Electroencephalography (EEG) spectral signatures of selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs) and vortioxetine in major depressive disorder: A systematic review.

BACKGROUND: Converging evidence suggests electroencephalography (EEG) methods may elucidate alterations in global structural and functional connectivity that underlie the pathophysiology of depressive disorders. Extant literature suggests SSRIs and SNRIs may broadly induce alterations to EEG-measured neural activity. Herein, this systematic review comprehensively evaluates changes to EEG spectral signatures associated with vortioxetine and each FDA-approved agent within the SSRI and SNRI class. METHODS: We conducted a systematic review of studies investigating changes to EEG spectral signatures associated with SSRI, SNRI, and/or vortioxetine treatment in persons with MDD. Database search occurred from database inception to May 3, 2024. RESULTS: Our search yielded 15 studies investigating overall spectral signature changes associated with SSRI- and/or SNRI-treatment. The existing literature presents with mixed findings. Notwithstanding, we did observe a pattern in which the SSRI and SNRI agents reproducibly affect EEG spectral signatures. We observed overlapping yet distinct spectral patterns for each agent within- and between-drug classes of SSRIs and SNRIs. Changes in resting/wake EEG were also observed. LIMITATIONS: The findings from our systematic review are mixed. Heterogeneity exists with sample size, composition, dosing of antidepressants, duration of antidepressant exposure, as well as the type of EEG devices used. DISCUSSIONS: Our findings provide support to the notion that although SSRIs, SNRIs and vortioxetine block reuptake of the serotonin transporter; they are different in their profile of pharmacology as evidenced by differential EEG signatures. EEG changes associated with SSRIs, SNRIs and vortioxetine are also highly replicated findings across mixed studies and populations.

Association between rumination, suicidal ideation and suicide attempts in persons with depressive and other mood disorders and healthy controls: A systematic review and meta-analysis.

INTRODUCTION: Suicidal ideation and behaviors are a leading cause of disability worldwide. Approximately 90 % of suicide completers have a diagnosable mood disorder. Extant literature reports rumination mediates functional impairment across mood disorders. Herein, we report the association between rumination and suicidality amongst persons with psychiatric disorders and healthy controls. METHODS: Our systematic review and meta-analysis included relevant articles retrieved from Web of Science, OVID and PubMed from inception to March 20, 2024. Random effects model was used to calculate the correlation between rumination, suicidal ideation and attempt. RESULTS: A total of 27 eligible studies were included in our systematic review and meta-analysis. Rumination (r = 0.25 [95 % CI: -0.03, 0.49]), reflection (r = 0.15 [-0.71, 0.83]) and brooding (r = 0.13 [-0.58, 0.73]) were nonsignificantly correlated with suicidal ideation in mood disorders. Suicide attempt history was significantly associated with greater odds of rumination in persons with depressive disorders (OR = 1.13 [0.42, 3.02]). In healthy controls, rumination (r = 0.30 [0.21, 0.38]), reflection (r = 0.23 [0.13, 0.32]) and brooding (r = 0.24 [0.12, 0.36]) were significantly correlated with suicidal ideation. Rumination also predicted lifetime history of suicide attempts in healthy controls (OR = 1.70 [1.16, 2.49]). LIMITATIONS: There were inadequate sample sizes of persons with different mood and psychiatric disorders which may have underpowered our ability to detect clinically meaningful associations. DISCUSSION: Our study reports a transdiagnostic association between measures of rumination and suicidality. Future research vistas should parse the neurobiological substrates subserving rumination and identify targeted therapies and their association with general cognition and treatment response.

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.

Subjective and objective measures of cognitive function are correlated in persons with Post-COVID-19 Condition: a secondary analysis of a Randomized Controlled Trial.

BACKGROUND: It remains unclear whether subjective and objective measures of cognitive function in Post COVID-19 Condition (PCC) are correlated. The extent of correlation has mechanistic and clinical implications. METHODS: This post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial contains baseline data of subjective and objective measures of cognition in a rigorously characterized cohort living with PCC. Herein, we evaluated the association between subjective and objective condition function, as measured by the Perceived Deficits Questionnaire, 20-item (PDQ-20) and the Digit Symbol Substitution Test (DSST) and Trails Making Test (TMT)-A/B, respectively. RESULTS: A total of 152 participants comprised the baseline sample. Due to missing data, our statistical analyses included 150 for self-reported PDQ-20, 147 individuals for combined DSST-measured cognitive function (composite z-score of the Pen/Paper plus Online CogState Version, NcombinedDSST), 71 for in-person DSST-measured cognitive function (Pen/Paper Version), 70 for TMT-A-measured cognitive function, and 70 for TMT-B-measured cognitive function. After adjusting for age, sex, and education, PDQ-20 was significantly correlated with pen-and-paper DSST (ß = -0.003, p = 0.002) and TMT-B (ß = 0.003, p = 0.008) scores, but not with TMT-A scores (ß = -0.001, p = 0.751). CONCLUSIONS: Overall, a statistically significant correlation was observed between subjective and objective cognitive functions. Clinicians providing care for individuals with PCC who have subjective cognitive function complaints may consider taking a measurement-based approach to cognition at the point of care that focuses exclusively on patient-reported measures.

Glucagon-like peptide 1 agonist and effects on reward behaviour: A systematic review.

INTRODUCTION: The roles of metabolic signals, including Glucagon-like peptide 1 (GLP-1), have been implicated in multiple domains outside metabolic regulation. There is a growing interest in repurposing Glucagon-like peptide 1 receptor agonists (GLP-1RAs) as therapeutics for motivation and reward-related behavioural disturbances. Herein, we aim to systematically review the extant evidence on the potential effects of GLP-1RAs on the reward system. METHODS: The study followed PRISMA guidelines using databases such as OVID, PubMed, Scopus, and Google Scholar. The search focused on "Reward Behavior" and "Glucagon Like Peptide 1 Receptor Agonists" and was restricted to human studies. Quality assessment achieved by the NIH's Quality Assessment of Controlled Intervention Studies RESULTS: GLP-1RAs consistently reduced energy intake and influenced reward-related behaviour. These agents have been associated with decreased neurocortical activation in response to higher rewards and food cues, particularly high-calorie foods, and lowered caloric intake and hunger levels. DISCUSSION: GLP-1RAs show promise in addressing reward dysfunction linked to food stimuli, obesity, and T2DM. They normalize insulin resistance, and might also modulate dopaminergic signalling and reduce anhedonia. Their effects on glycemic variability and cravings suggest potential applications in addiction disorders.

Subjective and Objective Measures of Cognitive Function are Correlated in Persons with Post-COVID-19 Condition: A Secondary Analysis of a Randomized Controlled Trial.

Background: It remains unclear whether subjective and objective measures of cognitive function in Post COVID-19 Condition (PCC) are correlated. The extent of correlation has mechanistic and clinical implications. Methods: This post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial contains baseline data of subjective and objective measures of cognition in a rigorously characterized cohort living with PCC. Herein, we evaluated the association between subjective and objective condition function, as measured by the Perceived Deficits Questionnaire, 20-item (PDQ-20) and the Digit Symbol Substitution Test (DSST) and Trails Making Test (TMT)-A/B, respectively. Results: A total of 152 participants comprised the baseline sample. Due to missing data, our statistical analyses included 150 for self-reported PDQ-20, 147 individuals for combined DSST-measured cognitive function (composite z-score of the Pen/Paper plus Online CogState Version, N combinedDSST ), 71 for in-person DSST-measured cognitive function (Pen/Paper Version), 70 for TMT-A-measured cognitive function, and 70 for TMT-B-measured cognitive function. After adjusting for age, sex, and education, PDQ-20 was significantly correlated with pen-and-paper DSST (ß = -0.003, p = 0.002) and TMT-B (ß = 0.003, p = 0.008) scores, but not with TMT-A scores (ß = -0.001, p = 0.751). Conclusions: Overall, a statistically significant correlation was observed between subjective and objective cognitive functions. Clinicians providing care for individuals with PCC who have subjective cognitive function complaints may consider taking a measurement-based approach to cognition at the point of care that focuses exclusively on patient-reported measures.

Impact of elevated body mass index (BMI) on cognitive functioning and inflammation in persons with post-COVID-19 condition: a secondary analysis.

BACKGROUND: Individuals who have recovered from the acute stage of SARS-CoV-2 infection may be at risk of developing post-COVID-19 condition (PCC), characterised by a spectrum of persisting, non-specific, and functionally impairing symptoms across multiple organ systems. Obesity has been implicated as a risk factor for PCC, mediated by chronic systemic inflammation. The foregoing has also been separately reported to mediate cognitive dysfunction in PCC. METHODS: This is a post-hoc analysis of a randomised, double-blinded, placebo-controlled clinical trial evaluating vortioxetine treatment for cognitive impairments in persons with PCC who received vortioxetine or placebo for eight weeks. This analysis comprises baseline data, examining the impact of BMI on cognitive functioning measured by the Digit Symbol Substitution Test (DSST) and Trails Making Tests (TMT)-A/B, as well as inflammation, via serum c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). RESULTS: Complete data from 70 participants were statistically analysed and adjusted for age and sex. BMI was negatively correlated with performance on the DSST (ß = -0.003, p = 0.047), TMT-A (ß = -0.006, p = 0.025), and TMT-B (ß = -0.006, p = 0.002). BMI was positively correlated with serum CRP (unstandardized ß = 0.193, standardized ß = 0.612, p < 0.001) and ESR (ß = 0.039, p < 0.001) levels. CONCLUSION: We observed a significant negative correlation between BMI and cognitive functioning, and a significant positive correlation between BMI and inflammation in persons with PCC, suggesting a bidirectional interplay between BMI, PCC, and cognitive function; individuals with an elevated BMI may be at a greater risk of developing PCC and/or presenting with greater cognitive deficits mediated by chronic systemic inflammation.

Spectral signatures of psilocybin, lysergic acid diethylamide (LSD) and ketamine in healthy volunteers and persons with major depressive disorder and treatment-resistant depression: A systematic review.

BACKGROUND: Electrophysiologic measures provide an opportunity to inform mechanistic models and possibly biomarker prediction of response. Serotonergic psychedelics (SPs) (i.e., psilocybin, lysergic acid diethylamide (LSD)) and ketamine represent new investigational and established treatments in mood disorders respectively. There is a need to better characterize the mechanism of action of these agents. METHODS: We conducted a systematic review investigating the spectral signatures of psilocybin, LSD, and ketamine in persons with major depressive disorder (MDD), treatment-resistant depression (TRD), and healthy controls. RESULTS: Ketamine and SPs are associated with increased theta power in persons with depression. Ketamine and SPs are also associated with decreased spectral power in the alpha, beta and delta bands in healthy controls and persons with depression. When administered with SPs, theta power was increased in persons with MDD when administered with SPs. Ketamine is associated with increased gamma band power in both healthy controls and persons with MDD. LIMITATIONS: The studies included in our review were heterogeneous in their patient population, exposure, dosing of treatment and devices used to evaluate EEG and MEG signatures. Our results were extracted entirely from persons who were either healthy volunteers or persons with MDD or TRD. CONCLUSIONS: Extant literature evaluating EEG and MEG spectral signatures indicate that ketamine and SPs have reproducible effects in keeping with disease models of network connectivity. Future research vistas should evaluate whether observed spectral signatures can guide further discovery of therapeutics within the psychedelic and dissociative classes of agents, and its prediction capability in persons treated for depression.

Adjunctive cariprazine for major depressive disorder: a systematic review and meta-analysis.

Converging evidence has suggested that treatment augmentation with a second-generation atypical antipsychotic (SGA) may improve treatment outcomes in major depressive disorder (MDD) patients after an incomplete response to a first-line antidepressant. Cariprazine is a recently approved SGA for MDD augmentation. Herein, we evaluate both continuous (ie, change in depressive symptom severity scores over time) and categorical (ie, remission and response rates) outcomes. Following a full-text review, four randomized controlled trials (RCTs) were included in our meta-analysis, while five studies were included for a qualitative review. Risk ratios (RRs) were calculated for all included randomized controlled studies to determine the relative response and remission rates of cariprazine compared to placebo augmentation. The RR for all-cause dropout was also determined as a proxy for overall acceptability. Two studies found a statistically significant treatment response using cariprazine augmentation. One study observed depressive symptom remission for cariprazine compared to placebo. Our random-effects model revealed moderate antidepressant effects of cariprazine, with a standardized mean difference (SMD) in Montgomery-Åsberg Depression Rating Scale (MADRS) scores of -1.79 (95% CI): -2.89, -0.69). Our pooled response RR and remission RR were calculated as 1.21 (95% CI: 1.05, 1.39, P=0.008) and 0.99 (95% CI: 0.84, 1.17, P=0.91), respectively. The RR for response was statistically significant (P<0.05). However, the RR for remission was not statistically significant. The findings from our meta-analysis include a variable magnitude of effects. Evidence suggests cariprazine may be an effective treatment for MDD; however, further results are needed to clarify this relation.

The efficacy of zuranolone in postpartum depression and major depressive disorder: a review & number needed to treat (NNT) analysis.

INTRODUCTION: Major depressive disorder (MDD) is a common and debilitating mental illness. Postpartum depression (PPD) impacts women globally and is one of the most common complications of childbirth that is underdiagnosed and undertreated, adversely impacting the mental health of women, children, and partners.Available antidepressant medications require weeks to months before showing effect. In this setting, zuranolone, an oral neuroactive steroid and a positive allosteric modulator of GABAA receptors, is an attractive alternative as a rapid-acting antidepressant treatment. AREAS COVERED: This article reviews zuranolone (SAGE217), focusing on available clinical studies in individuals with PPD and MDD. This paper adds to the extant literature by presenting the efficacy data as Number Needed to Treat (NNT) to facilitate indirect comparisons with other antidepressants. EXPERT OPINION: Zuranolone is a novel rapid-acting (i.e. two week course) oral antidepressant for the treatment of adults with PPD with ongoing clinical trials evaluating its efficacy in adults with MDD. Zuranolone is well tolerated with no significant safety concerns in any clinical trials completed to date. Zuranolone will be scheduled by the Drug Enforcement Agency (DEA).

Vortioxetine for the treatment of post-COVID-19 condition: a randomized controlled trial.

Hitherto no therapeutic has received regulatory approval for the treatment of post-COVID-19 condition (PCC). Cognitive deficits, mood symptoms and significant reduction in health-related quality of life (HRQoL) are highly replicated and debilitating aspects of PCC. We sought to determine the impact of vortioxetine on the foregoing symptoms and HRQoL in persons living with PCC. An 8-week randomized, double-blind, placebo-controlled study of adults ≥ 18 years of age residing in Canada and who are experiencing symptoms of World Health Organization (WHO)-defined PCC, with a history of confirmed SARS-CoV-2 infection, was conducted. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled (487 invited: 121 ineligible and 59 eligible but declined participation; 307 cleared pre-screening stage), a total of 149 participants were randomized (1:1) to receive either vortioxetine (5-20 mg, n = 75) or placebo (n = 74) daily for 8 weeks of double-blind treatment (i.e. end point). The primary outcome was the change from baseline-to-end point in the Digit Symbol Substitution Test. Secondary outcomes included the effect on depressive symptoms and HRQoL, as measured by changes from baseline-to-end point on the Quick Inventory of Depressive Symptomatology 16-item and WHO Wellbeing Scale 5-item, respectively. A total of 68 (90.7%) participants randomized to vortioxetine and 73 (98.6%) participants randomized to placebo completed all 8 weeks. Between-group analysis did not show a significant difference in the overall change in cognitive function [P = 0.361, 95% confidence interval (CI) (-0.179, 0.492)]. However, in the fully adjusted model, a significant treatment × time interaction was observed in favour of vortioxetine treatment with baseline c-reactive protein (CRP) as a moderator (P = 0.012). In addition, a significant improvement in Digit Symbol Substitution Test scores were observed in vortioxetine versus placebo treated participants in those whose baseline CRP was above the mean (P = 0.045). Moreover, significant improvement was obtained in measures of depressive symptoms [P < 0.001, 95% CI (-4.378, -2.323)] and HRQoL [P < 0.001, 95% CI (2.297, 4.647)] in vortioxetine-treated participants and between the treatment groups [depressive symptoms: P = 0.026, 95% CI (-2.847, -0.185); HRQoL: P = 0.004, 95% CI (0.774, 3.938)]. Although vortioxetine did not improve cognitive function in the unadjusted model, when adjusting for CRP, a significant pro-cognitive effect was observed; antidepressant effects and improvement in HRQoL in this debilitating disorder were also noted.

Glucagon-like peptide 1 (GLP-1) receptor agonists as a protective factor for incident depression in patients with diabetes mellitus: A systematic review.

Glucagon-like peptide 1 (GLP-1) receptor agonists are widely used for glycemic control in patients with diabetes mellitus (DM) and are primarily indicated for type 2 diabetes mellitus (T2DM). GLP-1 receptor agonists have also been shown to have neuroprotective and antidepressant properties. Replicated evidence suggests that individuals with DM are significantly more likely to develop depression. Herein, we aim to investigate whether GLP-1 receptor agonists can be used prophylactically on patients with DM to lower the risk of incident depression. We conducted a systematic search for English-language articles published on the PubMed/MEDLINE, Scopus, Embase, APA, PsycInfo, Ovid and Google Scholar databases from inception to June 6, 2022. Four retrospective observational studies were identified that evaluated the neuroprotective effects of GLP-1 receptor agonists on incident depression in patients with DM. We found mixed results with regards to lowering the risk of incident depression, with two studies demonstrating a significant reduction in risk and two studies showing no such effect. A single study found that dulaglutide may lower susceptibility to depression. Our results were limited by high interstudy heterogeneity, paucity of literature, and lack of controlled trials. While we did not find evidence of GLP-1 receptor agonists significantly lowering risk of incident depression in patients with DM, promising neuroprotective data presented in two of the included papers, specifically on dulaglutide where information is scarce, provide the impetus for further investigation. Future research should focus on better elucidating the neuroprotective potential of different classes and doses of GLP-1 receptor agonists using controlled trials.

Indirect Calorimetry to Measure Metabolic Rate and Energy Expenditure in Psychiatric Populations: A Systematic Review.

Psychiatric and metabolic disorders are highly comorbid and the relationship between these disorders is bidirectional. The mechanisms underlying the association between psychiatric and metabolic disorders are presently unclear, which warrants investigation into the dynamics of the interplay between metabolism, substrate utilization, and energy expenditure in psychiatric populations, and how these constructs compare to those in healthy controls. Indirect calorimetry (IC) methods are a reliable, minimally invasive means for assessing metabolic rate and substrate utilization in humans. This review synthesizes the extant literature on the use of IC on resting metabolism in psychiatric populations to investigate the interaction between psychiatric and metabolic functioning. Consistently, resting energy expenditures and/or substrate utilization values were significantly different between psychiatric and healthy populations in the studies contained in this review. Furthermore, resting energy expenditure values were systematically overestimated when derived from predictive equations, compared to when measured by IC, in psychiatric populations. High heterogeneity between study populations (e.g., differing diagnoses and drug regimens) and methodologies (e.g., differing posture, time of day, and fasting status at measurement) impeded the synthesis of results. Standardized IC protocols would benefit this line of research by enabling meta-analyses, revealing trends within and between different psychiatric disorders.

COVID-19 vaccination for the prevention and treatment of long COVID: A systematic review and meta-analysis.

Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N = 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.

Evaluating the neural substrates of effort-expenditure for reward in adults with major depressive disorder and obesity.

Converging evidence has suggested that disturbances in monetary reward processing may subserve the shared biosignature between major depressive disorder (MDD) and obesity. However, there remains a paucity of studies that have evaluated the deficits in specific subcomponents of reward functioning in populations with MDD and obesity comorbidity. We evaluated the association between effort-expenditure for monetary reward and neural activation in regions associated with reward-based decision making (i.e., the caudate nucleus, anterior cingulate cortex (ACC) and hippocampus) in people with MDD and obesity comorbidity. We acquired structural and functional magnetic resonance imaging (fMRI) in 12 participants and performed a spherical region-of-interest analysis (ROI) using previously defined peak MNI coordinates. A one-sample t-test was employed to compare ROI-specific blood-oxygen-level-dependent (BOLD) signal change during the task choice selection window (i.e., high-effort vs. low-effort task) of the effort-expenditure for reward task (EEfRT). We observed no change in activation of the caudate nucleus, ACC or hippocampus in participants with increased BMI when contrasting the high effort > low effort reward magnitude condition for the EEfRT. The findings from our exploratory study evaluated the disturbances in fundamental reward processes, including cost-benefit decision making, in people MDD and obesity. Future studies should further investigate this relationship with a larger sample size.

Changes in insulin resistance following antidepressant treatment mediate response in major depressive disorder.

BACKGROUND: Insulin resistance (IR) is a potential predictor of antidepressant treatment response. AIMS: We assess changes in IR after antidepressant treatment and whether these changes have any effect on treatment response. Also, to see whether changes in IR mediates relationship between C-reactive protein (CRP) and antidepressant efficacy. METHODS: This is a secondary analysis of an 8-week, open-label clinical trial with 95 adults experiencing a major depressive episode. Response to vortioxetine was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). Generalized estimating equation models were utilized for this intent-to-treat analysis. RESULTS: When adjusted for age, sex, and body mass index, there was a significant increase in IR following treatment in the overall sample (p = 0.035). This finding was detected in treatment non-responders (p = 0.019), whereas it was not observed in responders (p = 0.329). Mediation analysis revealed that change in IR during treatment was responsible for change in MADRS as well as the relationship between baseline CRP and treatment response. CONCLUSIONS: Exacerbation of IR during antidepressant treatment mediated non-response. Conversely in treatment responders IR reduced. Like previous studies, baseline CRP moderated treatment response. This relationship was also mediated by changes in IR. These findings further elucidate the role of IR in terms of antidepressant response as well as potentially explain inflammation's relationship with the latter.

Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression.

BACKGROUND: Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. METHODS: This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment-resistant bipolar I/II depression (n = 66) received four sub-anesthetic doses of IV ketamine (0.5-0.75 mg/kg) over a two-week period. Symptoms of depression, suicidality, anxiety, and functioning were assessed with validated self-report measures. RESULTS: Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16 ) with further reductions in depressive symptoms observed after each subsequent infusion (n = 66; mean QIDS-SR16 reduction of 6.08+/-1.39; p < 0.0001). Significant reductions of suicidal thoughts (QIDS-SR16 -Suicide Item) and anxiety (Generalized Anxiety Disorder-7) were also observed with functional improvements on the Sheehan Disability Scale (p < 0.0001 on all measures). Moreover, the response rate (QIDS-SR16 total score decrease ≥50% from baseline) was 35% and remission rate (QIDS-SR16 total score ≤5) was 20% after four infusions. Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis. CONCLUSIONS: Real-world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability.

Real-World Effectiveness of Repeated Ketamine Infusions for Treatment-Resistant Bipolar Depression.

Background: Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. Methods: This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment-resistant bipolar I/II depression (n = 66) received four sub-anesthetic doses of IV ketamine (0.5-0.75 mg/kg) over a two-week period. Symptoms of depression, suicidality, anxiety, and functioning were assessed with validated self-report measures. Results: Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16) with further reductions in depressive symptoms observed after each subsequent infusion (n = 66; mean QIDS-SR16 reduction of 6.08+/-1.39; p < 0.0001). Significant reductions of suicidal thoughts (QIDS-SR16-Suicide Item) and anxiety (Generalized Anxiety Disorder-7) were also observed with functional improvements on the Sheehan Disability Scale (p < 0.0001 on all measures). Moreover, the response rate (QIDS-SR16 total score decrease ≥50% from baseline) was 35% and remission rate (QIDS-SR16 total score ≤5) was 20% after four infusions. Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis. Conclusions: Real-world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability.Reprinted from Bipolar Disord 2023; 25:99-109, with permission from John Wiley and Sons. Copyright © 2023.