2 In the

absence of combined treatments, not more than 5% of responders to wake will maintain a stable euthymia in the days of subsequent normal sleep,20 thus limiting the diffusion of this technique alone.32 Soon in the early studies, however, SD was observed to produce rapid benefits in the broadly defined depressive syndrome: in endogenous, reactive, unipolar, bipolar, secondary, and schizoaffective, depression; in the elderly and in children; in depression secondary to Parkinson’s disease or schizophrenia; or Enzalutamide associated with pregnancy and postpartum and premenstrual dysphoric disorder,10,20 and with better effects Inhibitors,research,lifescience,medical observed in endogenous primary depression compared with reactive and/or secondary depression, and in the treatment of Bipolar Disorder compared with Primary Depressive Disorder.33 In order to prevent the relapse into depression after SD, single-night SD or repeated SD was combined with serotonergic antidepressants, lithium salts, or other chronotherapeutic techniques.4 The Inhibitors,research,lifescience,medical simple repetition of SD over time has been tested for many schedules, including twice in 1 week,34 or twice a week for 3 weeks35,36 or for a month,37 or for twice in 1 week followed by partial SD twice,38 Inhibitors,research,lifescience,medical etc. Repeated SD once a week has also been proposed as a prophylactic treatment: preliminary studies in small samples showed that SD reduced the frequency Inhibitors,research,lifescience,medical of relapses and increased

the duration of normothymia in roughly one half of the patients.39,40 Our group developed

a treatment schedule based on repeated total SD, three times during 1 week, resulting in a lengthening of the sleep-wake period from the usual 24 to 48 hours.41-49 When combined with light therapy and with lithium salts, the mainstay for the long-term treatment of bipolar disorder, this therapy is able to trigger an acute response also in patients drug resistant to both serotonergic and tricyclic antidepressants, and to lead to a stable, euthymia for 9 months in roughly 60% of bipolar patients without a history of drug resistance.47 Despite Inhibitors,research,lifescience,medical early concerns due to the close link between sleep loss and the onset of mania,50 this result is achieved with a risk of switch which is around 6% and leads to easily controlled manic reactions,51 thus comparable to the reported switch rate for placebo. Considering the 15%-to-25% risk of treatment-emergent mania linked with Phosphoprotein phosphatase antidepressant drug treatment in bipolar patients,16,17 and the 30% of responders mantaining euthymia when discontinuing drug treatments before 6 months,18 these data warrant the highest clinical interest in using these techniques as firstchoice treatments for bipolar depression. Light therapy The scientific approach to the treatment of depression with bright light started in the 1980s.52-54 Early on, antidepressant bright light therapy (LT) was administered 1 to 2 hours before the usual time of awakening.