Introduction: The ultimate goal in major depressive disorder (MDD) treatment is recovery. A proportion of MDD patients with formal remission experience persistent difficulties, which impair their daily functioning. Residual insomnia is one of the most common residual symptoms. Patients with residual insomnia experience relapse significantly earlier and have a poor prognosis. Little is known about possible ways of treatment and what subtype of insomnia is mostly reported.Methods: A systematic literature review was carried out in PubMed and Web of Science to synthesize the current status of knowledge about effective treatment methods and insomnia subtypes in residual insomnia in MDD.Results: A few non-pharmacological treatment methods e.g., Cognitive Behavioral Therapy for Insomnia (CBT-I), Mindfulness-Based Cognitive Therapy (MBCT), behavioral activation (BA) and pharmacological methods (gabapentin, clonazepam) have proven to mitigate residual insomnia. Cognitive Behavioral Therapy for Depression (CBT-D) ameliorates insomnia complaints to a limited extent. Mid-nocturnal insomnia is the most common residual insomnia subtype in MDD patients.Conclusion: Residual insomnia is a very common complaint and most often appears as mid-nocturnal insomnia. Scarce data points out the benefits from pharmacotherapy, psychotherapy, and BA. More research is needed.

Background: Depression is a debilitating disease with a high socioeconomic burden. Regular antidepressants usually require several weeks to ameliorate symptoms; however, numerous patients do not achieve remission. What is more, sleep disturbances are one of the most common residual symptoms. Ketamine is a novel antidepressant with rapid onset of action with a proven antisuicidal effect. Little is known about its impact on sleep–wake and circadian rhythm alterations. The aim of this systematic review is to research the impact ketamine has on sleep disturbances in depression. Methods: PubMed, Web of Science, and APA PsycINFO were searched for relevant studies on ketamine’s impact on sleep disturbances in depression. Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA2020 methodology was applied. The systematic review protocol was registered in the PROSPERO Registry (CRD42023387897). Results: Five studies were included in this review. Two studies reported significant improvement in sleep measured by MADRS (Montgomery–Åsberg Depression Rating Scale) and QIDS-SR16 (Quick Inventory of Depressive Symptomatology Self-Report (16-item)) scales after intravenous ketamine and intranasal esketamine administration. One case report showed mitigation of symptoms in PSQI (Pittsburgh Sleep Quality Index) and ISI (Insomnia Severity Index) during 3-month treatment with esketamine. In two studies, sleep was objectively measured by nocturnal EEG (electroencephalography) and showed a decrease in nocturnal wakefulness accompanied by an increase in slow wave (SWS) and rapid eye movement (REM) sleep. Conclusion: Ketamine reduces the severity of sleep insomnia in depression. Robust data are lacking. More research is needed.

Residual symptoms are prevalent in major depressive disorder (MDD), encompassing a wide spectrum of symptoms such as sleep disturbances, changes in weight and appetite, cognitive impairment, and anxiety. These symptoms consistently impair daily functioning, diminish quality of life, and forecast disease relapse. Despite their clinical significance, residual symptoms lack a unified definition, potentially leading to confusion with treatment-emergent symptoms and ambiguity across studies, thereby hindering the generalizability of research findings. While some research identifies insomnia and mood disturbances as critical indicators, other studies emphasize different symptoms or find no significant correlation. Inconsistencies in defining residual symptoms, as well as methodological differences across studies, contribute to these conflicting results. While clinicians focus on alleviating negative symptoms to improve functional status, patients often prioritize achieving positive affect and overall well-being as essential components of successful treatment. It necessitates a comprehensive approach to patient care in depression. This review explores the phenomenon of residual symptoms in MDD, focusing on the ambiguity in definitions, clinical characteristics, and their impact on long-term outcomes. The lack of a standardized regulatory or academic definition for residual symptoms leads to varied interpretations among clinicians, underscoring the need for standardized terminology to guide effective treatment strategies and future research.

Introduction: Psychedelic agents have regained the attention of pharmaceutical companies as promising treatments for depressive episodes. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), an atypical psychedelic, is emerging as a potentially effective, novel rapid-acting antidepressant. In this systematic review, we analyze the safety and tolerability evidence from clinical trials.Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, electronic databases (PubMed, SCOPUS, Web of Science, EMBASE, and EBSCO) were searched from inception until 15 May 2024 to identify clinical trials (regardless of phase) reporting on short-term safety and tolerability profile of 5-MeO-DMT using the following keywords in various combinations: 5-methoxy-N, N-dimethyltryptamine, 5-MeO-DMT, safety, adverse, adverse reaction, side effects, tolerability, dropout, healthy volunteer, healthy participant, depression, major depressive disorder. Only studies written in English were considered.Results: Initial search yielded 100 records, out of which 3 met the inclusion criteria. These studies reported on the results from clinical trial phases I and I/II, with a total of 78 participants included; two studies involved healthy volunteers, and one included patients with treatment-resistant depression. Although the data is limited, it confirms a good short-term safety and tolerability profile for 5-MeO-DMT, with no serious adverse events (SAEs) reported. Furthermore, no drop-outs were reported.Conclusion: 5-MeO-DMT administration in human subjects presents favorable short-term safety and tolerability profile. Importantly, no SAEs have been documented, and no adverse events led to participant withdrawal from the studies There is a need for future randomized, double-blind, placebo-controlled trials with larger samples and follow-up to assess potential chronic adverse events.