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.
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.
Journal of Psychiatric Research
July 1, 2021
Ashley N. Siegel, Shakila Meshkat, Katie Benitah et al.
101 citations
A review of clinical trials registered on clinicaltrials.gov as of December 3, 2020, shows that 70 studies are evaluating psychedelics (excluding ketamine) for psychiatric disorders. Most studies focus on MDMA (45.7%) and psilocybin (41.4%), with fewer investigating ayahuasca, LSD, ibogaine, salvia divinorum, 5-MeO-DMT, and DMT fumarate. MDMA and psilocybin are primarily studied for PTSD and major depressive disorder; LSD for depression, anxiety, and severe somatic disorders; ibogaine for substance use disorders; and 5-MeO-DMT and DMT for major depressive disorder. Only 21 of the 70 studies had published results; most are ongoing.
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
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.
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 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 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
January 1, 2022
Joshua D. Di Vincenzo, Orly Lipsitz, Nelson B Rodrigues et al.
11 citations
A small proportion of people with treatment-resistant depression experience clinically significant worsening of symptoms during a course of intravenous ketamine, but the rate is very low—between 1.83% and 5.49% across infusion time points—and similar to that seen with conventional antidepressants. In a retrospective analysis of 164 adults (142 with unipolar depression and 22 with bipolar depression) who received four ketamine infusions over two weeks, no individuals with bipolar depression reported worsening. The findings suggest that symptomatic worsening with ketamine is uncommon, though the study's uncontrolled, single-center design limits certainty.
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.