– Quetipaine

Quetiapine was developed in 1985, with much of the basic research on the compound occurring right here in Delaware, by ICI, later Zeneca, and then what has became Astra-Zeneca.   It was initially approved for medical use in the United States in 1997, and the FDA eventually approved it for the treatment of schizophrenia and for acute manic episodes associated with bipolar disorder (bipolar mania) and finally for treatment of bipolar depression.  In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.

Quetiapine meets the definition of an atypical antipsychotic in that it antagonizes both the D2 and 5HT2-A receptors, but with greater antagonism for serotonin receptors than for dopamine receptors.  Like all atypical antipsychotics, quetiapine binds to a multitude of other receptors, and while it is tempting to ascribe certain drug characteristics to a specific receptor, to do so is premature based on what is the true state of our scientific understanding of the brain and these neural pathways.  Nonetheless, the drug does have significant α1-adrenergic (IC50 = 94nM) and α2-adrenergic receptor (IC50 = 271nM) antagonist binding affinities, and is a very potent H1 receptor (IC50 = 30nM) antagonist.

Thus, quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine.  PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated rapid disassociation from the D2 receptor.  Theoretically, this allows for normal physiological surges of dopamine to elicit normal effects in areas such as the nigrostriatal and tuberoinfundibular pathways, thus minimizing the risk of side effects of pseudo-parkinsonism as well as elevations in prolactin.

At very low doses, quetiapine acts primarily as a histamine receptor blocker (antihistamine) and α1-adrenergic blocker. Thus, side effects of sedation and orthostatsis would be predicted, and indeed are among the most common seen with quetiapine.  Others include: constipation, dryness, upset stomach, fatigue, weight gain, blurred vision, weight gain, metabolic syndrome, dyslipidemia, and diabetes.  Off-label prescriptions, (e.g. for chronic insomnia,) of low-dose quetiapine is not recommended due to side effects and cost.  It is important to teach patients that many antipsychotics may make reduce sweating, placing them at greater risk for heat stroke. 

Like most of the agents in this class, there are warnings for TD, NMS, prolactin elevation, pregnancy, QTc, and the cautionary statement regarding avoiding these medications in patients with dementia.  There was a question regarding the potential linkage between use of quetiapine and cataracts, but this appears to have been limited to animals during testing and has not been a significant problem in humans. 

 

Schizophrenia:

A Cochrane review comparing quetiapine to typical antipsychotics concluded that quetiapine: has efficacy against positive symptoms that appears no better than typical antipsychotics, but might be more efficacious for negative symptoms; has discontinuation rates similar to those of typical antipsychotics, but fewer of these discontinuations were due to adverse events; produces fewer side effects, particularly movement related side effects; and produces suicide attempt, suicide, death, QTc prolongation, low blood pressure, tachycardia, sedation, gynaecomastia, galactorrhoea, menstrual irregularity, and white blood cell count at a rate similar to first generation antipsychotics.

Regarding efficacy, a Cochrane review comparing quetiapine to other atypical antipsychotic agents tentatively concluded that it may be less efficacious than olanzapine and risperidone; produce fewer movement related side effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine; and produce weight gain similar to risperidone, clozapine and aripiprazole.

Bipolar disorder:

In those patients with bipolar disorder, quetiapine is used to treat depressive episodes, acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium, valproate or lamotrigine), and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex.