American Journal of Psychiatry
March 17, 2021
R. Mcintyre, J. Rosenblat, C. Nemeroff et al.
694 citations
Ketamine and esketamine are the first non-monoamine-based antidepressants with rapid-onset efficacy for adults with treatment-resistant depression, offering hope to those who do not recover fully with standard antidepressants. However, concerns remain about their safety, tolerability, and appropriate placement in treatment algorithms. An international group of mood disorder experts synthesizes evidence on efficacy, safety, and tolerability, and provides guidance for clinical implementation, including practice parameters at point of care. Areas of consensus and future research directions are discussed.
Journal of Affective Disorders
November 1, 2020
R. Mcintyre, Isabelle P. Carvalho, L. Lui et al.
186 citations
Ketamine is a rapid and effective treatment for adults with treatment-resistant depression, but different formulations and routes of delivery vary in effect size. A meta-analysis of studies found that intranasal ketamine or esketamine had a large effect on depression symptoms at 24 hours and again at 7-20 days. Intravenous ketamine or esketamine showed a large but not statistically significant effect at 2-6 days. Oral ketamine had a moderate effect at 21-28 days. No conclusions about which formulation or route is best could be drawn because direct comparisons are lacking. More studies with larger samples are needed, especially for oral ketamine.
Journal of Psychiatric Research
May 1, 2022
Yazen Alnefeesi, D. Chen-Li, Ella Krane et al.
177 citations
Ketamine shows substantial real-world antidepressant effects in treatment-resistant depression, with about 45% of patients responding and 30% achieving remission, based on a systematic review and meta-analysis of 79 studies involving 2665 patients. The effect varies considerably among individuals; more treatment-resistant cases remit less often, but response rates do not differ. The therapeutic benefit does not significantly decline with repeated treatments, indicating that even the most treatment-resistant patients may benefit and that mid-to-long term treatment is effective for many.
Journal of Psychiatric Research
May 1, 2022
Tuyen T. Le, Isabel Pazos Cordero, Muhammad Youshay Jawad et al.
82 citations
Ketamine and its enantiomers show different abuse liability. Preclinical evidence indicates that (R,S)-ketamine and (S)-ketamine carry greater risk for abuse than (R)-ketamine, which at antidepressant-relevant doses in rodents appears safe with minimal liability. In clinical settings, limited studies suggest that single or repeated ketamine administrations under professional control did not lead to misuse, dependence, diversion, or gateway activity in patients with treatment-resistant depression. However, most clinical studies were retrospective and lacked systematic evaluation with validated scales. The review identified 65 eligible studies (55 preclinical, 10 clinical), with only 4 preclinical studies evaluating enantiomer abuse liability.
Journal of Psychiatric Research
March 1, 2021
Joshua D. Di Vincenzo, Ashley N. Siegel, Orly Lipsitz et al.
59 citations
Most antidepressant medication trials have focused on adults aged 18-65, leaving gaps in knowledge about older and younger populations. Ketamine shows promise for treatment-resistant depression, but its effects in adolescents and older adults are not well understood. This systematic review of 13 studies found that ketamine produced rapid antidepressant effects (within two weeks) in ten studies, with better results from larger, repeated doses and in open-label rather than blinded settings. Two case reports in adolescents noted rapid anti-suicidal effects. Ketamine appeared safe and well-tolerated in these age groups. However, the small number of studies, high heterogeneity, and generally low quality prevent firm conclusions, and rigorous randomized controlled trials are still needed.
Expert Opinion on Drug Safety
June 15, 2020
Nelson B Rodrigues, R. Mcintyre, Orly Lipsitz et al.
50 citations
Intravenous ketamine is safe and well-tolerated in community-based clinics for treatment-resistant depression. Among 203 patients, fewer than 5% withdrew due to tolerability concerns. Blood pressure increased significantly during infusion, with 44.3% meeting criteria for treatment-emergent hypertension (≥165/100 mmHg), and 12% of those with hypertension required medication. Common adverse events were drowsiness (56.4%), dizziness (45.2%), dissociation (35.6%), and nausea (13.3%). Dissociation severity lessened after the first infusion then plateaued. No patients developed psychosis, mania, or new onset suicidality.
Frontiers in Psychiatry
March 29, 2016
M. Zhang, R. Ho
39 citations
Ketamine, an NMDA receptor antagonist, shows rapid antidepressant effects, with reductions in suicidal ideation ranging from 29% to 79% after intravenous administration. However, long-term use raises safety concerns: chronic use can cause memory impairments, dissociative symptoms, and urological problems like cystitis. A study of 11 recreational ketamine users found spatial memory disturbances linked to decreased activation in the right hippocampus and left parahippocampal gyrus. Conversely, some research suggests acute low-dose ketamine may improve visual and working memory in treatment-resistant depression, possibly through mechanisms involving BDNF and mTORC1. These conflicting findings highlight the need for further research, including comparisons with other antidepressants.
Neuropharmacology
November 1, 2022
Muhammad Youshay Jawad, Joshua D. Di Vincenzo, Sebastian Badulescu et al.
29 citations
Ketamine is an effective rapid-acting antidepressant, but most research has focused on overall depression severity rather than specific symptom domains. This narrative review synthesizes evidence on ketamine's effects on cognition, anhedonia, suicidality, and psychosocial functionality. The strongest evidence supports ketamine's ability to reduce suicidality, and its rapid action may help prevent suicide. Evidence for other domains is weak, largely because few robust studies have assessed them as primary outcomes. The authors call for future research to examine ketamine's effects on specific depression domains to optimize treatment.
Psychiatry Research
October 1, 2021
Tuyen T. Le, Joshua D. Di Vincenzo, K. Teopiz et al.
26 citations
Psychotic depression, a severe form of major depression with hallucinations or delusions, affects 0.35-1% of people over a lifetime. Current treatments, such as antidepressants combined with antipsychotics or electroconvulsive therapy, often lead to relapse and side effects like tardive dyskinesia. Some case studies suggest ketamine may improve both mood and psychotic symptoms in treatment-resistant patients, but its safety is debated because ketamine can induce psychotomimetic effects. Most clinical trials have excluded these patients, so it remains unknown whether ketamine would worsen psychosis. Future research should include people with psychotic features to determine ketamine's safety and effectiveness.
Journal of Affective Disorders
March 1, 2021
R. Mcintyre, Nelson B Rodrigues, Orly Lipsitz et al.
10 citations
The McIntyre and Rosenblat Rapid Response Scale (MARRRS) is a brief self-report measure of depression symptom severity that is sensitive to change with the rapid-acting antidepressant ketamine. In 64 adults with treatment-resistant depression receiving intravenous ketamine, the MARRRS showed high internal consistency and strong convergent validity with the established 16-Item Quick Inventory Depressive Symptoms Self-Report. The scale detected symptom changes across four infusions and loaded onto two factors: dysphoria and psychic anxiety. The findings suggest that outcome measures validated for rapid-acting treatments are needed to inform treatment progress and decisions.
BMC Complementary and Alternative Medicine
August 8, 2017
R. Ho, Adrian H Y Wan, Jessie S. M. Chan et al.
4 citations
A planned randomized controlled trial will compare mindfulness and Baduanjin (a form of Qigong) against a waitlist control group for people with colorectal cancer. The study aims to see whether these mind-body exercises improve cancer-related symptoms, mental health, quality of life, and stress levels. One hundred eighty-nine participants will be randomly assigned to one of three groups: mindfulness training, Baduanjin practice, or a waitlist. Both intervention groups will receive 8 weeks of their respective program. Assessments will occur at baseline, 4 weeks, 8 weeks, and 6 months after the intervention. Based on prior research, the authors expect both interventions to lead to better outcomes than the control group.
Advances in Therapy
April 30, 2021
Eric P. Mcmullen, Yena Lee, Orly Lipsitz et al.
Ketamine can rapidly improve symptoms in adults with treatment-resistant depression, but its effects often last only a median of 2–4 weeks. This systematic review examined strategies to prolong ketamine's acute antidepressant effects. After searching PubMed/MEDLINE, 22 studies were included: 10 randomized controlled trials, 8 open-label trials, 1 retrospective chart review, and 3 case reports. No treatment modality—including pharmacological interventions, psychotherapies, electroconvulsive therapy, or transcranial magnetic stimulation—significantly prolonged the effects of intravenous ketamine, except for repeat-dose IV ketamine itself. Maintenance esketamine is effective in responders. More multimodality strategies are needed.
Journal of Affective Disorders
December 29, 2020
Nelson B Rodrigues, R. Mcintyre, Orly Lipsitz et al.
A 6-item short form of the Clinician-Administered Dissociative States Scale (CADSS-6) strongly correlates with the full 23-item version in patients with treatment-resistant depression receiving IV ketamine. Using retrospective data from 260 patients split into two groups, the CADSS-6 was derived from items most sensitive to ketamine-induced dissociation. Correlations between the short and full scale ranged from 0.91 to 0.95 across four infusions. The CADSS-6 offers a brief clinical assessment for dissociation, though it remains unvalidated in this population and requires prospective validation.