A chronopharmacological diagnostic test and treatment for bipolar disorder and depression: Nitric oxide release during sleep causes it to become depressogenic in a subset of patients

Summary 

In some patients sleep can have a depressogenic effect and sleep reduction can result in mania. The hypothesis on which this model is based postulates that it is nitric oxide release during sleep that causes it to become depressogenic in a subset of patients. That subset is comprised of patients with genetic polymorphisms in nitric oxide genes and/or in serotonin and melatonin genes. The nature of the dynamic equilibrium between nitric oxide, on the one hand, and serotonin and melatonin, on the other, determines whether or not sleep is likely to have a depressogenic effect.

Changes throughout the sleep cycle thereby impart a chronological factor to the dynamic equilibrium. Other writers have postulated, but not defined, a certain so-called “critical period” during the sleep cycle when sleep can become particularly depressogenic. This model assumes that in fact there is such a critical period and that it is stage IV sleep.

In addition to the chronological influences on the dynamic equilibrium, the aging process also exerts an influence. The increased sleep fragmentation associated with the aging process causes stage IV sleep to become increasingly more depressogenic because of a concept called delta rebound. Delta rebound results in deeper sleep intensity. It is associated with increased nitric oxide production and the concomitant serotonin suppression that is associated with it.

The chronopharmacological test that is proposed challenges the dynamic equilibrium between nitric oxide, on the one hand, and serotonin and melatonin on the other. It consists of melatonin taken at bedtime and the antidepressant moclobemide, taken as close to the onset of stage IV sleep as possible. If there is a noticeable lessening of depressive symptoms the following morning, then drug treatments that increase serotonin and/or melatonin are appropriate and drugs that suppress or block serotonin or melatonin, or that increase nitric oxide, are not.