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Depressive Disorders

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression

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

Abstract

Ketamine’s pharmacological profile makes it an interesting and useful drug to challenge treatment-resistant-depression (TRD). Emerging adverse events associated with single-slow-sub-anaesthetic doses for the treatment of depression are common, although generally transient and self-limited. Nevertheless, data on the safety of this practice are scarce. Thus, it seems timely before ketamine is used for clinical treatment of depression to recommend careful monitoring and reporting of all potential adverse events related to ketamine administration. Here, we describe a case of apnea during slow sub-anaesthetic infusion of intravenous ketamine for the treatment of resistant depression. As far as we are concerned, this is an uncommon, previously unreported, and potentially severe adverse event that clinicians should be aware of, and specific management measures should be implemented.

Gómez-Revuelta, M., Fernández-Rodríguez, M., Boada-Antón, L., & Vázquez-Bourgon, J. (2020). Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. Therapeutic advances in psychopharmacology, 10, 2045125320981498. https://doi.org/10.1177/2045125320981498

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Ketamine as an adjunctive therapy for major depression – a randomised controlled pragmatic pilot trial (Karma-Dep Trial)

January 27, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , , ,

Abstract

Background: Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response. Methods: The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as an adjunctive therapy for depression. The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick’s Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up. Results: In total, 1581 admissions to St Patrick’s Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well tolerated. Conclusions: This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible. Trial registration: ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.

Gallagher, B., Foley, M., Slattery, C. M., Gusciute, G., Shanahan, E., & McLoughlin, D. M. (2020). Ketamine as an adjunctive therapy for major depression – a randomised controlled pragmatic pilot trial (Karma-Dep Trial). HRB open research, 3, 90. https://doi.org/10.12688/hrbopenres.13182.1

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Subanesthetic dose of ketamine for the antidepressant effects and the associated cognitive impairments of electroconvulsive therapy in elderly patients-A randomized, double-blind, controlled clinical study

January 21, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , ,

Abstract

Objectives: We previously confirmed that low-dose ketamine, as an adjunctive anesthetic for electroconvulsive therapy (ECT) in adult patients with depression, accelerates the effects of ECT and reduces the ECT-induced learning and memory deficits. This study explored the efficacy and safety of low-dose ketamine in elderly patients with depression.

Methods: Elderly patients with depression (N = 157) were randomly divided into two groups: propofol anesthesia group (group P) and propofol combined with ketamine anesthesia group (group KP). Patients in group KP were given low-dose ketamine (0.3 mg/kg) for each ECT treatment; patients in group P were given the same amount of normal saline. Depressive symptoms and global cognitive functions were assessed using the 24-item Hamilton Depression Rating Scale and Mini-Mental State Examination, respectively, at baseline, 1 day after the 1st, 2nd, 4th, and 6th ECT sessions, and 1 day after the end of the ECT course. ECT effects of and complications were recorded.

Results: In total, 67 patients in group KP and 70 in group P completed the study. After the ECT, the response and remission rates were 82.09% and 73.13%, respectively, in group KP, and 81.43% and 68.57%, respectively, in group P; there was no statistical difference between groups. However, the incidence of cognitive function impairment was lower in group KP (10.4%) than in group P (25.7%), while different electrical dose and seizure duration were required during the course of treatment between the two groups. There was no difference in the complications of ECT between groups.

Conclusions: Low-dose ketamine is safe as an adjunct anesthetic for elderly patients subjected to ECT. It has a protective effect on cognitive function and may accelerate the antidepressant effects of ECT.

Zou, L., Min, S., Chen, Q., Li, X., & Ren, L. (2021). Subanesthetic dose of ketamine for the antidepressant effects and the associated cognitive impairments of electroconvulsive therapy in elderly patients-A randomized, double-blind, controlled clinical study. Brain and behavior, 11(1), e01775. https://doi.org/10.1002/brb3.1775

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Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression

January 27, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , ,

Abstract

Changes in serum copper concentration are observed in patients with depressive symptoms. Unmet needs in contemporary antidepressant treatment have increased interest in non-monoaminergic antidepressants, such as ketamine, an anaesthetic drug that has demonstrated a rapid antidepressant effect in patients with treatment-resistant depression (TRD). The purpose of this study was to examine whether serum copper concentrations change during ketamine treatment and whether there is an association between the copper concentrations and treatment response measured using psychometric scale scores. Moreover, the interlink between somatic comorbidities and copper concentration was studied. Patients with major depressive disorder or bipolar disorder were rated weekly by a clinician using the Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Copper level assessments were carried out weekly before the start of ketamine treatment and then after every second infusion and one week after the last ketamine infusion. The serum concentration of copper before ketamine treatment was significantly higher than that after the fifth infusion (p = 0.016), and the serum concentration after the treatment was significantly higher than that after the fifth infusion (p = 0.048). No significant correlations between changes in the copper serum concentrations and MADRS or YMRS were found. The serum copper level was not associated with somatic comorbidities during the course of treatment. This study provides data on the role of copper in short-term intravenous ketamine treatment in TRD, although no clear evidence of a connection between the copper level and treatment response was found.

Słupski, J., Cubała, W. J., Górska, N., Słupska, A., & Gałuszko-Węgielnik, M. (2020). Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression. Brain sciences, 10(12), 971. https://doi.org/10.3390/brainsci10120971

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Effectiveness of intravenous ketamine in mood disorder patients with a history of neurostimulation

January 21, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , , , , , , , , , , , , ,

Abstract

Background: Patients unsuccessfully treated by neurostimulation may represent a highly intractable subgroup of depression. While the efficacy of intravenous (IV) ketamine has been established in patients with treatment-resistant depression (TRD), there is an interest to evaluate its effectiveness in a subpopulation with a history of neurostimulation.

Methods: This retrospective, posthoc analysis compared the effects of four infusions of IV ketamine in 135 (x̄ = 44 ± 15.4 years of age) neurostimulation-naïve patients to 103 (x̄ = 47 ± 13.9 years of age) patients with a history of neurostimulation. The primary outcome evaluated changes in depression severity, measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16). Secondary outcomes evaluated suicidal ideation (SI), anxiety severity, measured by the Generalized Anxiety Disorder 7-Item (GAD-7), and consummatory anhedonia, measured by the Snaith-Hamilton Pleasure Scale (SHAPS).

Results: Following four infusions, both cohorts reported a significant reduction in QIDS-SR16 Total Score (F (4, 648) = 73.4, P < .001), SI (F (4, 642) = 28.6, P < .001), GAD-7 (F (2, 265) = 53.8, P < .001), and SHAPS (F (2, 302) = 45.9, P < .001). No between-group differences emerged. Overall, the neurostimulation-naïve group had a mean reduction in QIDS-SR16 Total Score of 6.4 (standard deviation [SD] = 5.3), whereas the history of neurostimulation patients reported a 4.3 (SD = 5.3) point reduction.

Conclusion: IV ketamine was effective in reducing symptoms of depression, SI, anxiety, and anhedonia in both cohorts in this large, well-characterized community-based sample of adults with TRD.

Rodrigues, N. B., Siegel, A., Lipsitz, O., Cha, D. S., Gill, H., Nasri, F., Simonson, K., Shekotikhina, M., Lee, Y., Subramaniapillai, M., Kratiuk, K., Lin, K., Ho, R., Mansur, R. B., McIntyre, R. S., & Rosenblat, J. D. (2020). Effectiveness of intravenous ketamine in mood disorder patients with a history of neurostimulation. CNS spectrums, 1–7. Advance online publication. https://doi.org/10.1017/S1092852920002187

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Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine

January 21, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , ,

Abstract

Acute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine’s effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.

Tarrés-Gatius, M., Miquel-Rio, L., Campa, L., Artigas, F., & Castañé, A. (2020). Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine. Translational psychiatry, 10(1), 427. https://doi.org/10.1038/s41398-020-01110-y

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The Ketamine Antidepressant Story: New Insights

January 21, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By /

Abstract

Ketamine is a versatile agent primarily utilized as a dissociative anesthetic, which acts by blocking the excitatory receptor N-methyl-d-aspartate receptor (NMDA). It functions to inhibit the current of both Na+ and K+ voltage-gated channels, thus preventing serotonin and dopamine reuptake. Studies have indicated that administering a single subanesthetic dose of ketamine relieves depression rapidly and that the effect is sustained. For decades antidepressant agents were based on the monoamine theory. Although ketamine may not be the golden antidepressant, it has opened new avenues toward mechanisms involved in the pathology of treatment-resistant depression and achieving rapid antidepressant effects. Thus, preclinical studies focusing on deciphering the molecular mechanisms involved in the antidepressant action of ketamine will assist in the development of a new antidepressant. This review was conducted to elucidate the emerging pathways that can explain the complex dose-dependent mechanisms achieved by administering ketamine to treat major depressive disorders. Special attention was paid to reviewing the literature on hydroxynorketamines, which are ketamine metabolites that have recently attracted attention in the context of depression.

Alshammari T. K. (2020). The Ketamine Antidepressant Story: New Insights. Molecules (Basel, Switzerland), 25(23), 5777. https://doi.org/10.3390/molecules25235777

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Modulation of the functional connectome in major depressive disorder by ketamine therapy

January 7, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , , , , , , , ,

Abstract

Background: Subanesthetic ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depression. How single and repeated ketamine treatment modulates the whole-brain functional connectome to affect clinical outcomes remains uncharacterized.

Methods: Data-driven whole brain functional connectivity (FC) analysis was used to identify the functional connections modified by ketamine treatment in patients with major depressive disorder (MDD). MDD patients (N = 61, mean age = 38, 19 women) completed baseline resting-state (RS) functional magnetic resonance imaging and depression symptom scales. Of these patients, n = 48 and n = 51, completed the same assessments 24 h after receiving one and four 0.5 mg/kg intravenous ketamine infusions. Healthy controls (HC) (n = 40, 24 women) completed baseline assessments with no intervention. Analysis of RS FC addressed effects of diagnosis, time, and remitter status.

Results: Significant differences (p < 0.05, corrected) in RS FC were observed between HC and MDD at baseline in the somatomotor network and between association and default mode networks. These disruptions in FC in MDD patients trended toward control patterns with ketamine treatment. Furthermore, following serial ketamine infusions, significant decreases in FC were observed between the cerebellum and salience network (SN) (p < 0.05, corrected). Patient remitters showed increased FC between the cerebellum and the striatum prior to treatment that decreased following treatment, whereas non-remitters showed the opposite pattern.

Conclusion: Results support that ketamine treatment leads to neurofunctional plasticity between distinct neural networks that are shown as disrupted in MDD patients. Cortico-striatal-cerebellar loops that encompass the SN could be a potential biomarker for ketamine treatment.

Sahib, A. K., Loureiro, J. R., Vasavada, M., Anderson, C., Kubicki, A., Wade, B., Joshi, S. H., Woods, R. P., Congdon, E., Espinoza, R., & Narr, K. L. (2020). Modulation of the functional connectome in major depressive disorder by ketamine therapy. Psychological medicine, 1–10. Advance online publication. https://doi.org/10.1017/S0033291720004560

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Does body mass index predict response to intravenous ketamine treatment in adults with major depressive and bipolar disorder? Results from the Canadian Rapid Treatment Center of Excellence

January 7, 2022 / Depressive Disorders, Ketamine, Papers, Psychiatry & Medicine / Leave a Comment / By / , , , , , , , , ,

Abstract

Background: Higher body mass index (BMI) has been found to predict greater antidepressant response to intravenous (IV) ketamine treatment. We evaluated the association between BMI and response to repeat-dose IV ketamine in patients with treatment-resistant depression (TRD).

Methods: Adults (N = 230) with TRD received four infusions of IV ketamine at a community-based clinic. Changes in symptoms of depression (ie, Quick Inventory for Depressive Symptomatology-Self-Report 16; QIDS-SR16), suicidal ideation (SI; ie, QIDS-SR16 SI item), anxiety (ie, Generalized Anxiety Disorder-7 Scale), anhedonic severity (ie, Snaith-Hamilton Pleasure Scale), and functioning (ie, Sheehan Disability Scale) following infusions were evaluated. Participants were stratified by BMI as normal (18.0-24.9 kg/m2; n = 72), overweight (25-29.9 kg/m2; n = 76), obese I (30-34.9 kg/m2; n = 47), or obese II (≥35.0 kg/m2; n = 35).

Results: Similar antidepressant effects with repeat-dose ketamine were reported between BMI groups (P = .261). In addition, categorical partial response (P = .149), response (P = .526), and remission (P = .232) rates were similar between the four BMI groups.

Conclusions: The findings are limited by the observational, open-label design of this retrospective analysis. Pretreatment BMI did not predict response to IV ketamine, which was effective regardless of BMI.

Lipsitz, O., McIntyre, R. S., Rodrigues, N. B., Lee, Y., Gill, H., Subramaniapillai, M., Kratiuk, K., Nasri, F., Mansur, R. B., & Rosenblat, J. D. (2020). Does body mass index predict response to intravenous ketamine treatment in adults with major depressive and bipolar disorder? Results from the Canadian Rapid Treatment Center of Excellence. CNS spectrums, 1–9. Advance online publication. https://doi.org/10.1017/S1092852920002102

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The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action

February 6, 2022 / Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / , , , , , , , , , , , , , , , ,

Abstract

Serotonergic agonist psilocybin is a psychedelic with antidepressant potential. Sleep may interact with psilocybin’s antidepressant properties like other antidepressant drugs via induction of neuroplasticity. The main aim of the study was to evaluate the effect of psilocybin on sleep architecture on the night after psilocybin administration. Regarding the potential antidepressant properties, we hypothesized that psilocybin, similar to other classical antidepressants, would reduce rapid eye movement (REM) sleep and prolong REM sleep latency. Moreover, we also hypothesized that psilocybin would promote slow-wave activity (SWA) expression in the first sleep cycle, a marker of sleep-related neuroplasticity. Twenty healthy volunteers (10 women, age 28-53) underwent two drug administration sessions, psilocybin or placebo, in a randomized, double-blinded design. Changes in sleep macrostructure, SWA during the first sleep cycle, whole night EEG spectral power across frequencies in non-rapid eye movement (NREM) and REM sleep, and changes in subjective sleep measures were analyzed. The results revealed prolonged REM sleep latency after psilocybin administration and a trend toward a decrease in overall REM sleep duration. No changes in NREM sleep were observed. Psilocybin did not affect EEG power spectra in NREM or REM sleep when examined across the whole night. However, psilocybin suppressed SWA in the first sleep cycle. No evidence was found for sleep-related neuroplasticity, however, a different dosage, timing, effect on homeostatic regulation of sleep, or other mechanisms related to antidepressant effects may play a role. Overall, this study suggests that potential antidepressant properties of psilocybin might be related to changes in sleep.

Dudysová, D., Janků, K., Šmotek, M., Saifutdinova, E., Kopřivová, J., Bušková, J., Mander, B. A., Brunovský, M., Zach, P., Korčák, J., Andrashko, V., Viktorinová, M., Tylš, F., Bravermanová, A., Froese, T., Páleníček, T., & Horáček, J. (2020). The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action. Frontiers in pharmacology, 11, 602590. https://doi.org/10.3389/fphar.2020.602590

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