Introduction

According to the World Health Organization (WHO), bipolar or unipolar depression is the leading cause of ill health and disability worldwide. Depression affects nearly 20% of the population with an increase of more than 18% having been observed between 2005 and 2015 (WHO: WHO | Depression [Internet]. Depression. 2019). Depression is associated with a reduced quality of life, with the WHO predicting several years ago that it would become the greatest cause of disability worldwide by 2030 ( ). People affected by major depression show increased mortality, with an estimated 50% risk increase compared to nondepressed individuals ( ), with suicide accounting for nearly 20% of the deaths ( ).

Most antidepressant drugs need several weeks to achieve therapeutic effects and several trials show that no difference can be expected during the first 2 weeks between active and placebo treatments ( ). Moreover, long-term use of antidepressant drugs often generates significant side effects, leading to treatment discontinuation and consequent relapses. When facing bipolar depression, iatrogenic mania or rapid cycling are associated risks. Indeed, all effective standard antidepressant medications have been associated with treatment-emergent mania and the administration of chronic antidepressant drugs has been linked to an acceleration of the rate of cycling without an induction to actual mania ( ).

Furthermore, antidepressant drugs show low-to-moderate response in most patients, with at least 40% of patients treated for depression not responding to the first administered antidepressant medication, and several further treatment trials not showing an antidepressant effect in at least one-half of these patients ( ; ). This clinical condition characterized by an inadequate response to two or more consecutive antidepressant drugs administered at adequate doses for an adequate length is referred to as treatment-resistant depression (TRD), and it is a persistent source of morbidity and mortality for patients and contributes substantially to the burden of disease ( ; ). Comparing unipolar with bipolar depressed patients, unresponsiveness to antidepressant drugs affects up to 30% of unipolar depressed patients and was found to be 1.6 times more common in people affected by bipolar disorder. Moreover, bipolar patients showed a loss of response to antidepressant drugs 3.4 times more frequently than unipolar ones ( ).

Resistance to antidepressant treatment has been associated with functional impairment and poorer quality of life, increased mortality and suicide risk, and higher relapse rates ( ). Because of the morbidity linked to treatment-resistant depression, the development of novel, rapidly acting antidepressants is crucial for patients affected by this condition.

Many augmentation strategies have been developed to increase the efficacy of antidepressant drugs. However, for many patients, medication augmentation may be risky or demanding treatment strategies in terms of adverse effects and drug interactions. A growing evidence base supports the usefulness of chronotherapeutic interventions, which are nonpharmaceutical psychiatric treatments developed from the study of circadian rhythm organization and sleep physiology. These techniques exploit the control of the exposure to environmental stimuli that act on biological rhythms. They include sleep deprivation and sleep phase advancement, which manipulate sleep-wake cycle, and light therapy which acts through exposure to light.

Chronobiological interventions had been widely used as augmentation strategies for several years in clinical settings. Although relatively few studies have focused on patients with well-defined TRD, recent clinical studies have confirmed their efficacy in TRD and other forms of difficult to treat depression.

Light therapy

The scientific approach to the treatment of depression with bright light was introduced by Rosenthal and his colleagues in the 1980s for winter seasonal affective disorder. Over the subsequent years, several trials extended the use of light therapy (LT) to nonseasonal unipolar depression ( ). More recently, the utility and safety of light therapy (LT) was confirmed in patients with bipolar depression ( ).

The conventional LT system consists of a set of white fluorescent bulbs installed in a box with a diffusing screen that filters out ultraviolet (UV)-wavelength light. During LT sessions, patients sit in front of a light box. The therapeutic response to LT critically depends on the time of delivery, with best results having been found when the therapy is administered considering the personal circadian phase, influenced by the onset of melatonin secretion. Since this chronobiological phenomenon strongly correlates with Morningness-Eveningness Questionnaire (MEQ) scores, a predictive algorithm based on MEQ scores has been developed to define the individual optimal timing of LT administration, and it is now regularly used in clinical settings ( ). The optimum dose of light is 10,000 lx for 30 min/day. Although lower intensities of light have antidepressant efficacy, substantially longer exposure durations are needed ( ). Moreover, some observations have suggested that bipolar patients could be highly sensitive to the antidepressant properties of light, including at intensities as low as 500 lx ( ). When combined with standard antidepressant drugs, LT has been shown to hasten recovery, with patients perceiving benefits during the first week of treatment ( ; ). Moreover, after 1 month of treatment, depressed patients who were given LT augmentation therapy had a 30% greater reduction in depression severity than patients treated with drug plus placebo. These augmentation effects were similar between patients who received LT and selective serotonergic antidepressant drugs and those who received LT and tricyclic antidepressants ( ). The beneficial effects of LT are also clinically evident in patients with unipolar and bipolar major depression after LT is added to ongoing treatment with ineffective medications, highlighting its potential utility in people with TRD ( ; ). The effectiveness of adjunctive LT in patients with TRD was demonstrated in both the acute phase of treatment and after LT discontinuation, with patients remaining euthymic for up to 8 weeks following the end of treatment ( ). In a recent study focusing on TRD, LT was found to accelerate antidepressant response to neuromodulation treatments such as high-frequency repetitive transcranial magnetic stimulation, showing a reduction of depressive symptomatology as early as during the first week of treatment ( ).

Sleep deprivation therapy and combined chronotherapies

The first clinical report about antidepressant effect of sleep deprivation was published in 1959 by Schulte, suggesting that sleep deprivation (SD) might benefit depressed patients. This opinion was based on anecdotal reports from three depressed patients who improved clinically after accidentally staying awake all night ( ). It was not until the 1970s that the first experimental trials were conducted focusing on this intervention’s efficacy for depressed patients ( ).

Conclusions

For patients with major depression, chronobiological therapies have response effects sizes that are similar to the most effective antidepressant drugs, but with a much shorter latency of therapeutic effects. Chronobiological therapies appear to have only marginal or absent side effects, and can therefore be considered for the rapid treatment of depressed patients for whom drug therapy may be contraindicated or for whom medications may not be desired, such as pregnant women and people undergoing treatment with medications that should not be combined with antidepressants.

In the specific case of using chronobiological therapies in the management of TRD patients, promising results have also been documented, especially when such treatment is used adjunctively with ongoing pharmacotherapy. However, only a few studies have focused on the antidepressant efficacy of chronobiological therapies in patients with well-defined TRD.

In conclusion, chronobiological therapies are relatively safe, rapidly acting interventions that could fill therapeutic gaps—such as a long lag time to therapeutic benefit, treatment-limiting adverse effects, and potentially significant drug-drug interactions—that are left by traditional antidepressant drugs for treating mood disorders, even when TRD is taken into account. Further research is needed, however, to optimize chronotherapeutic protocols in order to both increase antidepressant response rates and extend the duration of acute antidepressant effects.