Out Of The Pipeline

Sildenafil has revolutionized management of erectile dysfunction (ED) over the past 5 years. The FDA recently approved two additional medications, vardenafil and tadalafil, for treating ED.

How vardenafil and tadalafil work

Like sildenafil, vardenafil and tadalafil are selective inhibitors of the phosphodiesterase (PDE) isoenzyme PDE-5, which is predominantly responsible for degrading cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

During sexual stimulation, nitric oxide is released from cavernous nerves and endothelial cells and activates the enzyme guanylate cyclase, resulting in increased cGMP synthesis. The cGMP triggers relaxation of smooth muscles, allowing increased blood flow into the penis and expansion of sinusoidal spaces; this prevents venous blood outflow and results in erection. The PDE-5 inhibitors can potentiate erections by enhancing and prolonging the smooth musclerelaxant effects of the nitric oxide-cGMP cascade in the corpus cavernosum.¹ PDE-5 inhibitors have no effect without sexual stimulation.

Table 1

Pharmacokinetics of the PDE-5 inhibitors

Although the three PDE-5 inhibitors have similar mechanisms of action, their selectivity differs for PDE-5 compared with the PDE-6 and PDE-11 isoenzymes. Sildenafil and vardenafil have lower selectivity than tadalafil for PDE-5 over PDE-6, which plays a role in phototransduction, the process by which light impulses are converted into nerve impulses in the retina. Thus, tadalafil is less likely than the other agents to cause visual disturbances such as abnormal color vision, increased brightness of light, or mild haziness.

Tadalafil shows lower selectivity than sildenafil or vardenafil for PDE-5 over PDE-11, meaning that tadalafil inhibits PDE-11 at clinical doses. PDE-11 is found in various tissues, but its physiologic significance and consequences of its inhibition are unknown.²

Pharmacokinetics

Vardenafil, tadalafil, and sildenafil have different pharmacokinetic characteristics (Table 1). A lower starting dosage is required with vardenafil than with sildenafil because of the former agent’s greater in vitro and in vivo potency, but whether this results in greater clinical efficacy or tolerability is unknown.³

Vardenafil and sildenafil reach maximum plasma concentration within 30 minutes to 2 hours (median 1 hour for sildenafil and 0.7 hour for vardenafil). By contrast, tadalafil reaches maximum concentration within 30 minutes to 6 hours (median 2 hours). However, studies of time to onset of erection indicate that about one-third of patients using the maximum recommended doses of any of these agents will experience onset within 14 to 16 minutes.^4-6

Absorption rates for sildenafil and vardenafil are reduced when they are taken with a high-fat meal. High-fat foods do not affect tadalafil’s absorption rate.

Table 2

Vardenafil: Fast facts

Because of its 17.5-hour half-life, tadalafil has a longer period of activity than the other PDE-5 inhibitors. Most patients can complete sexual intercourse up to 36 hours after taking tadalafil, which potentially allows spontaneous sexual activity. Sildenafil and vardenafil each are effective for about 4 hours.

All three PDE-5 inhibitors are eliminated by hepatic metabolism, mainly by the CYP 3A4 hepatic enzyme. Therefore, concomitant use with CYP 3A4 inhibitors—such as ketoconazole, ritonavir, grapefruit juice, or erythromycin —results in increased plasma levels of these agents, and the use of CYP 3A4 inducers such as rifampin reduces plasma levels of the concomitant agent.

Table 3

Tadalafil: Fast facts

Efficacy

Vardenafil (Table 2). In a placebo-controlled, 12-week trial,⁷ 601 men with mildly to severely impaired erectile function received placebo or 5, 10, or 20 mg of vardenafil. Subjects receiving vardenafil at any dose saw significantly greater improvement in erectile function than did the placebo group. Percentage of successful intercourse ranged between 71% and 74% for the three vardenafil doses. For the 20-mg dose, 80% of patients experienced improved erections compared with 30% of those taking placebo.⁷

In another trial of 805 men with mild to severe ED,⁸ vardenafil in 5-mg, 10-mg, and 20-mg doses demonstrated efficacy versus placebo. Eighty-five percent of men using vardenafil, 20 mg, reported improved erections at 26 weeks compared with 28% in the placebo group.

Vardenafil, 10 mg and 20 mg, was also an effective ED treatment in men with type 1 or type 2 diabetes mellitus⁹ and in men who underwent radical prostatectomy.¹⁰

Tadalafil (Table 3). An integrated analysis¹¹ of five randomized, placebo-controlled trials of tadalafil at 2.5, 5, 10, or 20 mg for at least 12 weeks found that the agent at all doses significantly enhanced erectile function in mild to severe ED compared with placebo. Successful intercourse was reported in 61% and 75% of sexual encounters among men treated with tadalafil, 10 and 20 mg respectively, compared with 32% in controls. Eighty-one percent of men taking tadalafil, 20 mg, reported improved erections compared with 35% of those taking placebo.

Tadalafil, 10 and 20 mg, also improved erectile function in men with type 1 or type 2 diabetes.¹²

Tolerability

All three PDE-5 inhibitors have been shown in clinical trials to be generally safe and well-tolerated. Apart from visual disturbances, all three agents have similar side effects.

• Patients taking vardenafil most commonly reported headaches, flushing, rhinitis, and dyspepsia. These effects were generally mild to moderate, dose-related, and transient.¹
• Headache, back pain, myalgia, and dyspepsia were most commonly reported with tadalafil.¹³ Similarly, adverse events were mild or moderate, dose-related, and generally abated with treatment.

Treatment-related visual disturbances have been reported in 3% of patients taking sildenafil, >0.1% to <1% of men taking vardenafil, and <0.1% of those taking tadalafil.¹ Laboratory parameters have been unaffected by treatment with the PDE-5 inhibitors, and treatment discontinuation due to adverse events has been consistently low.¹

All three PDE-5 inhibitors cause vasodilatory effects and are contraindicated in patients using organic nitrates. Consensus guidelines have been developed for using PDE-5 inhibitors in patients with cardiovascular conditions.¹⁴

Related resources

• Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003;92(suppl):9M-18M.
• The Process of Care Consensus Panel. Position paper: the process of care model for evaluation and treatment of erectile dysfunction. Int J Impot Res 1999;11:59-74.
• American Foundation for Urologic Disease. www.afud.org

Drug brand names

• Ketoconazole • Nizoral
• Rifampin • Rifadin
• Ritonavir • Kaletra, Norvir
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra

Disclosure

The author receives research/grant support and is a consultant to and speaker for Eli Lilly and Co. and Pfizer Inc.

Sildenafil has revolutionized management of erectile dysfunction (ED) over the past 5 years. The FDA recently approved two additional medications, vardenafil and tadalafil, for treating ED.

How vardenafil and tadalafil work

Like sildenafil, vardenafil and tadalafil are selective inhibitors of the phosphodiesterase (PDE) isoenzyme PDE-5, which is predominantly responsible for degrading cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

During sexual stimulation, nitric oxide is released from cavernous nerves and endothelial cells and activates the enzyme guanylate cyclase, resulting in increased cGMP synthesis. The cGMP triggers relaxation of smooth muscles, allowing increased blood flow into the penis and expansion of sinusoidal spaces; this prevents venous blood outflow and results in erection. The PDE-5 inhibitors can potentiate erections by enhancing and prolonging the smooth musclerelaxant effects of the nitric oxide-cGMP cascade in the corpus cavernosum.¹ PDE-5 inhibitors have no effect without sexual stimulation.

Table 1

Pharmacokinetics of the PDE-5 inhibitors

Although the three PDE-5 inhibitors have similar mechanisms of action, their selectivity differs for PDE-5 compared with the PDE-6 and PDE-11 isoenzymes. Sildenafil and vardenafil have lower selectivity than tadalafil for PDE-5 over PDE-6, which plays a role in phototransduction, the process by which light impulses are converted into nerve impulses in the retina. Thus, tadalafil is less likely than the other agents to cause visual disturbances such as abnormal color vision, increased brightness of light, or mild haziness.

Tadalafil shows lower selectivity than sildenafil or vardenafil for PDE-5 over PDE-11, meaning that tadalafil inhibits PDE-11 at clinical doses. PDE-11 is found in various tissues, but its physiologic significance and consequences of its inhibition are unknown.²

Pharmacokinetics

Vardenafil, tadalafil, and sildenafil have different pharmacokinetic characteristics (Table 1). A lower starting dosage is required with vardenafil than with sildenafil because of the former agent’s greater in vitro and in vivo potency, but whether this results in greater clinical efficacy or tolerability is unknown.³

Vardenafil and sildenafil reach maximum plasma concentration within 30 minutes to 2 hours (median 1 hour for sildenafil and 0.7 hour for vardenafil). By contrast, tadalafil reaches maximum concentration within 30 minutes to 6 hours (median 2 hours). However, studies of time to onset of erection indicate that about one-third of patients using the maximum recommended doses of any of these agents will experience onset within 14 to 16 minutes.^4-6

Absorption rates for sildenafil and vardenafil are reduced when they are taken with a high-fat meal. High-fat foods do not affect tadalafil’s absorption rate.

Table 2

Vardenafil: Fast facts

Because of its 17.5-hour half-life, tadalafil has a longer period of activity than the other PDE-5 inhibitors. Most patients can complete sexual intercourse up to 36 hours after taking tadalafil, which potentially allows spontaneous sexual activity. Sildenafil and vardenafil each are effective for about 4 hours.

All three PDE-5 inhibitors are eliminated by hepatic metabolism, mainly by the CYP 3A4 hepatic enzyme. Therefore, concomitant use with CYP 3A4 inhibitors—such as ketoconazole, ritonavir, grapefruit juice, or erythromycin —results in increased plasma levels of these agents, and the use of CYP 3A4 inducers such as rifampin reduces plasma levels of the concomitant agent.

Table 3

Tadalafil: Fast facts

Efficacy

Vardenafil (Table 2). In a placebo-controlled, 12-week trial,⁷ 601 men with mildly to severely impaired erectile function received placebo or 5, 10, or 20 mg of vardenafil. Subjects receiving vardenafil at any dose saw significantly greater improvement in erectile function than did the placebo group. Percentage of successful intercourse ranged between 71% and 74% for the three vardenafil doses. For the 20-mg dose, 80% of patients experienced improved erections compared with 30% of those taking placebo.⁷

In another trial of 805 men with mild to severe ED,⁸ vardenafil in 5-mg, 10-mg, and 20-mg doses demonstrated efficacy versus placebo. Eighty-five percent of men using vardenafil, 20 mg, reported improved erections at 26 weeks compared with 28% in the placebo group.

Vardenafil, 10 mg and 20 mg, was also an effective ED treatment in men with type 1 or type 2 diabetes mellitus⁹ and in men who underwent radical prostatectomy.¹⁰

Tadalafil (Table 3). An integrated analysis¹¹ of five randomized, placebo-controlled trials of tadalafil at 2.5, 5, 10, or 20 mg for at least 12 weeks found that the agent at all doses significantly enhanced erectile function in mild to severe ED compared with placebo. Successful intercourse was reported in 61% and 75% of sexual encounters among men treated with tadalafil, 10 and 20 mg respectively, compared with 32% in controls. Eighty-one percent of men taking tadalafil, 20 mg, reported improved erections compared with 35% of those taking placebo.

Tadalafil, 10 and 20 mg, also improved erectile function in men with type 1 or type 2 diabetes.¹²

Tolerability

All three PDE-5 inhibitors have been shown in clinical trials to be generally safe and well-tolerated. Apart from visual disturbances, all three agents have similar side effects.

• Patients taking vardenafil most commonly reported headaches, flushing, rhinitis, and dyspepsia. These effects were generally mild to moderate, dose-related, and transient.¹
• Headache, back pain, myalgia, and dyspepsia were most commonly reported with tadalafil.¹³ Similarly, adverse events were mild or moderate, dose-related, and generally abated with treatment.

Treatment-related visual disturbances have been reported in 3% of patients taking sildenafil, >0.1% to <1% of men taking vardenafil, and <0.1% of those taking tadalafil.¹ Laboratory parameters have been unaffected by treatment with the PDE-5 inhibitors, and treatment discontinuation due to adverse events has been consistently low.¹

All three PDE-5 inhibitors cause vasodilatory effects and are contraindicated in patients using organic nitrates. Consensus guidelines have been developed for using PDE-5 inhibitors in patients with cardiovascular conditions.¹⁴

Related resources

• Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003;92(suppl):9M-18M.
• The Process of Care Consensus Panel. Position paper: the process of care model for evaluation and treatment of erectile dysfunction. Int J Impot Res 1999;11:59-74.
• American Foundation for Urologic Disease. www.afud.org

Drug brand names

• Ketoconazole • Nizoral
• Rifampin • Rifadin
• Ritonavir • Kaletra, Norvir
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra

Disclosure

The author receives research/grant support and is a consultant to and speaker for Eli Lilly and Co. and Pfizer Inc.

Sildenafil has revolutionized management of erectile dysfunction (ED) over the past 5 years. The FDA recently approved two additional medications, vardenafil and tadalafil, for treating ED.

How vardenafil and tadalafil work

Like sildenafil, vardenafil and tadalafil are selective inhibitors of the phosphodiesterase (PDE) isoenzyme PDE-5, which is predominantly responsible for degrading cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

During sexual stimulation, nitric oxide is released from cavernous nerves and endothelial cells and activates the enzyme guanylate cyclase, resulting in increased cGMP synthesis. The cGMP triggers relaxation of smooth muscles, allowing increased blood flow into the penis and expansion of sinusoidal spaces; this prevents venous blood outflow and results in erection. The PDE-5 inhibitors can potentiate erections by enhancing and prolonging the smooth musclerelaxant effects of the nitric oxide-cGMP cascade in the corpus cavernosum.¹ PDE-5 inhibitors have no effect without sexual stimulation.

Table 1

Pharmacokinetics of the PDE-5 inhibitors

Although the three PDE-5 inhibitors have similar mechanisms of action, their selectivity differs for PDE-5 compared with the PDE-6 and PDE-11 isoenzymes. Sildenafil and vardenafil have lower selectivity than tadalafil for PDE-5 over PDE-6, which plays a role in phototransduction, the process by which light impulses are converted into nerve impulses in the retina. Thus, tadalafil is less likely than the other agents to cause visual disturbances such as abnormal color vision, increased brightness of light, or mild haziness.

Tadalafil shows lower selectivity than sildenafil or vardenafil for PDE-5 over PDE-11, meaning that tadalafil inhibits PDE-11 at clinical doses. PDE-11 is found in various tissues, but its physiologic significance and consequences of its inhibition are unknown.²

Pharmacokinetics

Vardenafil, tadalafil, and sildenafil have different pharmacokinetic characteristics (Table 1). A lower starting dosage is required with vardenafil than with sildenafil because of the former agent’s greater in vitro and in vivo potency, but whether this results in greater clinical efficacy or tolerability is unknown.³

Vardenafil and sildenafil reach maximum plasma concentration within 30 minutes to 2 hours (median 1 hour for sildenafil and 0.7 hour for vardenafil). By contrast, tadalafil reaches maximum concentration within 30 minutes to 6 hours (median 2 hours). However, studies of time to onset of erection indicate that about one-third of patients using the maximum recommended doses of any of these agents will experience onset within 14 to 16 minutes.^4-6

Absorption rates for sildenafil and vardenafil are reduced when they are taken with a high-fat meal. High-fat foods do not affect tadalafil’s absorption rate.

Table 2

Vardenafil: Fast facts

Because of its 17.5-hour half-life, tadalafil has a longer period of activity than the other PDE-5 inhibitors. Most patients can complete sexual intercourse up to 36 hours after taking tadalafil, which potentially allows spontaneous sexual activity. Sildenafil and vardenafil each are effective for about 4 hours.

All three PDE-5 inhibitors are eliminated by hepatic metabolism, mainly by the CYP 3A4 hepatic enzyme. Therefore, concomitant use with CYP 3A4 inhibitors—such as ketoconazole, ritonavir, grapefruit juice, or erythromycin —results in increased plasma levels of these agents, and the use of CYP 3A4 inducers such as rifampin reduces plasma levels of the concomitant agent.

Table 3

Tadalafil: Fast facts

Efficacy

Vardenafil (Table 2). In a placebo-controlled, 12-week trial,⁷ 601 men with mildly to severely impaired erectile function received placebo or 5, 10, or 20 mg of vardenafil. Subjects receiving vardenafil at any dose saw significantly greater improvement in erectile function than did the placebo group. Percentage of successful intercourse ranged between 71% and 74% for the three vardenafil doses. For the 20-mg dose, 80% of patients experienced improved erections compared with 30% of those taking placebo.⁷

In another trial of 805 men with mild to severe ED,⁸ vardenafil in 5-mg, 10-mg, and 20-mg doses demonstrated efficacy versus placebo. Eighty-five percent of men using vardenafil, 20 mg, reported improved erections at 26 weeks compared with 28% in the placebo group.

Vardenafil, 10 mg and 20 mg, was also an effective ED treatment in men with type 1 or type 2 diabetes mellitus⁹ and in men who underwent radical prostatectomy.¹⁰

Tadalafil (Table 3). An integrated analysis¹¹ of five randomized, placebo-controlled trials of tadalafil at 2.5, 5, 10, or 20 mg for at least 12 weeks found that the agent at all doses significantly enhanced erectile function in mild to severe ED compared with placebo. Successful intercourse was reported in 61% and 75% of sexual encounters among men treated with tadalafil, 10 and 20 mg respectively, compared with 32% in controls. Eighty-one percent of men taking tadalafil, 20 mg, reported improved erections compared with 35% of those taking placebo.

Tadalafil, 10 and 20 mg, also improved erectile function in men with type 1 or type 2 diabetes.¹²

Tolerability

All three PDE-5 inhibitors have been shown in clinical trials to be generally safe and well-tolerated. Apart from visual disturbances, all three agents have similar side effects.

• Patients taking vardenafil most commonly reported headaches, flushing, rhinitis, and dyspepsia. These effects were generally mild to moderate, dose-related, and transient.¹
• Headache, back pain, myalgia, and dyspepsia were most commonly reported with tadalafil.¹³ Similarly, adverse events were mild or moderate, dose-related, and generally abated with treatment.

Treatment-related visual disturbances have been reported in 3% of patients taking sildenafil, >0.1% to <1% of men taking vardenafil, and <0.1% of those taking tadalafil.¹ Laboratory parameters have been unaffected by treatment with the PDE-5 inhibitors, and treatment discontinuation due to adverse events has been consistently low.¹

All three PDE-5 inhibitors cause vasodilatory effects and are contraindicated in patients using organic nitrates. Consensus guidelines have been developed for using PDE-5 inhibitors in patients with cardiovascular conditions.¹⁴

Related resources

• Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003;92(suppl):9M-18M.
• The Process of Care Consensus Panel. Position paper: the process of care model for evaluation and treatment of erectile dysfunction. Int J Impot Res 1999;11:59-74.
• American Foundation for Urologic Disease. www.afud.org

Drug brand names

• Ketoconazole • Nizoral
• Rifampin • Rifadin
• Ritonavir • Kaletra, Norvir
• Sildenafil • Viagra
• Tadalafil • Cialis
• Vardenafil • Levitra

Disclosure

The author receives research/grant support and is a consultant to and speaker for Eli Lilly and Co. and Pfizer Inc.

Patients with chronic schizophrenia are notoriously inconsistent in adhering to medications.¹ Partial compliance is a serious problem because the resulting psychotic relapses often lead to progressive neurologic and clinical deterioration as well as social and vocational impairment.

Long-acting, “depot” formulations of first-generation antipsychotics (haloperidol decanoate and fluphenazine decanoate) have been used over the past 25 years to ensure adherence in the least-compliant patients. These formulations, however, are not widely used because of the risks of tardive dyskinesia (TD) and other movement disorders.

Atypical antipsychotics—with their reduced risk of TD—have become the standard of care in managing schizophrenia and related psychosis over the long term.² All are administered orally, however, and—until now—none has been available in a long-acting formulation.

The FDA recently approved a long-acting, injectable form of risperidone (Table 1), based on results of a 12-week, placebo-controlled trial and a 1-year open-label trial. The clinical and functional improvements seen in chronic schizophrenia patients who received long-acting risperidone for 1 to 3 years may change prevailing notions of the potential to stabilize and restore function in this severe brain disorder.

Table 1

Injectable, long-acting risperidone: Fast facts

HOW LONG-ACTING RISPERIDONE WORKS

Long-acting injectable risperidone has the same mechanism of action as oral risperidone. The injectable form is delivered into muscle tissue by microspheres that encapsulate the drug into a biodegradable polymer. The microspheres undergo gradual hydrolysis, resulting in a gradual release of risperidone into the blood stream. The drug then crosses the blood-brain barrier to block dopamine D2 and serotonin 5HT2A receptors in brain tissue, which is accepted as the pharmacodynamic basis for the efficacy of atypical antipsychotics. Risperidone’s receptor-binding profile is shown in Table 2.

CLINICAL PHARMACOKINETICS

Full release of long-acting risperidone from the gradually hydrolyzing microspheres starts about 3 weeks after an intramuscular (IM) injection. Thus, supplemental oral risperidone is recommended during the first 3 weeks of IM injections. Release is then maintained for 4 to 6 weeks. Steady-state plasma levels are reached after four biweekly injections. Risperidone is absorbed completely from the microspheres, which are biodegradable to carbon dioxide and water.

In plasma, risperidone is oxidized by the cytochrome P-450 isoenzyme CYP 2D6 to 9-hydroxy risperidone, an active metabolite similar to risperidone in its pharmacologic characteristics and efficacy. Risperidone is also metabolized via N-dealkylation. The plasma protein binding of risperidone is 90% and that of 9-hydroxy risperidone is 77%. After several biweekly IM injections of 25 or 50 mg during clinical trials, median trough and peak plasma concentrations of active moiety fluctuated between 9.9 and 19.2 ng/ml and 17.9 and 45.5 ng/ml, respectively.

Table 2

Receptor-binding profile of risperidone long-acting formulation

Risperidone plasma concentrations may be affected by interactions with other psychotropics that inhibit or induce the oxidative enzyme CYP 2D6 (Table 3).

Clearance of risperidone and 9-hydroxy risperidone is decreased by 60% in patients with severe kidney disease, as compared with healthy subjects. Plasma levels and maximum drug concentrations are 25 to 32% lower with long-acting risperidone than with oral risperidone. This difference may account for the injectable formulation’s more favorable side-effect profile because lower peaks means a lower likelihood of side effects.

Table 3

Potential drug-drug interactions with risperidone long-acting microspheres

RESULTS FROM CLINICAL TRIALS

Long-acting risperidone was tested at doses of 25, 50, and 75 mg in a 12-week, double-blind trial of 400 patients with acute relapse of schizophrenia.⁴ During the 3-week initial titration, patients also received the usual dosage of oral risperidone (3 to 5 mg/d) for schizophrenia. Oral risperidone can be discontinued 3 weeks after the first injection (ie, 1 week after the second injection). Measurement of serum concentrations is not needed because the microspheres encapsulating risperidone have been shown in bioavailability studies to begin disintegrating and releasing risperidone 3 weeks after being deposited into muscle tissue.

All three doses were more effective than placebo in reducing total, positive, and negative symptom scores, as measured by the Positive and Negative Syndrome Scale (PANSS). The 75-mg dose showed no greater efficacy than the 50-mg dose.

In a second, open-label study, 775 stable outpatients with schizophrenia or schizoaffective disorder received biweekly injections of 25, 50, or 75 mg of long-acting risperidone for 1 year. All three doses improved the baseline PANSS scores significantly, above and beyond the patients’ stable clinical status. These results indicate that injectable long-acting risperidone can further stabilize schizophrenia beyond the usual response to oral antipsychotics.⁵

Notably, patients’ quality-of-life scores—as measured by the 36-item Short-Form Health Survey (SF-36)—were significantly lower than U.S. norms at baseline. At the end of the study, patients’ scores had increased to within the norm range.⁶ The completion rate in this 1-year study was 65%; patients dropped out because of insufficient response (7%) or adverse events (5%), or they withdrew consent (15%) or were lost to follow-up (3%).

SAFETY AND TOLERABILITY

Few side effects were seen in the 12-week and 1-year trials. Extrapyramidal symptoms as measured by the Extrapyramidal Symptom Rating Scale declined from baseline by 67% with the 25-mg dose, by 50% with the 50-mg dose, and by 33% with the 75-mg dose in the 12-week study. Patients who had TD at baseline also improved by the end of the 1-year study, suggesting that long-acting risperidone has a low risk of TD.⁷ Also:

• Although prolactin levels were elevated compared with baseline, they were 18% lower with long-acting risperidone than with oral risperidone, possibly because of lower plasma peaks of the drug in the long-acting formulation.
• Injection site pain or redness was minimal, as measured by patient ratings.
• Mean weight gain after 12 weeks was 0.5 kg with the 25-mg dose, 1.2 kg with the 50-mg dose, and 1.9 kg with the 75-mg dose. After 52 weeks, weight gain was 1.8 kg, 2.1 kg, and 2.7 kg, respectively.
• QTc prolongation—as measured with random ECGs—was negligible with all doses.

REPARATIVE EFFECTS?

Based on clinical trial results, long-acting risperidone appears to be highly effective in treating and preventing relapse of acute psychotic episodes in schizophrenia. Its injectable formulation ensures that compliance is far more consistent than with oral atypical antipsychotics.

Patients who had been disabled with chronic schizophrenia improved dramatically after about 1 year of biweekly injections of long-acting risperidone. Many were able to return to school to finish a degree, go back to holding full-time jobs, or develop close personal relationships such as dating. Total PANSS scores after 1 year of treatment approached the low 40s in some patients, which is similar to what a healthy person might score on the PANSS on certain days. This pattern, which justifies the term “recovery,” suggests that uninterrupted, long-term atypical antipsychotic treatment may have reparative and/or neuroprotective effects on the brain in schizophrenia.⁸

Candidates for long-acting injectable risperidone include:

• first-episode patients
• patients with a history of partial or complete noncompliance
• patients who become violent or assaultive when they relapse
• and those receiving depot injections of haloperidol decanoate or fluphenazine decanoate.

Long-acting injectable atypical antipsychotics may become the standard of care for treating newonset schizophrenia.⁹ The goal would be to return patients to baseline functioning as soon as possible, rather than resorting to a long-acting antipsychotic only after repetitive relapses, adverse neuroplastic changes, and psychosocial decline.

Related resources

• Lasser R, Bossie C, Zhu Y, Gharahawi G. Does constant therapy infer optimal efficacy in schizophrenia? Moving to an advanced pharmacotherapeutic option. Schizophr Res 2003;60:291.
• Risperdal Consta Web site. www.risperdalconsta.com

Drug brand names

• Carbamazepine • Tegretol
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Paroxetine • Paxil

Disclosure

The author participated in the 12-week controlled clinical trial of long-acting, injectable risperidone and in an open-label extension for more than 3 additional years.

Dr. Nasrallah reports that he also receives research/grant support from and is a consultant to and speaker for AstraZeneca Pharmaceuticals, Janssen Pharmaceutica, and Pfizer Inc., and is a consultant to and speaker for Bristol-Myers Squibb Co. and Abbott Laboratories.

Acknowledgment

The author thanks Peggy Grause for her assistance in preparing this manuscript for publication.

Patients with chronic schizophrenia are notoriously inconsistent in adhering to medications.¹ Partial compliance is a serious problem because the resulting psychotic relapses often lead to progressive neurologic and clinical deterioration as well as social and vocational impairment.

Long-acting, “depot” formulations of first-generation antipsychotics (haloperidol decanoate and fluphenazine decanoate) have been used over the past 25 years to ensure adherence in the least-compliant patients. These formulations, however, are not widely used because of the risks of tardive dyskinesia (TD) and other movement disorders.

Atypical antipsychotics—with their reduced risk of TD—have become the standard of care in managing schizophrenia and related psychosis over the long term.² All are administered orally, however, and—until now—none has been available in a long-acting formulation.

The FDA recently approved a long-acting, injectable form of risperidone (Table 1), based on results of a 12-week, placebo-controlled trial and a 1-year open-label trial. The clinical and functional improvements seen in chronic schizophrenia patients who received long-acting risperidone for 1 to 3 years may change prevailing notions of the potential to stabilize and restore function in this severe brain disorder.

Table 1

Injectable, long-acting risperidone: Fast facts

HOW LONG-ACTING RISPERIDONE WORKS

Long-acting injectable risperidone has the same mechanism of action as oral risperidone. The injectable form is delivered into muscle tissue by microspheres that encapsulate the drug into a biodegradable polymer. The microspheres undergo gradual hydrolysis, resulting in a gradual release of risperidone into the blood stream. The drug then crosses the blood-brain barrier to block dopamine D2 and serotonin 5HT2A receptors in brain tissue, which is accepted as the pharmacodynamic basis for the efficacy of atypical antipsychotics. Risperidone’s receptor-binding profile is shown in Table 2.

CLINICAL PHARMACOKINETICS

Full release of long-acting risperidone from the gradually hydrolyzing microspheres starts about 3 weeks after an intramuscular (IM) injection. Thus, supplemental oral risperidone is recommended during the first 3 weeks of IM injections. Release is then maintained for 4 to 6 weeks. Steady-state plasma levels are reached after four biweekly injections. Risperidone is absorbed completely from the microspheres, which are biodegradable to carbon dioxide and water.

In plasma, risperidone is oxidized by the cytochrome P-450 isoenzyme CYP 2D6 to 9-hydroxy risperidone, an active metabolite similar to risperidone in its pharmacologic characteristics and efficacy. Risperidone is also metabolized via N-dealkylation. The plasma protein binding of risperidone is 90% and that of 9-hydroxy risperidone is 77%. After several biweekly IM injections of 25 or 50 mg during clinical trials, median trough and peak plasma concentrations of active moiety fluctuated between 9.9 and 19.2 ng/ml and 17.9 and 45.5 ng/ml, respectively.

Table 2

Receptor-binding profile of risperidone long-acting formulation

Risperidone plasma concentrations may be affected by interactions with other psychotropics that inhibit or induce the oxidative enzyme CYP 2D6 (Table 3).

Clearance of risperidone and 9-hydroxy risperidone is decreased by 60% in patients with severe kidney disease, as compared with healthy subjects. Plasma levels and maximum drug concentrations are 25 to 32% lower with long-acting risperidone than with oral risperidone. This difference may account for the injectable formulation’s more favorable side-effect profile because lower peaks means a lower likelihood of side effects.

Table 3

Potential drug-drug interactions with risperidone long-acting microspheres

RESULTS FROM CLINICAL TRIALS

Long-acting risperidone was tested at doses of 25, 50, and 75 mg in a 12-week, double-blind trial of 400 patients with acute relapse of schizophrenia.⁴ During the 3-week initial titration, patients also received the usual dosage of oral risperidone (3 to 5 mg/d) for schizophrenia. Oral risperidone can be discontinued 3 weeks after the first injection (ie, 1 week after the second injection). Measurement of serum concentrations is not needed because the microspheres encapsulating risperidone have been shown in bioavailability studies to begin disintegrating and releasing risperidone 3 weeks after being deposited into muscle tissue.

All three doses were more effective than placebo in reducing total, positive, and negative symptom scores, as measured by the Positive and Negative Syndrome Scale (PANSS). The 75-mg dose showed no greater efficacy than the 50-mg dose.

In a second, open-label study, 775 stable outpatients with schizophrenia or schizoaffective disorder received biweekly injections of 25, 50, or 75 mg of long-acting risperidone for 1 year. All three doses improved the baseline PANSS scores significantly, above and beyond the patients’ stable clinical status. These results indicate that injectable long-acting risperidone can further stabilize schizophrenia beyond the usual response to oral antipsychotics.⁵

Notably, patients’ quality-of-life scores—as measured by the 36-item Short-Form Health Survey (SF-36)—were significantly lower than U.S. norms at baseline. At the end of the study, patients’ scores had increased to within the norm range.⁶ The completion rate in this 1-year study was 65%; patients dropped out because of insufficient response (7%) or adverse events (5%), or they withdrew consent (15%) or were lost to follow-up (3%).

SAFETY AND TOLERABILITY

Few side effects were seen in the 12-week and 1-year trials. Extrapyramidal symptoms as measured by the Extrapyramidal Symptom Rating Scale declined from baseline by 67% with the 25-mg dose, by 50% with the 50-mg dose, and by 33% with the 75-mg dose in the 12-week study. Patients who had TD at baseline also improved by the end of the 1-year study, suggesting that long-acting risperidone has a low risk of TD.⁷ Also:

• Although prolactin levels were elevated compared with baseline, they were 18% lower with long-acting risperidone than with oral risperidone, possibly because of lower plasma peaks of the drug in the long-acting formulation.
• Injection site pain or redness was minimal, as measured by patient ratings.
• Mean weight gain after 12 weeks was 0.5 kg with the 25-mg dose, 1.2 kg with the 50-mg dose, and 1.9 kg with the 75-mg dose. After 52 weeks, weight gain was 1.8 kg, 2.1 kg, and 2.7 kg, respectively.
• QTc prolongation—as measured with random ECGs—was negligible with all doses.

REPARATIVE EFFECTS?

Based on clinical trial results, long-acting risperidone appears to be highly effective in treating and preventing relapse of acute psychotic episodes in schizophrenia. Its injectable formulation ensures that compliance is far more consistent than with oral atypical antipsychotics.

Patients who had been disabled with chronic schizophrenia improved dramatically after about 1 year of biweekly injections of long-acting risperidone. Many were able to return to school to finish a degree, go back to holding full-time jobs, or develop close personal relationships such as dating. Total PANSS scores after 1 year of treatment approached the low 40s in some patients, which is similar to what a healthy person might score on the PANSS on certain days. This pattern, which justifies the term “recovery,” suggests that uninterrupted, long-term atypical antipsychotic treatment may have reparative and/or neuroprotective effects on the brain in schizophrenia.⁸

Candidates for long-acting injectable risperidone include:

• first-episode patients
• patients with a history of partial or complete noncompliance
• patients who become violent or assaultive when they relapse
• and those receiving depot injections of haloperidol decanoate or fluphenazine decanoate.

Long-acting injectable atypical antipsychotics may become the standard of care for treating newonset schizophrenia.⁹ The goal would be to return patients to baseline functioning as soon as possible, rather than resorting to a long-acting antipsychotic only after repetitive relapses, adverse neuroplastic changes, and psychosocial decline.

Related resources

• Lasser R, Bossie C, Zhu Y, Gharahawi G. Does constant therapy infer optimal efficacy in schizophrenia? Moving to an advanced pharmacotherapeutic option. Schizophr Res 2003;60:291.
• Risperdal Consta Web site. www.risperdalconsta.com

Drug brand names

• Carbamazepine • Tegretol
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Paroxetine • Paxil

Disclosure

The author participated in the 12-week controlled clinical trial of long-acting, injectable risperidone and in an open-label extension for more than 3 additional years.

Dr. Nasrallah reports that he also receives research/grant support from and is a consultant to and speaker for AstraZeneca Pharmaceuticals, Janssen Pharmaceutica, and Pfizer Inc., and is a consultant to and speaker for Bristol-Myers Squibb Co. and Abbott Laboratories.

Acknowledgment

The author thanks Peggy Grause for her assistance in preparing this manuscript for publication.

Patients with chronic schizophrenia are notoriously inconsistent in adhering to medications.¹ Partial compliance is a serious problem because the resulting psychotic relapses often lead to progressive neurologic and clinical deterioration as well as social and vocational impairment.

Long-acting, “depot” formulations of first-generation antipsychotics (haloperidol decanoate and fluphenazine decanoate) have been used over the past 25 years to ensure adherence in the least-compliant patients. These formulations, however, are not widely used because of the risks of tardive dyskinesia (TD) and other movement disorders.

Atypical antipsychotics—with their reduced risk of TD—have become the standard of care in managing schizophrenia and related psychosis over the long term.² All are administered orally, however, and—until now—none has been available in a long-acting formulation.

The FDA recently approved a long-acting, injectable form of risperidone (Table 1), based on results of a 12-week, placebo-controlled trial and a 1-year open-label trial. The clinical and functional improvements seen in chronic schizophrenia patients who received long-acting risperidone for 1 to 3 years may change prevailing notions of the potential to stabilize and restore function in this severe brain disorder.

Table 1

Injectable, long-acting risperidone: Fast facts

HOW LONG-ACTING RISPERIDONE WORKS

Long-acting injectable risperidone has the same mechanism of action as oral risperidone. The injectable form is delivered into muscle tissue by microspheres that encapsulate the drug into a biodegradable polymer. The microspheres undergo gradual hydrolysis, resulting in a gradual release of risperidone into the blood stream. The drug then crosses the blood-brain barrier to block dopamine D2 and serotonin 5HT2A receptors in brain tissue, which is accepted as the pharmacodynamic basis for the efficacy of atypical antipsychotics. Risperidone’s receptor-binding profile is shown in Table 2.

CLINICAL PHARMACOKINETICS

Full release of long-acting risperidone from the gradually hydrolyzing microspheres starts about 3 weeks after an intramuscular (IM) injection. Thus, supplemental oral risperidone is recommended during the first 3 weeks of IM injections. Release is then maintained for 4 to 6 weeks. Steady-state plasma levels are reached after four biweekly injections. Risperidone is absorbed completely from the microspheres, which are biodegradable to carbon dioxide and water.

In plasma, risperidone is oxidized by the cytochrome P-450 isoenzyme CYP 2D6 to 9-hydroxy risperidone, an active metabolite similar to risperidone in its pharmacologic characteristics and efficacy. Risperidone is also metabolized via N-dealkylation. The plasma protein binding of risperidone is 90% and that of 9-hydroxy risperidone is 77%. After several biweekly IM injections of 25 or 50 mg during clinical trials, median trough and peak plasma concentrations of active moiety fluctuated between 9.9 and 19.2 ng/ml and 17.9 and 45.5 ng/ml, respectively.

Table 2

Receptor-binding profile of risperidone long-acting formulation

Risperidone plasma concentrations may be affected by interactions with other psychotropics that inhibit or induce the oxidative enzyme CYP 2D6 (Table 3).

Clearance of risperidone and 9-hydroxy risperidone is decreased by 60% in patients with severe kidney disease, as compared with healthy subjects. Plasma levels and maximum drug concentrations are 25 to 32% lower with long-acting risperidone than with oral risperidone. This difference may account for the injectable formulation’s more favorable side-effect profile because lower peaks means a lower likelihood of side effects.

Table 3

Potential drug-drug interactions with risperidone long-acting microspheres

RESULTS FROM CLINICAL TRIALS

Long-acting risperidone was tested at doses of 25, 50, and 75 mg in a 12-week, double-blind trial of 400 patients with acute relapse of schizophrenia.⁴ During the 3-week initial titration, patients also received the usual dosage of oral risperidone (3 to 5 mg/d) for schizophrenia. Oral risperidone can be discontinued 3 weeks after the first injection (ie, 1 week after the second injection). Measurement of serum concentrations is not needed because the microspheres encapsulating risperidone have been shown in bioavailability studies to begin disintegrating and releasing risperidone 3 weeks after being deposited into muscle tissue.

All three doses were more effective than placebo in reducing total, positive, and negative symptom scores, as measured by the Positive and Negative Syndrome Scale (PANSS). The 75-mg dose showed no greater efficacy than the 50-mg dose.

In a second, open-label study, 775 stable outpatients with schizophrenia or schizoaffective disorder received biweekly injections of 25, 50, or 75 mg of long-acting risperidone for 1 year. All three doses improved the baseline PANSS scores significantly, above and beyond the patients’ stable clinical status. These results indicate that injectable long-acting risperidone can further stabilize schizophrenia beyond the usual response to oral antipsychotics.⁵

Notably, patients’ quality-of-life scores—as measured by the 36-item Short-Form Health Survey (SF-36)—were significantly lower than U.S. norms at baseline. At the end of the study, patients’ scores had increased to within the norm range.⁶ The completion rate in this 1-year study was 65%; patients dropped out because of insufficient response (7%) or adverse events (5%), or they withdrew consent (15%) or were lost to follow-up (3%).

SAFETY AND TOLERABILITY

Few side effects were seen in the 12-week and 1-year trials. Extrapyramidal symptoms as measured by the Extrapyramidal Symptom Rating Scale declined from baseline by 67% with the 25-mg dose, by 50% with the 50-mg dose, and by 33% with the 75-mg dose in the 12-week study. Patients who had TD at baseline also improved by the end of the 1-year study, suggesting that long-acting risperidone has a low risk of TD.⁷ Also:

• Although prolactin levels were elevated compared with baseline, they were 18% lower with long-acting risperidone than with oral risperidone, possibly because of lower plasma peaks of the drug in the long-acting formulation.
• Injection site pain or redness was minimal, as measured by patient ratings.
• Mean weight gain after 12 weeks was 0.5 kg with the 25-mg dose, 1.2 kg with the 50-mg dose, and 1.9 kg with the 75-mg dose. After 52 weeks, weight gain was 1.8 kg, 2.1 kg, and 2.7 kg, respectively.
• QTc prolongation—as measured with random ECGs—was negligible with all doses.

REPARATIVE EFFECTS?

Based on clinical trial results, long-acting risperidone appears to be highly effective in treating and preventing relapse of acute psychotic episodes in schizophrenia. Its injectable formulation ensures that compliance is far more consistent than with oral atypical antipsychotics.

Patients who had been disabled with chronic schizophrenia improved dramatically after about 1 year of biweekly injections of long-acting risperidone. Many were able to return to school to finish a degree, go back to holding full-time jobs, or develop close personal relationships such as dating. Total PANSS scores after 1 year of treatment approached the low 40s in some patients, which is similar to what a healthy person might score on the PANSS on certain days. This pattern, which justifies the term “recovery,” suggests that uninterrupted, long-term atypical antipsychotic treatment may have reparative and/or neuroprotective effects on the brain in schizophrenia.⁸

Candidates for long-acting injectable risperidone include:

• first-episode patients
• patients with a history of partial or complete noncompliance
• patients who become violent or assaultive when they relapse
• and those receiving depot injections of haloperidol decanoate or fluphenazine decanoate.

Long-acting injectable atypical antipsychotics may become the standard of care for treating newonset schizophrenia.⁹ The goal would be to return patients to baseline functioning as soon as possible, rather than resorting to a long-acting antipsychotic only after repetitive relapses, adverse neuroplastic changes, and psychosocial decline.

Related resources

• Lasser R, Bossie C, Zhu Y, Gharahawi G. Does constant therapy infer optimal efficacy in schizophrenia? Moving to an advanced pharmacotherapeutic option. Schizophr Res 2003;60:291.
• Risperdal Consta Web site. www.risperdalconsta.com

Drug brand names

• Carbamazepine • Tegretol
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Paroxetine • Paxil

Disclosure

The author participated in the 12-week controlled clinical trial of long-acting, injectable risperidone and in an open-label extension for more than 3 additional years.

Dr. Nasrallah reports that he also receives research/grant support from and is a consultant to and speaker for AstraZeneca Pharmaceuticals, Janssen Pharmaceutica, and Pfizer Inc., and is a consultant to and speaker for Bristol-Myers Squibb Co. and Abbott Laboratories.

Acknowledgment

The author thanks Peggy Grause for her assistance in preparing this manuscript for publication.

A typical antipsychotics have enhanced outcomes in schizophrenia while helping patients avert the troublesome motor effects associated with older agents. Some side effects, such as weight gain and prolactin elevation, have remained a concern, however.

Aripiprazole, a novel antipsychotic recently FDA-approved for treating schizophrenia, exhibited efficacy and tolerability in preclinical and clinical trials.

How aripiprazole works

Aripiprazole’s mechanism of action is important to our understanding of the dopamine hypothesis of antipsychotic effect.¹

The dopamine hypothesis remains the predominant explanation of how antipsychotics work.² However, the evolution of antipsychotic therapy has led to further refinement of the dopamine hypothesis, including selective dopamine (D4) antagonism, rapid dissociation from dopamine receptors, dopamine-serotonin receptor system interactions, dopamine-GABA system interactions, and now (with aripiprazole) partial agonist effects at dopamine (and selective serotonin) receptors.^1,2

Table

ARIPIPRAZOLE: FASTFACTS

Table 1

ARIPIPRAZOLE’S RECEPTOR-BINDING PROFILE

Table 2

POTENTIAL DRUG-DRUG INTERACTIONS WITH ARIPIPRAZOLE

Unlike other antipsychotics, which appear to act through dopamine receptor antagonism, aripiprazole is a potent partial agonist at both the dopamine (D2) and serotonin (5HT1A) receptors.^1,2Table 1 describes the agent’s receptor-binding profile.

The agent offers 78% bioavailability. It is metabolized through the hepatic microenzyme system, specifically the cytochrome P450 enzymes 2D6 and 3A4. Use of nicotine does not alter the agent’s plasma levels. Its active moiety is aripiprazole with minor contributions from the derivative dehydro-aripiprazole.

Aripiprazole therapy can be started at 10 or 15 mg/d; the starting dosage—15 mg/d in most cases—may also suffice as maintenance therapy for many patients. If the patient does not respond, it is prudent to wait several weeks before increasing the dosage beyond 15 mg/d.

The FDA-approved maximum dosage for aripiprazole is 30 mg/d. However, information from clinical trials indicates that increasing the dosage from 15 to 30 mg/d does not enhance the antipsychotic’s efficacy.^3,4 Because of its absorption properties, the agent can be taken with or without food.

Aripiprazole has a relatively long half-life (75 hours), so it can be administered once daily. This provides an advantage when switching treatments. Some information suggests that patients may be switched directly to aripiprazole,⁵ although cross-titration is recommended.³

Although data in clinical populations are insufficient, studies in normal volunteers suggest that aripiprazole can be given at regular dosages to older patients and to those with renal or hepatic impairment.³Table 2 highlights potential drug-drug interactions with agents that can influence the hepatic microenzyme system.

Efficacy

Aripiprazole has demonstrated efficacy in clinical studies of patients with schizophrenia and schizoaffective disorder.^3-8

• In a placebo-controlled, 4-week trial, patients who received aripiprazole, 15 to 30 mg/d, or haloperidol, 10 mg/d, reported similar improvements in positive and negative symptoms, psychopathology, and overall function.⁶
• A placebo-controlled, 4-week trial of aripiprazole, 20 and 30 mg/d, compared with risperidone, 6 mg/d, revealed similar efficacy with respect to symptom improvement and overall functioning.⁷
• Aripiprazole and olanzapine demonstrated comparable efficacy in a 28-week study. However, patients in the aripiprazole group showed greater improvement at 8 weeks and sustained improvement through 28 weeks in a measure of verbal memory.⁸

Researchers have not yet compared aripiprazole with clozapine, quetiapine, or ziprasidone. Also, information on the dosing, efficacy, and tolerability of aripiprazole in patients with first-episode or treatment-refractory schizophrenia is limited. According to the manufacturers’ prescription information, aripiprazole’s long-term efficacy in schizophrenia treatment has not been established. Data on 1-year treatment with aripiprazole appear encouraging.³

Preliminary data suggest that aripiprazole may help treat nonpsychotic conditions, although which ones has yet to be determined. A 3-week, placebo-controlled study demonstrated that aripiprazole, 30 mg/d, helped ameliorate symptoms of mania.⁹

Tolerability

Aripiprazole’s side-effect profile, revealed in preclinical and clinical trials, suggests that the drug could be well tolerated among a broad range of patients.¹⁰

In the 4-week, placebo-controlled comparison with haloperidol, rates of extrapyramidal symptoms (EPS) among aripiprazole-treated patients were much lower than those in the haloperidol group and similar to those in the placebo group.⁶ There is no evidence that higher dosages of aripiprazole lead to increased EPS. It is also not known whether aripiprazole will cause EPS in children and in patients older than 65, who are more susceptible than other age groups to antipsychotic-induced motor side effects.

Aripiprazole is believed to be less likely than typical antipsychotics to induce tardive dyskinesia, but more long-term information is needed.³

Studies have associated aripiprazole use with some weight gain, but (marginally) less than risperidone,⁷ less than haloperidol,⁶ and substantially less than olanzapine.⁸ Direct comparisons with other atypicals are not yet available.

Aripiprazole’s effect on glucose metabolism has not been determined, but early information suggests a favorable profile with respect to metabolic indices. Aripiprazole does not appear to elevate prolactin or cause cardiac QTc prolongation. Sedation appears to be the most pronounced side effect; this effect also appears to increase with higher dosages.

As has happened with the other atypicals, the pattern of use for aripiprazole will unfold over time as clinicians gain experience with using this agent in distinct patient groups.

Related resources

• Jordan S, Koprivica V, Chen R, et al. The antipsychotic aripiprazole is a potent, partial agonist at the human 5HT(1A) receptor. Eur J Pharmacol 2002;50:873-83.
• Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-71.

Drug brand names

• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Buckley receives grant support from, is a consultant to, and is a speaker for AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Dr. Sinha is a consultant to Bristol-Myers Squibb Co.

Dr. Sebastian is a consultant to Eli Lilly and Co.

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

A typical antipsychotics have enhanced outcomes in schizophrenia while helping patients avert the troublesome motor effects associated with older agents. Some side effects, such as weight gain and prolactin elevation, have remained a concern, however.

Aripiprazole, a novel antipsychotic recently FDA-approved for treating schizophrenia, exhibited efficacy and tolerability in preclinical and clinical trials.

How aripiprazole works

Aripiprazole’s mechanism of action is important to our understanding of the dopamine hypothesis of antipsychotic effect.¹

The dopamine hypothesis remains the predominant explanation of how antipsychotics work.² However, the evolution of antipsychotic therapy has led to further refinement of the dopamine hypothesis, including selective dopamine (D4) antagonism, rapid dissociation from dopamine receptors, dopamine-serotonin receptor system interactions, dopamine-GABA system interactions, and now (with aripiprazole) partial agonist effects at dopamine (and selective serotonin) receptors.^1,2

Table

ARIPIPRAZOLE: FASTFACTS

Table 1

ARIPIPRAZOLE’S RECEPTOR-BINDING PROFILE

Table 2

POTENTIAL DRUG-DRUG INTERACTIONS WITH ARIPIPRAZOLE

Unlike other antipsychotics, which appear to act through dopamine receptor antagonism, aripiprazole is a potent partial agonist at both the dopamine (D2) and serotonin (5HT1A) receptors.^1,2Table 1 describes the agent’s receptor-binding profile.

The agent offers 78% bioavailability. It is metabolized through the hepatic microenzyme system, specifically the cytochrome P450 enzymes 2D6 and 3A4. Use of nicotine does not alter the agent’s plasma levels. Its active moiety is aripiprazole with minor contributions from the derivative dehydro-aripiprazole.

Aripiprazole therapy can be started at 10 or 15 mg/d; the starting dosage—15 mg/d in most cases—may also suffice as maintenance therapy for many patients. If the patient does not respond, it is prudent to wait several weeks before increasing the dosage beyond 15 mg/d.

The FDA-approved maximum dosage for aripiprazole is 30 mg/d. However, information from clinical trials indicates that increasing the dosage from 15 to 30 mg/d does not enhance the antipsychotic’s efficacy.^3,4 Because of its absorption properties, the agent can be taken with or without food.

Aripiprazole has a relatively long half-life (75 hours), so it can be administered once daily. This provides an advantage when switching treatments. Some information suggests that patients may be switched directly to aripiprazole,⁵ although cross-titration is recommended.³

Although data in clinical populations are insufficient, studies in normal volunteers suggest that aripiprazole can be given at regular dosages to older patients and to those with renal or hepatic impairment.³Table 2 highlights potential drug-drug interactions with agents that can influence the hepatic microenzyme system.

Efficacy

Aripiprazole has demonstrated efficacy in clinical studies of patients with schizophrenia and schizoaffective disorder.^3-8

• In a placebo-controlled, 4-week trial, patients who received aripiprazole, 15 to 30 mg/d, or haloperidol, 10 mg/d, reported similar improvements in positive and negative symptoms, psychopathology, and overall function.⁶
• A placebo-controlled, 4-week trial of aripiprazole, 20 and 30 mg/d, compared with risperidone, 6 mg/d, revealed similar efficacy with respect to symptom improvement and overall functioning.⁷
• Aripiprazole and olanzapine demonstrated comparable efficacy in a 28-week study. However, patients in the aripiprazole group showed greater improvement at 8 weeks and sustained improvement through 28 weeks in a measure of verbal memory.⁸

Researchers have not yet compared aripiprazole with clozapine, quetiapine, or ziprasidone. Also, information on the dosing, efficacy, and tolerability of aripiprazole in patients with first-episode or treatment-refractory schizophrenia is limited. According to the manufacturers’ prescription information, aripiprazole’s long-term efficacy in schizophrenia treatment has not been established. Data on 1-year treatment with aripiprazole appear encouraging.³

Preliminary data suggest that aripiprazole may help treat nonpsychotic conditions, although which ones has yet to be determined. A 3-week, placebo-controlled study demonstrated that aripiprazole, 30 mg/d, helped ameliorate symptoms of mania.⁹

Tolerability

Aripiprazole’s side-effect profile, revealed in preclinical and clinical trials, suggests that the drug could be well tolerated among a broad range of patients.¹⁰

In the 4-week, placebo-controlled comparison with haloperidol, rates of extrapyramidal symptoms (EPS) among aripiprazole-treated patients were much lower than those in the haloperidol group and similar to those in the placebo group.⁶ There is no evidence that higher dosages of aripiprazole lead to increased EPS. It is also not known whether aripiprazole will cause EPS in children and in patients older than 65, who are more susceptible than other age groups to antipsychotic-induced motor side effects.

Aripiprazole is believed to be less likely than typical antipsychotics to induce tardive dyskinesia, but more long-term information is needed.³

Studies have associated aripiprazole use with some weight gain, but (marginally) less than risperidone,⁷ less than haloperidol,⁶ and substantially less than olanzapine.⁸ Direct comparisons with other atypicals are not yet available.

Aripiprazole’s effect on glucose metabolism has not been determined, but early information suggests a favorable profile with respect to metabolic indices. Aripiprazole does not appear to elevate prolactin or cause cardiac QTc prolongation. Sedation appears to be the most pronounced side effect; this effect also appears to increase with higher dosages.

As has happened with the other atypicals, the pattern of use for aripiprazole will unfold over time as clinicians gain experience with using this agent in distinct patient groups.

Related resources

• Jordan S, Koprivica V, Chen R, et al. The antipsychotic aripiprazole is a potent, partial agonist at the human 5HT(1A) receptor. Eur J Pharmacol 2002;50:873-83.
• Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-71.

Drug brand names

• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Buckley receives grant support from, is a consultant to, and is a speaker for AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Dr. Sinha is a consultant to Bristol-Myers Squibb Co.

Dr. Sebastian is a consultant to Eli Lilly and Co.

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

A typical antipsychotics have enhanced outcomes in schizophrenia while helping patients avert the troublesome motor effects associated with older agents. Some side effects, such as weight gain and prolactin elevation, have remained a concern, however.

Aripiprazole, a novel antipsychotic recently FDA-approved for treating schizophrenia, exhibited efficacy and tolerability in preclinical and clinical trials.

How aripiprazole works

Aripiprazole’s mechanism of action is important to our understanding of the dopamine hypothesis of antipsychotic effect.¹

The dopamine hypothesis remains the predominant explanation of how antipsychotics work.² However, the evolution of antipsychotic therapy has led to further refinement of the dopamine hypothesis, including selective dopamine (D4) antagonism, rapid dissociation from dopamine receptors, dopamine-serotonin receptor system interactions, dopamine-GABA system interactions, and now (with aripiprazole) partial agonist effects at dopamine (and selective serotonin) receptors.^1,2

Table

ARIPIPRAZOLE: FASTFACTS

Table 1

ARIPIPRAZOLE’S RECEPTOR-BINDING PROFILE

Table 2

POTENTIAL DRUG-DRUG INTERACTIONS WITH ARIPIPRAZOLE

Unlike other antipsychotics, which appear to act through dopamine receptor antagonism, aripiprazole is a potent partial agonist at both the dopamine (D2) and serotonin (5HT1A) receptors.^1,2Table 1 describes the agent’s receptor-binding profile.

The agent offers 78% bioavailability. It is metabolized through the hepatic microenzyme system, specifically the cytochrome P450 enzymes 2D6 and 3A4. Use of nicotine does not alter the agent’s plasma levels. Its active moiety is aripiprazole with minor contributions from the derivative dehydro-aripiprazole.

Aripiprazole therapy can be started at 10 or 15 mg/d; the starting dosage—15 mg/d in most cases—may also suffice as maintenance therapy for many patients. If the patient does not respond, it is prudent to wait several weeks before increasing the dosage beyond 15 mg/d.

The FDA-approved maximum dosage for aripiprazole is 30 mg/d. However, information from clinical trials indicates that increasing the dosage from 15 to 30 mg/d does not enhance the antipsychotic’s efficacy.^3,4 Because of its absorption properties, the agent can be taken with or without food.

Aripiprazole has a relatively long half-life (75 hours), so it can be administered once daily. This provides an advantage when switching treatments. Some information suggests that patients may be switched directly to aripiprazole,⁵ although cross-titration is recommended.³

Although data in clinical populations are insufficient, studies in normal volunteers suggest that aripiprazole can be given at regular dosages to older patients and to those with renal or hepatic impairment.³Table 2 highlights potential drug-drug interactions with agents that can influence the hepatic microenzyme system.

Efficacy

Aripiprazole has demonstrated efficacy in clinical studies of patients with schizophrenia and schizoaffective disorder.^3-8

• In a placebo-controlled, 4-week trial, patients who received aripiprazole, 15 to 30 mg/d, or haloperidol, 10 mg/d, reported similar improvements in positive and negative symptoms, psychopathology, and overall function.⁶
• A placebo-controlled, 4-week trial of aripiprazole, 20 and 30 mg/d, compared with risperidone, 6 mg/d, revealed similar efficacy with respect to symptom improvement and overall functioning.⁷
• Aripiprazole and olanzapine demonstrated comparable efficacy in a 28-week study. However, patients in the aripiprazole group showed greater improvement at 8 weeks and sustained improvement through 28 weeks in a measure of verbal memory.⁸

Researchers have not yet compared aripiprazole with clozapine, quetiapine, or ziprasidone. Also, information on the dosing, efficacy, and tolerability of aripiprazole in patients with first-episode or treatment-refractory schizophrenia is limited. According to the manufacturers’ prescription information, aripiprazole’s long-term efficacy in schizophrenia treatment has not been established. Data on 1-year treatment with aripiprazole appear encouraging.³

Preliminary data suggest that aripiprazole may help treat nonpsychotic conditions, although which ones has yet to be determined. A 3-week, placebo-controlled study demonstrated that aripiprazole, 30 mg/d, helped ameliorate symptoms of mania.⁹

Tolerability

Aripiprazole’s side-effect profile, revealed in preclinical and clinical trials, suggests that the drug could be well tolerated among a broad range of patients.¹⁰

In the 4-week, placebo-controlled comparison with haloperidol, rates of extrapyramidal symptoms (EPS) among aripiprazole-treated patients were much lower than those in the haloperidol group and similar to those in the placebo group.⁶ There is no evidence that higher dosages of aripiprazole lead to increased EPS. It is also not known whether aripiprazole will cause EPS in children and in patients older than 65, who are more susceptible than other age groups to antipsychotic-induced motor side effects.

Aripiprazole is believed to be less likely than typical antipsychotics to induce tardive dyskinesia, but more long-term information is needed.³

Studies have associated aripiprazole use with some weight gain, but (marginally) less than risperidone,⁷ less than haloperidol,⁶ and substantially less than olanzapine.⁸ Direct comparisons with other atypicals are not yet available.

Aripiprazole’s effect on glucose metabolism has not been determined, but early information suggests a favorable profile with respect to metabolic indices. Aripiprazole does not appear to elevate prolactin or cause cardiac QTc prolongation. Sedation appears to be the most pronounced side effect; this effect also appears to increase with higher dosages.

As has happened with the other atypicals, the pattern of use for aripiprazole will unfold over time as clinicians gain experience with using this agent in distinct patient groups.

Related resources

• Jordan S, Koprivica V, Chen R, et al. The antipsychotic aripiprazole is a potent, partial agonist at the human 5HT(1A) receptor. Eur J Pharmacol 2002;50:873-83.
• Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-71.

Drug brand names

• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Buckley receives grant support from, is a consultant to, and is a speaker for AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Dr. Sinha is a consultant to Bristol-Myers Squibb Co.

Dr. Sebastian is a consultant to Eli Lilly and Co.

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