Journal of affective disorders
April 1, 2026
Kayla M Teopiz, Gia Han Le, Sabrina Wong et al.
A systematic review of 13 preclinical studies and 1 human study found that dextromethorphan (DXM), a glutamatergic modulator with antidepressant properties, attenuates reward-seeking behavior in rats, as measured by conditioned place preference and behavioral sensitization. In the single human study involving 20 healthy participants, self-reported drug-liking for DXM (400 mg/70 kg) was significantly lower compared to psilocybin (20 mg and 30 mg) 7 hours after dosing. The review highlights a paucity of human studies and suggests that future research should investigate DXM's effects on reward function using validated paradigms in people with anhedonia.
Journal of affective disorders
February 4, 2026
Raquel Kosted, Alli Waddell, Ken Adolph et al.
Depression symptoms improved over time in patients receiving five ketamine infusions, with faster initial improvement that slowed later. Higher scores on the Adverse Childhood Experiences (ACE) survey were linked to greater symptom reduction, regardless of whether patients received ketamine-assisted therapy or infusions alone. Younger adults showed a stronger response to infusions alone compared to ketamine-assisted therapy, while older adults showed the opposite pattern. The association between higher ACE scores and greater symptom reduction was particularly pronounced in younger adults and reversed in older adults. These findings suggest ketamine may offer a targeted benefit for people with early life stress, especially younger adults.
Journal of affective disorders
February 2, 2026
Alene Sze Jing Yong, Aimee Freeburn, Suzie Bratuskins et al.
Australia became the first country to allow authorized prescribing of MDMA for PTSD outside clinical trials. Interviews with 21 clinicians, researchers, and patients who had direct experience with MDMA-assisted psychotherapy or PTSD revealed eleven themes, including the importance of expectation management, comprehensive baseline screening, shared decision-making, flexible treatment protocols, ongoing consent, strong therapeutic alliance, and post-treatment continuity of care. The findings emphasize the need for safeguards, provider training, and integration of care as MDMA-assisted psychotherapy enters clinical practice.
Journal of affective disorders
January 30, 2026
Yao-Zu Li, Cai-Qun Zhao, Mu-Yan Zuo et al.
A multimodal therapy combining esketamine with dexmedetomidine patient-controlled sleep (PCSL) was associated with sustained improvements in depressive symptoms and sleep quality over 6 months in 233 patients with treatment-resistant depression. Antidepressant response rates were 62% at 1 month, 59.73% at 3 months, and 58.49% at 6 months. Use of PCSL was linked to response at all time points, while additional esketamine during follow-up was associated with response at 3 months but not statistically significantly at 6 months. Age and disease duration also influenced response. No serious adverse events occurred.
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.
Journal of affective disorders
June 18, 2025
Julia Myerson, Katrina A Rufino, Sanjay J Mathew et al.
Electroconvulsive therapy (ECT) shows stronger antidepressant effects than intravenous ketamine for severe depression. In a retrospective chart review of 146 patients aged 18 to 74 with major depressive episodes, 94 received ketamine infusions twice weekly and 52 received ECT two to three times weekly. Overall, 45.2% of participants showed clinical symptom change on the Montgomery-Asberg Depression Rating Scale. ECT had a response rate of 67.3% and remission rate of 60.0%, compared to 45.7% and 46.1% for ketamine. Chi-square tests indicated a significant association between treatment type and symptom improvement, favoring ECT.
Journal of affective disorders
December 15, 2024
Rodrigo Machado-Vieira, Gregory H Jones, Alan C Courtes et al.
Fatigue, a multidimensional condition that often overlaps with depression, responds only modestly to standard antidepressants and mood stabilizers but has shown positive response to intravenous ketamine, which is limited by cost and access. This study evaluated a single 50 mg dose of intranasal ketamine in 28 individuals with major depressive disorder or bipolar depression, about 60% of whom also had alcohol use disorder. The group by time interaction for the NIH-Brief Fatigue Inventory score was significant, favoring intranasal ketamine over placebo at 4, 24, and 48 hours post-treatment. Intranasal ketamine was well-tolerated with minimal adverse effects. The findings suggest intranasal ketamine induces rapid anti-fatigue effects and may serve as an alternative rapid-acting option for fatigue across different medical conditions.
Journal of affective disorders
October 1, 2023
Olivier Brown
A letter to the editor raises methodological concerns about a published study on psilocybin therapy for depression. The original study reported increased low-frequency brain responses to music after treatment, but the letter questions the ANOVA region-of-interest analysis, noting that potential confounds such as age and biological sex may have influenced the reported variance attributed to psilocybin treatment. The letter does not present new data but critiques the statistical approach and suggests the findings may be less robust than claimed.
Journal of affective disorders
July 16, 2026
Sara Massetti, Sanne Y Smith-Apeldoorn, Jolien K E Veraart et al.
Ketamine and its enantiomer esketamine are effective in only 30-35% of patients with treatment-resistant depression. Increased serum brain-derived neurotrophic factor (BDNF) after a single intravenous dose has been proposed as a biomarker of antidepressant response, but effects under different treatment schedules are unclear. In a randomized, placebo-controlled trial of six-week, low-dose, oral esketamine (90 mg/day, three 30 mg intakes), depression severity and serum BDNF were measured in 54 patients at baseline, end of treatment, and after a four-week washout. BDNF levels did not significantly differ between esketamine and placebo groups during treatment or washout. An increase in BDNF occurred regardless of treatment condition.
Journal of affective disorders
March 15, 2026
Patrícia Cavalcanti-Ribeiro, Lara Carvalho Araújo Melo De Souza, Vagner Deuel O de Tavares et al.
In a small open-label trial of 22 patients with treatment-resistant depression who received seven weekly subcutaneous doses of esketamine, those with elevated baseline C-reactive protein (CRP > 1 mg/L) showed significant reductions in CRP by week 4 and week 8, while patients without inflammation showed no change. By week 8, CRP levels in both groups were comparable. Although the inflammation group had a greater average reduction in depression severity (15.88 points on the MADRS scale versus 11.14 points), this difference was not statistically significant, and changes in CRP did not predict symptom improvement. Larger controlled studies are needed.
Journal of affective disorders
February 15, 2026
Tomas Lindegaard, Anton Käll
Psychedelic-assisted psychotherapy (PAP) shows large to very large effects on symptoms of depression and anxiety at post-treatment and follow-up, with Hedge's g values ranging from 0.98 to 1.83. A meta-analysis of 23 clinical trials found some evidence that two dosing sessions produce larger between-group effects than one session, though this finding was not robust across all analyses and needs replication. Only three studies used evidence-based psychotherapy protocols, limiting analysis of that moderator. The field would benefit from more thorough reporting of psychotherapy protocols to enable comparison between studies.
Journal of affective disorders
February 1, 2026
Kayla M Teopiz, Sabrina Wong, Gia Han Le et al.
Reward processing disruptions in major depressive disorder (MDD) may relate to altered frontostriatal brain activity. Glutamatergic modulators might improve reward function. This systematic review examined 11 fMRI studies testing glutamatergic agents—ketamine (9 studies), nitrous oxide (1), and memantine (1)—on frontostriatal activity in people with MDD or healthy controls. Preliminary evidence suggests intravenous ketamine may alter functional connectivity in striatal regions, potentially relevant to improved reward function in treatment-resistant depression. More research is needed on how these modulators affect reward-related brain structures, the timing of effects, and baseline characteristics predicting antidepressant response.
Journal of affective disorders
June 1, 2023
Gustavo C Leal, Breno Souza-Marques, Rodrigo P Mello et al.
In a small pilot trial, the antidepressant arketamine was compared with placebo for treatment-resistant depression. Ten participants received both arketamine (0.5 mg/kg) and saline one week apart in a randomized, double-blind, crossover design. Depression improved over time, but there was no significant difference between arketamine and placebo. Dissociation and other adverse events were minimal. The study was underpowered, and the authors conclude that arketamine was not superior to placebo but was extremely safe, recommending larger trials with different dosing strategies.
Journal of affective disorders
December 1, 2022
Anastasia Levinta, Shakila Meshkat, Roger S McIntyre et al.
Ketamine rapidly reduces depressive symptoms in people with treatment-resistant depression, but its effectiveness may diminish as the number of prior failed treatments increases. A systematic review of 18 randomized controlled trials found that ketamine and esketamine worked at both lower and higher stages of treatment resistance, yet effect sizes and duration of benefits were greater in studies involving patients with fewer prior antidepressant failures. Variability in how studies defined treatment resistance and measured outcomes prevented clear comparisons of efficacy across different resistance stages. The authors conclude that while ketamine remains broadly effective, more failed treatment trials may reduce its efficacy, and participant-level data are needed to clarify the relationship between resistance level and response.
Journal of affective disorders
October 15, 2022
Isak Joneborg, Yena Lee, Joshua D Di Vincenzo et al.
A systematic review of five randomized-controlled trials found that ketamine-assisted psychotherapy (KAP) had a significant positive effect on primary outcome measures for adults with substance use disorders and treatment-resistant depression, but the data is mixed. The single trial examining KAP for treatment-resistant depression found no benefit. The review notes a lack of large, replicated clinical trials and no studies actively examining mechanisms of action. Evidence suggests temporary neural changes caused by ketamine, such as NMDAR inhibition and increased synaptic neuroplasticity, may affect treatment outcomes. Preliminary findings also suggest adjunct psychotherapy, changes in perspective, and spirituality may play a role.
Journal of affective disorders
August 15, 2017
James W Murrough, Elizabeth Wade, Sehrish Sayed et al.
A combination of dextromethorphan and quinidine, given at up to 45/10 mg twice daily for 10 weeks, reduced depression scores in patients with treatment-resistant depression. Twenty patients with unipolar treatment-resistant depression enrolled; six discontinued early. Depression scores on the Montgomery-Asberg Depression Rating Scale dropped by an average of 13 points, and on the Quick Inventory of Depressive Symptomatology by nearly 6 points. Response and remission rates were 45% and 35%, respectively. No treatment-emergent suicidal thoughts, psychosis, or dissociation occurred. The open-label, proof-of-concept design limits conclusions, but results suggest the combination is tolerable and warrants larger placebo-controlled trials.