Journal of affective disorders
August 1, 2026
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
2 citations
In people with treatment-resistant depression receiving 25 mg psilocybin with monitoring and support, the therapeutic alliance before dosing had only weak correlations with improvement in depression scores at three weeks. Stronger correlations were seen with the intensity of the psychedelic experience itself, particularly emotional breakthrough and visual restructuring. Path analysis suggested that therapeutic alliance helped facilitate the psychedelic experience, but it was the psychedelic experience—not the alliance—that had stronger direct effects on clinical outcomes. The alliance's direct effect on antidepressant response was limited or absent.
Journal of affective disorders
October 15, 2025
Mary Lou Chatterton, Johana Kevin Perez, Thao Thai et al.
2 citations
Subcutaneous ketamine appears cost-effective for treatment-resistant depression from a health sector perspective when the costs of the control treatment (midazolam) are included, but not from a societal perspective. A cost-utility analysis alongside a randomized controlled trial with 174 participants compared ketamine to midazolam given twice weekly for four weeks. At the end of the trial, quality of life scores were significantly higher for ketamine. When control arm costs were included, ketamine was less costly and more effective, with an 89% probability of being cost-effective at a $50,000 per quality-adjusted life year threshold. Excluding those costs made ketamine not cost-effective, highlighting the importance of comparator choice.
Journal of affective disorders
July 23, 2025
Joyce Xu Hao Jin, Heidi Ka Ying Lo, Iris Wai Tung Tsui et al.
2 citations
In people with major depressive disorder (MDD) and bipolar disorder (BD), positive psychological traits such as mindfulness and grit interact with negative affect to influence positive mental health. Over two weeks, 29 people with MDD, 29 with BD, and 30 healthy controls reported their negative affect, pleasure attainment, and meaning in life five times daily. Lower negative affect strengthened the link between mindfulness and meaning in life in the MDD group but not in the BD or control group. Higher grit reduced the harmful effect of negative affect on pleasure attainment in the BD group but not in the other groups. These findings highlight complex relationships between positive traits and mental health in mood disorders.
Journal of affective disorders
June 12, 2025
David Williamson, Linda Williamson, Viola Vaccarino et al.
2 citations
Dissociative symptoms are common in many patients with PTSD and also appear during the first esketamine treatment for treatment-resistant depression. Comparing 134 PTSD patients and 759 TRD patients receiving their first esketamine dose, dissociative symptoms were more prevalent overall in the esketamine group. However, the pattern differed: PTSD patients more often reported dissociative amnesia and identity fragmentation, while esketamine patients most frequently experienced depersonalization and derealization. This distinct pattern suggests that the underlying causes of dissociative symptoms may differ between these conditions.
Journal of affective disorders
September 15, 2026
Rutger Boesjes, Claudia Oosterveld, Jeanine Kamphuis et al.
1 citation
Ketamine and its enantiomers show rapid antidepressant effects for major depressive disorder and bipolar disorder, but responses vary widely. This systematic review of 26 studies (1694 participants) found that ketamine treatment is linked to improved subjective sleep quality. Preliminary evidence suggests that baseline sleep disturbances and early sleep improvements may predict antidepressant response. Some studies also indicate beneficial effects on objective sleep and circadian rhythmicity, but this finding is tentative due to few published articles. The authors call for more research on objective circadian measures and potential synergy with chronotherapies.
Journal of affective disorders
February 1, 2026
Lauren N Vale, Maya Ibrahim, Leonardo Fávaro-pereira et al.
1 citation
People with bipolar disorder who have used classic psychedelics like psilocybin or LSD hold more positive attitudes toward these substances and score higher on openness to experience compared to those who are only considering use. The two groups do not differ in sociodemographic background or mental health status. Those who have used psychedelics endorse certain motives for use more strongly, while those contemplating use express greater concerns about potential negative effects. The findings suggest that prior psychedelic experience shapes perceptions and motivations, and highlight topics for discussion with individuals with bipolar disorder who may consider psychedelic use, including in clinical trials.
Journal of affective disorders
January 21, 2026
Jan Sarlon, Deanne Thomi, Annette B Brühl et al.
1 citation
Intranasal racemic ketamine is non-inferior to esketamine for reducing depression symptoms in adults with treatment-resistant depression, with comparable symptom improvement over four weeks. However, remission rates were higher with esketamine (38.7%) than with racemic ketamine (15.6%), and racemic ketamine failed to meet non-inferiority for remission. Safety profiles were similar, though racemic ketamine caused slightly more transient blood pressure elevations. Racemic ketamine may be a cost-effective alternative where esketamine access is limited, but higher remission with esketamine warrants further study.
Journal of affective disorders
November 18, 2025
Randi Brown, Jennifer Lissemore, Kenneth Shinozuka et al.
1 citation
Among 30 male Veterans with traumatic brain injury from repeated blast/combat exposures, those who reported more intense mystical experiences during magnesium-ibogaine therapy showed larger reductions in PTSD severity both immediately and one month after treatment. Greater mystical experience intensity was also linked to larger reductions in peak alpha frequency one month later. The findings suggest that mystical experiences may contribute to improvements in PTSD following magnesium-ibogaine and may relate to persisting decreases in peak alpha frequency.
Journal of affective disorders
July 15, 2025
Theresa R Lii, Josephine R Flohr, Robin L Okada et al.
1 citation
The endogenous opioid system may influence the placebo antidepressant response. A post hoc analysis of a randomized, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery tested whether baseline opioid use affected antidepressant responses. The analysis found that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, pain intensity, and ethnicity. The findings, based on a small sample, require confirmation by prospective controlled studies. Opioid use at baseline attenuated the placebo antidepressant response independently of pain, while the antidepressant response was preserved in opioid users who received ketamine.
Journal of affective disorders
June 8, 2025
Junjie Zhang, Rui Xiong, Yujuan Su et al.
1 citation
Repeated esketamine exposure during early postnatal development in mice led to significant hippocampal injury, including downregulation of glutamatergic neuronal markers and persistent cognitive dysfunction in adolescence. These adverse outcomes were strongly associated with elevated expression of Kcnq2 in the hippocampus. Both pharmacological blockade and genetic knockdown of Kcnq2 mitigated the cognitive deficits. Mechanistically, activation of Kcnq2 drove dephosphorylation of key signaling molecules within the Akt1/GSK-3β pathway. The findings identify Kcnq2 as a novel therapeutic target for preventing anesthesia-related cognitive deficits in pediatric populations.
Journal of affective disorders
January 15, 2025
Jia-Ru Li, Kuo-Tung Chiang, Yu-Chen Kao et al.
1 citation
The antidepressant effects of psychedelics may be overestimated in trials using pre-post single-arm, non-active-drug-as-placebo, and waitlist-control designs. A systematic review of 19 trials found that psilocybin and MDMA showed large to medium effect sizes in non-active-placebo designs (psilocybin: Hedges' g = 0.87; MDMA: g = 0.65), but effects were not statistically significant in active-placebo designs. Psilocybin effect sizes were very large in pre-post (g = 2.51) and waitlist-control (g = 2.88) designs. Ayahuasca also showed large effects in pre-post (g = 1.88) and non-active-placebo (g = 1.60) designs. LSD was significant only in non-active-placebo design (g = 1.49). Limited sample sizes, difficulty maintaining participant blinding, and high expectancy likely inflate apparent efficacy.
Journal of affective disorders
November 1, 2026
Dian-Jeng Li, Tien-Wei Hsu, Te-Chang Changchien et al.
Patients with major depressive disorder who are prescribed esketamine have higher rates of comorbid substance use disorders compared to those treated with antidepressants or repetitive transcranial magnetic stimulation. Among esketamine users, those with a substance use disorder face greater risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality. The findings indicate a prescription bias toward patients with comorbid substance use disorders and highlight the need for careful monitoring and specialized care for this population.
Journal of affective disorders
November 1, 2026
Carlton M Kelly, Mathieu Fradet, Catherine M Bostian et al.
A single 25-mg dose of psilocybin with psychological support was associated with sustained improvements in anxiety, quality of life, functioning, and PTSD symptoms in 15 veterans with treatment-resistant depression. Anxiety scores dropped 59% from baseline at three weeks and remained lower through 12 months. Quality of life increased 24% and functional impairment decreased 46% at three weeks, though these effects were no longer statistically significant after accounting for concurrent improvements in depression. PTSD symptom reductions were observed at all timepoints. Acute subjective experiences did not correlate with treatment response. The study is limited by its small sample and open-label design.
Journal of affective disorders
November 1, 2026
Tse-Hwei Choo, Hanga C Galfalvy, John G Keilp et al.
A midazolam-controlled trial of intravenous ketamine for suicidal depressed patients found that ketamine rapidly reduced suicidal ideation within 24 hours. An exploratory analysis measured saliva cortisol awakening response at baseline and 24 hours after infusion. Waking cortisol significantly increased 24 hours after ketamine treatment. The increase in waking cortisol from baseline to post-infusion showed a small to medium, nonsignificant correlation with decreased suicidal ideation. These preliminary results, pending replication, align with evidence that moderate cortisol increases may enhance stress-resilience.
Journal of affective disorders
November 1, 2026
Lindsay L Benster, Jordan N Kohn, Benjamin Wade et al.
In a real-world comparison of two FDA-approved treatments for treatment-resistant depression, intranasal esketamine led to faster improvement than repetitive transcranial magnetic stimulation (rTMS). Over 90 days, esketamine patients responded a median of 36 days versus 49 days for rTMS, and suicidal ideation resolved more quickly (median 9 vs. 26 days). However, by about 90 days, overall response and remission rates were similar between the groups (68.8% and 45.2% for esketamine; 59.4% and 40.1% for rTMS), suggesting a difference in speed rather than ultimate effectiveness. For rTMS, slower response was predicted by comorbid anxiety and benzodiazepine use, while former tobacco use predicted faster response. No such predictors were found for esketamine.
Journal of affective disorders
September 1, 2026
Nesreen Sedeek, Carley Rivers, Lucas Williamson et al.
Ketamine's rapid antidepressant effects in treatment-resistant depression are linked to changes in brain activity, but previous studies have been hard to compare due to differences in imaging techniques, analysis methods, and timing. A review combining fMRI and PET studies found that ketamine-related effects commonly appear in subcortical brain regions, with more variable effects in cortical areas like the prefrontal and anterior cingulate cortices. Network-level patterns suggest involvement of the default-mode, ventral attention, and visual systems. These findings are hypothesis-generating and highlight the need for future studies that harmonize methods to directly connect circuit changes to molecular mechanisms and clinical outcomes.
Journal of affective disorders
August 15, 2026
Michał Walaszek, Wiesław Jerzy Cubała, Zofia Kachlik et al.
Anhedonia, a core symptom of major depressive disorder linked to poor outcomes, may be reduced by ketamine. In a retrospective analysis of 34 inpatients with treatment-resistant depression receiving short-term ketamine as an add-on to standard care, 16 patients (47.1%) did not respond to treatment, defined as less than a 50% reduction on the Snaith-Hamilton Pleasure Scale. Non-responders were more likely to be single, had fewer lifetime depressive episodes, and lower rates of prior substance use disorder. These factors suggest that psychosocial and demographic characteristics influence anhedonia treatment outcomes, supporting a personalized approach to mood disorder treatment.
Journal of affective disorders
August 1, 2026
Ching-Hua Julie Lee, Yunzhe Qian, Weiqun Yu et al.
Compared with injectable ketamine, esketamine was linked to higher risks of suicidal ideation (24% increase), generalized anxiety disorder (55% increase), insomnia (25% increase), and cardiac arrest (57% increase). Compared with oral antidepressants in treatment-resistant depression, esketamine was associated with lower risks of suicidal ideation (11% decrease), suicide attempt (29% decrease), and generalized anxiety disorder (18% decrease), but a higher risk of cardiac arrest (109% increase). Injectable ketamine showed a more favorable safety and effectiveness profile than esketamine. Head-to-head clinical trials are needed to validate these findings.
Journal of affective disorders
August 1, 2026
Taro Kishi, Kenji Sakuma, Masakazu Hatano et al.
A systematic review and meta-analysis of six randomized controlled trials examined how psilocybin's effects on major depressive disorder change over time. Standard-dose psilocybin (25 mg/session or 20-30 mg/70 kg/session) was superior to control conditions (placebo, waiting-list, niacin, or 1 mg psilocybin) in reducing depressive symptoms. Sensitivity analyses excluding waiting-list controls confirmed this benefit with reduced heterogeneity. Standard-dose psilocybin also produced higher response and remission rates at 2-3 weeks and sustained response at 6-12 weeks, and lower all-cause discontinuation. However, it was associated with more headaches and nausea within 1-9 days, which resolved. Low-dose psilocybin showed no superior efficacy. The authors suggest standard-dose psilocybin is a promising treatment but note considerable methodological heterogeneity across trials.
Journal of affective disorders
August 1, 2026
João Paulo Atidio, Rodrigo Simonini Delfino, Igor Saque Garios et al.
In patients with treatment-resistant depression receiving subcutaneous esketamine over six weeks, depressive symptoms improved significantly, with MADRS scores dropping by an average of 2.82 points per week. Those also taking benzodiazepines had higher depression scores throughout treatment, while lamotrigine and lithium showed no significant effect on outcomes. No medication altered the rate of improvement over time. The findings suggest benzodiazepine use may blunt the antidepressant response to esketamine, but further prospective research is needed.
Journal of affective disorders
July 15, 2026
Iman Kiani, Giulia Cattarinussi, Fabio Sambataro et al.
A systematic review of fifteen neuroimaging studies identifies potential brain-based markers that could predict which patients with major depressive disorder will respond to ketamine. The anterior cingulate cortex and amygdala, along with their connections to other brain regions, frequently predicted better response. Higher fractional anisotropy in the cingulum, larger hippocampus volume, and a higher Glx/glutamate ratio in the dorsomedial prefrontal cortex also correlated with response. Task-based imaging showed that anterior cingulate cortex activity predicted antidepressant response. The review notes limitations due to differences in assessments, follow-up times, ketamine doses, and imaging methods across studies.
Journal of affective disorders
June 29, 2026
Yao Ge, Lijuan Chen, Yu Shen et al.
In people with major depressive disorder, the balance between excitation and inhibition across the brain's cortex is disrupted, particularly in the parietal and prefrontal-cingulate regions. Using resting-state functional magnetic resonance imaging data from 254 patients and 451 healthy controls, the Hurst exponent—a proxy for excitation-inhibition balance—was found to be significantly reduced in patients. This imbalance was linked to specific gene expression related to neuronal structure, metabolism, and mitochondrial function, as well as to neurotransmitter systems including GABA, opioid, serotonin, and synaptic density. In a separate trial of 32 patients with treatment-resistant depression, ketamine increased the Hurst exponent in the anterior cingulate and medial prefrontal cortices, suggesting that restoring excitation-inhibition balance may underlie ketamine's antidepressant effects.
Journal of affective disorders
June 15, 2026
Marc J Weintraub, Jessica K Jeffrey, Megan C Ichinose et al.
Pairing psilocybin with cognitive behavioral therapy (CBT) is acceptable, feasible, and associated with substantial improvements in major depressive disorder. In a small open-label trial, 16 adults with at least moderately severe depression received two psilocybin doses (10 mg and 25 mg) and 12 CBT sessions over four months. All participants completed the 7-month study with no serious adverse events. By treatment end, 13 of 16 showed at least 25% improvement in depressive symptoms, and 9 had fully remitted. Gains in depressive symptoms and psychosocial functioning were sustained three months later, with large effect sizes (Hedges' g = 1.9–2.7). Improvements correlated with better emotion regulation and more positive cognitive schemas.
Journal of affective disorders
May 1, 2026
Michel Danon, Gabriela Ostronoff, Anne-Cécile Petit et al.
Regulatory approvals for intranasal esketamine in treatment-resistant depression differ on its indication for suicidal ideation. In a two-center observational study of 261 adults with moderate-to-severe treatment-resistant depression, eight esketamine sessions over four weeks improved both depressive symptoms and suicidal ideation. However, after statistically adjusting for the antidepressant effect, the reduction in suicidal ideation was no longer significant. The findings suggest that esketamine's anti-suicidal effect does not persist independently of its antidepressant effect.
Journal of affective disorders
April 15, 2026
Jen-Ping Chen, Chih-Wei Hsu, Yi-Ting Chen et al.
Among adults with treatment-resistant depression, repetitive transcranial magnetic stimulation (rTMS) was associated with fewer medical complications than esketamine over the first year, including lower risks of hospitalization, arrhythmia, and any injury. Suicide-related outcomes were broadly comparable overall, though esketamine showed a protective advantage during the 30-90-day interval and among patients aged 45-65 years. The analysis used target trial emulation with propensity score matching on 50 covariates, drawing on electronic health records of 1,690 matched patients per treatment group. The findings suggest rTMS has a more favorable overall medical safety profile, while suicide risks were similar except for specific subgroups and time periods.