IV-TR diagnosis of schizophrenia, had ≥3-year history of the illness, had undergone treatment with ≥1 antipsychotic, and had a history of relapse or symptom exacerbation when not receiving antipsychotics. Psychopathology was measured by the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity scale, the Clinical Global Impression-Improvement (CGI-I) scale, and the Clinical Global Impression-Severity of Suicide (CGI-SS) scale.¹

The trial lasted 52 weeks, was divided into 4 phases, and concluded early because of demonstrated efficacy.

Phase I: Conversion phase switched patients from a different antipsychotic to oral aripiprazole. This phase lasted 4 to 6 weeks and included 633 patients. An additional 210 patients already receiving aripiprazole were entered directly into Phase II.

Phase II: Open-label, oral stabilization phase included 710 patients (60% males) age 18 to 60 who had a mean PANSS score 66. Patients received 10 to 20 mg/d of oral aripiprazole until they achieved stabilization, defined as PANSS score

Phase III: IM depot stabilization (uncontrolled single blind) included 576 patients. Patients were started on depot aripiprazole, 400 mg monthly, and continued to take 10 to 20 mg/d of oral aripiprazole for 14 consecutive days. Depot aripiprazole was decreased to 300 mg monthly if a patient developed adverse effects. Patients continued to the double-blind phase when stabilization was achieved, as evidenced by PANSS score

Phase IV: Maintenance (double-blind, randomized, placebo-controlled) included 403 patients. Two-thirds of patients continued to take the same dose of depot aripiprazole they took in Phase III. One-third of patients were switched to placebo. The primary efficacy endpoint was time to impending relapse, defined as the first occurrence of ≥1 criteria: hospitalization due to psychosis; violence toward self, others, or property; CGI-SS score ≥4 on part I or ≥7 on part II; or CGI-I score ≥5 and any individual PANSS score >4 for disorganization, hallucinations, suspiciousness, or abnormal thought content.¹

Patients randomized to continue depot aripiprazole took longer to relapse or worsening of symptoms compared with the placebo group. Of 403 patients, 10% taking an active drug and 39.6% taking placebo relapsed within 360 days of randomization. This difference was statistically significant (P 1

Tolerability

One possible problem with any long-acting medication is increased duration of adverse effects (AEs), if they develop. Therefore, assessment of safety and tolerability is more important in depot formulations than in oral drugs. During the clinical trial, depot aripiprazole was well tolerated.⁶

During clinical trials, the most common AEs—insomnia (>5%), anxiety, and tremors—were mild to moderate and occurred within the first 4 weeks. Discontinuation of the medication because of AEs was low, and pain at the injection site was minimal.⁶ There were 2 deaths during the trial, which were unrelated to depot aripiprazole.⁶

Aripiprazole’s activity on the D2 receptor can cause extrapyramidal AEs. In head-to-head trials, patients taking aripiprazole had fewer extrapyramidal AEs than those taking risperidone or ziprasidone, but more than patients receiving olanzapine.⁷ Its moderate antagonism on α-adrenergic and histamine 1 (H1) receptors translates to low orthostatic hypotension, H1-mediated weight gain, and sedation. In clinical trials, weight gain and metabolic changes were comparable with placebo. In head-to-head trials, aripiprazole caused less weight gain and a higher incidence of increased cholesterol than olanzapine and risperidone, and less increase in blood glucose than olanzapine, but more than risperidone.⁸ Muscarinic 1-mediated cognitive impairment, dry mouth, constipation, urinary retention, and increased intraocular pressure were low.⁸ See Table 3 for aripiprazole's receptor binding profile.

Table 3

Aripiprazole’s receptor binding profile

Unique clinical issues

Clinical features for depot aripiprazole can be partially deduced based on data on oral aripiprazole. Advantages over other depot SGAs might include aripiprazole’s more favorable weight and metabolic profile.

Contraindications

Depot aripiprazole is contraindicated in patients with known sensitivity to aripiprazole or other components of the formulation. Because of pharmacokinetic drug-drug interactions, using depot aripiprazole should be avoided in patients taking strong CYP3A4 inducers (eg, rifampin and carbamazepine). Dose adjustment is recommended in patients who are taking moderate CYP2D6 and 3A4 inhibitors, such as paroxetine, fluoxetine, ketoconazole, or erythromycin.¹ A “black-box” warning of increased mortality in older patients with dementia-related psychosis applies for depot aripiprazole as well as for other atypical antipsychotics.¹

Depot aripiprazole is pregnancy category C and should be used in pregnant or breastfeeding mothers only when benefits outweigh the risks. Use of depot aripiprazole in geriatric and pediatric populations has not been studied; however, patients age ≥65 who received oral aripiprazole, 15 mg/d, showed decreased clearance by 20%.¹

Dosing

Depot aripiprazole is available as a lyophilized powder that needs to be reconstituted in sterile water. The drug can be stored at room temperature. The kit includes two 21-gauge needles, a 1.5-inch needle for non-obese patients and a 2-inch needle for obese patients. Depot aripiprazole should be given to patients who demonstrate tolerability to oral aripiprazole. The starting and maintenance dose of depot aripiprazole is 400 mg injected into the gluteal muscle, once a month. If a patient develops an AE, decrease the monthly dose to 300 mg. Rotate the injection site between gluteal muscles to reduce AEs from injection.

Because of the potential for significant pharmacokinetic drug-drug interactions, dose adjustment is recommended for patients who are CYP2D6 poor metabolizers and those taking certain other medications (Table 4).¹ See Table 4 for the recommended dosage adjustment in the case of missed doses.

Table 4

Adjusting depot aripiprazole after missed doses

After depot aripiprazole is injected into the gluteal muscle, the patient receives 10 to 20 mg/d of oral aripiprazole for 14 consecutive days to avoid a drop in plasma concentrations into subtherapeutic levels.

Related Resource

• Abilify Maintena [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Company; 2013.

Drug Brand Names

• Aripiprazole • Abilify
• Aripiprazole depot • Maintena
• Carbamazepine • Tegretol
• Desvenlafaxine • Pristiq
• Dextromethorphan • Delsym
• Erythromycin • E-Mycin
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Itraconazole • Sporanox
• Ketoconazole • Nizoral
• Lithium • Eskalith, Lithobid
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Paliperidone • Invega
• Paroxetine • Paxil
• Quinidine • Quinidex
• Rifampin • Rifadin
• Risperidone • Risperdal
• Valproate • Depakote
• Venlafaxine • Effexor
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosure

Dr. Lincoln receives grant or research support from the Wichita Center for Graduate Medical Education.

Staging of medical illness is common in oncology and cardiology, but not in psychiatry. Staging can provide important information about illness severity, appropriate therapeutic intervention for that stage, treatment outcomes, and long-term prognosis.

In psychiatry, clinicians generally give a DSM label to a disorder once symptoms emerge and if it persists, simply categorize it as chronic. It’s time for psychiatry to adopt a clinically meaningful staging schema for its major disorders. Several researchers already have proposed such staging models.

The momentum for staging major psychiatric disorders such as schizophrenia, bipolar disorder (BD), and major depressive disorder is being stoked by 2 major research advances: 1) accelerating recognition and characterization of the prodrome as a preclinical stage of psychiatric disorders, and 2) rapidly accruing neurobiologic discoveries about the deleterious biochemical and neural changes that evolve with each successive episode. However, early attempts and current proposals for staging psychiatric disorders are broadly clinical and descriptive.^1-4

Clinical staging

McGorry et al⁵ have proposed the following staging model:

Stage 0: Increased risk of psychotic or mood disorders, although no symptoms are present.

Stage 1a: Mild, nonspecific symptoms.

Stage 1b: Moderate, subthreshold symptoms.

Stage 2: Onset of first episode of a psychotic or mood disorder.

Stage 3a: Incomplete remission from the first episode.

Stage 3b: Recurrence or relapse of a psychotic or mood disorder.

Stage 3c: Multiple relapses, worsening of clinical severity and impact of illness.

Stage 4: Severe, persistent, or unremitting illness.

Although this is a good start, it does not incorporate the emerging neurobiologic findings of progressive psychotic and mood disorders from the preclinical stage to chronic deteriorative state. These pathologies include inflammation, oxidative stress, loss of neurotropic growth factors, and impaired neuroplasticity, all of which result in deleterious neuropathologic progression of damage to key brain circuits. Acute psychotic or mood episodes are recognized to have serious neurotoxic effects, just as myocardial infarction damages the myocardium. This is why patients who experience a first episode of psychosis, mania, or depression must be protected from relapsing: evidence is mounting that second (and certainly subsequent) episodes can be more damaging to the brain than first episodes and would require more aggressive treatment, similar to more advanced cancer stages. This has been well documented clinically, with excellent response to medication and remission in two-thirds of patients with first-episode schizophrenia,⁶ but far lower remission rates after multiple relapses.

Consider the following advances about the adverse neurobiologic events associated with psychotic or mood episodes at various stages of the illness:

In utero, the risk genes, copy number variations, and random mutations in the thousands of genes involved in brain development probably account for smaller brain volume and hypoplasia of certain brain regions.

In the premorbid phase (childhood and early adolescence), negative symptoms and low cognition are evident as asociality and mediocre grades.

In the prodrome phase (mid-to-late adolescence), cortical changes and cognitive decline as well as mood symptoms are more apparent. Only omega-3 fatty acids—but not atypical antipsychotics—prevented a switch to psychosis better than placebo.⁷ This suggests the emergence of a neuroinflammatory process that may respond to omega-3 fatty acids.

In the first psychotic episode, a stunning new finding⁸ reveals brain edema, with a swollen brain and smaller ventricles, caused by water diffusion into extra cellular space of both gray and white matter. Such water diffusion can trigger neuroinflammation and the beginning of serious tissue damage, which can be slowed down by antipsychotics. Increased dopamine activity is associated with an increase of free radicals (oxidative stress) and suppression of growth factors. Glutamate hypofunction, another putative factor in schizophrenia, may be associated with cognitive decline and impaired neuroplasticity.

In the second episode of psychosis, recurrent water diffusion and continued neuroinflammation lead to axonal damage and more serious neurodegeneration.⁸ This confirms the observation of more serious clinical and functional deterioration after the second episode compared with the first, and becomes much worse if the patient does not adhere to treatment and relapses. Drug response also declines, possibly because of neurodegeneration and further oxidative stress,⁹ inflammation, breakdown in white matter, disruption in neuroplasticity, and further dysconnectivity across brain regions.¹⁰

In the treatment-resistant or refractory phase, clozapine is the only agent that has been shown to improve persistent psychotic symptoms. Although its exact mechanism of action remains unknown, recent studies indicate it may be exerting some of its effects by inhibiting microglial activation,¹¹ which is the main pathway for neuroinflammation in degenerative brain disorders.

Ultimately, after multiple episodes the chromosomal telomere becomes shorter in BD and schizophrenia,¹² which is known to predict mortality. This may explain premature death in chronically mentally ill patients (apart from cardiovascular risk factors caused by obesity).

Based on the above, I propose the following clinico-biologic staging model:

Stage 0: Abnormal brain development in utero due to genetic and nongenetic factors.

Stage 1a: Poor premorbid function in childhood (asociality, mediocre school performance).

Stage 1b: The prodrome, with noticeable negative symptoms, cognitive dysfunction, and gray and white matter changes.

Stage 2: First psychotic episode, with delusions and hallucinations, increasing negative symptoms, and marked cognitive decline, accompanied by frontal, parietal, and hippocampal volume losses, white matter pathology, brain edema, inflammatory markers, oxidative stress, and decreased neurotropic growth factors.

Stage 3: Second psychotic episode, with more intense psychotic and negative symptoms, cognitive dysfunction, and worsening social and vocational functioning. Biologic signs include neuroinflammation, oxidative stress and impaired neuroplasticity biomarkers, axonal degeneration and further brain tissue loss, and slower response to antipsychotics.

Stage 4: Several psychotic episodes (subchronic phase), with residual positive and negative symptoms and continued cognitive impairment especially in memory, executive function, attention and verbal learning, accompanied by glial cell death, decline in dendritic spines, retraction or neurite extension, and low response to antipsychotics, with a Global Assessment of Functioning (GAF) score of 30 to 40.

Stage 5: Refractory, unremitting psychosis (chronic phase), with poor response to antipsychotics, severe clinical, social, and functional deterioration, inability to care for oneself, severe neurodegeneration (widespread brain atrophy and dysconnectivity), and GAF score ≤30.

This staging model implies that early intervention to prevent the first or second episode may be the best approach to arrest (and perhaps reverse) psychobiologic deterioration and modify the trajectory of serious psychiatric brain disorders. More can be done to prevent a downhill course in psychosis, and emphasizing the clinical and neurobiologic features of each stage of illness may serve as a roadmap for aggressive treatment approaches early in the illness course. Until a cure is found, prevention and early intervention are the best approaches. Staging models should be incorporated in future versions of the DSM so that psychiatric practitioners can implement the optimal treatment algorithm at the earliest stage possible. Readers’ opinions are welcome!

Staging of medical illness is common in oncology and cardiology, but not in psychiatry. Staging can provide important information about illness severity, appropriate therapeutic intervention for that stage, treatment outcomes, and long-term prognosis.

In psychiatry, clinicians generally give a DSM label to a disorder once symptoms emerge and if it persists, simply categorize it as chronic. It’s time for psychiatry to adopt a clinically meaningful staging schema for its major disorders. Several researchers already have proposed such staging models.

The momentum for staging major psychiatric disorders such as schizophrenia, bipolar disorder (BD), and major depressive disorder is being stoked by 2 major research advances: 1) accelerating recognition and characterization of the prodrome as a preclinical stage of psychiatric disorders, and 2) rapidly accruing neurobiologic discoveries about the deleterious biochemical and neural changes that evolve with each successive episode. However, early attempts and current proposals for staging psychiatric disorders are broadly clinical and descriptive.^1-4

Clinical staging

McGorry et al⁵ have proposed the following staging model:

Stage 0: Increased risk of psychotic or mood disorders, although no symptoms are present.

Stage 1a: Mild, nonspecific symptoms.

Stage 1b: Moderate, subthreshold symptoms.

Stage 2: Onset of first episode of a psychotic or mood disorder.

Stage 3a: Incomplete remission from the first episode.

Stage 3b: Recurrence or relapse of a psychotic or mood disorder.

Stage 3c: Multiple relapses, worsening of clinical severity and impact of illness.

Stage 4: Severe, persistent, or unremitting illness.

Although this is a good start, it does not incorporate the emerging neurobiologic findings of progressive psychotic and mood disorders from the preclinical stage to chronic deteriorative state. These pathologies include inflammation, oxidative stress, loss of neurotropic growth factors, and impaired neuroplasticity, all of which result in deleterious neuropathologic progression of damage to key brain circuits. Acute psychotic or mood episodes are recognized to have serious neurotoxic effects, just as myocardial infarction damages the myocardium. This is why patients who experience a first episode of psychosis, mania, or depression must be protected from relapsing: evidence is mounting that second (and certainly subsequent) episodes can be more damaging to the brain than first episodes and would require more aggressive treatment, similar to more advanced cancer stages. This has been well documented clinically, with excellent response to medication and remission in two-thirds of patients with first-episode schizophrenia,⁶ but far lower remission rates after multiple relapses.

Consider the following advances about the adverse neurobiologic events associated with psychotic or mood episodes at various stages of the illness:

In utero, the risk genes, copy number variations, and random mutations in the thousands of genes involved in brain development probably account for smaller brain volume and hypoplasia of certain brain regions.

In the premorbid phase (childhood and early adolescence), negative symptoms and low cognition are evident as asociality and mediocre grades.

In the prodrome phase (mid-to-late adolescence), cortical changes and cognitive decline as well as mood symptoms are more apparent. Only omega-3 fatty acids—but not atypical antipsychotics—prevented a switch to psychosis better than placebo.⁷ This suggests the emergence of a neuroinflammatory process that may respond to omega-3 fatty acids.

In the first psychotic episode, a stunning new finding⁸ reveals brain edema, with a swollen brain and smaller ventricles, caused by water diffusion into extra cellular space of both gray and white matter. Such water diffusion can trigger neuroinflammation and the beginning of serious tissue damage, which can be slowed down by antipsychotics. Increased dopamine activity is associated with an increase of free radicals (oxidative stress) and suppression of growth factors. Glutamate hypofunction, another putative factor in schizophrenia, may be associated with cognitive decline and impaired neuroplasticity.

In the second episode of psychosis, recurrent water diffusion and continued neuroinflammation lead to axonal damage and more serious neurodegeneration.⁸ This confirms the observation of more serious clinical and functional deterioration after the second episode compared with the first, and becomes much worse if the patient does not adhere to treatment and relapses. Drug response also declines, possibly because of neurodegeneration and further oxidative stress,⁹ inflammation, breakdown in white matter, disruption in neuroplasticity, and further dysconnectivity across brain regions.¹⁰

In the treatment-resistant or refractory phase, clozapine is the only agent that has been shown to improve persistent psychotic symptoms. Although its exact mechanism of action remains unknown, recent studies indicate it may be exerting some of its effects by inhibiting microglial activation,¹¹ which is the main pathway for neuroinflammation in degenerative brain disorders.

Ultimately, after multiple episodes the chromosomal telomere becomes shorter in BD and schizophrenia,¹² which is known to predict mortality. This may explain premature death in chronically mentally ill patients (apart from cardiovascular risk factors caused by obesity).

Based on the above, I propose the following clinico-biologic staging model:

Stage 0: Abnormal brain development in utero due to genetic and nongenetic factors.

Stage 1a: Poor premorbid function in childhood (asociality, mediocre school performance).

Stage 1b: The prodrome, with noticeable negative symptoms, cognitive dysfunction, and gray and white matter changes.

Stage 2: First psychotic episode, with delusions and hallucinations, increasing negative symptoms, and marked cognitive decline, accompanied by frontal, parietal, and hippocampal volume losses, white matter pathology, brain edema, inflammatory markers, oxidative stress, and decreased neurotropic growth factors.

Stage 3: Second psychotic episode, with more intense psychotic and negative symptoms, cognitive dysfunction, and worsening social and vocational functioning. Biologic signs include neuroinflammation, oxidative stress and impaired neuroplasticity biomarkers, axonal degeneration and further brain tissue loss, and slower response to antipsychotics.

Stage 4: Several psychotic episodes (subchronic phase), with residual positive and negative symptoms and continued cognitive impairment especially in memory, executive function, attention and verbal learning, accompanied by glial cell death, decline in dendritic spines, retraction or neurite extension, and low response to antipsychotics, with a Global Assessment of Functioning (GAF) score of 30 to 40.

Stage 5: Refractory, unremitting psychosis (chronic phase), with poor response to antipsychotics, severe clinical, social, and functional deterioration, inability to care for oneself, severe neurodegeneration (widespread brain atrophy and dysconnectivity), and GAF score ≤30.

This staging model implies that early intervention to prevent the first or second episode may be the best approach to arrest (and perhaps reverse) psychobiologic deterioration and modify the trajectory of serious psychiatric brain disorders. More can be done to prevent a downhill course in psychosis, and emphasizing the clinical and neurobiologic features of each stage of illness may serve as a roadmap for aggressive treatment approaches early in the illness course. Until a cure is found, prevention and early intervention are the best approaches. Staging models should be incorporated in future versions of the DSM so that psychiatric practitioners can implement the optimal treatment algorithm at the earliest stage possible. Readers’ opinions are welcome!

Staging of medical illness is common in oncology and cardiology, but not in psychiatry. Staging can provide important information about illness severity, appropriate therapeutic intervention for that stage, treatment outcomes, and long-term prognosis.

In psychiatry, clinicians generally give a DSM label to a disorder once symptoms emerge and if it persists, simply categorize it as chronic. It’s time for psychiatry to adopt a clinically meaningful staging schema for its major disorders. Several researchers already have proposed such staging models.

The momentum for staging major psychiatric disorders such as schizophrenia, bipolar disorder (BD), and major depressive disorder is being stoked by 2 major research advances: 1) accelerating recognition and characterization of the prodrome as a preclinical stage of psychiatric disorders, and 2) rapidly accruing neurobiologic discoveries about the deleterious biochemical and neural changes that evolve with each successive episode. However, early attempts and current proposals for staging psychiatric disorders are broadly clinical and descriptive.^1-4

Clinical staging

McGorry et al⁵ have proposed the following staging model:

Stage 0: Increased risk of psychotic or mood disorders, although no symptoms are present.

Stage 1a: Mild, nonspecific symptoms.

Stage 1b: Moderate, subthreshold symptoms.

Stage 2: Onset of first episode of a psychotic or mood disorder.

Stage 3a: Incomplete remission from the first episode.

Stage 3b: Recurrence or relapse of a psychotic or mood disorder.

Stage 3c: Multiple relapses, worsening of clinical severity and impact of illness.

Stage 4: Severe, persistent, or unremitting illness.

Although this is a good start, it does not incorporate the emerging neurobiologic findings of progressive psychotic and mood disorders from the preclinical stage to chronic deteriorative state. These pathologies include inflammation, oxidative stress, loss of neurotropic growth factors, and impaired neuroplasticity, all of which result in deleterious neuropathologic progression of damage to key brain circuits. Acute psychotic or mood episodes are recognized to have serious neurotoxic effects, just as myocardial infarction damages the myocardium. This is why patients who experience a first episode of psychosis, mania, or depression must be protected from relapsing: evidence is mounting that second (and certainly subsequent) episodes can be more damaging to the brain than first episodes and would require more aggressive treatment, similar to more advanced cancer stages. This has been well documented clinically, with excellent response to medication and remission in two-thirds of patients with first-episode schizophrenia,⁶ but far lower remission rates after multiple relapses.

Consider the following advances about the adverse neurobiologic events associated with psychotic or mood episodes at various stages of the illness:

In utero, the risk genes, copy number variations, and random mutations in the thousands of genes involved in brain development probably account for smaller brain volume and hypoplasia of certain brain regions.

In the premorbid phase (childhood and early adolescence), negative symptoms and low cognition are evident as asociality and mediocre grades.

In the prodrome phase (mid-to-late adolescence), cortical changes and cognitive decline as well as mood symptoms are more apparent. Only omega-3 fatty acids—but not atypical antipsychotics—prevented a switch to psychosis better than placebo.⁷ This suggests the emergence of a neuroinflammatory process that may respond to omega-3 fatty acids.

In the first psychotic episode, a stunning new finding⁸ reveals brain edema, with a swollen brain and smaller ventricles, caused by water diffusion into extra cellular space of both gray and white matter. Such water diffusion can trigger neuroinflammation and the beginning of serious tissue damage, which can be slowed down by antipsychotics. Increased dopamine activity is associated with an increase of free radicals (oxidative stress) and suppression of growth factors. Glutamate hypofunction, another putative factor in schizophrenia, may be associated with cognitive decline and impaired neuroplasticity.

In the second episode of psychosis, recurrent water diffusion and continued neuroinflammation lead to axonal damage and more serious neurodegeneration.⁸ This confirms the observation of more serious clinical and functional deterioration after the second episode compared with the first, and becomes much worse if the patient does not adhere to treatment and relapses. Drug response also declines, possibly because of neurodegeneration and further oxidative stress,⁹ inflammation, breakdown in white matter, disruption in neuroplasticity, and further dysconnectivity across brain regions.¹⁰

In the treatment-resistant or refractory phase, clozapine is the only agent that has been shown to improve persistent psychotic symptoms. Although its exact mechanism of action remains unknown, recent studies indicate it may be exerting some of its effects by inhibiting microglial activation,¹¹ which is the main pathway for neuroinflammation in degenerative brain disorders.

Ultimately, after multiple episodes the chromosomal telomere becomes shorter in BD and schizophrenia,¹² which is known to predict mortality. This may explain premature death in chronically mentally ill patients (apart from cardiovascular risk factors caused by obesity).

Based on the above, I propose the following clinico-biologic staging model:

Stage 0: Abnormal brain development in utero due to genetic and nongenetic factors.

Stage 1a: Poor premorbid function in childhood (asociality, mediocre school performance).

Stage 1b: The prodrome, with noticeable negative symptoms, cognitive dysfunction, and gray and white matter changes.

Stage 2: First psychotic episode, with delusions and hallucinations, increasing negative symptoms, and marked cognitive decline, accompanied by frontal, parietal, and hippocampal volume losses, white matter pathology, brain edema, inflammatory markers, oxidative stress, and decreased neurotropic growth factors.

Stage 3: Second psychotic episode, with more intense psychotic and negative symptoms, cognitive dysfunction, and worsening social and vocational functioning. Biologic signs include neuroinflammation, oxidative stress and impaired neuroplasticity biomarkers, axonal degeneration and further brain tissue loss, and slower response to antipsychotics.

Stage 4: Several psychotic episodes (subchronic phase), with residual positive and negative symptoms and continued cognitive impairment especially in memory, executive function, attention and verbal learning, accompanied by glial cell death, decline in dendritic spines, retraction or neurite extension, and low response to antipsychotics, with a Global Assessment of Functioning (GAF) score of 30 to 40.

Stage 5: Refractory, unremitting psychosis (chronic phase), with poor response to antipsychotics, severe clinical, social, and functional deterioration, inability to care for oneself, severe neurodegeneration (widespread brain atrophy and dysconnectivity), and GAF score ≤30.

This staging model implies that early intervention to prevent the first or second episode may be the best approach to arrest (and perhaps reverse) psychobiologic deterioration and modify the trajectory of serious psychiatric brain disorders. More can be done to prevent a downhill course in psychosis, and emphasizing the clinical and neurobiologic features of each stage of illness may serve as a roadmap for aggressive treatment approaches early in the illness course. Until a cure is found, prevention and early intervention are the best approaches. Staging models should be incorporated in future versions of the DSM so that psychiatric practitioners can implement the optimal treatment algorithm at the earliest stage possible. Readers’ opinions are welcome!

Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).^1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.³ These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.

In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.

CYP2D6: Many variants

CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.⁴

Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).^5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).¹⁰

Box

Table

CYP450 enzymes involved in biotransformation of SSRIs

Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.³ These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.¹¹ PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.

Suicide and CYP2D6 status

The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.¹² Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte¹² found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.¹² Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.^13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.¹⁶

A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.¹⁶ The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.¹⁷ The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.

Case reports and observational studies^18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al¹⁸ described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al¹⁹ described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al²⁰ found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al²¹ found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.

Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al²² found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al²³ found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.²⁴ Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.

Effects on serotonin, dopamine

CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.²⁵ This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.^26,27

Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.²⁸ Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.²⁹ Yu et al²⁷ found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.³⁰ Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.

Dopamine also is generated from tyramine through CYP2D6,³¹ and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.³² The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,³³ and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,² which play an important role in the development of anxiety and impulsivity.

CYP2D6 in clinical practice

Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.

Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.³⁴ The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.

Related Resources

• Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
• Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.

Drug Brand Names

• Citalopram • Celexa
• Clomipramine • Anafranil
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Nortriptyline • Aventyl, Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft

Disclosure

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

Acknowledgment

The authors thank Marwah Shahid and Ijlal Yazdani for their assistance with this article.

Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).^1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.³ These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.

In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.

CYP2D6: Many variants

CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.⁴

Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).^5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).¹⁰

Box

Table

CYP450 enzymes involved in biotransformation of SSRIs

Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.³ These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.¹¹ PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.

Suicide and CYP2D6 status

The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.¹² Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte¹² found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.¹² Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.^13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.¹⁶

A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.¹⁶ The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.¹⁷ The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.

Case reports and observational studies^18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al¹⁸ described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al¹⁹ described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al²⁰ found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al²¹ found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.

Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al²² found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al²³ found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.²⁴ Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.

Effects on serotonin, dopamine

CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.²⁵ This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.^26,27

Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.²⁸ Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.²⁹ Yu et al²⁷ found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.³⁰ Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.

Dopamine also is generated from tyramine through CYP2D6,³¹ and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.³² The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,³³ and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,² which play an important role in the development of anxiety and impulsivity.

CYP2D6 in clinical practice

Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.

Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.³⁴ The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.

Related Resources

• Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
• Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.

Drug Brand Names

• Citalopram • Celexa
• Clomipramine • Anafranil
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Nortriptyline • Aventyl, Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft

Disclosure

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

Acknowledgment

The authors thank Marwah Shahid and Ijlal Yazdani for their assistance with this article.

Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).^1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.³ These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.

In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.

CYP2D6: Many variants

CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.⁴

Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).^5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).¹⁰

Box

Table

CYP450 enzymes involved in biotransformation of SSRIs

Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.³ These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.¹¹ PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.

Suicide and CYP2D6 status

The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.¹² Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte¹² found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.¹² Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.^13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.¹⁶

A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.¹⁶ The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.¹⁷ The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.

Case reports and observational studies^18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al¹⁸ described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al¹⁹ described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al²⁰ found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al²¹ found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.

Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al²² found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al²³ found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.²⁴ Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.

Effects on serotonin, dopamine

CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.²⁵ This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.^26,27

Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.²⁸ Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.²⁹ Yu et al²⁷ found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.³⁰ Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.

Dopamine also is generated from tyramine through CYP2D6,³¹ and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.³² The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,³³ and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,² which play an important role in the development of anxiety and impulsivity.

CYP2D6 in clinical practice

Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.

Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.³⁴ The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.

Related Resources

• Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
• Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.

Drug Brand Names

• Citalopram • Celexa
• Clomipramine • Anafranil
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Nortriptyline • Aventyl, Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft

Disclosure

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

Acknowledgment

The authors thank Marwah Shahid and Ijlal Yazdani for their assistance with this article.

“The delirious substance abuser” (Cases That Test Your Skills, Current Psychiatry, January 2012, p. 58-67) was an excellent review of the complex presentations when patients use multiple substances. Recently, we admitted a patient presenting with delirium with psychosis. She presented with similar symptoms as Ms. K in your article, with the addition of severe tactile hallucinosis that led our patient to jump out of a moving vehicle because she thought bugs were crawling over her. She eventually admitted to using “bath salts” (methylenedioxypyrovalerone) orally and her psychotic symptoms remitted in 3 days.

Vineet Mehta, MD
Consulting Psychiatrist
Health First
Melbourne, FL
Private Practice
Indialantic, FL

“The delirious substance abuser” (Cases That Test Your Skills, Current Psychiatry, January 2012, p. 58-67) was an excellent review of the complex presentations when patients use multiple substances. Recently, we admitted a patient presenting with delirium with psychosis. She presented with similar symptoms as Ms. K in your article, with the addition of severe tactile hallucinosis that led our patient to jump out of a moving vehicle because she thought bugs were crawling over her. She eventually admitted to using “bath salts” (methylenedioxypyrovalerone) orally and her psychotic symptoms remitted in 3 days.

Vineet Mehta, MD
Consulting Psychiatrist
Health First
Melbourne, FL
Private Practice
Indialantic, FL

“The delirious substance abuser” (Cases That Test Your Skills, Current Psychiatry, January 2012, p. 58-67) was an excellent review of the complex presentations when patients use multiple substances. Recently, we admitted a patient presenting with delirium with psychosis. She presented with similar symptoms as Ms. K in your article, with the addition of severe tactile hallucinosis that led our patient to jump out of a moving vehicle because she thought bugs were crawling over her. She eventually admitted to using “bath salts” (methylenedioxypyrovalerone) orally and her psychotic symptoms remitted in 3 days.

Vineet Mehta, MD
Consulting Psychiatrist
Health First
Melbourne, FL
Private Practice
Indialantic, FL

Because psychiatric medications are complex to manage, I oppose psychologists being certified to prescribe. During medical school, I received 4 years of advanced training in physiology and pharmacology. After medical school, I completed a full year of preliminary internal medicine and an additional 3-year psychiatry residency to further increase my knowledge in managing mental illness. I am certified by the American Board of Psychiatry and Neurology, a process that included written and oral examinations over 2 years after residency to prove my expertise in psychopharmacology, diagnosis, treatment, risk assessment, and psychotherapy. I provide medications and psychotherapy for my patients as indicated. This is the rigorous path most physicians take to becoming a psychiatrist in the United States. One of my biggest concerns about psychologists prescribing is lack of medical training to make a complete differential diagnosis that includes medical causes of a mental disturbance, limited knowledge of drug-drug interactions, and potential to harm patients because of their lack of medical training. For example, a patient taking the blood thinner warfarin may have their ability to clot fatally impaired by a psychotropic drug because of a lack of adequate medical evaluation by a “prescriber” who has limited training in medical management and pharmacology. Another example of the need for medical training to fully evaluate psychiatric patients is an apathetic, depressed patient who continues to be treated with antidepressants while his or her underlying neurologic problem, thyroid condition, or undeclared substance abuse goes undiagnosed.

Lithium is the gold standard medication for bipolar disorder, but if managed incorrectly, without considering the patient’s overall medical condition, drug interactions, and daily physical activities, this drug can lead to kidney failure, coma, brain damage, and death. Many, if not all, psychotropics require ordering and interpreting diagnostic laboratory blood testing before and after initiating treatment to monitor for life-threatening complications, including diabetes and neuroleptic malignant syndrome, and changes in white blood cell count, potassium and sodium levels, and ECG data.

Medical education is long and challenging because the human body—especially the mind—is a complex system that requires a great deal of study to comprehend. A physician’s duty is to do no harm; extensive training is the most important tool for preventing unnecessary harm.

Shalini Varma, MDPrivate PracticeKenosha, WIVernon Hills, IL

Because psychiatric medications are complex to manage, I oppose psychologists being certified to prescribe. During medical school, I received 4 years of advanced training in physiology and pharmacology. After medical school, I completed a full year of preliminary internal medicine and an additional 3-year psychiatry residency to further increase my knowledge in managing mental illness. I am certified by the American Board of Psychiatry and Neurology, a process that included written and oral examinations over 2 years after residency to prove my expertise in psychopharmacology, diagnosis, treatment, risk assessment, and psychotherapy. I provide medications and psychotherapy for my patients as indicated. This is the rigorous path most physicians take to becoming a psychiatrist in the United States. One of my biggest concerns about psychologists prescribing is lack of medical training to make a complete differential diagnosis that includes medical causes of a mental disturbance, limited knowledge of drug-drug interactions, and potential to harm patients because of their lack of medical training. For example, a patient taking the blood thinner warfarin may have their ability to clot fatally impaired by a psychotropic drug because of a lack of adequate medical evaluation by a “prescriber” who has limited training in medical management and pharmacology. Another example of the need for medical training to fully evaluate psychiatric patients is an apathetic, depressed patient who continues to be treated with antidepressants while his or her underlying neurologic problem, thyroid condition, or undeclared substance abuse goes undiagnosed.

Lithium is the gold standard medication for bipolar disorder, but if managed incorrectly, without considering the patient’s overall medical condition, drug interactions, and daily physical activities, this drug can lead to kidney failure, coma, brain damage, and death. Many, if not all, psychotropics require ordering and interpreting diagnostic laboratory blood testing before and after initiating treatment to monitor for life-threatening complications, including diabetes and neuroleptic malignant syndrome, and changes in white blood cell count, potassium and sodium levels, and ECG data.

Medical education is long and challenging because the human body—especially the mind—is a complex system that requires a great deal of study to comprehend. A physician’s duty is to do no harm; extensive training is the most important tool for preventing unnecessary harm.

Shalini Varma, MDPrivate PracticeKenosha, WIVernon Hills, IL

Because psychiatric medications are complex to manage, I oppose psychologists being certified to prescribe. During medical school, I received 4 years of advanced training in physiology and pharmacology. After medical school, I completed a full year of preliminary internal medicine and an additional 3-year psychiatry residency to further increase my knowledge in managing mental illness. I am certified by the American Board of Psychiatry and Neurology, a process that included written and oral examinations over 2 years after residency to prove my expertise in psychopharmacology, diagnosis, treatment, risk assessment, and psychotherapy. I provide medications and psychotherapy for my patients as indicated. This is the rigorous path most physicians take to becoming a psychiatrist in the United States. One of my biggest concerns about psychologists prescribing is lack of medical training to make a complete differential diagnosis that includes medical causes of a mental disturbance, limited knowledge of drug-drug interactions, and potential to harm patients because of their lack of medical training. For example, a patient taking the blood thinner warfarin may have their ability to clot fatally impaired by a psychotropic drug because of a lack of adequate medical evaluation by a “prescriber” who has limited training in medical management and pharmacology. Another example of the need for medical training to fully evaluate psychiatric patients is an apathetic, depressed patient who continues to be treated with antidepressants while his or her underlying neurologic problem, thyroid condition, or undeclared substance abuse goes undiagnosed.

Lithium is the gold standard medication for bipolar disorder, but if managed incorrectly, without considering the patient’s overall medical condition, drug interactions, and daily physical activities, this drug can lead to kidney failure, coma, brain damage, and death. Many, if not all, psychotropics require ordering and interpreting diagnostic laboratory blood testing before and after initiating treatment to monitor for life-threatening complications, including diabetes and neuroleptic malignant syndrome, and changes in white blood cell count, potassium and sodium levels, and ECG data.

Medical education is long and challenging because the human body—especially the mind—is a complex system that requires a great deal of study to comprehend. A physician’s duty is to do no harm; extensive training is the most important tool for preventing unnecessary harm.

Shalini Varma, MDPrivate PracticeKenosha, WIVernon Hills, IL

I would like to thank Drs. Hatters Friedman and Hall for their excellent article, “Antidepressant use during pregnancy: How to avoid clinical and legal pitfalls” (Current Psychiatry, February 2013, p. 10-17; http://bit.ly/1EIIYvD). Their emphasis on the risks of untreated depression was much appreciated and resonated deeply with me because of my own experiences.

During the second year of my residency, I treated a 31-year-old woman who experienced depressive symptoms starting in her first trimester of pregnancy. She was suffering from major depressive disorder, single episode, mild type, and was referred to me for psychotherapy. As the therapy and her pregnancy progressed, her depression worsened and I faced the difficult decision of starting a pregnant woman on psychotropics.

Despite her worsening symptoms, I was hesitant to offer her medication because she was pregnant. My discussion with my psychotherapy supervisor was the first in a series of events that made me aware of the stigma regarding prescribing psychotropics to pregnant women. I was amazed when he expressed his views of “not exposing pregnant women to medications” without a reasonable discussion of benefits. While discussing the risks, my patient replied bitterly: “You doctors won’t even say Tylenol is safe…everybody only thinks about the baby. What about me? I stopped being a person the day I became pregnant.”

After a careful risk-benefit discussion, and with guidance from my psychopharmacology supervisor, we started my patient on sertraline. More than 6 years later, I still recall my patient’s description of her attempt to fill her prescription. She said the pharmacist refused to fill the prescription and told her that a pregnant woman should not be taking that medication, implying she was being a “bad mother.” She said to me, “I did not have the strength to walk across the road to the other pharmacy. This incident again confirmed that I don’t exist; I am just a body for the baby.” I was horrified. Are we not taught to discuss the risks and the benefits of a treatment, and then help patients make the best decision for themselves? I am amazed at how often we let our personal views bias the way we look at objective evidence and how little we think of what a patient wants or needs.

After a few weeks, my patient started sertraline and responded well. She continued to attend therapy regularly. For months after her symptoms remitted, she described how disconnected she had felt from herself and how she later grieved for the time lost. Although she never blamed me, I always felt guilty for adding a few weeks to her suffering by not starting her on medication earlier.

This experience had a lasting personal impact. I am committed to ensuring that my residents and I are up-to-date about prescribing psychotropics for pregnant patients. However, the need for these well balanced and well written articles is ongoing, because I continue to see patients whose psychosis or depression worsens dramatically because their psychiatrist abruptly stopped maintenance medications during pregnancy.

Rashi Aggarwal, MDAssistant ProfessorUMDNJ-New Jersey Medical SchoolNewark, NJ

I would like to thank Drs. Hatters Friedman and Hall for their excellent article, “Antidepressant use during pregnancy: How to avoid clinical and legal pitfalls” (Current Psychiatry, February 2013, p. 10-17; http://bit.ly/1EIIYvD). Their emphasis on the risks of untreated depression was much appreciated and resonated deeply with me because of my own experiences.

During the second year of my residency, I treated a 31-year-old woman who experienced depressive symptoms starting in her first trimester of pregnancy. She was suffering from major depressive disorder, single episode, mild type, and was referred to me for psychotherapy. As the therapy and her pregnancy progressed, her depression worsened and I faced the difficult decision of starting a pregnant woman on psychotropics.

Despite her worsening symptoms, I was hesitant to offer her medication because she was pregnant. My discussion with my psychotherapy supervisor was the first in a series of events that made me aware of the stigma regarding prescribing psychotropics to pregnant women. I was amazed when he expressed his views of “not exposing pregnant women to medications” without a reasonable discussion of benefits. While discussing the risks, my patient replied bitterly: “You doctors won’t even say Tylenol is safe…everybody only thinks about the baby. What about me? I stopped being a person the day I became pregnant.”

After a careful risk-benefit discussion, and with guidance from my psychopharmacology supervisor, we started my patient on sertraline. More than 6 years later, I still recall my patient’s description of her attempt to fill her prescription. She said the pharmacist refused to fill the prescription and told her that a pregnant woman should not be taking that medication, implying she was being a “bad mother.” She said to me, “I did not have the strength to walk across the road to the other pharmacy. This incident again confirmed that I don’t exist; I am just a body for the baby.” I was horrified. Are we not taught to discuss the risks and the benefits of a treatment, and then help patients make the best decision for themselves? I am amazed at how often we let our personal views bias the way we look at objective evidence and how little we think of what a patient wants or needs.

After a few weeks, my patient started sertraline and responded well. She continued to attend therapy regularly. For months after her symptoms remitted, she described how disconnected she had felt from herself and how she later grieved for the time lost. Although she never blamed me, I always felt guilty for adding a few weeks to her suffering by not starting her on medication earlier.

This experience had a lasting personal impact. I am committed to ensuring that my residents and I are up-to-date about prescribing psychotropics for pregnant patients. However, the need for these well balanced and well written articles is ongoing, because I continue to see patients whose psychosis or depression worsens dramatically because their psychiatrist abruptly stopped maintenance medications during pregnancy.

Rashi Aggarwal, MDAssistant ProfessorUMDNJ-New Jersey Medical SchoolNewark, NJ

I would like to thank Drs. Hatters Friedman and Hall for their excellent article, “Antidepressant use during pregnancy: How to avoid clinical and legal pitfalls” (Current Psychiatry, February 2013, p. 10-17; http://bit.ly/1EIIYvD). Their emphasis on the risks of untreated depression was much appreciated and resonated deeply with me because of my own experiences.

During the second year of my residency, I treated a 31-year-old woman who experienced depressive symptoms starting in her first trimester of pregnancy. She was suffering from major depressive disorder, single episode, mild type, and was referred to me for psychotherapy. As the therapy and her pregnancy progressed, her depression worsened and I faced the difficult decision of starting a pregnant woman on psychotropics.

Despite her worsening symptoms, I was hesitant to offer her medication because she was pregnant. My discussion with my psychotherapy supervisor was the first in a series of events that made me aware of the stigma regarding prescribing psychotropics to pregnant women. I was amazed when he expressed his views of “not exposing pregnant women to medications” without a reasonable discussion of benefits. While discussing the risks, my patient replied bitterly: “You doctors won’t even say Tylenol is safe…everybody only thinks about the baby. What about me? I stopped being a person the day I became pregnant.”

After a careful risk-benefit discussion, and with guidance from my psychopharmacology supervisor, we started my patient on sertraline. More than 6 years later, I still recall my patient’s description of her attempt to fill her prescription. She said the pharmacist refused to fill the prescription and told her that a pregnant woman should not be taking that medication, implying she was being a “bad mother.” She said to me, “I did not have the strength to walk across the road to the other pharmacy. This incident again confirmed that I don’t exist; I am just a body for the baby.” I was horrified. Are we not taught to discuss the risks and the benefits of a treatment, and then help patients make the best decision for themselves? I am amazed at how often we let our personal views bias the way we look at objective evidence and how little we think of what a patient wants or needs.

After a few weeks, my patient started sertraline and responded well. She continued to attend therapy regularly. For months after her symptoms remitted, she described how disconnected she had felt from herself and how she later grieved for the time lost. Although she never blamed me, I always felt guilty for adding a few weeks to her suffering by not starting her on medication earlier.

This experience had a lasting personal impact. I am committed to ensuring that my residents and I are up-to-date about prescribing psychotropics for pregnant patients. However, the need for these well balanced and well written articles is ongoing, because I continue to see patients whose psychosis or depression worsens dramatically because their psychiatrist abruptly stopped maintenance medications during pregnancy.

Rashi Aggarwal, MDAssistant ProfessorUMDNJ-New Jersey Medical SchoolNewark, NJ

Mrs. L, age 27, has a history of major depressive disorder with symptoms of anxiety. She was managed successfully for 2 years with bupropion XL, 300 mg/d, but was switched to venlafaxine, titrated to 225 mg/d, after she developed seizures secondary to a head injury sustained in a car accident. After the switch, Mrs. L’s mood deteriorated and she was hospitalized. Since then, she’s received several medication trials, including paroxetine, 30 mg/d, a selective serotonin reuptake inhibitor (SSRI), and the tricyclic antidepressant (TCA) nortriptyline, 75 mg/d, but she could not tolerate these medications because of severe xerostomia.

After taking sertraline, 150 mg/d, for 8 weeks, Mrs. L improves and has a Patient Health Questionnaire score of 6, indicating mild depression. Her initial complaints of diarrhea and nausea have resolved, but Mrs. L now reports that she and her husband are having marital difficulties because she cannot achieve orgasm during sexual intercourse. She did not have this problem when she was taking bupropion. Her husband occasionally takes the phosphodiesterase type 5 (PDE5) inhibitor sildenafil before intercourse, and Mrs. L asks you if this medication will help her achieve orgasm.

DSM-IV-TR defines sexual dysfunction as disturbances in sexual desire and/or in the sexual response cycle (excitement, plateau, orgasm, and resolution) that result in marked distress and interpersonal difficulty.¹ Sexual dysfunction can occur with the use of any antidepressant with serotonergic activity; it affects an estimated 50% to 70% of patients who take SSRIs.² Sexual dysfunction can occur with all SSRIs; however, higher rates of sexual dysfunction are found with citalopram, fluoxetine, paroxetine, and sertraline.³ Studies have suggested there may be a dose-side effect relationship with SSRI-induced sexual dysfunction.⁴

Several factors can increase a patient’s risk of sexual dysfunction and should be considered before prescribing an antidepressant or when a patient presents with new or worsening sexual dysfunction (Table 1).⁵ In general, nonserotonergic agents such as bupropion, mirtazapine, and nefazodone are associated with lower rates of sexual dysfunction. The pharmacology of these agents explains their decreased propensity to cause sexual dysfunction. These agents increase levels of dopamine in the mesolimbic dopaminergic system either by blocking reuptake (bupropion) or antagonizing the serotonin subtype-2 receptor and facilitating disinhibition of decreased dopamine downstream (nefazodone and mirtazapine).

Table 1

Risk factors for sexual dysfunction

One option for treating antidepressant-induced sexual dysfunction in women is PDE5 inhibitors, which are used to treat erectile dysfunction (ED). These medications ameliorate ED by inhibiting degradation of cyclic guanosine monophosphate by PDE5, which increases blood flow to the penis during sexual stimulation. Although these medications are not FDA-approved for treating sexual dysfunction in women, adjunctive PDE5 inhibitor treatment may be beneficial for sexual dysfunction in females because similar mediators, such as nitric oxide and cyclic guanosine monophosphate, involved in the nonadrenergic-noncholinergic signaling that controls sexual stimulation in men also are found in female genital tissue.⁶

When treating a woman with SSRI-induced sexual dysfunction, consider nonpharmacologic treatments both before and during pharmacotherapy (Table 2).^7,8 See Table 3 for a comparison of pharmacokinetics, side effects, and drug interactions of the 4 FDA-approved PDE5 inhibitors—avanafil, sildenafil, tadalafil, and vardenafil.

Table 2

Management strategies for SSRI-induced sexual dysfunction

Table 3

Phosphodiesterase type 5 inhibitors: A comparison

Limited evidence for sildenafil

Case reports, a few small open-label trials, and 1 prospective, randomized controlled trial (RCT) have evaluated sildenafil as an adjunctive treatment for serotonergic antidepressant-associated sexual dysfunction in women.^6,9 Nurnberg et al⁶ examined the efficacy of adjunctive sildenafil in women with SSRI-induced sexual dysfunction. This 8-week, placebo-controlled, double-blind, RCT used a flexible dose (50 or 100 mg), intention-to-treat design to assess the effect of sildenafil on 98 premenopausal women whose depression was in remission. Ten patients were taking the serotonin-norepinephrine inhibitor venlafaxine, 1 was taking the TCA clomipramine, and 87 were receiving an SSRI. Patients were instructed to take sildenafil or placebo 1 to 2 hours before sexual activity. The primary outcome was mean change from baseline on the Clinical Global Impression-Sexual Function (CGI-SF) scale.

Women taking sildenafil showed significant improvement compared with those taking placebo, with a treatment difference between groups of 0.8 (95% CI, 0.6 to 1.0; =.001). Additionally, 23% of sildenafil-treated patients reported no improvement with the intervention, compared with 73% of patients receiving placebo. Secondary outcomes using 3 validated scales that evaluated specific phases of sexual function found that patients’ orgasmic function significantly benefited from sildenafil treatment, while desire, arousal, and overall satisfaction were not significantly different.

Although these findings seem to support sildenafil for treating serotonergic antidepressant-associated sexual dysfunction in women, the study had a relatively small treatment effect in a well-defined patient population; therefore, replication in future trials and different patient populations is warranted. Overall, sildenafil was well tolerated, despite patient reports of headaches, flushing, visual disturbances, dyspepsia, nasal congestion, and palpitations. Finally, cost vs benefit should be considered; PDE5 inhibitors may not be covered by insurance or may require prior authorization.

CASE CONTINUED: Symptoms resolve

Bupropion is not an appropriate choice for Mrs. L because of her seizure risk. Mirtazapine is ruled out because in the past she experienced excessive somnolence that impaired her ability to function. You are not comfortable prescribing nefazodone because of its risk of hepatotoxicity or suggesting that Mrs. L take a “drug holiday” (stop taking any antidepressants for a short period) because of the risk of depressive relapse. You suggest that Mrs. L continue to take sertraline because sometimes antidepressant-induced sexual dysfunction resolves after ≥6 months of treatment with the same agent, but she is adamant that her relationship with her husband will deteriorate if she waits that long. She also declines cognitive-behavioral therapy because her job doesn’t allow the time or flexibility to commit to the sessions.

You prescribe sildenafil, 50 mg, and instruct Mrs. L to take 1 tablet 1 to 2 hours before sexual activity. This treatment improves her ability to achieve orgasm. She tolerates the drug well and after 8 weeks of treatment her CGI-SF score improves from 6 at baseline, indicating extreme dysfunction, to 2, indicating normal function. Ten months into her sertraline treatment, Mrs. L discovers she no longer requires sildenafil to achieve orgasm.

Related Resources

• Nurnberg HG. An evidence-based review updating the various treatment and management approaches to serotonin reuptake inhibitor-associated sexual dysfunction. Drugs Today (Barc). 2008;44(2):147-168.
• NIH Medline Plus. Sexual problems in women. www.nlm.nih.gov/medlineplus/sexualproblemsinwomen.html.
• Sturpe DA, Mertens MK, Scoville C. What are the treatment options for SSRI-related sexual dysfunction? J Fam Pract. 2002;51(8):681.

Drug Brand Names

• Amantadine • Symadine, Symmetrel
• Avanafil • Stendra
• Bupropion • Wellbutrin, Zyban
• Buspirone • BuSpar
• Citalopram • Celexa
• Clomipramine • Anafranil
• Fluoxetine • Prozac
• Granisetron • Kytril
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nitroglycerin • Nitrostat
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra
• Venlafaxine • Effexor

Disclosures

Dr. Burghardt receives grant or research support from the University of Michigan Depression Center.

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

Mrs. L, age 27, has a history of major depressive disorder with symptoms of anxiety. She was managed successfully for 2 years with bupropion XL, 300 mg/d, but was switched to venlafaxine, titrated to 225 mg/d, after she developed seizures secondary to a head injury sustained in a car accident. After the switch, Mrs. L’s mood deteriorated and she was hospitalized. Since then, she’s received several medication trials, including paroxetine, 30 mg/d, a selective serotonin reuptake inhibitor (SSRI), and the tricyclic antidepressant (TCA) nortriptyline, 75 mg/d, but she could not tolerate these medications because of severe xerostomia.

After taking sertraline, 150 mg/d, for 8 weeks, Mrs. L improves and has a Patient Health Questionnaire score of 6, indicating mild depression. Her initial complaints of diarrhea and nausea have resolved, but Mrs. L now reports that she and her husband are having marital difficulties because she cannot achieve orgasm during sexual intercourse. She did not have this problem when she was taking bupropion. Her husband occasionally takes the phosphodiesterase type 5 (PDE5) inhibitor sildenafil before intercourse, and Mrs. L asks you if this medication will help her achieve orgasm.

DSM-IV-TR defines sexual dysfunction as disturbances in sexual desire and/or in the sexual response cycle (excitement, plateau, orgasm, and resolution) that result in marked distress and interpersonal difficulty.¹ Sexual dysfunction can occur with the use of any antidepressant with serotonergic activity; it affects an estimated 50% to 70% of patients who take SSRIs.² Sexual dysfunction can occur with all SSRIs; however, higher rates of sexual dysfunction are found with citalopram, fluoxetine, paroxetine, and sertraline.³ Studies have suggested there may be a dose-side effect relationship with SSRI-induced sexual dysfunction.⁴

Several factors can increase a patient’s risk of sexual dysfunction and should be considered before prescribing an antidepressant or when a patient presents with new or worsening sexual dysfunction (Table 1).⁵ In general, nonserotonergic agents such as bupropion, mirtazapine, and nefazodone are associated with lower rates of sexual dysfunction. The pharmacology of these agents explains their decreased propensity to cause sexual dysfunction. These agents increase levels of dopamine in the mesolimbic dopaminergic system either by blocking reuptake (bupropion) or antagonizing the serotonin subtype-2 receptor and facilitating disinhibition of decreased dopamine downstream (nefazodone and mirtazapine).

Table 1

Risk factors for sexual dysfunction

One option for treating antidepressant-induced sexual dysfunction in women is PDE5 inhibitors, which are used to treat erectile dysfunction (ED). These medications ameliorate ED by inhibiting degradation of cyclic guanosine monophosphate by PDE5, which increases blood flow to the penis during sexual stimulation. Although these medications are not FDA-approved for treating sexual dysfunction in women, adjunctive PDE5 inhibitor treatment may be beneficial for sexual dysfunction in females because similar mediators, such as nitric oxide and cyclic guanosine monophosphate, involved in the nonadrenergic-noncholinergic signaling that controls sexual stimulation in men also are found in female genital tissue.⁶

When treating a woman with SSRI-induced sexual dysfunction, consider nonpharmacologic treatments both before and during pharmacotherapy (Table 2).^7,8 See Table 3 for a comparison of pharmacokinetics, side effects, and drug interactions of the 4 FDA-approved PDE5 inhibitors—avanafil, sildenafil, tadalafil, and vardenafil.

Table 2

Management strategies for SSRI-induced sexual dysfunction

Table 3

Phosphodiesterase type 5 inhibitors: A comparison

Limited evidence for sildenafil

Case reports, a few small open-label trials, and 1 prospective, randomized controlled trial (RCT) have evaluated sildenafil as an adjunctive treatment for serotonergic antidepressant-associated sexual dysfunction in women.^6,9 Nurnberg et al⁶ examined the efficacy of adjunctive sildenafil in women with SSRI-induced sexual dysfunction. This 8-week, placebo-controlled, double-blind, RCT used a flexible dose (50 or 100 mg), intention-to-treat design to assess the effect of sildenafil on 98 premenopausal women whose depression was in remission. Ten patients were taking the serotonin-norepinephrine inhibitor venlafaxine, 1 was taking the TCA clomipramine, and 87 were receiving an SSRI. Patients were instructed to take sildenafil or placebo 1 to 2 hours before sexual activity. The primary outcome was mean change from baseline on the Clinical Global Impression-Sexual Function (CGI-SF) scale.

Women taking sildenafil showed significant improvement compared with those taking placebo, with a treatment difference between groups of 0.8 (95% CI, 0.6 to 1.0; =.001). Additionally, 23% of sildenafil-treated patients reported no improvement with the intervention, compared with 73% of patients receiving placebo. Secondary outcomes using 3 validated scales that evaluated specific phases of sexual function found that patients’ orgasmic function significantly benefited from sildenafil treatment, while desire, arousal, and overall satisfaction were not significantly different.

Although these findings seem to support sildenafil for treating serotonergic antidepressant-associated sexual dysfunction in women, the study had a relatively small treatment effect in a well-defined patient population; therefore, replication in future trials and different patient populations is warranted. Overall, sildenafil was well tolerated, despite patient reports of headaches, flushing, visual disturbances, dyspepsia, nasal congestion, and palpitations. Finally, cost vs benefit should be considered; PDE5 inhibitors may not be covered by insurance or may require prior authorization.

CASE CONTINUED: Symptoms resolve

Bupropion is not an appropriate choice for Mrs. L because of her seizure risk. Mirtazapine is ruled out because in the past she experienced excessive somnolence that impaired her ability to function. You are not comfortable prescribing nefazodone because of its risk of hepatotoxicity or suggesting that Mrs. L take a “drug holiday” (stop taking any antidepressants for a short period) because of the risk of depressive relapse. You suggest that Mrs. L continue to take sertraline because sometimes antidepressant-induced sexual dysfunction resolves after ≥6 months of treatment with the same agent, but she is adamant that her relationship with her husband will deteriorate if she waits that long. She also declines cognitive-behavioral therapy because her job doesn’t allow the time or flexibility to commit to the sessions.

You prescribe sildenafil, 50 mg, and instruct Mrs. L to take 1 tablet 1 to 2 hours before sexual activity. This treatment improves her ability to achieve orgasm. She tolerates the drug well and after 8 weeks of treatment her CGI-SF score improves from 6 at baseline, indicating extreme dysfunction, to 2, indicating normal function. Ten months into her sertraline treatment, Mrs. L discovers she no longer requires sildenafil to achieve orgasm.

Related Resources

• Nurnberg HG. An evidence-based review updating the various treatment and management approaches to serotonin reuptake inhibitor-associated sexual dysfunction. Drugs Today (Barc). 2008;44(2):147-168.
• NIH Medline Plus. Sexual problems in women. www.nlm.nih.gov/medlineplus/sexualproblemsinwomen.html.
• Sturpe DA, Mertens MK, Scoville C. What are the treatment options for SSRI-related sexual dysfunction? J Fam Pract. 2002;51(8):681.

Drug Brand Names

• Amantadine • Symadine, Symmetrel
• Avanafil • Stendra
• Bupropion • Wellbutrin, Zyban
• Buspirone • BuSpar
• Citalopram • Celexa
• Clomipramine • Anafranil
• Fluoxetine • Prozac
• Granisetron • Kytril
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nitroglycerin • Nitrostat
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra
• Venlafaxine • Effexor

Disclosures

Dr. Burghardt receives grant or research support from the University of Michigan Depression Center.

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

Mrs. L, age 27, has a history of major depressive disorder with symptoms of anxiety. She was managed successfully for 2 years with bupropion XL, 300 mg/d, but was switched to venlafaxine, titrated to 225 mg/d, after she developed seizures secondary to a head injury sustained in a car accident. After the switch, Mrs. L’s mood deteriorated and she was hospitalized. Since then, she’s received several medication trials, including paroxetine, 30 mg/d, a selective serotonin reuptake inhibitor (SSRI), and the tricyclic antidepressant (TCA) nortriptyline, 75 mg/d, but she could not tolerate these medications because of severe xerostomia.

After taking sertraline, 150 mg/d, for 8 weeks, Mrs. L improves and has a Patient Health Questionnaire score of 6, indicating mild depression. Her initial complaints of diarrhea and nausea have resolved, but Mrs. L now reports that she and her husband are having marital difficulties because she cannot achieve orgasm during sexual intercourse. She did not have this problem when she was taking bupropion. Her husband occasionally takes the phosphodiesterase type 5 (PDE5) inhibitor sildenafil before intercourse, and Mrs. L asks you if this medication will help her achieve orgasm.

DSM-IV-TR defines sexual dysfunction as disturbances in sexual desire and/or in the sexual response cycle (excitement, plateau, orgasm, and resolution) that result in marked distress and interpersonal difficulty.¹ Sexual dysfunction can occur with the use of any antidepressant with serotonergic activity; it affects an estimated 50% to 70% of patients who take SSRIs.² Sexual dysfunction can occur with all SSRIs; however, higher rates of sexual dysfunction are found with citalopram, fluoxetine, paroxetine, and sertraline.³ Studies have suggested there may be a dose-side effect relationship with SSRI-induced sexual dysfunction.⁴

Several factors can increase a patient’s risk of sexual dysfunction and should be considered before prescribing an antidepressant or when a patient presents with new or worsening sexual dysfunction (Table 1).⁵ In general, nonserotonergic agents such as bupropion, mirtazapine, and nefazodone are associated with lower rates of sexual dysfunction. The pharmacology of these agents explains their decreased propensity to cause sexual dysfunction. These agents increase levels of dopamine in the mesolimbic dopaminergic system either by blocking reuptake (bupropion) or antagonizing the serotonin subtype-2 receptor and facilitating disinhibition of decreased dopamine downstream (nefazodone and mirtazapine).

Table 1

Risk factors for sexual dysfunction

One option for treating antidepressant-induced sexual dysfunction in women is PDE5 inhibitors, which are used to treat erectile dysfunction (ED). These medications ameliorate ED by inhibiting degradation of cyclic guanosine monophosphate by PDE5, which increases blood flow to the penis during sexual stimulation. Although these medications are not FDA-approved for treating sexual dysfunction in women, adjunctive PDE5 inhibitor treatment may be beneficial for sexual dysfunction in females because similar mediators, such as nitric oxide and cyclic guanosine monophosphate, involved in the nonadrenergic-noncholinergic signaling that controls sexual stimulation in men also are found in female genital tissue.⁶

When treating a woman with SSRI-induced sexual dysfunction, consider nonpharmacologic treatments both before and during pharmacotherapy (Table 2).^7,8 See Table 3 for a comparison of pharmacokinetics, side effects, and drug interactions of the 4 FDA-approved PDE5 inhibitors—avanafil, sildenafil, tadalafil, and vardenafil.

Table 2

Management strategies for SSRI-induced sexual dysfunction

Table 3

Phosphodiesterase type 5 inhibitors: A comparison

Limited evidence for sildenafil

Case reports, a few small open-label trials, and 1 prospective, randomized controlled trial (RCT) have evaluated sildenafil as an adjunctive treatment for serotonergic antidepressant-associated sexual dysfunction in women.^6,9 Nurnberg et al⁶ examined the efficacy of adjunctive sildenafil in women with SSRI-induced sexual dysfunction. This 8-week, placebo-controlled, double-blind, RCT used a flexible dose (50 or 100 mg), intention-to-treat design to assess the effect of sildenafil on 98 premenopausal women whose depression was in remission. Ten patients were taking the serotonin-norepinephrine inhibitor venlafaxine, 1 was taking the TCA clomipramine, and 87 were receiving an SSRI. Patients were instructed to take sildenafil or placebo 1 to 2 hours before sexual activity. The primary outcome was mean change from baseline on the Clinical Global Impression-Sexual Function (CGI-SF) scale.

Women taking sildenafil showed significant improvement compared with those taking placebo, with a treatment difference between groups of 0.8 (95% CI, 0.6 to 1.0; =.001). Additionally, 23% of sildenafil-treated patients reported no improvement with the intervention, compared with 73% of patients receiving placebo. Secondary outcomes using 3 validated scales that evaluated specific phases of sexual function found that patients’ orgasmic function significantly benefited from sildenafil treatment, while desire, arousal, and overall satisfaction were not significantly different.

Although these findings seem to support sildenafil for treating serotonergic antidepressant-associated sexual dysfunction in women, the study had a relatively small treatment effect in a well-defined patient population; therefore, replication in future trials and different patient populations is warranted. Overall, sildenafil was well tolerated, despite patient reports of headaches, flushing, visual disturbances, dyspepsia, nasal congestion, and palpitations. Finally, cost vs benefit should be considered; PDE5 inhibitors may not be covered by insurance or may require prior authorization.

CASE CONTINUED: Symptoms resolve

Bupropion is not an appropriate choice for Mrs. L because of her seizure risk. Mirtazapine is ruled out because in the past she experienced excessive somnolence that impaired her ability to function. You are not comfortable prescribing nefazodone because of its risk of hepatotoxicity or suggesting that Mrs. L take a “drug holiday” (stop taking any antidepressants for a short period) because of the risk of depressive relapse. You suggest that Mrs. L continue to take sertraline because sometimes antidepressant-induced sexual dysfunction resolves after ≥6 months of treatment with the same agent, but she is adamant that her relationship with her husband will deteriorate if she waits that long. She also declines cognitive-behavioral therapy because her job doesn’t allow the time or flexibility to commit to the sessions.

You prescribe sildenafil, 50 mg, and instruct Mrs. L to take 1 tablet 1 to 2 hours before sexual activity. This treatment improves her ability to achieve orgasm. She tolerates the drug well and after 8 weeks of treatment her CGI-SF score improves from 6 at baseline, indicating extreme dysfunction, to 2, indicating normal function. Ten months into her sertraline treatment, Mrs. L discovers she no longer requires sildenafil to achieve orgasm.

Related Resources

• Nurnberg HG. An evidence-based review updating the various treatment and management approaches to serotonin reuptake inhibitor-associated sexual dysfunction. Drugs Today (Barc). 2008;44(2):147-168.
• NIH Medline Plus. Sexual problems in women. www.nlm.nih.gov/medlineplus/sexualproblemsinwomen.html.
• Sturpe DA, Mertens MK, Scoville C. What are the treatment options for SSRI-related sexual dysfunction? J Fam Pract. 2002;51(8):681.

Drug Brand Names

• Amantadine • Symadine, Symmetrel
• Avanafil • Stendra
• Bupropion • Wellbutrin, Zyban
• Buspirone • BuSpar
• Citalopram • Celexa
• Clomipramine • Anafranil
• Fluoxetine • Prozac
• Granisetron • Kytril
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nitroglycerin • Nitrostat
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra
• Venlafaxine • Effexor

Disclosures

Dr. Burghardt receives grant or research support from the University of Michigan Depression Center.

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