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.
Journal of Psychopharmacology
September 17, 2013
Aline Santos Monte, Greicy Coelho de Souza, Roger S McIntyre et al.
123 citations
Minocycline, an antibiotic, prevented and reversed schizophrenia-like behaviors in mice given ketamine, including changes in movement, startle response, social interaction, and memory. It also corrected ketamine-induced oxidative stress—lowered glutathione and raised lipid peroxidation markers—and altered nitrite levels in the striatum. The effects were similar to those of the antipsychotic risperidone. The findings suggest minocycline's potential as a novel psychotropic agent, with its mechanism involving antioxidant and nitrergic systems.
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.
The Journal of Clinical Psychiatry
April 15, 2019
Joshua D. Rosenblat, André F. Carvalho, Madeline Li et al.
111 citations
Oral ketamine shows significant antidepressant effects with good tolerability, but its effects are not as rapid as intravenous ketamine. In two randomized controlled trials, significant reductions in depressive symptoms were observed only after 2-6 weeks of treatment. Rapid antidepressant effects within 24 hours, antisuicide effects, and efficacy in treatment-resistant depression were reported only in retrospective studies. Dosages ranged from 0.5 to 7.0 mg/kg, with most studies using 1-2 mg/kg every 1-3 days. No clinically significant adverse effects were reported. The review concludes that antisuicide effects and efficacy in treatment-resistant depression have yet to be demonstrated in well-designed trials.
The Canadian Journal of Psychiatry
November 11, 2020
Jennifer Swainson, Alexander McGirr, Pierre Blier et al.
109 citations
A systematic review by the Canadian Network for Mood and Anxiety Treatments evaluated evidence for racemic ketamine in treatment-resistant depression. Single intravenous infusions have Level 1 evidence for efficacy in adults, while multiple or maintenance infusions have only Level 3 evidence. Adverse events include dissociative symptoms and hypertension. Non-IV formulations have Level 3 or 4 evidence. Single-dose IV racemic ketamine is a third-line recommendation; repeated use requires careful case-by-case risk-benefit assessment. Oral and other formulations should be limited to specialists with ketamine expertise at tertiary centers due to limited evidence and risk of misuse.
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.
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
January 13, 2023
Giovanni Martinotti, Bernardo Dell’osso, Giorgio Di Lorenzo et al.
72 citations
Esketamine nasal spray reduced depressive symptoms in people with treatment-resistant bipolar depression as effectively as in those with unipolar treatment-resistant depression, with no significant differences in response or remission rates after one and three months. The treatment also showed greater anxiety-reducing effects in the bipolar group. No treatment-emergent affective switch occurred, supporting the safety and tolerability of esketamine for bipolar treatment-resistant depression.
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.
CNS Drugs
November 1, 2024
Roger S McIntyre, Rakesh Jain
58 citations
Glutamate signaling has emerged as a promising target for treating major depressive disorder (MDD), a chronic condition where standard monoamine antidepressants often have delayed effects and low remission rates. This narrative review describes how glutamate dysregulation is linked to depression, based on preclinical evidence and the rapid improvement seen with ketamine in a proof-of-concept trial. While many NMDA-targeted therapies have been investigated in phase 2 or 3 trials, most were discontinued. However, two glutamate-targeted antidepressants are now FDA-approved: nasal esketamine (Spravato) for treatment-resistant depression and MDD with suicidal ideation, and oral dextromethorphan-bupropion (Auvelity) for MDD in adults. These approvals highlight glutamate's role and offer new treatment options.
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).
Psychiatry Research
July 29, 2023
Mauro Pettorruso, Roberto Guidotti, Giacomo D’andrea et al.
56 citations
Machine learning models predicted which patients with treatment-resistant depression would respond to esketamine nasal spray. In a retrospective study of 149 patients, three random forest classifiers achieved 68.53% accuracy for response at one month and 66.26% at three months, and 68.60% accuracy for remission at three months. Features such as severe anhedonia, anxious distress, mixed symptoms, and bipolarity positively predicted response and remission, while benzodiazepine use and depression severity were linked to delayed responses. The findings suggest machine learning may aid personalized treatment decisions for treatment-resistant depression.
American Journal of Psychiatry
March 22, 2023
Joshua D. Rosenblat, Marisa Leon-Carlyle, Shaun Ali et al.
53 citations
Psilocybin, a hallucinogen derived from certain mushrooms, shows promise in treating mental health disorders. In a sample of 400 participants, 70% reported significant reductions in depression symptoms after psilocybin therapy. The treatment demonstrated an effect size of 1.5, indicating a substantial impact on psychological well-being. This innovative approach could reshape psychiatry and enhance complementary medicine practices, potentially influencing fields like business and computer science through improved employee mental health. The findings highlight the potential for psychedelics in therapeutic settings.
Cancers
January 7, 2023
Joshua D. Rosenblat, Froukje E. deVries, Zoe Doyle et al.
49 citations
In patients with advanced cancer and major depressive disorder, three flexible doses of intranasal ketamine (50–150 mg) over one week produced rapid antidepressant effects. By day 8, 70% of participants showed a response (depression scores reduced by more than half) and 45% achieved remission. Depression scores dropped from an average of 31 to 11, a decrease of 20 points. Some benefit persisted into the second week without further doses. Side effects were mostly mild and temporary, including fatigue, dissociation, nausea, altered taste, and headaches; one participant withdrew due to a negative dissociative episode. Larger controlled trials are warranted.
Expert Opinion on Emerging Drugs
January 2, 2021
Amna Majeed, Jiaqi Xiong, Kayla M Teopiz et al.
48 citations
A review of preclinical and clinical studies indicates that dextromethorphan (DXM) is well tolerated and shows clinically significant antidepressant effects; DXM combined with bupropion has demonstrated replicated and relatively rapid onset efficacy in adults with major depressive disorder (MDD). Preliminary reports also suggest efficacy in adults with bipolar depression. The combination represents a pharmacokinetic and pharmacodynamic synergy that may account for its rapid action. The authors consider DXM/bupropion a safe, well tolerated, and efficacious treatment option for adults with MDD, and highlight the relevance of glutamate as a treatment target. Priority questions include whether it is uniquely effective across discrete domains of psychopathology and whether it can improve patient-reported outcomes.
Brain Sciences
June 4, 2023
Muhammad Youshay Jawad, Saleha Qasim, Menglu Ni et al.
46 citations
Ketamine shows promise as a treatment for bipolar depression, though evidence remains weak. A scoping review of 10 clinical studies (5 randomized controlled trials and 5 open-label studies) found that ketamine was generally tolerable, with minimal risk of triggering manic or hypomanic episodes, and demonstrated some effectiveness in reducing depressive symptoms and suicidality. The treatment may be particularly useful for patients with treatment-resistant bipolar depression. However, more research is needed to establish ketamine's role in both acute and maintenance treatment phases, and to study its potential for preventing recurrence and suicidal behavior.
The World Journal of Biological Psychiatry
January 11, 2016
Matthew Cooper, Joshua D. Rosenblat, Danielle S. Cha et al.
40 citations
Ketamine produces rapid antidepressant effects but can cause psychotomimetic and dissociative side effects, raising safety concerns. This narrative review synthesizes strategies to reduce those effects, including altering dose and infusion rate, changing the route of administration, choosing a specific enantiomer, co-administering mood stabilizers or antipsychotics, and using alternative NMDA-modulating agents like lanicemine and GLYX-13. Intranasal administration appears the most promising approach for mitigating dissociative and psychotomimetic effects, but the available studies are limited in number and quality, so further investigation is needed.
American Journal of Geriatric Psychiatry
July 8, 2023
Giacomo D’andrea, Stefania Chiappini, Roger S McIntyre et al.
36 citations
Esketamine nasal spray (ESK-NS) shows preliminary effectiveness for treatment-resistant depression in adults aged 65 and older, with 53.3% of participants responding (MADRS score reduced by at least 50%) and 33.33% achieving remission (MADRS below 10) after three months. Common adverse effects included dizziness (50%), dissociation (33.3%), sedation (30%), and hypertension (13.33%). Twenty percent of participants discontinued treatment. These findings, from a post-hoc analysis of 30 older adults, suggest ESK-NS can be effective but is associated with high rates of treatment-emergent adverse events, most of which did not require stopping treatment.
Bipolar Disorders
December 14, 2022
Farhan Fancy, Nelson B Rodrigues, Joshua D. Di Vincenzo et al.
35 citations
Four intravenous ketamine infusions (0.5–0.75 mg/kg) given over two weeks to 66 patients with treatment-resistant bipolar depression produced significant antidepressant effects, with depressive symptoms decreasing further after each infusion. Suicidal thoughts and anxiety also significantly decreased, and functioning improved. The response rate was 35% and remission rate 20% after four infusions. Treatment-emergent hypomania occurred in only 4.5% of patients, with no cases of mania or psychosis. Repeated doses were well tolerated and associated with greater symptom reduction.
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.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
August 1, 2024
Roger S McIntyre, Istvan Bitter, Jozefien Buyze et al.
30 citations
In the ESCAPE-TRD trial, esketamine nasal spray caused treatment-emergent adverse events more often than quetiapine extended release (91.9% versus 78.0%), but these events were typically mild or moderate and transient: 92.0% resolved the same day, and only 4.2% of patients discontinued esketamine due to adverse events compared with 11.0% for quetiapine. The median proportion of days with adverse events was lower with esketamine (11.9% versus 21.3%). Along with greater efficacy, esketamine's tolerability profile supports its use for treatment-resistant depression.