Lancet (London, England)
July 22, 2025
Balwinder Singh, Holly A Swartz, Alfredo B Cuellar-Barboza et al.
66 citations
Bipolar disorder, marked by hypomania or mania and predominantly depression, affects about 40 million people worldwide and carries substantial psychosocial, medical, and financial burdens, along with increased suicide risk. Diagnosis is often delayed due to symptom overlap with ADHD, major depression, psychotic disorders, and personality disorders. Recent research points to multigene risk and possible infectious and mitochondrial causes. Treatment combines pharmacotherapy, psychotherapy, and lifestyle changes, tailored to individual goals. Future priorities include expanding self-management psychosocial interventions, addressing treatment-resistant depression, deepening understanding of pathophysiology, and exploring novel options like ketamine, esketamine, and neuromodulation.
Journal of Clinical Psychiatry
February 1, 2023
Balwinder Singh, S. Kung, Vanessa K. Pazdernik et al.
64 citations
In adults with treatment-resistant depression, intravenous (IV) ketamine and intranasal (IN) esketamine produced similar rates of symptom improvement and remission, but remission was reached in fewer treatment sessions with IV ketamine. Over up to six IV or eight IN treatments, depressive symptoms were measured before and 24 hours after each session. Among 62 participants (median age 50, 65% female), neither the change in symptom scores nor the proportion achieving response or remission differed significantly between groups. However, time to remission—adjusting for age, sex, body mass index, and baseline severity—was five times faster with IV ketamine than with IN esketamine. A randomized controlled trial is needed to confirm these results.
Journal of affective disorders
July 1, 2024
Ashok Seshadri, Larry J Prokop, Balwinder Singh
50 citations
A systematic review and meta-analysis of 12 randomized controlled trials found that intravenous ketamine reduces depression symptoms in treatment-resistant depression at doses as low as 0.2 mg/kg, with increasing response at 0.5 mg/kg but no additional benefit at 1 mg/kg. Intranasal esketamine doses of 56–84 mg were more effective than 28 mg. Higher intravenous doses above 0.5 mg/kg did not lead to greater treatment response. The overall quality of evidence was low, limited by few studies, and publication bias was high.
Journal of psychiatric practice
November 1, 2015
Ajay K Parsaik, Balwinder Singh, Darrow Khosh-Chashm et al.
42 citations
A single intravenous dose of ketamine significantly reduces symptoms of treatment-resistant bipolar depression compared with placebo, with maximum improvement observed 40 minutes after infusion. The meta-analysis of three randomized controlled trials (69 subjects) showed a large effect (standardized mean difference -1.01). No serious side effects occurred, and side effects were similar between ketamine and placebo. Individual studies also reported reduced anhedonia and suicidal ideation after ketamine therapy.
Brain Sciences
December 22, 2023
Nicolas A. Nunez, Boney Joseph, Rakesh Kumar et al.
20 citations
Ketamine can rapidly reduce depression and suicidal thoughts in treatment-resistant depression, but its effectiveness for bipolar depression is less certain. An updated systematic review and meta-analysis of 11 studies, including 7 in the meta-analysis, found that a single ketamine infusion significantly improved depression symptoms measured by the MADRS scale at 1 and 2 days. Non-randomized studies showed a 53% response rate at study endpoint. Response and remission rates were similar for single versus serial infusions. The rate of switching to mania was about 2.4%. Evidence for esketamine in bipolar depression remains limited and based on small, non-randomized studies.
Psychiatry research
May 1, 2024
Balwinder Singh, Sagar V Parikh, Jennifer L Vande Voort et al.
18 citations
In a nonrandomized, open-label clinical trial, 74 adults with treatment-resistant depression received three intravenous ketamine infusions, with an additional four infusions for those who remitted. After the acute phase, 53% (39/74) experienced remission of depression symptoms. Higher baseline language domain scores on the RBANS cognitive assessment were associated with greater odds of remission. No significant association was found between remission and baseline immediate or delayed memory, visuospatial, or attention scores. During the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. The findings suggest cognitive improvement, not deterioration, with serial ketamine administration.
Pharmaceuticals
August 1, 2023
B. Joseph, N. Nuñez, S. Kung et al.
14 citations
For adults with treatment-resistant depression, taking lamotrigine alongside intravenous ketamine or intranasal esketamine does not significantly reduce the antidepressant effect of the treatments. In a historical cohort study, response and remission rates were similar whether patients were on lamotrigine or not. There was a trend toward lower dissociation scores among those taking lamotrigine, especially with IV ketamine. The study was limited by only 13 patients on lamotrigine, so the evidence is insufficient to conclude that lamotrigine attenuates the antidepressant effect, but it may reduce dissociation.
CNS drugs
August 1, 2024
Liliana Patarroyo-Rodriguez, Stefanie Cavalcanti, Jennifer L Vande Voort et al.
13 citations
Anhedonia, the inability to feel pleasure, is a symptom that appears in many mental disorders beyond just depression and schizophrenia, and it is linked to worse outcomes such as higher suicide risk and poor treatment response. Although brain imaging and biomarkers have improved understanding, the neural basis of anhedonia is still not fully known. Ketamine, a fast-acting antidepressant, also seems to reduce anhedonia through a separate mechanism from its antidepressant effects. Other potential treatments are being explored, but many questions remain, highlighting the need for more research.
Journal of Affective Disorders
January 1, 2024
Liliana Patarroyo-Rodriguez, Vanessa M. Pazdernik, Jennifer L. Vande Voort et al.
12 citations
Sleep disturbances affect 94% of patients with treatment-resistant depression, with middle and early insomnia being the most common. Patients who experience hypersomnia (excessive sleep) before treatment show higher response rates and greater improvement in depressive symptoms after receiving intravenous ketamine or intranasal esketamine. Additionally, 15% of patients have an atypical depression phenotype, and most of them also achieve a positive response with greater symptom reduction. A trend toward faster response is seen in both the hypersomnia and atypical depression groups. These sleep-related features may help predict which patients will benefit from ketamine-based treatments.
Therapeutic advances in psychopharmacology
January 1, 2025
Ahmed Elmosalamy, Idil Tarikogullari, Liliana Patarroyo-Rodriguez et al.
7 citations
About one-third of people with depression do not respond to standard treatments, a condition known as treatment-resistant depression (TRD). Intravenous (IV) ketamine and esketamine (given IV or as a nasal spray) are newer options for TRD, but only the nasal spray version of esketamine is FDA-approved. A meta-analysis of eight studies with 978 adults directly comparing IV ketamine with esketamine found that both treatments produced similar rates of response and remission after acute treatment, with a slight but not statistically significant advantage for IV ketamine. IV ketamine may work faster, but the evidence is mostly from observational studies, and large randomized trials are needed to confirm these findings.
CNS drugs
April 1, 2025
Balwinder Singh
6 citations
Trauma is common, with lifetime exposure estimates from 70% for a single event to 31% for multiple events. Many recover, but some develop post-traumatic stress disorder (PTSD), a debilitating condition with a lifetime prevalence of 6.8%, higher among women and veterans. Only two FDA-approved medications exist, paroxetine and sertraline, alongside psychotherapies like trauma-focused cognitive behavioral therapy and EMDR. Early-phase trials of MDMA-assisted therapy (MDMA-AT) showed promise, leading to FDA breakthrough therapy status in 2017. Phase 3 trials found nearly 70% of participants no longer met PTSD diagnostic criteria. However, in 2024 the FDA voted against approval due to concerns about trial design, blinding failure, missing safety assessments, and potential misconduct. Ongoing research must address blinding, long-term safety, and therapy variability.
Journal of affective disorders
September 15, 2025
Brandan K Penaluna, Jennifer L Vande Voort, William V Bobo et al.
4 citations
In people with treatment-resistant depression, intravenous ketamine improved symptoms across four depression subtypes: Sadness, Negative Thoughts, detachment/Interest and Activity, and Neurovegetative. After three infusions over 11 days, 53% of the 75 participants achieved remission. The Negative Thoughts subtype showed the least improvement, and the Neurovegetative subtype was the least responsive overall. Higher baseline Sadness scores were linked to lower remission rates, and a positive Sadness phenotype reduced the odds of remission (odds ratio 0.32). No meaningful sex differences in response were found by the end of treatment.
Journal of affective disorders
August 15, 2025
Stefanie Cavalcanti, Vanessa K Pazdernik, Jennifer L Vande Voort et al.
3 citations
Among adults with treatment-resistant depression receiving ketamine or esketamine, those reporting high perceived stress before treatment had lower odds of remission and needed more treatment sessions to achieve remission. In a cohort of 39 patients, 66.7% had high perceived stress. Each 5-point increase on the Perceived Stress Scale reduced the odds of remission by 60%, independent of baseline depression severity. Patients with high stress required a median of 3 treatments to reach remission versus 1 for those with low-to-moderate stress. The observational design and lack of a placebo group limit the findings.
The Journal of Clinical Psychiatry
August 25, 2024
Mark A. Frye, Balwinder Singh, Scott Breitinger et al.
2 citations
A man with alcohol use disorder (AUD) maintained sobriety while taking an SSRI and naltrexone, but stopped the SSRI to take part in a psilocybin ceremony, after which he relapsed to alcohol use. The case examines factors that likely contributed to the relapse, including the discontinuation of the SSRI, the context of the psilocybin experience, and the absence of structured follow-up care.
The Journal of clinical psychiatry
January 21, 2026
Matheus G Marques, Aysegul Özerdem, Simon Kung et al.
1 citation
For treatment-resistant depression (TRD), a panel of 10 psychiatrists reached strong consensus on recommending augmentation with second-generation antipsychotics, transcranial magnetic stimulation, and ketamine/esketamine as next-step treatments after three failed antidepressant trials. Treatment preferences shifted to include nonaugmentative antidepressants and electroconvulsive therapy depending on patient characteristics such as metabolic disease and age. The findings underscore the importance of tailoring TRD treatment strategies to individual patient factors beyond conventional guideline tiers.
Biological psychiatry global open science
July 1, 2025
Stephen A Murata, Zachary B Madaj, Colt D Capan et al.
1 citation
Higher baseline levels of anthranilic acid (AA), a metabolite in the kynurenine pathway, predicted remission in patients with treatment-resistant depression receiving intravenous ketamine. In an open-label trial of 74 patients, 52% achieved remission after three infusions. Composite ratios of AA to intercellular adhesion molecule-1 and AA to tryptophan improved predictive accuracy over AA alone. The findings suggest that immunometabolic biomarkers could guide personalized ketamine treatment.
CNS drugs
February 1, 2026
Matheus G Marques, Liliana Patarroyo-Rodriguez, Balwinder Singh
Bipolar disorder affects about 40 million people worldwide, with depression as its most disabling phase. Current treatments often work slowly, prompting interest in psilocybin, a psychedelic compound being studied in clinical trials combined with psychotherapy. Early research in bipolar II disorder (19 participants) shows encouraging results, but evidence is limited. Safety concerns include risk of mood switching and drug interactions. Regulatory hurdles, infrastructure needs, and uncertainties about the role of the psychedelic experience, especially with common bipolar medications, remain. Cautious research is needed to assess psilocybin's safety and efficacy for bipolar depression, particularly for bipolar I disorder and long-term outcomes.