This remarkable and immediate antidepressant modality has been recognized for 30 years, but is little used in everyday clinical practice. Perhaps it is the paradox of taking sleep away from the depressive insomniac that has a negative connotation for both patient and psychiatrist (“wake therapy” would be a more positive alternative name). Perhaps it is also the short-term nature of the response

that has hindered its use, though the magnitude of the clinical changes brought about by sleep deprivation still remain highly intriguing and may provide clues for understanding the pathophysiology of depression. Sleep deprivation Inhibitors,research,lifescience,medical is the paradigm par excellence for depression research: rapid, nonpharmacological, and short lasting. It may be the nonpharmacological Inhibitors,research,lifescience,medical nature of sleep deprivation (it cannot be patented) that has contributed to its status as an “orphan drug.”67 It is surprising that no pharmaceutical company has focused on this model to search for that much-needed rapid-acting antidepressant.8 This lack may be remedied in the future; new research reveals that, whereas Inhibitors,research,lifescience,medical sleep induces very few genes, wakefulness increases expression of several groups of genes,68 and here comparisons with

the effects of antidepressant drug treatment may narrow down the candidates. Some committed proponents of sleep deprivation have recognized its clinical usefulness to initiate rapid improvement, particularly in Inhibitors,research,lifescience,medical the most severely depressed

patients in whom time is of the essence. Sleep deprivation is effective in all diagnostic subgroups of depression. The problem is the relapse after recovery sleep, and new strategies have sought treatments to prevent this. Response appears to be well maintained by treatment with lithium, antidepressants (in particular SSRIs), or the 5-HT1A receptor Stem Cell Compound Library screening antagonist pindolol, Inhibitors,research,lifescience,medical as well as nonpharmacological adjuvants such as repetitive transcranial magnetic stimulation (rTMS),69 light therapy, or phase advance of the sleep-wake cycle, or various combinations thereof (see, for example, reference 36 and 70, reviewed in reference 8; Table I). Light therapy Light therapy can be considered to be the most successful clinical application of circadian below rhythm concepts in psychiatry to date. Light is the treatment of choice for SAD.71 The quality of recent SAD studies has been exemplary, and the response rate is well above placebo (in fact, superior to analogous trials with antidepressant drugs).72 The success of this nonpharmacological treatment has been astonishing, but it has taken rather long for light therapy to be accepted by establishment psychiatry,72 and trials of other indications are still in the research phase. Its very success in SAD has limited use in other forms of depression (characterized as “it’s a chronobiological treatment for a chronobiological subset of depressive patients”).