Melancholic Depression and Insomnia as Predictors of Response to Quetiapine in Patients With Major Depression

Response rates for even the most well-established antidepressants are poor, rarely exceeding 30%. This is likely due to fact that depression is a heterogeneous disorder. Using the DSM-5, two patients diagnosed with depression may not share a single symptom. Antidepressants also vary considerably in their mechanism of action, and research has shown that antidepressants also differ in their ability to treat certain symptoms. Thus, there is a great need to understand which patients respond to which antidepressants.

Quetiapine is commonly used to treat major depression and insomnia, although there is a commonly held view that sedation underlies its antidepressant effect. Unlike most antidepressants that bind to one or two receptor sites, quetiapine has a broad mechanism of action and binds to over a dozen neurotransmitter receptors, with varying affinities, at clinically relevant doses. Because of this, quetiapine has the ability to produce different effects at different doses, in which the relative occupancy at neurotransmitter receptor sites is changes accordingly. This is evidenced by the broad dosage range for quetiapine that varies based on the disorder being treated (e.g., higher doses for schizophrenia than major depression).

At low doses (e.g., 50 mg/day) quetiapine has more affinity for histamine and adrenergic receptors, the blocking of which is presumed to result in sedation. These are the doses in which quetiapine is commonly used as a sleep aid. At higher doses (150-300 mg/day) quetiapine has greater affinity for serotonin receptors and produces a greater inhibition of norepinephrine reuptake, which is believed to underlie its antidepressant effect, than it does at lower doses at which it is more likely to bind to histamine and adrenergic receptors. Not surprisingly, doses of 150-300 mg/day are recommended for the treatment of depression. It is puzzling, however, that in one trial (NCT00320268; D1448C00001, Moonstone) 50 mg/day of quetiapine was found to be just as effective as 150 and 300 mg/day as a monotherapy for patients with major depression. Although there is evidence that the antidepressant effect of high-dose quetiapine is independent of its sedating effect, to the researchers knowledge no study has adequately assessed specifically if low-dose quetiapine is an effective antidepressant in patients with depression not currently experiencing insomnia.

High-dose quetiapine does not have a broad-spectrum antidepressant effect, but appears to be most effective at treating certain depressive symptoms, including lack of pleasure/interest, guilt/pessimistic thoughts, reduced sleep, reduced appetite, and anxiety/tension, which commonly co-exist in a depressive subtype known as melancholic depression. This is not surprising because melancholic depression is well-known to be responsive to medications that increase serotonin and norepinephrine neurotransmission, compared to selective serotonergic antidepressants. To the researchers knowledge, no study has examined if patients with melancholic depression at baseline are more responsive to quetiapine, although the fact that quetiapine seems to be most effective at treating symptoms common in melancholic depression, as well as the fact that quetiapine has an active metabolite nor-quetiapine with strong affinity for inhibiting norepinephrine reuptake, suggests this may be the case. Given that insomnia is considered a symptom of melancholic depression, it would also be pertinent to demonstrate that the effect of quetiapine on melancholic depression is not due to its sedating effect.

Given the known lag-time between antidepressant initiation and response (roughly 4-6 weeks), trial-and-error prescribing is an inevitably lengthy process. A better understanding of predictors of response to medications such as quetiapine will lead to more timely and effective treatment of patients with depression, as well as reduced financial burden of diseases to society as a whole.