Synaptic plasticity model of therapeutic sleep deprivation in major depression

Summary

Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50–60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i.e., the neural basis of adaptive network function and behavior, represent a critical mechanism of therapeutic SD in MDD. Particularly, this article centers on two major hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, and on how they can be integrated into a novel synaptic plasticity model of therapeutic SD in MDD. As a major component, the model proposes that therapeutic SD, by homeostatically enhancing cortical synaptic strength, shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP) in patients with MDD in a more favorable window of associative plasticity. Research on the molecular effects of SD in animals and humans, including observations in the neurotrophic, adenosinergic, monoaminergic, and glutamatergic system, provides some support for the hypothesis of associative synaptic plasticity facilitation after therapeutic SD in MDD. The model proposes a novel framework for a mechanism of action of therapeutic SD that can be further tested in humans based on non-invasive indices and in animals based on direct studies of synaptic plasticity. Further determining the mechanisms of action of SD might contribute to the development of novel fast acting treatments for MDD, one of the major health problems worldwide.

Introduction

The World Health Organization (WHO) lists major depressive disorder (MDD) as the leading cause for illness-related reduction of quality of life worldwide (years of life lived with disability index; [1]). Current first-line treatments, i.e., antidepressants and psychotherapy, show a long latency to response. Still, only half of the patients achieve sustained remission with optimized treatment, indicating the need for further research [2].

Therapeutic sleep deprivation (SD) is a straight and rapid-acting treatment for MDD. Within hours, SD leads to a dramatic decrease in depressive symptoms in 50–60% of patients with MDD [3]. Yet, this effect is mostly transient. Approximately 80% of SD responders relapse into depression after the next night of sleep, and even brief daytime naps can reverse the therapeutic effect [4]. Strategies to preserve the clinical improvement, including concomitant pharmacotherapy, light therapy or sleep phase advance therapy, have shown some promise but are still not sufficient [5].

Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Within a short period of time and without pharmacological or psychotherapeutical interference, one person can be investigated in a depressed, transitional and non-depressed state. Since the first scientific description [6], numerous studies have tried to unravel the therapeutic mechanisms of SD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood.

The current article centers on the idea that sleep/wake-dependent shifts of synaptic plasticity, i.e., the neural basis of adaptive network function and behavior, represent a critical neural mechanism of therapeutic SD in MDD. As such, we revisit the long-standing idea of investigating sleep in MDD as a window to the brain (‘via regia’) with new concepts. Particularly, this article is based on two hypotheses, the synaptic plasticity hypothesis of MDD, a recent conception on the pathomechanisms of MDD [7], and the synaptic homeostasis hypothesis of sleep-wake regulation [8]. These two lines of research have been relatively independent up to now and the main objective of this review is to integrate them into a novel synaptic plasticity model of therapeutic SD in MDD. After a general outline of this model, we will further discuss the potential neural mechanisms of SD on synaptic plasticity derived from animal and human studies. Finally, limitations and areas for future research will be identified. Further elucidating the mechanisms of therapeutic SD in MDD is expected to contribute to deciphering the pathomechanisms of the disorder and, potentially, to open new pathways to treatment.