Advances in experimental medicine and biology
January 1, 2024
Berend Olivier, Jocelien D A Olivier
11 citations
About 30% of people with major depressive disorder do not respond to first-line treatment, leading to treatment-resistant depression (TRD), for which no consensus definition exists. Recent research has focused on two types of psychedelics: serotonergic (psilocybin, ayahuasca) and atypical glutamatergic (ketamine, esketamine). Both produce fast and long-lasting antidepressant effects that persist beyond the drug's presence in the body, suggesting downstream signaling cascades. Clinical development of psilocybin and esketamine for TRD is described, highlighting challenges with placebo due to psychotomimetic or dissociative effects. Intranasal esketamine has been approved for TRD, and psilocybin shows positive results. Adverse effects are generally acceptable. This development represents a breakthrough in psychiatry.
Advances in experimental medicine and biology
January 1, 2024
Marie Drüge, Lisa Guthardt, Elisa Haller et al.
8 citations
Depressive disorders impose a heavy societal burden due to their high prevalence and impact on relationships, emotions, and motivation. Cognitive behavioral therapy (CBT) is the gold standard treatment for major depression, while mindfulness-based cognitive therapy (MBCT) effectively prevents relapse and can be integrated into individual therapy. Various delivery modes, including therapist-guided digital CBT, blended therapy, and digitalized MBIs, offer efficacious supplements to face-to-face therapy, improving accessibility. This chapter reviews the principles and evidence for CBT and MBCT and different delivery modes for depressive disorders in adults, discussing integration opportunities and challenges, along with practice implications and future research recommendations.
Advances in experimental medicine and biology
January 1, 2021
Jose Carlos Bouso, Genís Ona, Rafael G Dos Santos et al.
6 citations
Research on psychedelic drugs for therapeutic use has grown, driven by the need for innovative psychiatric treatments. Clinical trials have assessed psilocybin and ayahuasca for mental disorders including major depression. This chapter reviews the history and terminology of psychedelic research, analyzes recent clinical trials administering these drugs to patients, describes neurobiological mechanisms that may underlie therapeutic effects, and notes that psychedelics are commonly used as adjuncts to psychotherapy. The chapter concludes by suggesting future challenges for this field.
Advances in experimental medicine and biology
January 1, 2026
Alessandro Spiti, Daniela Caldirola, Giampaolo Perna
1 citation
Major depressive disorder (MDD) remains difficult to treat due to its varied symptoms. Antidepressant development began with electroconvulsive therapy, monoamine oxidase inhibitors, and tricyclic antidepressants, which targeted the monoaminergic system but had safety and efficacy limits. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors improved tolerability yet left unmet needs like treatment resistance. Research then expanded to new mechanisms: NMDA receptor antagonists such as ketamine and esketamine provide fast-acting effects through glutamatergic modulation; GABA modulation via neurosteroids like zuranolone offers a new approach for postpartum depression; kappa-opioid receptor antagonism is...
Advances in experimental medicine and biology
January 1, 2026
Yunfei Tan, Kenji Hashimoto
1 citation
Treatment-resistant depression (TRD) affects about one-third of people with major depression, leading to higher suicide rates and impaired functioning. Originally defined as nonresponse to tricyclic antidepressants, TRD now includes inadequate response to multiple antidepressant classes, psychotherapy, and neuromodulation. Inconsistent criteria complicate prevalence estimates and diagnosis, with many presumed TRD cases actually involving bipolar depression or other disorders. Neurobiological research identifies glutamatergic dysregulation, default-mode network hyperactivity, impaired neuroplasticity, chronic inflammation, and epigenetic changes as markers. Clinically, patients experience persistent anhedonia, cognitive deficits, and sleep disturbances. Subtypes with distinct treatment responses have been identified, and biomarker-driven categories guide personalized care. Future work must standardize definitions and integrate multimodal biomarkers.
Advances in experimental medicine and biology
January 1, 2026
Berend Olivier, Jocelien D A Olivier
Major depressive disorder, including treatment-resistant depression, affects many people and carries high costs. About 30% of patients do not respond to first-line antidepressants like SSRIs and SNRIs. Research over the past two decades has produced two new drug classes: typical serotonergic psychedelics (psilocybin, ayahuasca) and atypical glutamatergic/NMDA psychedelics (ketamine, esketamine). Both provide fast, long-lasting antidepressant effects that outlast the drug's presence in the brain, though they cause short-lived side effects like psychotomimetic or dissociative symptoms. These developments represent a breakthrough, but the acute effects complicate blinded studies and placebo control. The field is now advancing new research methods and exploring underlying mechanisms.