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
| Drug brand name: Risperdal Consta |
| Class: Long-acting injectable atypical antipsychotic |
| FDA-approved indications: Schizophrenia |
| Approval date: Oct. 29, 2003 |
| Manufacturer: Janssen Pharmaceutica |
| Dosing forms: 25 mg, 37.5 mg, 50 mg |
| Recommended dosage: Most adult patients will be started at 25 mg every 2 weeks, with dosages titrated upward as needed |
| Estimated date of availability: By January 2004 |
| Dosing equivalencies (approximate): 25 mg IM biweekly = 3 mg/d oral 37.5 mg IM biweekly = 4.5 mg/d oral 50 mg IM biweekly = 5 to 6 mg/d oral |
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
| Receptor type | Effects |
|---|---|
| Dopamine D2 | Antagonism (< haloperidol) |
| Serotonin 5HT2A | Antagonism (170 times > haloperidol) |
| Alpha 1 | Low affinity |
| Alpha 2 | Low affinity |
| Histaminic | Low affinity |
| Muscarinic | No affinity |
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
| Drug | CYP enzyme affected | Effect on plasma concentration of risperidone |
|---|---|---|
| Fluphenazine | 2D6 | Increase |
| Paroxetine | 2D6 | Increase |
| Carbamazepine | 2D6 | Decrease |
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.