OPEN Foundation

Depression

Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies

Abstract

Objective: To conduct a systematic review of modern-era (post-millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented.

Method: A systematic literature search (1 Jan 2000 to 1 May 2020) was conducted in PubMed and PsychINFO for studies of patients undergoing treatment with a serotonergic psychedelic.

Results: Data from 16 papers, representing 10 independent psychedelic-assisted therapy trials (psilocybin = 7, ayahuasca = 2, LSD = 1), were extracted, presented in figures and tables, and narratively synthesized and discussed. Across these studies, a total of 188 patients suffering either cancer- or illness-related anxiety and depression disorders (C/I-RADD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD) or substance use disorder (SUD) were included. The reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. For a majority of patients, the therapeutic effects appeared to be long-lasting (weeks-months) after only 1 to 3 treatment session(s). All studies were conducted in line with guidelines for the safe conduct of psychedelic therapy, and no severe adverse events were reported.

Conclusion: The resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.

Andersen, K., Carhart-Harris, R., Nutt, D. J., & Erritzoe, D. (2021). Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies. Acta psychiatrica Scandinavica, 143(2), 101–118. https://doi.org/10.1111/acps.13249

Link to full text

Effect of Ketamine on Rumination in Treatment-Resistant Depressive Patients

Abstract

Background: A rapid antidepressant effect of ketamine has repeatedly been documented in the literature, and identifying clinical features associated with a better response to this treatment is currently an essential question. Considering the relationship between rumination and depression and the need to identify potential predictors of response to ketamine, we analyzed the effect of a single injection of ketamine 0.5 mg/kg on rumination in treatment-resistant depressive (TRD) patients and explored whether baseline ruminative style and early improvements of rumination would predict a greater antidepressant effect of ketamine.

Methods: Ten TRD outpatients who participated in a 4-week open study on the antidepressant effect of ketamine also completed the Ruminative Response Scale the day before, the day after, and a week after ketamine administration.

Results: We found that in our patients, a single rapid 1-minute intravenous injection of ketamine 0.5 mg/kg was efficacious in reducing rumination, but neither severity of rumination at baseline nor early improvements of rumination after ketamine injection predicted antidepressant response.

Conclusions: Our preliminary data suggest that a single injection of ketamine 0.5 mg/kg can be efficacious in reducing rumination in TRD patients but rumination does not seem to be a useful clinical predictor of response to ketamine. Larger studies are necessary to confirm these results.

Vidal, S., Jermann, F., Aubry, J. M., Richard-Lepouriel, H., & Kosel, M. (2020). Effect of Ketamine on Rumination in Treatment-Resistant Depressive Patients. Journal of clinical psychopharmacology, 40(6), 607–610. https://doi.org/10.1097/JCP.0000000000001305

Link to full text

Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies – PubMed

Abstract

Background: Most recent evidence support a rapid and sustained antidepressant effect of subanesthetic dose of intravenous ketamine in patients with major depressive disorder (MDD). However, clinical and animal studies investigating the effects of intravenous ketamine on specific functional domains disrupted by depression reported conflicting results. Therefore, the aim of this review is to provide an overview of the recent findings exploring the cognitive effects of ketamine in depression.
Methods: After a bibliographic search on PubMed, Medline and PsycInfo, we retrieved 11 original studies meeting our research criteria, 7 in humans with MDD or Treatment Resistant Disorder and 4 using rats models for depression.
Results: Overall the results showed that a) ketamine reduced activation and normalized connectivity measures of several brain regions related to depressive behaviors and reversed deficits in cognitive flexibility and coping response strategy in rats with depressive features, and b) ketamine leads to a no significant impairment on neurocognitive functions in most of the studies, with only three studies observing improvements in speed of processing, verbal learning, sustained attention and response control, verbal and working memory.
Limitations: The methodological heterogeneity, in terms of neuropsychological tests used and cognitive domain explored, of the studies included.
Conclusions: Most of the studies included showed no significant cognitive impairments in MDD patients after ketamine treatment. Furthermore, the results of the fMRI studies considered suggest that ketamine may have a normalizing effect on brain functions during attentional and emotional processing in MDD patients. However, further studies are needed to confirm these preliminary evidences.
Crisanti, C., Enrico, P., Fiorentini, A., Delvecchio, G., & Brambilla, P. (2020). Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies. Journal of Affective Disorders., 10.1016/j.jad.2020.07.119
Link to full text

Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression

Abstract

Background: Esketamine nasal spray is approved for treatment-resistant depression.

Objective: The objective of this study was to characterize the pharmacokinetics of esketamine and noresketamine in healthy subjects and patients with treatment-resistant depression.

Methods: Esketamine and noresketamine were measured in > 9000 plasma samples collected from 820 individuals who received esketamine by the intranasal, intravenous, and oral routes. An open linear model for esketamine (three compartments) and noresketamine (two compartments) that included a hepato-portal compartment was developed using NONMEM® VII. The effects of covariates on esketamine pharmacokinetics and a model evaluation were performed using conventional methods.

Results: The fraction of a 28-mg intranasal dose absorbed through the nasal cavity (FRn) is 54% (100% of this fraction is completely absorbed); the remaining 46% is swallowed and undergoes intestinal and first-pass metabolism and 18.6% of the swallowed dose reaches the systemic circulation. The absolute bioavailability of 56 and 84 mg of intranasal esketamine is 54 and 51%, respectively. Esketamine volume at steady state and clearance were 752 L and 114 L/h, respectively. Noresketamine volume at steady state and apparent clearance were 185 L and 38 L/h, respectively. Relative to non-Asian subjects, Asian subjects showed a 64.0 and 19.4% decrease in the esketamine elimination rate constant and noresketamine apparent clearance, respectively. Japanese subjects exhibited a 34% increase in FRn vs other races. Hepatic blood flow decreased by 21.9 L/h for each decade in age in subjects aged > 60 years. These changes resulted in esketamine and noresketamine maximum concentration and area under the concentration-time curve after 24 h post-dose values that were up to 36% higher than those observed in other races or in younger adult subjects.

Conclusions: Esketamine and noresketamine pharmacokinetics was successfully characterized in healthy subjects and patients with treatment-resistant depression. The model quantified esketamine absolute nasal and oral bioavailability, its hepatic flow-limited clearance and biotransformation to the major metabolite noresketamine, and the influence of intrinsic and extrinsic factors on esketamine pharmacokinetics. Clinical trials registration numbers of the studies included in the analysis: ESKETINTRD1001 (NCT01780259), ESKETINTRD1002 (NCT01980303), ESKETINTRD1003 (NCT02129088), ESKETINTRD1008 (NCT02846519), ESKETINTRD1009 (NCT02343289), ESKETINTRD1010 (NCT02568176), ESKETINTRD1012 (NCT02345148), 54135419TRD1015 (NCT02682225), ESKETINTRD2003 (NCT01998958), ESKETINSUI2001 (NCT02133001), ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), and ESKETINTRD3005 (NCT02422186).

Perez-Ruixo, C., Rossenu, S., Zannikos, P., Nandy, P., Singh, J., Drevets, W. C., & Perez-Ruixo, J. J. (2021). Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression. Clinical pharmacokinetics, 60(4), 501–516. https://doi.org/10.1007/s40262-020-00953-4

Link to full text

Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression

Abstract

Introduction: Ketamine exhibits antidepressant properties in treatment-resistant depression (TRD) with some concern over its cardiovascular safety and tolerability issues. This paper reports on the cardiovascular safety in short-term intravenous ketamine treatment in TRD inpatients with major depressive disorder (MDD) and bipolar disorder (BP).

Materials and methods: The observational study population comprises 35 MDD and 14 BP subjects treated with intravenous ketamine.

Results: Blood pressure (RR) and heart rate (HR) values returned to baseline within 1.5-hours post infusion with no sequelae for all study subjects. Six time points were analyzed for each infusion: 0′, 15′, 30′, 45′, 60′ and 90′ for RR and HR. After the infusion significant peaks in systolic (p = 0.004) and diastolic (p = 0.038) RR were seen. In concomitant medication with selective serotonin reuptake inhibitors (SSRIs), higher RR peaks (p = 0.020; p = 0.048) were seen as compared to other subjects. The decrease in HR was greater (p = 0.02) in the absence of concomitant medication with mood stabilizers as compared to subjects receiving mood stabilizing medication accompanied by the observation of a greater decrease in diastolic RR among those taking mood stabilizers (p = 0.009).

Limitations: The study may be underpowered due to the small sample size. The observations apply to an inhomogeneous TRD population in a single-site, pilot study, with no blinding and are limited to the acute administration.

Conclusion: The study demonstrates good safety and tolerability profile of intravenous ketamine as add-on intervention to current psychotropic medication in TRD, regardless of the MDD or BP type of mood disorders. The abatement of elevated RR and BP scores was observed in time with no sequelae nor harm. Still, cardiovascular risks appear to be more pronounced in subjects with comorbid arterial hypertension and diabetes mellitus.

Szarmach, J., Cubała, W. J., Włodarczyk, A., & Gałuszko-Węgielnik, M. (2020). Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression. Neuropsychiatric disease and treatment, 16, 2539–2551. https://doi.org/10.2147/NDT.S273287

Link to full text

Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial

Abstract

Rationale: Suicidality is a major public health concern with limited treatment options. Accordingly, there is a need for innovative interventions for suicidality. Preliminary evidence indicates that treatment with the psychedelic ayahuasca may lead to decreases in depressive symptoms among individuals with major depressive disorder (MDD). However, there remains limited understanding of whether ayahuasca also leads to reductions in suicidality.

Objective: To examine the acute and post-acute effect of ayahuasca on suicidality among individuals with MDD.

Methods: We conducted a secondary analysis of an open-label trial in which individuals with recurrent MDD received a single dose of ayahuasca (N = 17). Suicidality was assessed at baseline; during the intervention; and 1, 7, 14, and 21 days after the intervention.

Results: Among individuals with suicidality at baseline (n = 15), there were significant acute (i.e., 40, 80, 140, and 180 min after administration) and post-acute (1, 7, 14, and 21 days after administration) decreases in suicidality following administration of ayahuasca. Post-acute effect sizes for decreases in suicidality were large (Hedges’ g = 1.31-1.75), with the largest effect size 21 days after the intervention (g = 1.75).

Conclusions: When administered in the appropriate context, ayahuasca may lead to rapid and sustained reductions in suicidality among individuals with MDD. Randomized, double-blind studies with larger sample sizes are needed to confirm this early finding.

Zeifman, R. J., Singhal, N., Dos Santos, R. G., Sanches, R. F., de Lima Osório, F., Hallak, J., & Weissman, C. R. (2021). Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial. Psychopharmacology, 238(2), 453–459. https://doi.org/10.1007/s00213-020-05692-9

Link to full text

Predicting therapeutic response to oral ketamine for chronic suicidal ideation: a Bayesian network for clinical decision support

Abstract

Background: The glutamatergic modulator ketamine has been shown to result in rapid reductions in both suicidal ideation (SI) and depressive symptoms in clinical trials. There is a practical need for identification of pre-treatment predictors of ketamine response. Previous studies indicate links between treatment response and body mass index (BMI), depression symptoms and previous suicide attempts. Our aim was to explore the use of clinical and demographic factors to predict response to serial doses of oral ketamine for chronic suicidal ideation.

Methods: Thirty-two participants completed the Oral Ketamine Trial on Suicidality (OKTOS). Data for the current study were drawn from pre-treatment and follow-up time-points of OKTOS. Only clinical and sociodemographic variables were included in this analysis. Data were used to create a proof of concept Bayesian network (BN) model of variables predicting prolonged response to oral ketamine, as defined by the Beck Scale for Suicide Ideation (BSS).

Results: The network of potential predictors of response was evaluated using receiver operating characteristic (ROC) curve analyses. A combination of nine demographic and clinical variables predicted prolonged ketamine response, with strong contributions from BMI, Social and Occupational Functioning Assessment Scale (SOFAS), Montgomery-Asberg Depression Rating Scale (MADRS), number of suicide attempts, employment status and age. We evaluated and optimised the proposed network to increase the area under the ROC curve (AUC). The performance evaluation demonstrated that the BN predicted prolonged ketamine response with 97% accuracy, and AUC = 0.87.

Conclusions: At present, validated tools to facilitate risk assessment are infrequently used in psychiatric practice. Pre-treatment assessment of individuals’ likelihood of response to oral ketamine for chronic suicidal ideation could be beneficial in making more informed decisions about likelihood of success for this treatment course. Clinical trials registration number ACTRN12618001412224, retrospectively registered 23/8/2018.

Beaudequin, D., Can, A. T., Dutton, M., Jones, M., Gallay, C., Schwenn, P., Yang, C., Forsyth, G., Simcock, G., Hermens, D. F., & Lagopoulos, J. (2020). Predicting therapeutic response to oral ketamine for chronic suicidal ideation: a Bayesian network for clinical decision support. BMC psychiatry, 20(1), 519. https://doi.org/10.1186/s12888-020-02925-1

Link to full text

The effectiveness of intravenous ketamine in adults with treatment-resistant major depressive disorder and bipolar disorder presenting with prominent anxiety: Results from the Canadian Rapid Treatment Center of Excellence

Abstract

Background: Individuals meeting criteria for treatment-resistant depression (TRD) are differentially affected by high levels of anxiety symptoms.

Aims: There is a need to identify the efficacy of novel rapid-onset treatments in adults with mood disorders and comorbid anxious-distress.

Methods: This study included patients with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD) who were receiving intravenous (IV) ketamine treatment at a community-based clinic.Anxious-distress was proxied using items from the Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS-SR16) and Generalized Anxiety Disorder 7-item (GAD7) scales. The difference in QIDS-SR16 total score, QIDS-SR16 suicidal ideation (SI) item and GAD7 score were analyzed between groups.

Results: A total of 209 adults with MDD (n = 177) and BD (n = 26) were included in this analysis. From this sample, 94 patients (mean = 45 ± 13.9 years) met the criteria for anxious-distress. Individuals meeting the criteria for anxious-distress exhibited a significantly greater reduction in QIDS-SR16 total score following four infusions (p = 0.02) when compared with patients not meeting the anxious-distress criteria. Both anxious-distressed and low-anxiety patients exhibited a significant reduction in SI (p < 0.0001) following four infusions.Finally, there was a significantly greater reduction in anxiety symptoms in the anxious-distress group compared with the non-anxious distress group following three (p = 0.02) and four infusions (p < 0.001).

Conclusion: Patients with TRD and prominent anxiety receiving IV ketamine exhibited a significant reduction in depressive, SI and anxiety symptoms.

McIntyre, R. S., Rodrigues, N. B., Lipsitz, O., Nasri, F., Gill, H., Lui, L. M., Subramaniapillai, M., Kratiuk, K., Teopiz, K., Ho, R., Lee, Y., Mansur, R. B., & Rosenblat, J. D. (2021). The effectiveness of intravenous ketamine in adults with treatment-resistant major depressive disorder and bipolar disorder presenting with prominent anxiety: Results from the Canadian Rapid Treatment Center of Excellence. Journal of psychopharmacology (Oxford, England), 35(2), 128–136. https://doi.org/10.1177/0269881120954048

Link to full text

Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis

Abstract

Background: Ketamine appears to have a therapeutic role in certain mental disorders, most notably depression. However, the comparative performance of different formulations of ketamine is less clear.

Objectives: This study aimed to assess the comparative efficacy and tolerability of racemic and esketamine for the treatment of unipolar and bipolar major depression.

Design: Systematic review and meta-analysis.

Data sources: We searched PubMed, MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for relevant studies published since database inception and December 17, 2019.

Study eligibility criteria: We considered randomized controlled trials examining racemic or esketamine for the treatment of unipolar or bipolar major depression.

Outcomes: Primary outcomes were response and remission from depression, change in depression severity, suicidality, retention in treatment, drop-outs, and drop-outs due to adverse events.

Analysis: Evidence from randomized controlled trials was synthesized as rate ratios (RRs) for treatment response, disorder remission, adverse events, and withdrawals and as standardized mean differences (SMDs) for change in symptoms, via random-effects meta-analyses.

Findings: 24 trials representing 1877 participants were pooled. Racemic ketamine relative to esketamine demonstrated greater overall response (RR = 3.01 vs. RR = 1.38) and remission rates (RR = 3.70 vs. RR = 1.47), as well as lower dropouts (RR = 0.76 vs. RR = 1.37).

Conclusions: Intravenous ketamine appears to be more efficacious than intranasal esketamine for the treatment of depression.

Bahji, A., Vazquez, G. H., & Zarate, C. A., Jr (2021). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of affective disorders, 278, 542–555. https://doi.org/10.1016/j.jad.2020.09.071

Link to full text

Positive effects of psychedelics on depression and wellbeing scores in individuals reporting an eating disorder

Abstract

Purpose: Psychedelic therapy is showing promise for a broad range of mental health conditions, indicative of a transdiagnostic action. While the efficacy of symptom-focused treatments for eating disorders (EDs) is limited, improved mental health and psychological wellbeing are thought to contribute to greater treatment outcomes. This study provides the first quantitative exploration of the psychological effects of psychedelics in those reporting an ED diagnosis.

Methods: Prospective, online data were collected from individuals planning to take a psychedelic drug. Twenty-eight participants reporting a lifetime ED diagnosis completed measures of depressive symptomology (Quick Inventory of Depressive Symptomology; QIDS-SR16) and psychological wellbeing (Warwick-Edinburgh Mental Wellbeing Scale; WEMWBS) 1-2 weeks before, and 2 weeks after a psychedelic experience. Twenty-seven of these participants also completed a measure of emotional breakthrough [Emotional Breakthrough Inventory (EBI)] in relation to the acute psychedelic experience.

Results: Bayesian t tests demonstrated overwhelming evidence for improvements in depression and wellbeing scores following the psychedelic experience. Marginal evidence was also found for a correlation between emotional breakthrough and the relevant mental health improvements.

Conclusion: These findings provide supportive evidence for positive psychological aftereffects of a psychedelic experience that are relevant to the treatment of EDs. It is hoped that this will encourage further research and will bolster initiatives to directly examine the safety and efficacy of psychedelic assisted therapy as a treatment of EDs in future clinical trials.

Level of evidence: Level III, cohort study.

Spriggs, M. J., Kettner, H., & Carhart-Harris, R. L. (2021). Positive effects of psychedelics on depression and wellbeing scores in individuals reporting an eating disorder. Eating and weight disorders : EWD, 26(4), 1265–1270. https://doi.org/10.1007/s40519-020-01000-8

Link to full text