Atypical Antipsychotics: A Practical Review

Donna A. Wirshing, MD, William C. Wirshing, MD, Stephen R. Marder, MD, C. Scott Saunders, MD, Elizabeth H. Rossotto, PhD, Stephen M. Erhart, MD


Medscape Psychiatry & Mental Health eJournal. 1997;2(5) 

In This Article


Risperidone is a relatively new antipsychotic that is a potent antagonist at 5-HT2a and D2 receptors.[49] It is the most potent serotonin/dopamine antagonist available today. It also demonstrates relatively high affinity for alpha1 and H1 receptors but low affinity for beta-adrenergic or muscarinic receptors (Table I). Preclinical studies indicate that while risperidone is approximately equipotent to haloperidol at D2 antagonism, it is several times less potent than haloperidol at inducing catalepsy.[49] Risperidone is metabolized by CYP2D6, which indicates that it is likely to interact with a number of drugs, including selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Risperidone has been compared with both placebo and traditional antipsychotics in a number of double-blind studies.[50] Risperidone was consistently more effective than placebo and at least as effective as the other antipsychotics. The pivotal risperidone trial was carried out in Canada and the US.[51,52] In this study, 4 doses of risperidone (2, 6, 10, and 16mg/day) were compared with 20mg of haloperidol and placebo. The 3 highest doses of risperidone and haloperidol were significantly more effective than placebo for total scores and positive symptoms on the PANSS. Risperidone 6mg and 16mg, but not haloperidol, resulted in significant improvements in negative symptoms as measured by the PANSS. Overall, the 6-mg dose of risperidone was the most effective. Moreover, patients who received this dose had EPS scores that were statistically indistinguishable from placebo.

Davis[53] conducted a meta-analysis that pooled data from 5 controlled trials. The results indicated that 53% of risperidone patients met a priori criteria for improvement when their dose was greater than 6mg, compared with 40% of individuals who received a conventional antipsychotic (P<.001). Davis also reported that risperidone was 25% more effective for positive symptoms and 60% more effective for negative symptoms when compared with conventional agents.

The effectiveness of risperidone in patients refractory to other drugs is unclear. In the US multicenter study,[52] the advantage of 6mg of risperidone over haloperidol was greatest for patients who had been hospitalized for at least 6 months. Assuming that these patients were relatively unresponsive to the antipsychotic action of conventional medications, this finding suggests an advantage for risperidone in a treatment-refractory group. Bondolfi and colleagues[54] compared risperidone with clozapine in treatment-refractory patients. Both drugs were equally effective, but clozapine led to more weight gain and sedation. In a preliminary report, Ames and coworkers[55] demonstrated that risperidone resulted in greater improvement in treatment-refractory patients, compared with the improvement seen in the haloperidol group (24% vs 10%; P=0.03). Side effects, subjective intolerance, and the use of anticholinergics were greater for the patients assigned to haloperidol.

Taken together, these studies provide strong evidence that risperidone is at least as effective as traditional antipsychotics in the treatment of schizophrenia. Also, its relative lack of EPS at effective doses indicates that risperidone has a substantially better efficacy/side-effect ratio when compared with conventional compounds. Patients who are unable to tolerate other antipsychotics at doses that are needed to control psychotic symptoms are likely to respond better to risperidone. It may also be a more effective agent for patients with negative symptoms and in certain groups unresponsive to trials of typical agents.

Risperidone is increasingly being used for a number of different illnesses, for which minimal rigorous double-blind research data are available (Table II). However, there are multiple case reports, case series, and open-label studies about the utility of this medication in other psychiatric disorders.

The role of risperidone in mood disorders is unclear. Three open-label clinical reports indicated that risperidone can be helpful for patients with mania and psychosis and for patients with depression and psychosis.[56,57] A number of case reports have suggested that risperidone is useful in the treatment of bipolar disorder.[58,59,60] In contrast, Dwight and colleagues[61] noted that patients with schizoaffective disorders of a bipolar subtype who were treated with risperidone developed an increase in manic symptoms. These patients were managed by either decreasing the dose of risperidone or adding a mood-stabilizing agent. Because divalproex sodium is a first-line agent for treating mania, this medication is commonly used in conjunction with risperidone[56,62]; however, no controlled trials have specifically addressed the efficacy of this combination. Divalproex sodium preparation of valproate is metabolized via the hepatic mixed-function oxidase system, whereas risperidone utilizes the II-D6 isoenzyme system; thus, little pharmacokinetic interaction would be anticipated.

Risperidone (as well as clozapine) can lead to the emergence of obsessive-compulsive symptoms, probably as a result of its serotonergic activity. Nevertheless, there are reports suggesting that it can be effective as an adjunct for patients with obsessive-compulsive disorder who are also treated with an SSRI.[63,64] Risperidone appears to be a very effective compound for patients with Tourette's syndrome. The published reports are quite limited, but 1 study[65] reported improvement in 9 of 11 Tourette's patients treated with risperidone.

Haloperidol is frequently used to treat behavioral disturbances and psychoses in patients with developmental disorders. Risperidone and all of the newer agents have milder EPS profiles, which may constitute an important advantage for patients who often have difficulty describing their inner experiences. Vanden Borre and colleagues[66] administered risperidone (4-12mg) or placebo to 37 patients with behavioral disturbances. The patients treated with risperidone had significantly greater improvement in aberrant behaviors than did placebo controls.

Risperidone (1 or 2mg/day) may be particularly useful for patients with dementia because it causes less EPS than other high-potency drugs. Several open-label studies have confirmed this efficacy.[67,68,69] In addition, it is less sedating and causes fewer anticholinergic effects than do lower-potency drugs. This is advantageous because anticholinergic activity can worsen cognitive status. Patients should, however, be carefully observed for orthostatic hypotension.

Risperidone is associated with dose-related EPS (Table III). As noted previously, the severity of EPS is often minimal in risperidone's therapeutic range. As a result of its alpha-adrenergic activity, risperidone also causes orthostatic hypotension and reflex tachycardia. Thus, risperidone should be started at low doses--for example 0.5mg--in elderly patients. Other common side effects include sedation, erectile problems in men, weight gain, and decreased sexual interest.[51,52] A number of cases of neuroleptic malignant syndrome have been reported on risperidone.[3,70,71,72] This is not surprising given this drug's substantial antidopaminergic activity. Risperidone also increases plasma prolactin, an effect that can lead to galactorrhea and menstrual disturbances in some women and sexual dysfunction, gynecomastia, and testicular atrophy in men.

The North American trial[52] was the pivotal study that gained risperidone approval for use in the US. It demonstrated that all 4 doses of risperidone used in the trial (2, 6, 10, and 16mg) were more effective than placebo and as effective as haloperidol. However, at 10mg and above, the side-effect profile was similar to haloperidol. Indeed, about as many people needed anticholinergics on 16mg of risperidone (37%) as those receiving haloperidol (47%; Fig. 2).

Clinical efficacy and side effects in patients treated with risperidone, haloperidol, or placebo. EPS=extrapyramidal symptoms. Adapted with permission from Essential Psychopharmacol (1996;1:5-26), Copyright © 1996, The Hatherleigh Company, Ltd.[96]

The most compelling point emphasized by these data is that risperidone should not be dosed to the neuroleptic threshold. The greatest cost/benefit ratio will clearly occur at a dose below that necessary to induce clinically apparent neurotoxicity. Since it is impossible to predict the neuroleptic threshold in a given patient prior to treatment, it is necessary to begin therapy at a low dose and slowly titrate to efficacy, not toxicity. A general guideline is to begin dosing at 1mg bid (0.5mg daily for the elderly) and to slowly titrate by 1-mg increments every 5 to 7 days. Once target symptoms have begun to show a therapeutic response, the titration should be halted. The dose should be increased further only if the ultimate therapeutic effect obtained is inadequate. If demonstrable neurotoxicity (either parkinsonism or akathisia) emerges, the dose should be decreased. This is in marked distinction to the usual pattern with conventional medications, which generally call for the addition of an anti-EPS medication like benztropine or trihexyphenidyl. The most commonly prescribed dose range for chronic schizophrenia is 4 to 6mg. However, some patients can be managed with doses as low as 1mg, while others will require as much as 20mg. Regardless of the necessary optimum risperidone dosage, the guiding concept should be "dose to antipsychotic efficacy below the neuroleptic threshold."


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