Mechanisms of psilocybin on the treatment of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a condition that can develop after a traumatic event, causing distressing symptoms, including intrusive re-experiencing symptoms, alterations in mood and cognition, and changes in arousal and reactivity. Few treatment options exist for patients who find conventional psychotherapy and pharmacotherapy to be inaccessible, ineffective, or intolerable. We explore psilocybin as a potential treatment option for PTSD by examining the neurobiology of PTSD as well as psilocybin's mechanism of action. Based on both pharmacodynamic and psychoanalytic principles, psilocybin may be an underexplored treatment option for patients with PTSD, though further research is required.

Protocols and practices in psilocybin assisted psychotherapy for depression: A systematic review.

BACKGROUND: Psilocybin-assisted psychotherapy (PAP) is a promising treatment option for depression, with randomized controlled trials (RCTs) providing preliminary support for its safety and efficacy. However, there is a lack of consistency across existing treatment protocols and psychotherapeutic approaches. The objective of this review is to summarize and compare current psychotherapy methods of PAP in treating depression and distress in life-threatening illnesses. We sought to comprehensively summarize published psychotherapy protocols from clinical trials to provide insights for future practices. METHODS: A systematic search of four databases (Embase, MEDLINE, PsycINFO, CINAHL) for data relating to psychotherapy protocols was conducted by two independent reviewers. RESULTS: In total, our search identified 1869 articles; after removing duplicates, we screened 1107 articles. We included 70 articles in the full-text review and determined that 28 were eligible for the final review. All protocols include sessions before (preparatory) and after (integration) the psychedelic dosing session with supportive monitoring. However, there was substantial variability and inconsistencies in all other aspects of therapy protocols (e.g., duration and number of sessions, model of therapy). Additionally, significant limitations were identified in the frequent need for more clarity in the description of therapeutic approaches. CONCLUSION: In published clinical trials, PAP has consisted of preparation, supportive dosing, and integration sessions. Beyond this basic framework, significant heterogeneity and lack of clarity were identified in reported psychotherapy protocols, meaning a validated and universally agreed upon protocol for PAP currently does not exist. Future studies should more clearly define and report psychotherapeutic components to identify the safest and most efficacious approaches to PAP.

Association between cognitive functioning, suicidal ideation and suicide attempts in major depressive disorder, bipolar disorder, schizophrenia and related disorders: A systematic review and meta-analysis.

INTRODUCTION: Treatable mental disorders, such as psychotic, major depressive disorder (MDD), and bipolar disorder (BD), contribute to a substantial portion of suicide risk, often accompanied by neurocognitive deficits. We report the association between cognitive function and suicidal ideation/suicide attempts (SI/SA) in individuals with schizoaffective disorder, BD, and MDD. METHODS: A systematic search was conducted on PubMed, Ovid and Scopus databases for primary studies published from inception to April 2024. Eligible articles that reported on the effect size of association between cognition and SI/SA were pooled using a random effects model. RESULTS: A total of 41 studies were included for analysis. There was a negative association between executive functioning and SI/SA in schizoaffective disorder (SA: Corr = -0·78, 95 % CI [-1·00, 0·98]; SI: Corr = -0·06, 95 % CI [-0·85, 0·82]) and MDD (SA: Corr = -0·227, 95 % CI [-0·419, -0·017]; SI: Corr = -0·14, 95 % CI [-0·33, 0·06]). Results were mixed for BD, with a significant positive association between SA and global executive functioning (Corr = 0·08, 95 % CI [0·01, 0·15]) and negative association with emotion inhibition. Mixed results were observed for processing speed, attention, and learning and memory, transdiagnostically. LIMITATIONS: There is heterogeneity across sample compositions and cognitive measures. We did not have detailed information on individuals with respect to demographics and comorbidities. CONCLUSIONS: We observed a transdiagnostic association between measures of cognitive functions and aspects of suicidality. The interplay of cognitive disturbances, particularly in reward-based functioning, may underlie suicidality in individuals with mental disorders. Disturbances in impulse control, planning, and working memory may contribute to self-injurious behavior and suicide.

An update on potential pharmacotherapies for cognitive impairment in bipolar disorder.

INTRODUCTION: Cognitive impairment is a core feature of bipolar disorder (BD) that impedes recovery by preventing the return to optimal socio-occupational functioning and reducing quality of life. Presently, there are no efficacious treatments for cognitive impairment in BD, but many pharmacological interventions are being considered as they have the potential to target the underlying pathophysiology of the disorder. AREAS COVERED: This review summarizes the available evidence for pharmacological interventions for cognitive impairment in bipolar disorder. We searched PubMed, MedLine, and PsycInfo from inception to December 1st, 2022. Traditional treatments, such as lithium, anticonvulsants (lamotrigine), antipsychotics (aripiprazole, asenapine, cariprazine, lurasidone, and olanzapine), antidepressants (vortioxetine, fluoxetine, and tianeptine) and psychostimulants (modafinil), and emerging interventions, such as acetylcholinesterase inhibitors (galantamine and donepezil), dopamine agonists (pramipexole), erythropoietin, glucocorticoid receptor antagonists (mifepristone), immune modulators (infliximab, minocycline and doxycycline), ketamine, metabolic agents (insulin, metformin, and liraglutide), probiotic supplements, and Withania somnifera are discussed. EXPERT OPINION: The investigation of interventions for cognitive impairment in BD is a relatively under-researched area. In the past, methodological pitfalls in BD cognition trials have also been a critical limiting factor. Expanding on the existing literature and identifying novel pharmacological and non-pharmacological treatments for cognitive impairment in BD should be a priority.

Ketamine for bipolar depression: an updated systematic review.

Background: The therapeutic potential of subanesthetic doses of ketamine appears promising in unipolar depression; however, its effectiveness in treating bipolar depression (BD) remains uncertain. Objective: This systematic review aimed to summarize findings on the use of ketamine for the treatment of BD by assessing its efficacy, safety, and tolerability. Design: Systematic review. Methods: We conducted a systematic review of studies that investigated the use of ketamine for adults with BD. We searched PubMed and Embase for relevant randomized-controlled trials, open-label trials, and retrospective chart analyses published from inception to 13 March 2023. Results: Eight studies were identified [pooled n = 235; mean (SD) age: 45.55 (5.54)]. All participants who received intravenous (IV) ketamine were administered a dose of 0.5-0.75 mg/kg as an adjunctive treatment to a mood-stabilizing agent, whereas participants who received esketamine were administered a dosage ranging from 28 to 84 mg. Flexible dosing was used in real-world analyses. A total of 48% of participants receiving ketamine achieved a response (defined as ⩾50% reduction in baseline depression severity), whereas only 5% achieved a response with a placebo. Real-world studies demonstrated lower rates of response (30%) compared to the average across clinical trials (63%). Reductions in suicidal ideation were noted in some studies, although not all findings were statistically significant. Ketamine and esketamine were well tolerated in most participants; however, six participants (2% of the overall sample pool, 5 receiving ketamine) developed hypomanic/manic symptoms after infusions. Significant dissociative symptoms were observed at the 40-min mark in some trials. Conclusion: Preliminary evidence suggests IV ketamine as being safe and effective for the treatment of BD. Future studies should focus on investigating the effects of repeated acute and maintenance infusions using a randomized study design.

Oral ketamine for depression: An updated systematic review.

Objectives: Ketamine is a glutamate N-methyl-D-aspartate receptor antagonist that can be used to treat major depressive disorder by single or repeated infusions. However, the accessibility and scalability of oral ketamine make it preferred over intravenous ketamine. In this systematic review, we aim to evaluate the efficacy, tolerability, and safety of oral ketamine, esketamine and r-ketamine for unipolar and bipolar depression. Materials and methods: Electronic databases were searched from inception to September 2022 to identify relevant articles. Results: Twenty-two studies, including four randomized clinical trials (RCTs), one case series, six case reports, five open-label trials and six retrospective chart review studies involving 2336 patients with depression were included. All included studies reported significant improvement following ketamine administration. Ketamine was well tolerated without serious adverse events. However, RCTs had a high risk of bias due to analysis methods and adverse events monitoring. Ketamine dosage varied from 0.5 to 1.25 mg/kg. The frequency of administration was daily to monthly. Several important limitations were identified, most notably the small number of RCTs. Conclusions: Taken together, preliminary evidence suggests the potential for antidepressant effect of oral ketamine. However, further research with large sample size and long follow-up period is needed to better determine the antisuicidal effect and efficacy in treatment-resistant depression.

Psilocybin-assisted therapy for depression: A systematic review and meta-analysis.

The aim of this review was to determine the effect of psilocybin on depressive symptoms in patients diagnosed with life-threatening illnesses or major depressive disorder. Systematic searches were conducted to search for randomized clinical trials and open-label trials that evaluated depression symptoms after psilocybin therapy. Data was pooled using a random-effects model. The primary outcome was the standardized mean difference (SMD) in depression severity, determined by calculating the change in depression ratings from baseline to the primary endpoint in the psilocybin arm versus the control arm. The literature search yielded 1734 studies, and 13 studies (n = 686) were included in either qualitative and/or quantitative analyses. The meta-analysis included 9 studies (pooled n = 596) and yielded a large effect size in favour of psilocybin (SMD = -0.78; p<0.001). Risk ratios for response and remission were large and significant in favour of psilocybin. A review of open-label trials showed robust decreases in depressive symptoms following psilocybin administration. These findings provide preliminary evidence for antidepressant efficacy with psilocybin-assisted psychotherapy, however, further studies are needed to evaluate safety and efficacy and to optimize treatment protocols.