World Psychiatry
September 15, 2023
Roger S McIntyre, Mohammad Alsuwaidan, Bernhard T Baune et al.
712 citations
At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
CNS Drugs
November 17, 2021
Susan Ling, Felicia Ceban, Leanna M.W. Lui et al.
123 citations
Psilocybin, a naturally occurring psychoactive alkaloid found in Psilocybe mushrooms, acts as a non-selective agonist at many serotonin receptors, particularly the 5-HT2A receptor. Its antidepressant and psychedelic effects are thought to involve modulation of the serotonergic system, with downstream changes in gene expression, and indirect effects on dopaminergic and glutamatergic systems. Psilocybin also alters neural circuitry in brain regions implicated in depression, including the default mode network and amygdala. This review synthesizes current understanding of the receptor pharmacology and neuronal mechanisms underlying psilocybin's psychedelic and putative antidepressant properties.
Psychiatry Research
November 1, 2023
Sipan Haikazian, David C J Chen-Li, Danica E. Johnson et al.
121 citations
A systematic review and meta-analysis of 13 studies (686 participants) found that psilocybin therapy produced a large reduction in depressive symptoms compared to control conditions, with a standardized mean difference of -0.78. Response and remission rates were also significantly higher with psilocybin. Open-label trials showed robust decreases in depression after psilocybin administration. The findings suggest antidepressant efficacy for psilocybin-assisted psychotherapy, but the authors note that further studies are needed to confirm safety and efficacy and to optimize treatment protocols.
International Journal of Environmental Research and Public Health
April 17, 2018
Carola Rong, Caroline Park, Joshua D. Rosenblat et al.
116 citations
Ketamine produces rapid antidepressant effects in treatment-resistant depression associated with major depressive disorder and bipolar disorder. Identifying which patients will benefit remains a priority. This review identifies multiple pretreatment predictors of response, including high body mass index, family history of alcohol use disorder, history of suicide, adiponectin and vitamin B12 levels, delta sleep ratio abnormalities, glutamine/glutamate ratio, anterior cingulate cortex activity, the Val66Met BDNF allele, and processing speed. High BMI and family history of alcohol use disorder were the most replicated predictors. A complete pheno-biotype of depression likely to benefit from ketamine is far from complete, though metabolic-inflammatory alterations, especially cognitive impairment, are emerging as possible predictors.
Med (New York, N.Y.)
March 8, 2024
Joshua D. Rosenblat, Shakila Meshkat, Zoe Doyle et al.
97 citations
Psilocybin-assisted psychotherapy (PAP) is feasible for patients with complex, treatment-resistant depression, including those with bipolar II disorder and baseline suicidality. In a randomized trial with 30 adults, those receiving immediate PAP showed greater reductions in depression severity (MADRS) compared to a waitlist control, with a large effect size (Hedge's g = 1.07). Adverse events were transient and no serious adverse events occurred. Repeated doses over six months were associated with further improvement. The findings suggest PAP can be safely delivered to this population and warrants further study.
Journal of Clinical Psychopharmacology
December 12, 2015
Yena Lee, Kahlood Syeda, Nadia A. Maruschak et al.
75 citations
A single, low-dose administration of ketamine can rapidly reduce depressive symptoms in adults with treatment-resistant mood disorders and may also have antisuicide effects. The antidepressant effects may be partly mediated by targeting neural circuits involved in executive function and cognitive emotional processing. Pretreatment cognitive function predicts treatment outcomes, suggesting that beneficial effects on cognition could be a proximate mechanism for symptom relief, even though ketamine is known to impair cognitive function. Recent reviews and meta-analyses conclude that ketamine has possible clinical benefits in refractory mood disorders, and its salutary effects, particularly on suicidality, may involve procognitive mechanisms.
Bipolar Disorders
May 14, 2020
Roger S McIntyre, Orly Lipsitz, Nelson B Rodrigues et al.
64 citations
Intravenous ketamine reduces anxiety, irritability, agitation, and suicidal thoughts in adults with treatment-resistant major depressive disorder or bipolar disorder. In a retrospective analysis of 201 patients at a community clinic, those with elevated anxiety, irritability, and agitation showed significantly greater improvements in overall depressive symptoms, suicidal ideation, anxiety, irritability, and agitation compared to those without these features, regardless of the number of treatments. The findings suggest IV ketamine may be a rapid treatment option for mood disorder patients with mixed features.
Expert Review of Neurotherapeutics
September 21, 2020
Hartej Gill, Barjot Gill, David C J Chen-Li et al.
62 citations
Psychedelics like psilocybin and MDMA show promise as a new type of therapy for mental health disorders. Evidence suggests they may work with just one dose, produce rapid effects, and be effective for treatment-resistant conditions, possibly serving as a standalone treatment. More clinical trials are needed to test their safety, tolerability, and effectiveness in real-world patient populations.
The Canadian Journal of Psychiatry
August 17, 2022
Joshua D. Rosenblat, Muhammad Ishrat Husain, Yena Lee et al.
58 citations
Serotonergic psychedelics are being reconsidered as potential treatments for major depressive disorder. A Canadian task force systematically reviewed clinical trials from 1990 to 2021 and found that only psilocybin and ayahuasca have been tested in contemporary studies. Two pilot studies of single-dose ayahuasca for treatment-resistant depression showed preliminary positive effects (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy for major depressive disorder showed superiority to waitlist controls and comparable efficacy and safety to escitalopram with supportive psychotherapy, with additional trials showing efficacy in cancer-related depression (Level 3 evidence).
Journal of Affective Disorders
July 1, 2024
Cameron N Calder, Angela T H Kwan, Kayla M Teopiz et al.
31 citations
Ketamine is effective for adults with treatment-resistant depression. A systematic review of 21 placebo-controlled randomized trials with 2042 participants calculated the number needed to treat (NNT) for racemic ketamine: 7 at 4 hours, 3 from one day to one week, and 9 at four weeks. Esketamine had an NNT of 2 at one day and 11 at four weeks. Numbers needed to harm indicated low risk. The NNTs under 10 across observation intervals are considered highly clinically meaningful for this difficult-to-treat disorder. Limitations include potential functional unblinding and selective reporting bias.
Journal of Sleep Research
June 16, 2021
Nelson B Rodrigues, Roger S McIntyre, Orly Lipsitz et al.
28 citations
Sleep disturbances are common in treatment-resistant depression (TRD). Intravenous (IV) ketamine improved sleep symptoms, which partially mediated its antidepressant and anti-suicidal effects. In 323 adults with TRD receiving four IV ketamine infusions, self-reported improvements in insomnia, night-time restlessness, hypersomnia, early morning waking, and total sleep partially explained reductions in depression severity. Insomnia, night-time restlessness, early morning waking, and total sleep improvements also mediated reductions in suicidal ideation. Each point improvement in total sleep score was associated with 3.29 times higher odds of achieving response or remission (95% confidence interval 2.00–5.41).
Journal of Affective Disorders
June 15, 2024
Gia Han Le, Sabrina Wong, Sebastian Badulescu et al.
25 citations
A systematic review examined how serotonergic psychedelics (psilocybin, LSD) and ketamine affect brain wave patterns measured by EEG and MEG in people with major depressive disorder, treatment-resistant depression, and healthy controls. Ketamine and psychedelics both increase theta power in depressed individuals. In healthy controls and depressed persons, both drug classes decrease alpha, beta, and delta power. Ketamine also increases gamma power in both groups. Theta power specifically rises in those with major depressive disorder when given psychedelics. The studies varied in patient populations, dosing, and measurement devices. The findings support disease models involving altered network connectivity and may guide future treatment discovery.
CNS Spectrums
December 3, 2020
Orly Lipsitz, Roger S McIntyre, Nelson B Rodrigues et al.
25 citations
Higher body mass index (BMI) does not predict how well patients with treatment-resistant depression respond to intravenous (IV) ketamine. In a study of 230 adults who received four ketamine infusions, people with normal weight, overweight, and obesity (classes I and II) showed similar improvements in depression, suicidal thoughts, anxiety, anhedonia, and daily functioning. The antidepressant effects and rates of partial response, response, and remission were comparable across all BMI groups. The findings are limited by the observational, open-label design of this retrospective analysis.
The American journal of psychiatry
January 1, 2025
Roger S McIntyre, Angela T H Kwan, Rodrigo B. Mansur et al.
23 citations
Psychedelics show promise for treating difficult-to-treat psychiatric disorders like major depressive disorder, treatment-resistant depression, and posttraumatic stress disorder, with preliminary evidence also supporting efficacy in tobacco and alcohol use disorders. However, concerns exist about the interpretability and translatability of study results due to insufficiently characterized short- and long-term safety, abuse liability, and the essentiality of the psychedelic experience and psychological support. This overview reviews methodological aspects affecting inferences and interpretation of extant psychedelic studies and provides guidance for future research and development critical to study interpretation and clinical implementation.
Journal of Psychopharmacology
October 11, 2020
Roger S McIntyre, Nelson B Rodrigues, Orly Lipsitz et al.
19 citations
Adults with treatment-resistant depression or bipolar disorder who also have high anxiety show greater improvement in depressive and anxiety symptoms after intravenous ketamine treatment than those with low anxiety. Among 209 patients receiving four ketamine infusions, the 94 with anxious-distress had a significantly larger drop in depression scores and a greater reduction in anxiety symptoms after three and four infusions. Both groups experienced a significant decrease in suicidal thoughts. The findings suggest that ketamine may be particularly effective for people with treatment-resistant mood disorders and prominent anxiety.
CNS Spectrums
December 10, 2020
Nelson B Rodrigues, Ashley N. Siegel, Orly Lipsitz et al.
17 citations
Intravenous (IV) ketamine effectively reduces symptoms of depression, suicidal ideation, anxiety, and anhedonia in adults with treatment-resistant depression, regardless of whether they have previously undergone neurostimulation. In a retrospective analysis of 238 patients, those without prior neurostimulation experienced an average 6.4-point reduction on a depression severity scale, while those with a history of neurostimulation showed a 4.3-point reduction. No significant differences emerged between the groups, indicating that IV ketamine benefits even highly intractable patients.
Psychiatry Research
April 25, 2022
Hartej Gill, Parnian Puramat, Pankti Patel et al.
16 citations
Psilocybin shows promise as a treatment for major depressive disorder (MDD), potentially offering an alternative to conventional therapies. A systematic review of neuroimaging studies found that psilocybin administration decreased amygdala activity and reduced depressive symptoms in two studies involving MDD participants. In healthy populations, changes in functional connectivity and activation of prefrontal limbic structures, particularly the ventral medial prefrontal cortex and amygdala, were observed. However, high methodological heterogeneity across the thirteen included studies—ten in healthy populations and three in MDD participants—limits conclusions. Longitudinal research is needed to clarify psilocybin's long-term effects and sustained therapeutic potential for MDD.
Journal of Affective Disorders
October 15, 2024
Angela T H Kwan, Joshua D. Rosenblat, Rodrigo B. Mansur et al.
13 citations
Ketamine and esketamine are increasingly prescribed for treatment-resistant mood disorders and suicide risk, but ketamine is also misused. Analyzing reports in the World Health Organization pharmacovigilance database up to January 2024, ketamine showed elevated reporting odds ratios for alcohol abuse (3.24), substance dependence (12.48), substance use disorder (170.44), substance abuse (2.94), drug dependence (2.88), drug use disorder (11.54), and drug abuse (2.85). Esketamine had reduced odds for substance abuse (0.41), drug dependence (0.083), and drug abuse (0.052), and no increased odds for any alcohol or substance misuse parameter. These associations do not establish causation.
Journal of Affective Disorders
April 1, 2025
Angela T H Kwan, Moiz Lakhani, Kayla M Teopiz et al.
11 citations
An analysis of the FDA Adverse Event Reporting System found that reports of hepatobiliary disorders differ between ketamine and esketamine. Compared to acetaminophen, ketamine was associated with disproportionately lower reporting of hepatitis, liver injury, drug-induced liver injury, hepatic failure, and acute hepatic failure, but disproportionately higher reporting of hepatic function abnormalities and hepatic cytolysis. For esketamine, there was no disproportionate reporting of most hepatobiliary toxicities relative to acetaminophen, except for disproportionately higher reporting of hepatic failure. The authors recommend periodic monitoring of liver function tests and clinical surveillance for signs of hepatobiliary disease in individuals receiving chronic ketamine or esketamine, though causality has not been established.
CNS Spectrums
October 31, 2024
Sabrina Wong, Gia Han Le, Angela T H Kwan et al.
10 citations
A systematic review and meta-analysis of seven randomized controlled trials found that a single dose of esketamine given around childbirth significantly reduced the incidence of postpartum depression (PPD). Within one week of delivery, the odds of a PPD diagnosis were 70% lower for those who received esketamine compared to a control; between four and six weeks postpartum, the odds were 67% lower. The results suggest that esketamine may have preventive antidepressant effects during the postpartum period, with implications for both the mechanisms and clinical treatment of PPD.
Psychedelic Medicine
November 18, 2024
Shakila Meshkat, Erica Kaczmarek, Zoe Doyle et al.
8 citations
In a small subgroup analysis of four adults with treatment-resistant depression associated with bipolar II disorder, two 25 mg doses of psilocybin combined with psychotherapy were associated with reductions in depressive symptoms. The average depression score on the Montgomery–Åsberg Depression Rating Scale dropped from 32.5 at baseline to 20.3 two weeks after the first dose, and to 19 two weeks after the second dose; at six months the average score was 21.3. Mania ratings remained stable, and no mania, hypomania, or psychosis occurred. The authors suggest psilocybin may improve depressive symptoms in bipolar II disorder but call for larger studies to confirm the findings.
Journal of Affective Disorders
September 1, 2024
Angela T H Kwan, Joshua D. Rosenblat, Rodrigo B. Mansur et al.
8 citations
Ketamine and esketamine are effective for treatment-resistant depression and may help people with substance use disorder or alcohol use disorder when paired with behavioral therapy. However, concerns exist about their own abuse potential. Analyzing reports from the FDA Adverse Event Reporting System, ketamine showed significantly increased reporting odds for alcohol abuse, substance dependence, substance use disorder, substance abuse, drug dependence, drug use disorder, and drug abuse. In contrast, esketamine showed significantly reduced reporting odds for substance abuse, drug dependence, and drug abuse. Mixed results across different substance-related outcomes suggest possible beneficial effects, but causal links cannot be established due to data limitations.
Current Treatment Options in Psychiatry
April 26, 2024
Noah Chisamore, Erica Kaczmarek, Gia Han Le et al.
8 citations
No Summary
Psychiatry Research
May 8, 2025
Noah Chisamore, Lee Phan, Roger S McIntyre et al.
7 citations
A review of pre-clinical and clinical studies on non-hallucinatory psychedelics (NHPs) for mood and anxiety disorders found five animal studies showing antidepressant-like effects, assessed via forced swim test and open field test, without the head-twitch response that indicates hallucination. One case report described a patient who inadvertently combined trazodone and psilocybin and experienced potent antidepressant effects without psychedelic effects. These preliminary findings suggest that antidepressant benefits of psychedelics may be separable from hallucinatory effects, providing impetus for rigorous clinical trials in humans.
Expert Opinion on Drug Safety
June 21, 2024
Roger S McIntyre, Rodrigo B. Mansur, Joshua D. Rosenblat et al.
7 citations
Ketamine and esketamine reduce measures of suicidality in people with treatment-resistant depression, but whether they can worsen preexisting suicidality is unclear. Analysis of the FDA Adverse Event Reporting System from 1970 and 2019 through September 2023 found higher reporting odds ratios for suicidal ideation (7.58) and depression suicidal (14.19) with esketamine compared to lithium. In contrast, lower reporting odds ratios for suicide attempt were observed with both ketamine (0.15) and esketamine (0.57). The mixed results across different aspects of suicidality prevent any determination of causal effects, and the lower odds for suicide attempt cannot be interpreted as a direct therapeutic effect.