Current Psychiatry Reports
April 1, 2024
John L. Havlik, Syed Wahid, Kayla M Teopiz et al.
30 citations
Treatment-resistant depression (TRD) has historically had very limited options, but recent advances have expanded knowledge of effective interventions. Psychotherapy can help as an add-on but not alone. Adjunctive non-antidepressant drugs like buprenorphine and antipsychotics show little recent support; side effects and high discontinuation rates may outweigh benefits. Strong recent evidence supports interventional approaches: electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation. Research on TRD should use internationally defined inclusion criteria for generalizable results.
Expert Opinion on Drug Safety
April 6, 2022
Muhammad Youshay Jawad, Joshua D. Di Vincenzo, Felicia Ceban et al.
29 citations
Intranasal esketamine, when added to an oral antidepressant, is safe and more effective than a placebo nasal spray at reducing depressive symptoms in people with treatment-resistant depression and depression with suicidal thoughts or behavior. Pooling data from seven randomized controlled trials showed a small but significant improvement in depressive symptoms, with higher rates of response and remission. Year-long studies found lower relapse rates and no major long-term side effects. The treatment appears well tolerated and rapidly effective for these difficult-to-treat populations.
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).
Expert Opinion on Drug Safety
August 15, 2023
Roger S McIntyre
26 citations
The text discusses concerns about psilocybin, lysergic acid diethylamide (LSD), and ecstasy in relation to valvular heart disease, focusing on 5HT2B receptor agonism and FDA guidance. It highlights the potential risk of these substances to cause heart valve damage through activation of the 5HT2B receptor, a mechanism linked to certain drugs. The abstract underscores regulatory considerations from the FDA regarding this safety issue, suggesting that agonism at this receptor may be a key factor in assessing the cardiac risks of psychedelic compounds.
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.
Expert Opinion on Drug Safety
April 15, 2022
Marcus A. Doyle, Susan Ling, Leanna M.W. Lui et al.
24 citations
Hallucinogen persisting perception disorder (HPPD) is an uncommon but serious condition in which individuals repeatedly experience hallucinations and perceptual disturbances after prior hallucinogen use. As some hallucinogens are being developed to treat mental disorders, understanding HPPD becomes more important. A scoping review of the literature up to July 2021 covered treatments, prevalence, risk factors, and pathophysiology of HPPD. The renewed interest in psychedelics as potential treatments highlights the need to better characterize HPPD's frequency, risk and protective factors, key features, and clinical factors.
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.
Annals of Clinical Psychiatry
November 1, 2022
David C J Chen-Li, Leanna M.W. Lui, Joshua D. Rosenblat et al.
22 citations
Postpartum depression (PPD) is a severe mood disorder affecting mothers and children, and there is a need for rapid-acting treatments. This narrative review examined the available literature on ketamine for PPD, searching databases for preclinical studies, clinical trials, and reviews. Four clinical trials were identified. The review suggests that ketamine may be a favorable option due to its antidepressant and analgesic effects, short infusion time, and rapid clearance from the mother's bloodstream. However, evidence is insufficient to support its routine use, highlighting the need for more clinical research.
Journal of Psychiatric Research
August 1, 2024
Noah Chisamore, Danica E. Johnson, Margery J.q. Chen et al.
21 citations
Psilocybin-assisted psychotherapy shows promise for treating depression and distress in life-threatening illnesses, but a systematic review of 28 clinical trial protocols reveals substantial variability and inconsistency in therapeutic approaches beyond the basic framework of preparatory, dosing, and integration sessions. The review found no validated or universally agreed-upon protocol, with frequent lack of clarity in descriptions of therapy models, duration, and number of sessions. Future studies need to define and report psychotherapeutic components more clearly to identify the safest and most effective approaches.
Journal of Affective Disorders
April 1, 2024
Sabrina Wong, Angela T H Kwan, Kayla M Teopiz et al.
19 citations
A systematic review of randomized controlled trials compared the clinical efficacy of psilocybin and esketamine in adults with treatment-resistant depression. 25 mg of psilocybin significantly reduced depressive symptoms at 21 days post-dose, with a number needed to treat (NNT) of 5. Psilocybin-induced nausea had a number needed to harm (NNH) of 5. Fixed doses of esketamine (56 mg and 84 mg) showed significant effects at 28 days post-dose, with NNTs of 7. Esketamine-induced headache, nausea, dizziness, and dissociation had NNHs below 10. The preliminary results may reflect only a small portion of the patient population and require replication and longer-term studies. Both agents showed clinically meaningful NNT estimates and acceptable NNH profiles, underscoring their clinical relevance for treatment-resistant depression.
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.
Expert Opinion on Drug Safety
May 3, 2022
Danica Nogo, Hana Nazal, Yuetong Song et al.
17 citations
Ketamine is an established treatment for treatment-resistant depression, but long-term adverse effects from repeated doses are not well characterized. Animal models and studies of people with substance use disorder who use high daily doses of ketamine show clear neurotoxic effects, including potential brain lesions. No studies have specifically evaluated the effects of the lower, infrequent sub-anesthetic doses typically prescribed for depression. It is difficult to separate ketamine's direct effects from other factors like comorbidities and dose differences. It remains unknown whether repeated sub-anesthetic dosing in adults with depression causes brain lesions or other neuropathologies. Practitioners should remain vigilant, recognizing that depression itself is linked to neurodegenerative processes.
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.
Expert Opinion on Drug Safety
August 28, 2023
Roger S McIntyre
16 citations
The article reviews the pharmacology and therapeutic potential of psychedelics such as psilocybin and lysergic acid diethylamide, focusing on their mechanisms of action and regulatory status. It discusses how these compounds influence neurotransmitter receptors and their possible applications in treating mood disorders, including depression. The authors highlight the growing interest in psychedelic-assisted therapy and note that the FDA has granted breakthrough therapy designation for some psychedelic treatments, suggesting a shift in the medical and regulatory landscape toward these substances as antidepressants.
CNS Drugs
October 1, 2022
Niloufar Pouyan, Zahra Halvaei Khankahdani, Farnaz Younesi Sisi et al.
16 citations
A systematic review of psilocybin research organized by the Research Domain Criteria (RDoC) framework found that psilocybin has beneficial effects across multiple domains, particularly on positive valence systems, negative valence systems, and social processes. Short-term (23 assessments) and long-term (15 assessments) benefits were reported for positive valence systems. For the negative valence system, 12 outcome measures indicated increased fear, 19 showed no significant effect, and 7 parameters indicated lowered sustained threat over the long term. Thirty-four outcome measures revealed short-term alterations in social systems, including enhanced perception and understanding of others and affiliation. Cognitive systems findings mostly reported dyscognitive effects. Seven studies suggested transdiagnostic effects.
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 Clinical Psychopharmacology
Nicole Ledwos, Joshua D. Rosenblat, Daniel M. Blumberger et al.
16 citations
A critical appraisal of clinical trials on serotonergic psychedelics for major depressive disorder and end-of-life distress finds that current evidence is low-level due to methodological limitations. Small randomized trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy to an active comparator, with similar preliminary positive effects for single-dose ayahuasca in treatment-resistant depression and lysergic acid diethylamide for end-of-life distress. Adverse events were mild and transient. However, small homogenous samples, expectancy bias, functional unblinding, and lack of standardized psychotherapy limit all studies. Psychedelics should remain experimental interventions used within clinical trials.
Pharmaceuticals (Basel, Switzerland)
January 24, 2025
John E Donello, Roger S McIntyre, Donald B Pickel et al.
14 citations
Plastogens are a class of therapeutics that rapidly promote changes in neuroplasticity. Ketamine, a notable example, is an N-methyl-D-aspartate receptor (NMDAR) antagonist with rapid and long-term antidepressant effects but also psychotomimetic and dissociative side effects. Stinels—rapastinel, apimostinel, and zelquistinel—are plastogens with improved safety and tolerability profiles. This review clarifies the mechanism of stinels, defining them as positive allosteric modulators of NMDAR activity with a novel regulatory binding site, contrasting with earlier descriptions of glycine-like partial agonists. The review presents the rationale for targeting NMDARs in treatment-resistant depression and other psychiatric conditions.
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.
Frontiers in Psychiatry
January 1, 2022
Ryan Yip, Jennifer Swainson, Atul Khullar et al.
13 citations
Ketamine is increasingly used for treatment-resistant depression, but its intravenous administration often causes transient high blood pressure. Current psychiatric guidelines recommend aggressive monitoring and treatment of these hypertensive episodes. This review argues that those guidelines should be updated to align with standard best practices for managing hypertension, distinguishing between hypertensive emergency and asymptomatic hypertensive urgency. Adopting such an updated protocol could make ketamine therapy safer and more accessible for patients with depression.
Journal of Affective Disorders
August 1, 2025
Morgan C H Cheng, Christine E. Dri, Hana Ballum et al.
12 citations
Ketamine and esketamine produce rapid antidepressant effects in major depressive disorder and treatment-resistant depression, but their impact on patient-reported quality of life has been unclear. A systematic review of five studies found that both agents improve quality of life measures on scales such as the WHOQOL-BREF, Assessment of Quality of Life 8D, and EuroQol-5 Dimension-5 Layers, with statistically significant results. However, the studies had an overall moderate risk of bias and varied in the quality-of-life scales used and study duration. Further research should examine effects on specific quality-of-life domains.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
April 1, 2025
Eduard Vieta, Nahida Ahmed, Celso Arango et al.
12 citations
Patients with treatment-resistant depression who received esketamine nasal spray experienced 43.2% more weeks with functional remission over 32 weeks compared to those taking quetiapine extended release, a difference of 2.0 weeks. Esketamine also led to an 11.9% reduction in productivity loss due to absenteeism and a 14.2% reduction in overall work productivity loss. Both treatments were taken alongside an ongoing SSRI or SNRI. The findings suggest that esketamine provides greater improvements in daily functioning and workplace productivity for this patient group.
Psychiatry Research
May 1, 2024
Eric A. Miller, Houtan Totonchi Afshar, Jyoti Mishra et al.
12 citations
Ketamine helps some patients with treatment-resistant depression, but predicting who will respond is difficult. Analyzing symptom trajectories from 120 patients treated with ketamine or esketamine in a real-world clinic, all symptoms improved on average, with depressed mood improving faster than low energy. A principal component analysis identified overall treatment response and a second component reflecting differences between affective and somatic symptoms. Logistic regression classifiers predicted overall response better than chance using baseline symptoms alone. By adjusting decision thresholds, models identified 22% of patients who would not respond with over 96% negative predictive value, potentially guiding treatment recommendations to avoid ineffective treatments.
Journal of psychopharmacology (Oxford, England)
April 1, 2024
Nelson B Rodrigues, David C J Chen-Li, Joshua D. Di Vincenzo et al.
12 citations
Ketamine is a rapid antidepressant for people with treatment-resistant depression, but no reliable predictors of response have been identified. This study examined whether variants in the Val66Met and CYP2B6 genes predicted treatment outcomes in 85 participants with major depressive disorder who received four intravenous ketamine infusions. Participants showed significant overall reductions in depression, suicide, and anxiety, with 25% meeting response criteria and 15% meeting remission criteria. However, neither Val66Met nor CYP2B6 genotypes significantly predicted changes in depressive symptoms, suicidality, anxiety, or dissociation. The findings suggest that single-gene predictors are unlikely to be useful and that a broader genetic approach may be needed.