Quetiapine

Observational studies

Data from short-term clinical trials (6 weeks) suggest that quetiapine may be useful for the management of psychotic disorders in patients who do not tolerate adverse reactions to the typical antipsychotic drugs or clozapine [ ]. The most common adverse reactions to quetiapine were dizziness, hypotension, somnolence, and weight gain. Raised hepatic enzymes have also been reported. In addition, two patients with idiopathic Parkinson’s disease and psychosis were treated with quetiapine for 52 weeks [ ]. Psychotic symptoms were successfully controlled without worsening of motor disability.

A post-hoc analysis of the Spectrum trial, an international open non-comparative study, sponsored by AstraZeneca Pharmaceutical, has been published; this study was purportedly carried out to evaluate improvements in efficacy and tolerability gained by switching to quetiapine in patients who had previously taken haloperidol (n = 43), olanzapine (n = 66), or risperidone (n = 55) [ ]. Switching to quetiapine produced improvements from baseline in Positive and Negative Syndrome Scale and in Calgary Depression Scale for Schizophrenia scores. There were significant reductions in extrapyramidal adverse reactions on the Simpson–Angus scale and Barnes Akathisia scale. Patients who switched to quetiapine from haloperidol had a mean weight gain of 2 kg, while those who switched from olanzapine had a mean loss of 1 kg and those who switched from risperidone had a mean gain of 0.7 kg.

In seven patients with refractory schizophrenia taking high-dose quetiapine 1200–2400 mg/day, there were mild to marked improvements in positive symptoms, violent behavior, behavioral disturbances, and sociability [ ]. Sedation, orthostasis, dysphagia, and a nocturnal startle reaction were reported and were responsive to dosage reduction. Weight gain was 4.1 kg and there were no significant electrocardiogram abnormalities.

In an open pilot study, 20 adults with acute bipolar mania took quetiapine 200 mg on day 1, increased by 200 mg/day on days 2, 3, and 4 up to 800 mg/day taken in two divided doses on day 4 [ ]. From day 5 onward, patients took a flexible total dose of 400–800 mg/day until completion of 3 weeks’ treatment. There was significant improvement. Overall, 20% of patients withdrew because of adverse events: agitation was the most common cause. Dosage adjustment was required in 35% of patients because of adverse reactions after rapid dose administration was complete; the most common adverse effect was tremor (30%).

Tolerability to rapid introduction of high-dose quetiapine in eight patients with acute schizophrenia (n = 5) or mania (n = 3) has been evaluated [ ]. For most of these patients, rapid dose escalation (quetiapine 200–300 mg on day 1 to a maximum dose of 600–1200 mg over 4 weeks) was well tolerated; there were no serious adverse reactions and vital clinical parameters were unchanged; one patient had transient somnolence.

The results of a prospective, open, non-comparative, flexible-dose, 20-week study of quetiapine (mean dose 315 mg/day) in 14 patients with treatment-resistant depression has been published [ ]. Augmentation with quetiapine significantly reduced total scores and scores listed in the anxiety subscale of the Hamilton scale. Quetiapine add-on treatment significantly reduced the scores listed in the insomnia subscale after the second week of treatment. Of the 18 patients who entered this study, four patients dropped out because of persistent hypotension and lack of response to quetiapine.

Two adolescent girls with major depressive disorder, sleep disturbances, and cutting behaviors were successfully treated with quetiapine augmentation [ ].

In a 6-month open study in 35 consecutive patients with Parkinson’s disease with drug-induced psychosis, 19 with dementia, the intention-to-treat analysis did not show a significant effect of quetiapine; in the 24 who completed the study, quetiapine was more effective in those without dementia [ ]. Treatment was stopped in 11 patients (5 demented and 6 non-demented) because of lack of response (n = 8), or lack of response and adverse reactions (two with somnolence and one with orthostatic hypotension).

A 6-week open flexible-dose pilot study of quetiapine (at doses of 25–300 mg/day) for aggression secondary to traumatic brain injury has been conducted in seven patients [ ]. Quetiapine reduced irritability and aggression with associated improvement in cognitive function. Sedation was reported in three patients; in two cases it resolved by week 3 and in the remaining case it did not resolve until week 6. There were mild extrapyramidal adverse reactions and akathisia in one subject.

Quetiapine has been assessed in nine alcoholics with persistent craving, sleep disorder, excitement, depressive symptoms, or symptoms of anxiety after withdrawal [ ]. Eight patients were abstinent with quetiapine over 2–7 months; one of these relapsed after he stopped taking quetiapine on his own initiative after 10 weeks. The ninth stopped taking it immediately because of swollen nasal mucosa.

The safety of quetiapine in general practice in England has been examined in a Prescription Event Monitoring study in 1728 patients (median age 39 years, 53% women) [ ]. Drowsiness/sedation was the most frequently reported event during the first month of treatment (n = 47, 3% of the cohort) and the most common reason for stopping quetiapine (n = 51). There were low incidences of extrapyramidal symptoms (n = 21) and hyperprolactinemia (n = 3). There was new-onset diabetes mellitus in three cases. There were six pregnancies and four live births, with no reported congenital abnormalities. From the 56 deaths reported during this study, the most frequently reported causes were cardiovascular (n = 18) and respiratory (n = 15).

There was a high discontinuation rate in an open study (68%, mean duration 18 weeks) in patients with rapid-cycling bipolar disorder who received quetiapine either as monotherapy (n = 19) or as add-on therapy (n = 22) for up to 1 year (mean dose 196.6 mg/day, range 25–900 mg/day) [ ]. Mean body weight fell from 91 kg at baseline to 86 kg at end-point with quetiapine monotherapy but did not change in the whole sample.

Comparative studies

The efficacy of quetiapine in the treatment of mania or bipolar disorder has been assessed in several studies. In a double-blind study, 50 adolescents aged 12–18 years with bipolar I disorder with manic or mixed episodes were randomized to quetiapine 400–600 mg/day or sodium valproate (serum concentration 80–120 mg/l) for 28 days [ ]. The treatments were similar in efficacy. One serious adverse event occurred during the study; a patient taking sodium valproate was rehospitalized because of symptom exacerbation and treatment was withdrawn; no other patients withdrew because of treatment-related adverse reactions. The most common adverse reactions in both groups were sedation (quetiapine 60%, sodium valproate 36%), dizziness (quetiapine 36%, sodium valproate 36%), and gastrointestinal upset (quetiapine 24%, sodium valproate 28%).

Drug combination studies

Quetiapine (mean dosage 182 mg/day) has been added to SSRIs or venlafaxine in an 8-week, double-blind, placebo-controlled study in 58 patients with major depressive disorder [ ]. Eight out of 11 dropouts in the quetiapine group were because of adverse reactions (sedation/somnolence/lethargy, n = 6; weight gain and fatigue, n = 1; increased appetite, irritability, and somnolence, n = 1; total dropouts, n = 11); two patients withdrew from the placebo group (sedation/somnolence/lethargy, n = 1; increased irritability, n = 1).

Quetiapine has been added to antidepressants in elderly patients (n = 9, mean age 73 years) with major depressive disorder and cerebrovascular damage [ ], although it is not approved for this indication.

Placebo-controlled studies

Quetiapine has been approved by the FDA as monotherapy for the treatment of acute mania. It has been evaluated in combination with lithium or divalproex in 191 patients who had recently been manic [ ]. After treatment with quetiapine plus lithium or divalproex for 7–28 days, the patients were randomized to either additional quetiapine or placebo and followed for 3 weeks more. Early discontinuation was more frequent with placebo than with quetiapine. The intention-to-treat population included 81 taking quetiapine and 89 taking placebo. The mean dose during the last week in patients taking quetiapine was 504 mg/day. Patients taking quetiapine had a greater improvement in the Young Mania Rating Scale score (YMRS) than patients taking placebo. The response rate (50% or greater improvement from baseline using the YMRS) was significantly higher in the group with added quetiapine than added placebo. Common adverse events included somnolence, dry mouth, weakness, and postural hypotension.

In 542 outpatients with bipolar I or II disorder experiencing a major depressive episode, who were randomly assigned to 8 weeks of quetiapine (300 or 600 mg/day; n = 181 and n = 180 respectively) or placebo (n = 181), both doses produced statistically significant improvement in Montgomery–Asberg Depression Rating Scale (MADRS) total scores compared with placebo from week 1 onward [ ]. There were extrapyramidal symptoms in 8.9% of those who took 600 mg/day, 6.7% of those who took 300 mg/day, and 2.2% of those who took placebo. Patients who took quetiapine 600 mg/day had a mean weight gain of 1.6 kg, compared with 1.0 kg in those who took 300 mg/kg and 0.2 kg in those who took placebo.

Up to four different re-analyses of the same four double-blind, placebo-controlled studies of quetiapine in mania [ ], agitation and aggression in bipolar mania [ ], efficacy across a broad range of symptoms [ ], and target dose for efficacious treatment [ ] have been published; all were supported by AstraZeneca, the Marketing Authorization Holder. Quetiapine was claimed to be well tolerated.

In a 2-week, multicenter, randomized, open study funded by AstraZeneca patients with acute schizophrenia or schizoaffective disorder received quetiapine either rapidly (200 mg on day 1, 400 mg on day 2, 600 mg on day 3, and 800 mg on day 4; n = 139) or in a conventional regimen (50 mg on day 1, 100 mg on day 2, 200 mg on day 3, and 400 mg on day 4; n = 130) [ ]. In both cases treatment was followed by a flexible dosage of 400–800 mg/day (mean maximal dosages 786 mg/day and 508 mg/day respectively). During week 1, the rates of patients who had at least one adverse event were 39% with the rapid regimen and 25% with the conventional regimen. The most common adverse events in those taking quetiapine (somnolence, dizziness, and orthostatic hypotension) occurred in 10% and 5.4% of patients respectively. The most common adverse events overall were hypotension (14% with the rapid regimen versus 7.7% with standard therapy), tachycardia (9.4% versus 10%), somnolence (6.5% versus 3.8%), and sedation (5.8% versus 5.3%). There were no significant differences in withdrawal rates due to adverse events (rapid regimen, n = 3, 2.1%; conventional regimen, n = 4, 3.1%). The only serious adverse event was agitation in the rapid initiation group.

Quetiapine (n = 963, median dose 300 mg/day) and placebo (n = 292) for patients with schizophrenia have been compared in trials that have been re-analysed [ ]. Headache was the most common adverse event in both groups (18% versus 20%), followed by sedation, which was significantly more common with quetiapine (15% versus 6.2%; OR = 2.7, 95% CI = 1.6, 4.5); somnolence and orthostatic hypotension were also significantly more common with quetiapine. The frequencies of extrapyramidal symptoms were similar in the two groups (9.6% and 11% respectively).

There was no clinical improvement according to the Neuropsychiatric Inventory and the Clinical Global Impression of Change in elderly patients with Alzheimer’s disease and behavioral and psychological symptoms when they were randomized to quetiapine (n = 20, median dose 200 mg/day) or placebo (n = 20) in a 6-week double-blind trial [ ]. Extrapyramidal reactions did not differ significantly between the groups.