Atypical antipsychotic AA agents

♦ The choice of an AA agent is based largely on its ease of use and side-effect profile, as most antipsychotic agents, with few exceptions, have comparable efficacy in improving psychosis.

The main difference in the antipsychotic agents lies in their propensity to worsen motor functioning in this frail and already vulnerable population. Thus far, six drugs have been marketed in the USA and Europe as 'atypical': clozapine, risperi-done, olanzapine, quetiapine, ziprasidone, and aripiprazole.

The use of an AA agent may allow the clinician to control psychosis with fewer motor side-effects and, in some cases, without the need for cutting back on anti-PD medications. It remains unclear whether antipsychotic medications should be continued once they are initiated. There are some data that show persistence of hallucinations in PD patients with drug-induced psychosis after its initial occurrence. One study prospectively followed PD patients on v successful long-term treatment with quetiapine or J | clozapine as these drugs were withdrawn. The f study was aborted after enrolment of only six -§ §

patients due to an unacceptably high rate of psychosis recurrence (five patients, 83%). z o

Psychosis recurred within 2 months of the end of each taper. Clozapine.

O The cumulative experience of all open-label reports on clozapine in parkinsonism involving over 400 patients has been surprisingly consistent. Low doses are required (average of 25 mg/day). O A meta-analysis of all large clozapine reports on psychosis in PD showed an 85% improvement rate with acceptable tolerance. Most importantly, clozapine did not worsen motor symptoms. In some reports, it improved tremor.

O Clozapine remains difficult to use because of its potential for inducing agranulocytosis. The problem is idiosyncratic, so that even the small doses used in PD do not exempt patients from this side-effect. O In the USA, for the first 6 months, each patient on clozapine undergoes a weekly white blood cell (WBC) count, verified by the pharmacy, and can receive only 1 week's supply of the drug at a time. After 6 months the process becomes bi-weekly. In the UK and Europe, similar strict monitoring is mandatory through case registration.

Risperidone.

O Risperidone causes dose-related problems typical of conventional neuroleptics such as prolactin elevation and acute dystonic reactions.

O Almost all reports concerning risperidone in

PD have involved open-label studies. O Unfortunately, the studies showed mixed results. A meta-analysis of 82 PD patients treated with risperidone revealed that 23 (28%) experienced motor worsening. Olanzapine. This is a thiobenzodiazepine of similar chemical structure to clozapine. However, the 2002 Movement Disorders Society Task Force evidence-based review on the treatment of psychosis in PD concluded that there is 'insufficient evidence to demonstrate efficacy of olanzapine in drug-induced psychosis', and it carries an 'unacceptable risk of motor deterioration' even at 'low conventional doses', based on disappointing double-blind trial results in PD patients with hallucinations. Quetiapine.

O Quetiapine is a dibenzothiazepine with the closest pharmacological resemblance to clozapine but without the risk of agranulocytosis. O Unfortunately, quetiapine has been subject to only one small, single-centre double-blind trial.

O However, several open-label reports involving over 200 PD patients give a fairly solid, positive impression of the drug's standing as an AA agent. O Quetiapine appears to be slightly less effective than clozapine against psychosis. Unlike clozapine, it does not improve tremor, and may induce mild motor worsening. But, unlike olanzapine and risperidone, no reported motor worsening on quetiapine has precipitated hospitalization. O The mean daily dose was generally below

75 mg/day. Ziprasidone.

O Ziprasidone has a higher affinity for 5-HT2 than D2 receptors. There has been no report of its use in the PD population. O A panel of expert psychiatrists reviewing all available data on ziprasidone use in schizophrenia concluded that its extrapyramidal syndrome profile is 'better than risperidone, the same as olanzapine but not quite as good as quetiapine or clozapine'.

♦ Aripiprazole.

O Aripiprazole is the only AA agent that is a partial agonist at the D2 and 5-HT1A receptors and an antagonist at 5-HT2A receptors. It also has a high 5-HT2/D2 ratio and may therefore carry a low risk of extrapyramidal side-effects while alleviating psychosis in PD-vulnerable populations. O The preliminary experience, however, is mixed but not very encouraging. In one report, only two out of eight PD patients experienced near-complete resolution of their psychotic symptoms with aripiprazole. The other six patients discontinued aripi-prazole within 40 days, two due to motor worsening.

O Controlled studies are currently under way to definitively evaluate the safety and tolerabili-ty of aripiprazole use in parkinsonian patients.

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