Quetiapine

Quetiapine is a dibenzothiazepine atypical antipsychotic which has a close pharmacological resemblance to clozapine. In a number of small noncomparative clinical trials, quetiapine has been successfully used in the treatment of psychosis in patients with Parkinson’s disease. Psychosis in these patients is caused by current antiparkinsonian drug therapy, the underlying disease pathology or a combination of both factors.

In patients with Parkinson’s disease with or without previous exposure to antipsychotics, quetiapine reduced psychotic symptoms as measured by a reduction in Brief Psychiatric Rating Scale scores from baseline. Quetiapine was also effective after treatment failure with clozapine, risperidone or olanzapine, and in psychiatrically stable patients who were switched from either clozapine or olanzapine. Motor function was generally maintained in most patients. In 2 of the largest trials, patients with Parkinson’s disease reported adverse events such as headache, nausea, orthostatic hypotension, dizziness and diarrhoea after initiation of quetiapine therapy. In two 12-month trials no development or exacerbation of extrapyramidal symptoms (EPS) occurred after the initiation of quetiapine therapy in patients with Parkinson’s disease. In another trial, EPS were reported in 3% of patients with Parkinson’s disease given quetiapine after treatment failure with another atypical antipsychotic. The incidence of EPS was generally not significantly different between quetiapine (75 to 750 mg/day) and placebo in patients with schizophrenia.

Limited quantitative data are available on the pharmacodynamic profile of quetiapine in patients with Parkinson’s disease. Quetiapine, a dibenzothiazepine derivative pharmacologically similar to clozapine, is an antipsychotic with antagonist activity at serotonin 5-HT2A and dopamine D₂ receptors. Quetiapine has high affinity for 5-HT2A, α₁-adrenergic and histamine H₁ receptors and lower affinity for D₂ and α₂-adrenergic receptors. It has negligible affinity for cholinergic (muscarinic) or benzodiazapine receptors.

After repeated administration, quetiapine shows selectivity for the mesolimbic (A10) dopaminergic pathway as determined by electrophysiological studies in rats, although a more recent study has shown conflicting results. The higher affinity of quetiapine for 5-HT₂ receptors versus D₂ receptors coupled with its possible limbic selectivity may be responsible for its antipsychotic activity and reduced potential for causing extrapyramidal symptoms.

The pharmacokinetic properties of quetiapine have not yet been determined in patients with Parkinson’s disease and psychosis. In patients with schizophrenia, quetiapine is rapidly absorbed after oral administration and reaches peak plasma concentrations (C_max) after 1.5 to 1.8 hours. Coadministration with food enhances the absorption of quetiapine increasing C_max and area under the plasma concentration-time curve (AUC) by 25 and 15%, respectively. However, these effects are not considered to be clinically significant. Over 80% of the drug is protein bound and oral bioavailability is limited at 9%. Quetiapine is widely distributed throughout the body with a volume of distribution of 10 L/kg.

Quetiapine is extensively metabolised by the liver, with <5% of the drug excreted unchanged. Cytochrome P450 (CYP) enzymes, particularly 3A4, are primarily responsible for the metabolism of quetiapine into at least 20 compounds most of which are inactive. Sulfoxidation to the sulfide metabolite and oxidation to the parent acid metabolite are the major metabolic pathways. Quetiapine has a mean elimination half-life of 6 to 7 hours in young and elderly patients, respectively.

The mean clearance of oral quetiapine (25mg) was reduced by 25% in patients with hepatic impairment; these patients require a slower titration and a reduction in the maximum dose of quetiapine. However, in patients with severe renal impairment plasma quetiapine concentrations were within the normal range seen in healthy individuals given the same dosage, and therefore dosage adjustments are not necessary.

Quetiapine interacts with both inducers and inhibitors of CYP3A4. Phenytoin, a CYP3A4 inducer, increases the mean oral clearance of quetiapine 5-fold, while ketoconazole, a CYP3A4 inhibitor, decreases the oral clearance of quetiapine by 84%. Coadministration of quetiapine and thioridazine increased the oral clearance of quetiapine by 66%, reducing C_maxand AUC values by 48 and 41%, respectively.

In 4 small noncomparative trials quetiapine (mean dosage 49 to 75 mg/day) improved psychotic symptoms in patients with Parkinson’s disease and psychosis with or without previous exposure to antipsychotics, as reflected by a statistically significant decrease ranging from 24 to 45% in the Brief Psychiatric Rating Scale (BPRS) scores compared with baseline. This improvement in psychotic symptoms was achieved while motor function was generally maintained.

Quetiapine (mean dosage 62.5 mg/day) was also an effective alternative for improving psychosis in 29 patients unresponsive to or who could not tolerate other atypical antipsychotics (clozapine, risperidone or olanzapine), or those who were noncompliant with blood monitoring. A statistically significant reduction in BPRS scores from baseline was reported in a 6-month trial. This improvement in psychotic symptoms was accompanied by a nonsignificant improvement in motor function.

In 2 small trials, approximately 70 to 80% of psychiatrically stable patients were successfully switched from clozapine or olanzapine to quetiapine (mean dosage 49 to 62.5 mg/day) without any loss of antipsychotic effect and motor function was maintained. Crossover success was more likely when quetiapine was titrated gradually with a longer overlap period with the original antipsychotic.

In two 12-month trials in patients with Parkinson’s disease, no development or exacerbation of extrapyramidal symptoms (EPS) occurred after the initiation of quetiapine therapy (dosage range 25 to 800 mg/day). EPS were reported in 3% of patients given quetiapine (mean dosage 63 mg/day) after treatment failure with other atypical antipsychotics.

In general, in patients with schizophrenia, there were no significant differences in the reported incidence of EPS between quetiapine and placebo recipients. In a 1-month nonblind comparative trial, quetiapine (mean dosage 317 mg/day) was associated with a lower incidence of EPS than risperidone in 728 patients with a psychotic disorder.

At present there are no formal dosage recommendations for quetiapine in patients with Parkinson’s disease. The US prescribing information for the management of psychotic disorders states that the recommended oral daily dosage of quetiapine is between 300 and 400 mg/day administered 2 or 3 times daily. Treatment should generally be initiated at 25mg twice daily and titrated at 25 to 50mg increments given 2 or 3 times daily on the second or third day as tolerated. Titration to the target dose range should be completed by the fourth day. Additional dosage adjustments should generally be made at intervals of not less than 2 days.

The UK prescribing information recommends quetiapine is administered twice daily, starting with a dosage of 50 mg/day. Quetiapine should then be titrated to a dosage of 100 mg/day on day 2, 200 mg/day on the third day and 300 mg/day on the fourth day, to a target dosage of 300 to 450 mg/day. Quetiapine may be adjusted within the range of 150 to 750 mg/day based on clinical efficacy and tolerability. In clinical trials in patients with Parkinson’s disease the mean quetiapine dosage ranged from 49 to 75 mg/day (range of 12.5 to 800 mg/day).

In elderly patients, those who are debilitated or who have a predisposition to hypotensive reactions, a slower rate of titration and a lower target dose should be considered. In patients with hepatic impairment, the initial daily dose should be 25mg, with daily increments of 25 to 50mg to a target dose determined by clinical response and tolerability.

Care is needed when quetiapine is administered in patients with known cardiovascular or cerebrovascular disease and patients susceptible to postural hypotension. In addition, there is a possibility that when given concomitantly with certain antihypertensive agents, quetiapine may potentiate postural hypotension and dizziness.

Somnolence may occur, particularly during the initial titration period. Quetiapine may also potentiate the cognitive and motor effects of alcohol and antagonise the effects of levodopa and dopamine agonists.