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Spotlight: Rapid-acting NMDA and GABAergic Modulators in Mood Disorders: From Synaptic Mechanisms to Clinical Practice (Serretti, 2025)

"Depression is increasingly conceptualized as a disorder of impaired synaptic plasticity and excitation-inhibition imbalance within corticolimbic circuits. Ketamine, brexanolone, zuranolone, offer complementary approaches to restore circuit function."
Michael DeMarco, PhD

by Michael DeMarco, PhD

Rapid-acting NMDA and GABAergic Modulators in Mood Disorders: From Synaptic Mechanisms to Clinical Practice - PubMed
Depression is increasingly conceptualized as a disorder of impaired synaptic plasticity and excitation-inhibition imbalance within corticolimbic circuits. Two rapid-acting therapeutic classes, NMDA receptor modulators (ketamine, esketamine) and neuroactive-steroid GABA-A positive allosteric modulato …
PubMedAlessandro Serretti

(2025): "Clinically, intravenous ketamine and intranasal esketamine show superiority over placebo and active comparators in treatment-resistant depression (TRD), with esketamine supported for continuation-phase relapse prevention and, in the United States, is approved both as adjunctive therapy and as monotherapy in adults with TRD. Evidence of efficacy extends to bipolar depression with careful mood-stabilizer coverage. Both agents reduce suicidal ideation within hours to days, although effects on suicidal behavior have not been demonstrated. Safety profiles include dissociation and hemodynamic changes; concerns with prolonged or high-cumulative exposure include cystitis and misuse liability."

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Spotlight: A long, strange trip: Ketamine treatment in psychiatry (Nutt, et al, 2025)

"...mystical experiences were strongly related to immediate and sustained psychiatric benefits at the group level and on an individual, session-by-session basis across the six doses, providing mechanistic support for ketamine-psychotherapy pairings."

Spotlight: Personality profiles and trauma history in ketamine therapy for mood and anxiety disorders: A latent profile analysis of short-term outcomes (Gregoire, et al, 2025)

"Personality traits relate to baseline mental health severity but not short-term response to ketamine. Trauma history may predict greater benefit from treatment."

Spotlight: Changing your mind: neuroplastic mechanisms underlying the therapeutic effect of psychedelics in depression, PTSD, and addiction (Palhas, et al, 2025)

"Serotonergic psychedelics & ketamine appear to share common cellular mechanisms. They both recruit glutamatergic neurons to stimulate BDNF-trKB signaling, promoting synaptogenesis via the mTOR pathway. These changes may explain their efficacy in depression, anxiety, PTSD, & addiction."

Spotlight: Modulation of functional network co-activation pattern dynamics following ketamine treatment in major depression (Taraku, et al, 2025)

"findings suggest ketamine modulates brain network dynamics which may normalize dynamic patterns seen in TRD at baseline toward patterns seen in controls. Changes in Salience Network state dynamics may correspond to improvements in ruminative symptoms following ketamine therapy."

Spotlight: Intermittent ketamine and neuromodulation treatment evoke synergistic antidepressant-relevant action (Brown, et al, 2025)

"The rapid response that can be observed following ketamine treatment has reconceptualized how pharmacotherapy can treat depression. One subanesthetic infusion can alleviate symptoms within hours; however, sustained relief also requires multiple doses. "

Spotlight: LSD: Mechanisms and relevance to the treatment of depression (Bouloufa, et al, 2025)

"Psychedelics may be a potential alternative therapy for treatment-resistant depression. LSD has a complex mode of action which is not yet fully understood. Low doses of LSD can drastically increase brain plasticity."
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