Rapid-cycling bipolar disorder (RCBD) is a phase of bipolar disorder defined by the presence of ≥ 4 mood episodes in a year. It is a common phenomenon characterized by greater severity, a predominance of depression, higher levels of disability, and poorer overall outcomes. It is resistant to treatment by conventional pharmacotherapy. The existing literature underlines the scarcity of evi-dence and the gaps in knowledge about the optimal treatment strategies for RCBD. However, most reviews have considered only pharmacological treatment options for RCBD. Given the treatment-refractory nature of RCBD, nonpharmacological interventions could augment medications but have not been adequately examined. This review carried out an updated and comprehensive search for evidence regarding the role of nonpharmacological therapies as adjuncts to medications in RCBD. We identified 83 reviews and meta-analyses concerning the treatment of RCBD. Additionally, we found 42 reports on adjunctive nonpharmacological treatments in RCBD. Most of the evidence favoured concomitant electroconvulsive therapy as an acute and maintenance treatment. There was pre-liminary evidence to suggest that chronotherapeutic treatments can provide better outcomes when combined with medications. The research on adjunctive psychotherapy was particularly scarce but suggested that psychoeducation, cognitive behavioural therapy, family interventions, and supportive psychotherapy may be helpful. The overall quality of evidence was poor and suffered from several methodological shortcomings. There is a need for more methodologically sound research in this area, although clinicians can use the existing evidence to select and individualize nonpharmacological treatment options for better management of RCBD. Patient summaries are included to highlight some of the issues concerning the implementation of adjunctive nonpharmacological treatments.

Chronobiological therapies for mood disorders include manipulations of the sleep-wake cycle such as sleep deprivation and sleep phase advance and the controlled exposure to light and darkness. Their antidepressant efficacy can overcome drug resistance and targets the core depressive symptoms including suicide, thus making them treatment options to be tried either alone or as adjunctive treatments combined with common psychopharmacological interventions. The specific pattern of mood change observed with chronobiological therapies is characterized by rapid and sustained effects, when used among themselves or combined with drugs. Effects sizes are the same reported for the most effective psychiatric treatments, but side effects are usually marginal or absent. New treatment protocols are developed to adapt them in different clinical settings. This review deals with the general principles of clinical chronobiology and the latest findings in this rapidly developing field.

Rapid cycling (RC) bipolar disorder is often treatment-resistant to pharmacotherapy. Non-pharmacological methods, however, are reasonable considerations in treatment refractory cases of bipolar patients. Thus, such methods may be useful in the management of RC, especially when drugs are not shown to be effective.

This review is based on studies of all major non-pharmacological methods which are used in the management of bipolar disorder, by focusing on data regarding patients with a RC pattern of the illness.

Regarding biological treatments, for electroconvulsive therapy and sleep deprivation, there exists some evidence that they might be efficacious in RC patients for acute treatment as well as for prophylaxis from recurrences. Light therapy has not been shown to be efficacious in RC, while no published data exist for transcranial magnetic stimulation and vagus nerve stimulation. The non-biological treatments include psychotherapeutic and psychosocial interventions; these have not been tried particularly on RC patients, but their use should be expected to contribute to the overall management of the RC pattern as it does to that of mood disorder in general.

Many data on which this review is based are drawn from case reports or non-randomised trials.

Non-pharmacological methods, either biological or non-biological (psychotherapies and psychoeducation), may be applied in the management of RC patients. These methods might be used in combination with the administration of drug treatment, based on the clinical experience of the physician and the individual characteristics of the patient.

Up to 70% of depressed adults have an antidepressant response to sleep deprivation. To study the effects of sleep deprivation on depression severity and level of arousal in psychiatrically disturbed adolescents, we deprived 17 patients of sleep for 36 hours. Severity of depression and subjective arousal were assessed at baseline, during sleep deprivation, and after 1 night's recovery sleep. We found that severely depressed adolescents showed a significant decrease in depression severity, whereas depressed patients in remission and psychiatric controls worsened after sleep deprivation. Patients with depression in remission showed a significant decrease in subjective arousal after sleep deprivation. In contrast to findings in depressed adults, the effects of sleep deprivation persisted after 1 night of recovery sleep, and diurnal variation of mood did not predict response to sleep deprivation. These findings are consistent with those reported in the adult literature, and suggest a common psychophysiology between adult and adolescent depression.

We report a 64-year-old patient suffering from rapid cycling bipolar disorder who was studied by means of polysomnography, neuroendocrine tests and PET (positron emission tomography) imaging. In a manner only partly compatible with the cholinergic-aminergic imbalance model of mania and depression, a linkage of REM sleep disinhibition and depressive mood was observed, but no decisive REM sleep delay was seen on manic days. Growth hormone secretion after clonidine stimulation was blunted on depressive and hypomanic days. A series of total sleep deprivations led to a positive effect on psychopathology for about two weeks. Carbamazepine treatment normalized REM sleep variables, damped the amplitude of mood cycling of the patient, increased TSH and decreased FT4.

The therapeutic effect of total sleep deprivation (SD) given twice a week, for 4 weeks, was investigated in 16 drug-free patients with major affective disorders. The response was excellent in five patients, satisfactory in three and minimal in eight patients. Six of these patients were treated prophylactically once a week, and four had an excellent response. Additionally, out of five normothymic drug-free patients with affective illness treated prophylactically with SD, without prior therapeutic SD treatment, three had an excellent response. The majority of responders were rapid cycling patients. This method is worth applying to patients resistant to classical treatment.

This review reports, with as much detail as possible, on the literature relating to therapeutic sleep deprivation (or induced-wakefulness therapy) since it was first described in 1971. The antidepressive effect of sleep deprivation has been substantiated by numerous studies. A series of clinical predictors of response to sleep deprivation are also described. Partial sleep deprivation late in the night is equivalent to total sleep deprivation in terms of therapeutic value and--because of its simpler application--can be regarded today as the sleep deprivation method of choice. The status of sleep deprivation in the overall treatment schedule for depressive disorders is discussed in detail. Numerous findings, some of them contradictory, have been published on the effect of sleep deprivation on biological variables. To date, no unequivocal explanation has been found for the mechanism of action of sleep deprivation.

Previous investigations have shown that REM sleep deprived (REM SD) rats display an enhanced response to dopamine agonists. This action seems to be mediated through a supersensitivity of dopamine post-synaptic receptors. Accordingly, REM SD was performed on rats with an experimental model of Parkinson's disease. The animals were bilaterally lesioned in the nigrostriatal pathway through a stereotaxically directed electrical current. Seven days after the surgery the animals were REM SD for 72 hours and immediately after the end of this period were observed in an open field for ambulation, rearing, grooming, and latency. In comparison with non-deprived rats there was a significant increase in ambulation and rearing, a response that appeared again after a second REM SD period on day 21th after the surgery. These data of improvement of two parameters of an experimental model of Parkinson's disease suggest that SD may be useful in this condition.

The definition and clinical aspects of rapid cycling affective illness are reviewed and various factors associated with the onset and maintenance of rapid cycling enumerated. On the basis of this information and of reports of the response of rapid cycling patients to various treatment interventions, an approach is suggested to the evaluation and treatment of rapid cycling affective illness.

This paper reviews five different types of deliberate sleep-wake manipulations which are reported to have antidepressant effects: total sleep deprivation, partial sleep deprivation, a phase advance of the sleep periods, and REM deprivation. The effects of total sleep deprivation are best documented. Of 852 depressed patients studied, 493 or 57.9% improved following sleep deprivation. The REM deprivation procedure acts more slowly, but is of more lasting clinical value than the other forms. Partial sleep deprivation during the second half of the night may be as good as total sleep deprivation and better tolerated. The findings are reviewed in terms of psychological, neurophysiological, biochemical, and chronobiological perspectives.