Schizophrenia - quetiapine - antipsychotic - neuroleptic - atypical - pharmacology

Quetiapine fumarate, Bis [2-(2-[4-(dibenzo[b,f][1,4]thiazepin-11-yl]ethoxy)ethanol] fumarate (IUPAC)2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol-(E)-2-butanedioate (2:1) salt), [ICI 204,636], is a novel dibenzothiazepine antipsychotic developed by Zeneca. It is marketed under the trade name ‘Seroquel’Seroquel. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia.

The initial hope of investigators was that quetiapine would have antipsychotic potential and that it might share some of the properties of clozapine without its toxicity to white blood cells.

The effective dosage range is usually 300-450 mg/day split into two doses. The dose is titrated upwards from 25 mg twice dailybd from day one to 300mg/daya fuller dosage on day 4. Elderly patients or patients with liver problems should be started on lower doses. It is both superior to placebo and, and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 to 750 mg/day and is an effective treatment for in reducing negative symptoms at a dose of 300 mg/day.

Somnolence is the most common adverse event. Abnormalities of the QTqt interval on ECG appear very infrequently and there is no need for a baseline ECG or blood pressure monitoring as used to be the case with ssertindole. There is no need for haematological monitoring as with clozapine. Quetiapine, across the full dosage range, is associated with no greater extrapyramidal symptoms than placeboThere is a reduced potential for extrapyramidal symptoms compared with conventional antipsychotics.

Quetiapine’s general efficacy and side effect profile suggest that, unless there are unforeseen post-marketing complications, quetiapine deserves a major place in the initial and long term management of schizophreniform disorders.

Quetiapine fumarate, Bis [2-(2-[4-(dibenzo[b,f][1,4]thiazepin-11-yl]ethoxy)ethanol] fumarate (IUPAC) 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol-(E)-2-butanedioate (2:1) salt), [ICI 204,636], is a novel dibenzothiazepine antipsychotic developed by Zeneca Pharmaceuticals. It is marketed under the trade name ‘Seroquel’. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia.

Licensed indications vary from country to country. The following indications are derived from MEDLINE, Cochrane and PSYCLIT database searches. The primary indications are adult schizophrenia and related psychoses in adults and the elderly (Arvanitis & Miller, 1997, McManus etal, 1999). Affective and aggressive symptoms in schizophrenia (Hellewell et al, 1998), adolescent schizophrenia, schizoaffective disorder, bipolar affective disorder and mania, affective psychoses, behaviour and symptom control in dementia could form secondary indications, but more studies are awaited. The relatively greater ability to reduce negative symptoms compared to conventional antipsychotics provides an additional indication.

Indications that have cropped up in the literature include antipsychotic therapy in patients with Parkinson's - where there was a low propensity to aggravate motor symptoms (Parsa & Bastani, 1998).

Quetiapine and other antipsychotics have been proposed as first-line treatments for schizophrenia and there is some rationale for this (Lieberman, 1996). Clozapine has not been generally used as a first-line treatment due to its potential for agranulocytosis. Compared to conventional antipsychotics such as chlorpromazine and haloperidol, quetiapine and other atypical antipsychotics provide superior efficacy or, fewer less side effects, particularly extrapyramidal symptoms (EPS), and the possibility of better patient compliance. Drugs. Therefore the best use of drugs such as quetiapine may therefore be particularly appropriate in patients at the beginning of their illness as a first-line treatment of schizophrenia.

Health economic studies are currently ongoing.

In rodents, quetiapine produced mild levels of catalepsy, which suggested antipsychotic potential. It has a low propensity to cause dystonia in drug-naïve or haloperidol sensitised monkeys (Hirsch et al, 1996). Rats treated with apomorphine (APO) exhibit deficits in prepulse inhibition (PPI) of the acoustic startle response. This is thought to model schizophrenia. Clozapine restores PPI in APO-treated rats and this ability tends to correlate (Rs = 0.991) with the clinical potency of antipsychotics. Quetiapine similarly restores deficits in PPI, (Swerdlow et al, 1994).

In vitro binding affinity is more for 5-HT₂ receptors than dopamine DA₂ receptors and in vivo dopamine DA₂ and 5-HT₂ receptor occupancies are 27% and 58% respectively (see Table One).

Conventional antipsychotics block up to 80% of DA₂ receptors as measured using Positron Emission Tomography scans - see Figure Two (Kasper et al, 1997). Clozapine and quetiapine occupy about 30%, which may explain their low propensity to cause EPS. Only clozapine and quetiapine share a low affinity for dopamine DA₂ receptors and an antagonistic action at alpha2 adrenoceptors (Reynolds et al, 1998). The clinical import of this is not yet clear.

Compared to clozapine, quetiapine has much the same ratio of DA₂/5HT₂ occupancy (Gefvert et al, 1998).

Quetiapine binds to dopamine DA₂ receptors in the striatum and occupies 44% of receptors 2 hours (t[max]) after the last dose. After 26 hours occupancy dropped to the same level as in untreated healthy volunteers. Serotonin 5HT₂ receptor blockade in the frontal cortex was 72% after 2 hours, which fell to 50% after 26 hours. The terminal plasma half-life of quetiapine was found to be 5.3 hours (Gefvert et al, 1998).

Quetiapine is rapidly absorbed and has linear pharmacokinetics. The mean half-life for 375 mg/day is 6.9 hours. The steady state pharmacokinetics appear to be the same for men and women. At 2, 12 and 24 hours post dose quetiapine's 5-HT₂ occupancy was 72%, 48% and 50% respectively. It is only moderately bound to plasma protein (83%). Quetiapine is extensively metabolised by the liver involving mainly sulphoxidation by cytochrome P450 3A4 (Gunasekara & Spencer, 1998). It is extensively metabolised to over 20 metabolites - some are active, but the concentration of these active metabolites is low compared with the parent compound. Quetiapine is eliminated primarily in the form of metabolites, only 5% being excreted unchanged. About 73% is excreted in the urine and 21% in the faeces. Its half-life is about six hours.

Oral clearance in the elderly is half that of younger patients. Clearance is also reduced by hepatic or renal impairment.

Quetiapine binds to dopamine DA₂D2 receptors in the striatum and occupies 44% of receptors 2 hours (t[max]) after the last dose. After 26 hours occupancy dropped to the same level as in untreated healthy volunteers. Serotonin 5HT2 receptor blockade in the frontal cortex was 72% after 2 hours, which fell to 50% after 26 hours. The terminal plasma half-life of quetiapine was found to be 5.3 hours (Gefvert et al, 1998).

Conventional antipsychotics block up to 80% of DA₂ receptors as measured using PET scans (Kasper et al, 1997). Clozapine and quetiapine occupy about 30%, which may explain their low propensity to cause EPS.

Figure 2: Positron Emission Tomography (PET) derived DA₂ occupancy comparing quetiapine, clozapine and haloperidol.

Quetiapine is rapidly absorbed and has linear pharmacokinetics. The mean half-life for 375 mg/day is 6.9 hours. The steady state pharmacokinetics appear to be the same for men and women. At 2, 12 and 24 hours post dose quetiapine's 5-HT₂ occupancy was 72%, 48% and 50% respectively. It is only moderately bound to plasma protein (83%). Quetiapine is extensively metabolised by the liver involving mainly sulphoxidation by cytochrome P450 3A4 (Gunasekara & Spencer, 1998). It is extensively metabolised to over 20 metabolites - some are active, but the concentration of these active metabolites is low compared with the parent compound. Quetiapine is eliminated primarily in the form of metabolites, only 5% being excreted unchanged. About 73% is excreted in the urine and 21% in the faeces.

Oral clearance in the elderly is half that of younger patients. Clearance is also reduced by hepatic or renal impairment.

Only clozapine and quetiapine share a low affinity for dopamine DA₂ receptors and an antagonistic action at alpha2 adrenoceptors (Reynolds et al, 1998). The clinical import of this is not yet clear.

Compared to clozapine, quetiapine has much the same ratio of DA₂/5HT₂ occupancy (Gefvert et al, 1998).

Leucht et al's meta-analysis study (1999) of risperidone, olanzapine, sertindole and quetiapine suggest a similar efficacy profile compared to placebo, but that olanzapine, sertindole and quetiapine had more favourable  EPSE profiles.