The Journal of Clinical Psychiatry
May 26, 2020
George I. Papakostas, Naji C. Salloum, Rebecca S. Hock et al.
107 citations
Adjunctive intranasal esketamine is more effective than placebo for treating major depressive disorder. Pooling five randomized, double-blind trials with 774 patients, esketamine outperformed placebo on depression rating scale score change, response, and remission. The effect was statistically significant across different study samples and baseline antidepressant regimens. Esketamine appears to be an effective treatment strategy for patients who are treatment-resistant or acutely suicidal.
Pharmaceutics
March 25, 2025
Shakila Meshkat, Huda Al-Shamali, Argyrios Perivolaris et al.
22 citations
Psilocybin is rapidly converted to its active metabolite psilocin after oral intake. Psilocin reaches peak concentration in blood plasma between 1.8 and 4 hours, with maximum concentration ranging from 8.2 ng/mL in plasma to 871 ng/mL in urine, depending on dose. Its bioavailability is about 53%, and it distributes extensively into tissues, with volume of distribution between 277 and 1016 liters. Metabolism involves CYP2D6 and CYP3A4 enzymes, plus monoamine oxidase A, producing 4-hydroxyindole-3-acetic acid and 4-hydroxytryptophol. Elimination half-life ranges from 1.5 to 4 hours. These pharmacokinetics vary with dosage, route, and species, and the role of CYP enzymes indicates possible drug interactions.
The Journal of Clinical Psychiatry
November 14, 2022
Anna Feeney, Bettina B. Hoeppner, Marlene P. Freeman et al.
9 citations
Among people with treatment-resistant depression, those taking oral benzodiazepines alongside a single intravenous infusion of ketamine showed less improvement in depression scores 24 hours later if they were on higher benzodiazepine doses. The same pattern was not seen in those who received a midazolam placebo. By day 3 after the infusion, benzodiazepine use no longer affected depression scores. The findings suggest that higher doses of benzodiazepines may temporarily weaken ketamine's rapid antidepressant effect.
JAMA Psychiatry
December 1, 2023
Sanjay J. Mathew, Manish K. Jha, Amit Anand
8 citations
Electroconvulsive therapy (ECT) and ketamine are both used to treat treatment-resistant depression (TRD), but recent reports highlight important considerations when comparing them. This viewpoint examines key issues from several recent studies, including differences in how quickly each treatment works, their side effects, and the practical challenges of administering them. ECT remains highly effective but requires anesthesia and can cause memory problems, while ketamine offers rapid relief but its long-term effects and optimal dosing are still being studied. The authors suggest that neither treatment is clearly superior for all patients, and the choice depends on individual circumstances and preferences.
Journal of Clinical Medicine
February 20, 2025
Shakila Meshkat, Taha Malik, Jennifer Swainson et al.
3 citations
A systematic review examined whether psychedelic therapies can rapidly reduce suicide risk. Four randomized controlled trials reported significant reductions in suicidal ideation with psilocybin (three studies) and MDMA-assisted therapy (one study), with effect sizes (Cohen's d) ranging from 0.52 to 1.25 and no safety issues. Five additional randomized trials also showed reductions. Among 24 non-randomized and cross-sectional studies, results were mixed: psilocybin reduced suicidal ideation (odds ratios 0.40–0.75), MDMA-assisted therapy for PTSD showed a pooled effect of d = 0.61, while LSD was associated with increased odds of suicidality (odds ratios 1.15–2.08). DMT studies showed no significant effects. The evidence remains inconclusive, underscoring the need for further trials.
BMC Psychiatry
January 4, 2026
Carl D. Marci, Kruti Joshi, Stevan Geoffrey Severtson et al.
2 citations
Among 163 patients with treatment-resistant depression treated with esketamine nasal spray in real-world US settings, depressive symptoms improved significantly over six months. Average PHQ-9 scores dropped by 3.2 points within the first three months and by 4.4 points between three and six months after starting treatment. The proportion of patients with moderately severe or severe depression fell from 55.8% at baseline to 37.1% at three months and 25.0% at six months, while the share with minimal or mild depression increased. These findings suggest esketamine, approved in 2019 for treatment-resistant depression, is effective outside clinical trials.
Drugs - real world outcomes
March 1, 2025
Manish K. Jha, Maryia Zhdanava, Aditi Shah et al.
1 citation
Among US adults with treatment-resistant depression, those who started esketamine nasal spray had fewer mental-health-related disability days and lower associated costs six months later compared with the month before starting treatment. In the esketamine group, disability days fell by an average of 0.4 days and costs dropped by $312 per patient per month. Trends for other therapies varied: transcranial magnetic stimulation showed a $123 cost reduction with no change in disability days, second-generation antipsychotic augmentation showed little change, and electroconvulsive therapy was linked to increases in both disability days and costs. The findings suggest esketamine may reduce disability burden, but the study was descriptive and lacked statistical comparisons.
medRxiv Preprint Server
April 10, 2021
Agnes Norbury, Sarah B. Rutter, Abigail B. Collins et al.
1 citation
preprint
In a small randomized clinical trial, repeated doses of ketamine improved PTSD symptoms more than midazolam. Brain scans showed that symptom improvement was linked to increased communication between the ventromedial prefrontal cortex and amygdala when viewing emotional faces, especially in those who received ketamine. Ketamine-related improvement was also predicted by decreased activity in the dorsal anterior cingulate during emotional conflict and increased resting-state connectivity between the ventromedial prefrontal cortex and anterior insula. Further analysis indicated that ketamine specifically strengthened the prefrontal cortex's ability to inhibit amygdala responses to threatening social cues, suggesting a normalization of brain circuits involved in fear regulation.
FOCUS The Journal of Lifelong Learning in Psychiatry
April 1, 2026
Shakila Meshkat, Manish K. Jha, Venkat Bhat
Psilocybin, a serotonergic psychedelic, is being studied as a potential treatment for several psychiatric conditions. Clinical evidence from early-phase and small-scale trials suggests rapid but variable reductions in depressive symptoms, with some studies reporting sustained effects. Preliminary benefits have been shown for anxiety related to life-threatening illness and for reducing alcohol and tobacco dependence. Limited evidence supports possible effects in obsessive-compulsive disorder, body dysmorphic disorder, anorexia nervosa, and posttraumatic stress disorder. Adverse events like headache, nausea, and short-lived anxiety are typically transient and mild, though notable adverse reactions have occurred in larger trials. The evidence base remains limited by small sample sizes, selective populations, and short follow-up durations.
Journal of Affective Disorders
January 23, 2026
Reinhard Janssen-Aguilar, Jithin Joseph, Huda Al-Shamali et al.
In a retrospective chart review of 209 adults with treatment-resistant depression treated with intravenous ketamine, depressive and anxiety symptoms improved significantly over four or six infusions, but the improvements were modest and highly variable across individuals. Anxiety symptoms improved more slowly and less robustly than depressive symptoms. End-of-treatment response and remission rates were numerically higher after six infusions than after four, but the difference was not statistically significant. Four distinct patterns of symptom change emerged for both depression and anxiety, highlighting the heterogeneity of treatment response. Durability after six infusions could not be assessed because follow-up data were available only for the four-infusion group.
The Journal of Clinical Psychiatry
April 2, 2025
Adriana Feder, Oneysha Brown, Sarah B. Rutter et al.
Combining six ketamine infusions with a brief exposure-based psychotherapy, written exposure therapy (WET), produced large and durable reductions in PTSD symptoms for patients with chronic, severe PTSD. In an open-label trial, 13 of 14 patients completed treatment. PTSD symptom severity, measured by the CAPS-5, dropped from an average of 41.6 before treatment to 20.8 at 12 weeks, a large-magnitude improvement. Nine patients (69%) were treatment responders, and eight (61.5%) maintained improvement up to six months. The authors suggest the combined treatment may be effective but call for larger randomized controlled trials to confirm efficacy and synergy.
Current Medical Research and Opinion
February 1, 2025
Manish K. Jha, Amanda Teeple, Jason Shepherd et al.
Among 914 patients with treatment-resistant depression (TRD) or major depression with suicidal ideation (MDSI), moderate-to-very severe depression affected 36.5% of those with TRD and 48.3% of those with MDSI. Mean work impairment was 26% and overall impairment 34.7%. Most patients reported no-to-mild impairment in basic needs, social functioning, work, quality of life, and general health. Physicians underestimated the daily-life impact and unmet treatment need. Among 94 patients prescribed esketamine, improvements in clinical global impression occurred in 64.6-77.8% and in activities of daily living in 34-67%, indicating favorable outcomes.