CNS Spectrums
September 30, 2021
Xénia Gonda, Péter Döme, Joanna C. Neill et al.
77 citations
Major depressive disorder (MDD) and treatment-resistant depression (TRD) remain inadequately addressed by current antidepressants, which have limited efficacy or undesirable side effects linked to their actions on monoamine neurotransmitters (serotonin, norepinephrine, dopamine). New drugs targeting non-monoamine pathways, such as the recently approved intranasal Esketamine (a glutamatergic agent) combined with an oral antidepressant for adult TRD, offer promise. Several glutamatergic and GABAergic drugs are in clinical development, and preliminary positive trial results with psychedelics like psilocybin, Ayahuasca, 5-MeO-DMT, and LSD suggest they may become effective therapies. Expanding beyond monoamine targets appears to yield antidepressants with superior efficacy, safety, and tolerability.
CNS Spectrums
July 11, 2022
Seetal Dodd, Trevor R. Norman, Harris A. Eyre et al.
61 citations
Psilocybin, a tryptamine alkaloid found in Psilocybe mushrooms, is metabolized into the active compound psilocin, which produces psychoactive effects primarily by partially activating the 5HT2A receptor. Psilocin also binds to other receptor subtypes, though these actions are not fully understood. Clinical trials have tested psilocybin at hallucinogenic doses for addictive disorders, anxiety, and depression. This review assesses psilocybin and psilocin as potential neuropsychiatric treatments, weighing therapeutic benefits against potential harms. The authors conclude that careful evaluation of the number needed to harm versus the number needed to treat will determine clinical viability, and they call for a responsible path forward in this field.
CNS Spectrums
June 19, 2019
Gregor Hasler
31 citations
Around 50% of people with major depression respond to monoaminergic antidepressants, which modulate synapses but do not substantially influence synaptogenesis. They also increase brain-derived neurotrophic factor (BDNF), but for activity-dependent plasticity, BDNF release must work with synaptogenesis. Ketamine, in contrast, leads to fast changes in synaptic function and plasticity beyond classical antidepressants, suggesting it could enhance psychotherapy effects. Since ketamine's purely pharmacological effect is transient, such enhancement may become an important clinical indication. The editorial outlines mechanistic hypotheses for how Behavioral Activation, Trauma-Focused Psychotherapies, and Humanistic Psychotherapy may prolong ketamine's antidepressant effects.
CNS Spectrums
April 1, 2021
Steve Best, Dan G. Pavel, Natalie Haustrup
1 citation
Combining repetitive transcranial magnetic stimulation (rTMS) with intravenous ketamine infusions—called combination TMS with ketamine (CTK)—produced substantial and lasting reductions in depressive symptoms for 28 adults with treatment-resistant depression. Patients received three CTK sessions per week, with rTMS applied to the mid-prefrontal area and ketamine doses adjusted by biomarker levels. Symptom severity, measured by the Clinical Global Impression scale, dropped significantly after treatment, and the improvement persisted for at least two years. The findings suggest CTK may help patients who have not responded to other treatments, but randomized controlled trials are needed to confirm the results.
CNS Spectrums
March 10, 2026
Halima Faisal, Gia Han Le, Angela T.h. Kwan et al.
Ketamine rapidly alters brain reward circuitry in people with major depressive disorder, particularly in fronto-striatal and limbic networks. In a synthesis of 13 neuroimaging studies involving 623 participants (482 with depression, 141 controls), intravenous ketamine (typically 0.5 mg/kg over 40 minutes) changed resting-state connectivity in ventral striatal-prefrontal and default mode, salience, and executive networks within 2 to 48 hours, with some effects lasting up to 10 days. Task-based imaging showed altered ventral striatal responses during reward anticipation and feedback, and changes in medial prefrontal activity during emotion processing. PET scans indicated increased prefrontal-cingulate metabolism and region-specific serotonin receptor binding changes. Few studies directly measured anhedonia, suggesting the findings reflect broader antidepressant mechanisms.
CNS Spectrums
January 1, 2025
Emma O’leary, Seetal Dodd, Stephen Stahl
Psychoactive substances like psychedelics, cannabis, and stimulants are being reconsidered for therapeutic use, but their histories in non-medical contexts raise ethical and regulatory challenges. This review examines the ethical issues shaping research and prescribing, highlighting diverse perspectives from Indigenous, philosophical, psychiatric, and user communities. Key concerns include balancing therapeutic benefits against misuse risks, ensuring rigorous science, and addressing sociopolitical factors that influence public perception and policy. The article calls for evidence-based frameworks that prioritize patient safety and recognize social and commercial determinants of health, extending ethics beyond prescribing. It critically assesses the promise and limitations of repurposing these substances for contemporary psychiatric practice.
CNS Spectrums
January 1, 2025
Mathieu Fradet, Cecelia Kelly, Anna J. Donnelly et al.
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