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Ketamine

Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine

January 3, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , ,

Abstract

Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine’s antidepressant actions – such as cortical excitation, synaptogenesis, and involved molecular determinants – are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.

Kohtala, S., Alitalo, O., Rosenholm, M., Rozov, S., & Rantamäki, T. (2021). Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine. Pharmacology & therapeutics, 221, 107741. https://doi.org/10.1016/j.pharmthera.2020.107741

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Ketamine in Bipolar Disorder: A Review

January 6, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , ,

Abstract

Bipolar disorder (BD) is a psychiatric illness associated with high morbidity, mortality and suicide rate. It has neuroprogressive course and a high rate of treatment resistance. Hence, there is an unquestionable need for new BD treatment strategies. Ketamine appears to have rapid antidepressive and antisuicidal effects. Since most of the available studies concern unipolar depression, here we present a novel insight arguing that ketamine might be a promising treatment for bipolar disorder.

Wilkowska, A., Szałach, Ł., & Cubała, W. J. (2020). Ketamine in Bipolar Disorder: A Review. Neuropsychiatric disease and treatment, 16, 2707–2717. https://doi.org/10.2147/NDT.S282208

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Effect of Ketamine on Rumination in Treatment-Resistant Depressive Patients

November 26, 2021 / Depressive Disorders, Ketamine, Papers, Psychology / Leave a Comment / By / , , , ,

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

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

November 1, 2020 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , ,

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

November 30, 2021 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , , , ,

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

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

December 2, 2021 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , ,

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

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

November 30, 2021 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , , , , , , , ,

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

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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

November 26, 2021 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Papers, Psychology / Leave a Comment / By / , , , , , , , , , , , ,

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

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

November 26, 2021 / Depressive Disorders, Ketamine, Papers, Pharmacology & Chemistry, Psychology / Leave a Comment / By / , ,

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

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Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin

November 18, 2021 / Anxiety Disorders / PTSD, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / , , , ,

Abstract

The aim of this systematic review was to examine the efficacy of MDMA, ketamine, LSD, and psilocybin for the treatment of posttraumatic stress disorder (PTSD). A search of four databases for English language, peer-reviewed literature published from inception to 18th October 2019 yielded 2,959 records, 34 of which were screened on full-text. Observational studies and RCTs which tested the efficacy of MDMA, ketamine, LSD, or psilocybin for reducing PTSD symptoms in adults, and reported changes to PTSD diagnosis or symptomatology, were included. Nine trials (five ketamine and four MDMA) met inclusion criteria. Trials were rated on a quality and bias checklist and GRADE was used to rank the evidence. The evidence for ketamine as a stand-alone treatment for comorbid PTSD and depression was ranked “very low”, and the evidence for ketamine in combination with psychotherapy as a PTSD treatment was ranked “low”. The evidence for MDMA in combination with psychotherapy as a PTSD treatment was ranked “moderate”.

Varker, T., Watson, L., Gibson, K., Forbes, D., & O’Donnell, M. L. (2021). Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin. Journal of psychoactive drugs, 53(1), 85–95. https://doi.org/10.1080/02791072.2020.1817639

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