Synaptic Plasticity Model of Therapeutic Sleep Deprivation to Guide MDD Treatment

Use of the synaptic plasticity model of therapeutic sleep deprivation (SD) has been shown to offer a promising framework for the development of fast-acting treatments for patients with major depressive disorder (MDD). Results of the analysis were published in the Journal of Affective Disorders.

The investigators sought to explore whether homeostatically elevating net synaptic strength through therapeutic SD is able to shift the initially deficient inducibility of associative synaptic long-term potentiation (LTP)–like plasticity in individuals with MDD into a more favorable window of associative plasticity. They evaluated the primary hypothesis that SD responders (ie, participants with a ≥50% improvement in symptoms on the Hamilton Depression Rating Scale for Depression-6 [HAMD-6]) demonstrated an elevated inducibility of cortical associative plasticity (ie, PAS-induced changes in motor-evoked potential [MEP] amplitudes) compared with SD nonresponders following 1 night of therapeutic SD.

The current study, which was conducted among inpatients at the Department of Psychiatry and Psychotherapy, University Medical Center Freiburg in Germany, utilized noninvasive indices of synaptic plasticity in patients with MDD after 1 night of SD—that is, a paired associative stimulation (PAS) and transcranial magnetic stimulation (TMS) protocol.

A total of 28 patients (14 men and 14 women) with a diagnosis of severe unipolar depression were enrolled in the study. The average patient age was 40.4 ± 13.0 years (range, 19 to 61 years). At the time of evaluation, all of the participants were receiving psychotherapy and stable medication for >2 weeks with ≥1 antidepressants: venlafaxine, n10; bupropion, n=5; duloxetine; sertraline, n=2; citalopram, n=2; escitalopram, n=2; vortioxetine, n=2; quetiapine, n=1; and amitriptyline, n=1. Severity of depression was assessed with the Beck Depression Inventory – Second Edition (mean score: 24.6 ± 8.9). The duration of the current episode of depression was 104 ±

241 weeks. Additionally, the number of depression episodes (including the current episode) was 7.1 ± 10.3; the total duration of illness at the time of evaluation was 11.4 ± 12.0 years.

Results of the study showed a significantly different inducibility of associative plasticity in clinical responders to therapeutic SD (>50% improvement on the HAMD-6; n=13), compared with SD nonresponders (n=15), which was driven by a long-term depression-like response among SD responders (P <.001). Brain-derived neurotrophic factor serum levels were increased following SD in both groups, with responders demonstrating generally lower levels than nonresponders.

A major limitation of the current study is the fact that repetitive evaluations before and after treatment would be required to further establish potential mechanisms involved in participants’ response or lack of response.

The investigators concluded that targeting basic mechanisms of synaptic plasticity could possibly lead to more rapid-acting, as well as more robust and long-lasting, treatments for patients with MDD. These findings are consistent with synaptic mechanisms of rapid antidepressant therapeutic effects.

Reference

Kuhn M, Maier JG, Wolf E, et al. Indices of cortical plasticity after therapeutic sleep deprivation in patients with major depressive disorder. J Affect Disord. 2020;277: 425-435. doi: 10.1016/j.jad.2020.08.052