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


Quetiapine is a structural analogue of clozapine--a dibenzothiazepine derivative. It is distinct from virtually all other antipsychotic compounds in that it has a remarkable absence of binding preference to any of the receptor systems thought to correlate with either clinical efficacies or toxicities. In vivo studies have suggested that quetiapine has relatively low binding affinities for 5-HT1a, 5-HT2a, alpha1, alpha2, H1, D1, and D2 (Table I).[46] In humans it has a half-life of approximately 7 hours, and thus the various trials carried out to date have been with either 2 or 3 times daily dosing schedules. It is unclear, however, whether multiple daily doses will be necessary in chronically treated schizophrenic subjects. Quetiapine appears to be predominantly metabolized by the CYP3A3/4 isoenzyme system to quetiapine sulfoxide. These preliminary metabolic data suggest that some drug-drug interactions would be likely among quetiapine, antidepressants, benzodiazepines, and other antipsychotic compounds.

In an early trial,[46] a low-dose range of quetiapine (up to 250mg daily); a higher-dose range (up to 750mg); and a placebo were compared during a 6-week trial in 286 subjects. The higher-dose range of quetiapine was more effective than placebo for BPRS cluster scores for thought disturbance and hostility-suspiciousness. The higher-dose range was also significantly more effective for negative symptoms (as measured by the SANS). In a more definitive, phase III, fixed-dose trial, 361 patients treated over 6 weeks were assigned to 1 of 5 quetiapine groups (75, 150, 300, 600, or 750mg daily); 12mg haloperidol daily; or placebo. These data confirmed that quetiapine was virtually devoid of extrapyramidal toxicity at any dose tested, had its most powerful impact on positive symptoms and illness severity at the 4 highest doses, and demonstrated superiority over placebo at only the 300-mg dose in the treatment of negative symptoms.[47] Quetiapine showed no statistical superiority in efficacy over haloperidol. Overall, these data confirmed that quetiapine: (1) is a low-potency compound, (2) is essentially devoid of clinically pertinent EPS at the doses tested, (3) has a comparatively narrow dose-response curve, (4) has a binding affinity profile that is unlike any of the other atypical or typical compounds, and (5) appears to have a somewhat weaker impact on negative symptoms than that shown from its novel counterparts in earlier reports. This final observation may be due to a real difference between quetiapine and the other newer compounds. It is also possible that the apparent difference in power against negative symptoms is attributable to different study designs, patients studied, and rating instruments employed. Research is currently under way comparing quetiapine to other novel medications in both acute and long-term protocols.

There is not much available information on the use of quetiapine in affective illness, children's movement disorders (Table II), and developmental disorders. One open-label study of quetiapine in 152 geriatric patients suggested good clinical efficacy, but some patients experienced difficulty with drowsiness, dizziness, and postural hypotension.[48] Studies with other special populations are under way and results will likely be reported soon.

Quetiapine's minimal EPS profile has been discussed previously. The most common side effects of quetiapine are drowsiness, agitation, headache, insomnia, and dry mouth (Table III). Weight gain and orthostatic hypotension can also occur. All of these side effects occurred in the clinical trials at a relatively low incidence. Quetiapine did not elevate prolactin above the normal range.

As noted previously, the "average" patient will probably need 300 to 600mg/day. Predictably, younger, older, and new-onset patients will have their dose-response curve shifted to the left of their chronic counterparts, and the refractory population may very well require substantially higher doses.


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