Neural correlates of citalopram and placebo response in acute bipolar depression: A randomized trial.
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ABSTRACT:
SUBMITTER: Sretavan Wong K
PROVIDER: S-EPMC8192448 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
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Neural correlates of citalopram and placebo response in acute bipolar depression: A randomized trial.
Sretavan Wong Karianne K Migó Marta M Dougherty Darin D DD Ghaemi S Nassir SN
Journal of psychiatric research 20210430
While serotonin reuptake inhibitors are sometimes used in clinical practice to treat acute bipolar depression, the neurophysiological substrates underlying their efficacy are little studied. In the context of a larger clinical efficacy trial, the present study explored neural mechanisms associated with citalopram versus placebo treatment for bipolar depression. FDG-PET imaging examined whole-brain metabolic changes before and after treatment. Clinical efficacy was similar for citalopram versus p ...[more]
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Project description:ObjectiveThe authors evaluated the potential of methylphenidate to improve antidepressant response to citalopram, as assessed by clinical and cognitive outcomes, in elderly depressed patients.MethodThe authors conducted a 16-week randomized double-blind placebo-controlled trial for geriatric depression in 143 older outpatients diagnosed with major depression comparing treatment response in three treatment groups: methylphenidate plus placebo (N=48), citalopram plus placebo (N=48), and citalopram plus methylphenidate (N=47). The primary outcome measure was change in depression severity. Remission was defined as a score of 6 or less on the Hamilton Depression Rating Scale. Secondary outcomes included measures of anxiety, apathy, quality of life, and cognition.ResultsDaily doses ranged from 20 mg to 60 mg for citalopram (mean=32 mg) and from 5 mg to 40 mg for methylphenidate (mean=16 mg). All groups showed significant improvement in depression severity and in cognitive performance. However, the improvement in depression severity and the Clinical Global Impressions improvement score was more prominent in the citalopram plus methylphenidate group compared with the other two groups. Additionally, the rate of improvement in the citalopram plus methylphenidate group was significantly higher than that in the citalopram plus placebo group in the first 4 weeks of the trial. The groups did not differ in cognitive improvement or number of side effects.ConclusionsCombined treatment with citalopram and methylphenidate demonstrated an enhanced clinical response profile in mood and well-being, as well as a higher rate of remission, compared with either drug alone. All treatments led to an improvement in cognitive functioning, although augmentation with methylphenidate did not offer additional benefits.
| S-EPMC4451432 | biostudies-literature
Project description:Anhedonia--which is defined as diminished pleasure from, or interest in, previously rewarding activities-is one of two cardinal symptoms of a major depressive episode. However, evidence suggests that standard treatments for depression do little to alleviate the symptoms of anhedonia and may cause reward blunting. Indeed, no therapeutics are currently approved for the treatment of anhedonia. Notably, over half of patients diagnosed with bipolar disorder experience significant levels of anhedonia during a depressive episode. Recent research into novel and rapid-acting therapeutics for depression, particularly the noncompetitive N-Methyl-D-aspartate receptor antagonist ketamine, has highlighted the role of the glutamatergic system in the treatment of depression; however, it is unknown whether ketamine specifically improves anhedonic symptoms. The present study used a randomized, placebo-controlled, double-blind crossover design to examine whether a single ketamine infusion could reduce anhedonia levels in 36 patients with treatment-resistant bipolar depression. The study also used positron emission tomography imaging in a subset of patients to explore the neurobiological mechanisms underpinning ketamine's anti-anhedonic effects. We found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this reduction occurred independently from reductions in general depressive symptoms. Anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen. Our study emphasizes the importance of the glutamatergic system in treatment-refractory bipolar depression, particularly in the treatment of symptoms such as anhedonia.
| S-EPMC4350513 | biostudies-other
Project description:BackgroundSuicide is among the top 10 leading causes of death worldwide. Of people who died by suicide, the majority are diagnosed with depression. It is estimated that 25%-60% of people with bipolar depression (BD) will attempt suicide at least once, and 10%-15% will die by suicide. Several treatments, such as lithium, clozapine, electroconvulsive therapy, and cognitive behavioral therapy, have been shown to be effective in treating suicidality. However, these treatments can be difficult to tolerate or may take months to take effect. Ketamine, a glutamate N-methyl-D-aspartate antagonist, has been shown to have rapid antisuicidal effect and antidepressant qualities, and is thus a promising intervention to target acute suicidality in patients with BD. However, the biological mechanism underlying its therapeutic action remains poorly understood. Enhancing our understanding of underlying mechanisms of action for ketamine's effectiveness in reducing suicidality is critical to establishing biological markers of treatment response and developing tailored, personalized interventions for patients with BD.ObjectiveThis is an open-label clinical trial to test the safety and feasibility of repeated ketamine infusions to treat acute suicidality. The primary objective is to test the safety and feasibility of ketamine intervention. The secondary objective is to examine ketamine's potential neurophysiological mechanisms of action by assessing cortical excitation and inhibition to determine potential biomarkers of clinical response. Other objectives are to evaluate the effect of ketamine on acute suicidality and other clinical outcomes, such as depressive symptoms and quality of life, to inform a future larger trial.MethodsThis open-label clinical trial aims to test the safety and feasibility of repeated ketamine infusions in patients with BD for suicidality and to assess ketamine's neurophysiological effects. A sterile form of racemic ketamine hydrochloride will be administered over a 40-minute intravenous infusion 2 times per week on nonconsecutive days for 4 weeks (8 sessions). We will recruit 30 adults (24-65 year olds) over 2 years from an academic psychiatric hospital in Toronto, Canada.ResultsThis study is currently ongoing and actively recruiting participants. So far, 5 participants have completed the trial, 1 is currently in active treatment, and 8 participants are on the waitlist to be screened. We anticipate initial results being available in the fall of 2023. This proposal was presented as a poster presentation at the Research to Reality Global Summit on Psychedelic-Assisted Therapies and Medicine, held in May 2022 in Toronto, Canada.ConclusionsDeveloping effective interventions for acute suicidality in high-risk populations such as those with BD remains a major therapeutic challenge. Ketamine is a promising treatment due to its rapid antidepressant and antisuicidal effects, but its underlying neurophysiological mechanisms of action remain unknown.Trial registrationClinicalTrials.gov NCT05177146; https://clinicaltrials.gov/ct2/show/NCT05177146.International registered report identifier (irrid)DERR1-10.2196/41013.
| S-EPMC9919457 | biostudies-literature
Project description:OBJECTIVES:Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence supports a role for the glutamatergic system in the pathophysiology of BD. This double-blind, randomized, cross-over study sought to determine cerebral metabolic correlates of antidepressant response to ketamine. METHODS:Twenty-one subjects with BD currently in a depressed state underwent [(18) F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging after receiving a placebo infusion as well as after receiving a ketamine infusion. Metabolism was compared between ketamine and placebo infusions, and correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in regions of interest (ROIs) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were the main outcome measures. RESULTS:The study found that change in metabolism between sessions was significantly correlated with percentage change in MADRS scores in the right ventral striatum; subjects who showed the greatest improvement had the largest metabolic increase after ketamine infusion compared to placebo. In a voxel-wise analysis, subjects with BD had significantly lower glucose metabolism in the left hippocampus following the ketamine infusion than following the placebo infusion. In addition, metabolism in the subgenual anterior cingulate cortex (ACC) following the placebo infusion was positively correlated with percentage improvement in MADRS score following the ketamine infusion. CONCLUSIONS:Taken together, the results suggest that higher activity in the subgenual ACC may predict antidepressant response to ketamine. Ketamine administration altered glucose metabolism in areas known to be involved in mood disorders; these alterations may partially underlie ketamine's mechanism of action.
| S-EPMC3949142 | biostudies-literature
Project description:BackgroundA pilot study suggested lamotrigine may be more effective for bipolar depression with melancholic features. We tested this hypothesis in a pooled analysis of 5 randomized double-blind placebo-controlled trials of lamotrigine for acute bipolar depression.MethodsThe pooled sample consisted of 1072 adult outpatients. Depressive symptoms were assessed for 7 to 10 weeks with the Hamilton Depression Rating Scale and the Montgomery-Åsberg Depression Rating Scale. The outcome measure was end-trial response (score reduction ≥ 50%). Melancholic features were assessed with both the Structured Clinical Interview for DSM-IV and baseline depression scale items, according to DSM criteria.ResultsThe item-based melancholic specifier was associated with numerically larger treatment effects, although subgroup-treatment interactions in logistic regression models did not reach statistical significance. The small subgroup of patients with severe psychomotor retardation also appeared to benefit from lamotrigine. However, the Structured Clinical Interview for DSM-IV melancholic specifier was not associated with larger treatment effects. Baseline depression severity was inconsistently associated with response, depending on which scale was used to define severity. The 2 melancholia variables had poor agreement despite having similar prevalences.ConclusionsOur results do not clearly support the original hypothesis but do reinforce the importance of replicating secondary analyses of clinical trials with additional data.
| S-EPMC8083162 | biostudies-literature
Project description:ImportanceAcute agitation is common in patients with bipolar disorder and requires urgent management to relieve distress and to prevent escalation to aggressive behavior.ObjectiveTo evaluate the effect of orally absorbed, sublingual dexmedetomidine, a selective α2A-adrenergic receptor agonist on symptoms of acute agitation in patients with bipolar disorder.Design, setting, and participantsPhase 3, randomized, double-blind, placebo-controlled trial conducted in 15 sites in the US with enrollment between February 24, 2020, and April 27, 2020, and final follow-up on May 21, 2020. A total of 380 adults with bipolar I or II disorder were randomized and 362 completed the study.InterventionsParticipants were randomized to 3 groups: sublingual dexmedetomidine 180 μg (n = 127), sublingual dexmedetomidine 120 μg (n = 127), or placebo (n = 126).Main outcomes and measuresThe primary efficacy end point was the mean change from baseline at 2 hours for the Positive and Negative Syndrome Scale-Excited Component (PEC) total score. The range of possible total scores is 5 (absence of agitation) to 35 (extremely severe). The secondary end point was the earliest time of a statistically significant change in PEC total score from baseline for the drug vs placebo. On the primary efficacy end point, to account for multiplicity associated with comparing 2 sublingual dexmedetomidine doses with placebo, the 2-sided significance level for each dose vs placebo was set at .025.ResultsOf 380 patients randomized (mean age, 45.6 years; 54.8% women; and 56.1% Black individuals), 378 (99.5%) self-administered the study medication and completed the study. Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.0. Two hours after taking the medication, the mean changes from baseline in PEC total score were -10.4 for sublingual dexmedetomidine 180 μg, -9.0 for sublingual dexmedetomidine 120 μg, and -4.9 for placebo. Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were -5.4 (97.5% CI, -6.6 to -4.2) for 180 μg and -4.1 (97.5% CI, -5.3 to -2.9) for 120 μg (both doses P < .001 vs placebo). Treatment effects began 20 minutes after taking the medication among patients in the sublingual dexmedetomidine groups (least-square mean difference for 180 μg, -1.1 [97.5% CI, -2.0 to -0.2]; P = .007; for 120 μg, -1.0 [97.5% CI, -1.9 to -0.1]; P = .009). Adverse events occurred in 35.7% of patients taking 180 μg of dexmedetomidine, 34.9% taking 120 μg, and 17.5% taking placebo. The most common adverse events (≥5%) in the respective 180 μg, 120 μg, and placebo groups were somnolence (21.4% and 20.6% vs 4.8%); dry mouth (4.8% and 7.1% vs 0.8%); hypotension (6.3% and 4.8% vs 0%); and dizziness (5.6% and 5.6% vs 0.8%).Conclusions and relevanceAmong patients with mild to moderate agitation associated with bipolar disorder, treatment with a sublingual film formulation of dexmedetomidine 120 μg or 180 μg, compared with placebo, resulted in significantly greater reduction in the agitation score at 2 hours. Further research is needed to understand the spectrum of patients for whom this treatment would be effective and feasible and to better understand the clinical importance of the observed effect size.Trial registrationClinicalTrials.gov Identifier: NCT04276883.
| S-EPMC8864508 | biostudies-literature
Project description:Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression. We conducted a double-blind trial in which 35 patients with bipolar disorder type I or II in a depressive episode by DSM-IV criteria and in use of regular medication for the treatment of this phase of the disease were randomly allocated into two adjunctive treatment groups for 6 weeks: creatine monohydrate 6 g daily (N = 17) or placebo (N = 18). Primary efficacy was assessed by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS). We did not find a statistically significant difference in the comparison between groups for the change in score on the MADRS after 6 weeks in an intention-to-treat (ITT) analysis (p = 0.560; Cohen's d = 0.231). However, we found significant superiority of creatine add-on vs. placebo when we considered the remission criterion of a MADRS score ≤ 12 at week 6 analyzing the outcome of the 35 randomized patients on ITT (52.9% remission in the creatine group vs. 11.1% remission in the placebo group) and of the 23 completers (66.7% remission in the creatine group vs. 18.2% remission in the placebo group) (p = 0.012; OR = 9.0 and p = 0.036; OR = 9.0, respectively). Two patients who received creatine switched to hypomania/mania early in the trial. No clinically relevant physical side-effects were reported or observed. This proof-of-concept study, aiming to restore brain bioenergetics using an adjunctive mitochondrial modulator, is not conclusive on the efficacy of creatine add-on for bipolar depression, but suggests that this compound may have a role in the adjunctive treatment of this phase of the illness. Further investigation through randomized controlled trials with larger samples should be conducted to verify the efficacy of creatine supplementation for bipolar depression and also for subsyndromal depressive symptoms.
| S-EPMC5775367 | biostudies-literature
Project description:BackgroundBipolar I and II represent the most common and severe subtypes of bipolar disorder. Although bipolar I disorder is relatively well studied, the clinical characteristics and response to treatment of patients with bipolar II disorder are less well understood.MethodsTo compare the severity and burden of illness of patients with bipolar II versus bipolar I disorder, baseline demographic, clinical, and quality of life data were examined in 1900 patients with bipolar I and 973 patients with bipolar II depression, who were enrolled in five similarly designed clinical placebo-controlled trials of quetiapine immediate-release and quetiapine extended-release. Acute (8 weeks) response to treatment was also compared by assessing rating scale scores, including Montgomery-Åsberg depression rating scale, Hamilton rating scale for anxiety, Young mania rating scale, and clinical global impression-severity scores, in the bipolar I and II populations in the same pooled database.ResultsPatients with bipolar I and bipolar II depression were similar in demographics, baseline rating scale scores (depression, anxiety, mania, and quality of life), and mood episode histories. Symptom improvements in response to quetiapine were greater versus comparators (lithium, paroxetine, and placebo) at 4 and 8 weeks in both bipolar I and II patients. Patients with the bipolar II subtype initially showed slower responses to all treatments, but, by 8 weeks, attained similar symptom improvement as patients with bipolar I depression.ConclusionsPooled analysis of five clinical trials of quetiapine demonstrated that patients with bipolar II depression have a similar burden of illness and quality of life to patients with bipolar I. Bipolar II patients consistently showed a slower response to treatments than bipolar I patients, but, after 8 weeks of treatment with quetiapine, symptom improvements were similar between bipolar I and II disorder subtypes.
| S-EPMC4788818 | biostudies-literature
Project description:BackgroundGlutamatergic system abnormalities are implicated in the pathophysiology and treatment of both major depressive disorder and bipolar depression (BDep). Subsequent to studies demonstrating the rapid and robust antidepressant effects of ketamine, an N-methyl-D-aspartate receptor antagonist, other glutamatergic modulators are now being studied in clinical trials of mood disorders. A previous open-label study found that riluzole, administered in combination with the mood stabilizer lithium, had antidepressant effects.MethodsWe conducted a randomized, double-blind, placebo-controlled trial of riluzole monotherapy for the treatment of BDep. Nineteen subjects aged 18 to 70 years with bipolar disorder currently experiencing a depressive episode were tapered off of excluded medications and randomized to receive riluzole (50-200 mg/d) or placebo for 8 weeks. Rating scale scores (Montgomery-Åsberg Depression Rating Scale, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, and Young Mania Rating Scale) were obtained weekly.ResultsNo significant differences in depressive symptoms were observed between subjects treated with riluzole and those receiving placebo (P = 0.12). Anxiety scores were significantly lower in the placebo group (P = 0.046). An interim analysis was conducted that resulted in stopping the study because of futility; no subjects had achieved treatment response.ConclusionsAlthough we found no change in severity of depressive symptoms in BDep patients receiving riluzole compared with placebo, this trial was limited by the relatively high number of subject withdrawals and the small sample size. Thus, while riluzole monotherapy did not demonstrate efficacy for BDep, further studies examining riluzole as adjunctive therapy for this disorder may be warranted.Clinical Trials Identifier NCT00054704.
| S-EPMC5392145 | biostudies-literature
Project description:ImportanceTo our knowledge, no study has previously evaluated whether individuals with bipolar depression enriched a priori on the basis of biochemical and/or phenotypic immuno-inflammatory activation would differentially respond to an anti-inflammatory agent for the treatment of depressive symptoms.ObjectiveTo assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions.Design, setting, and participantsThis 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at 2 outpatient tertiary care sites in Canada and the United States. Eligible adults (aged 18-65 years) met DSM-5-defined criteria for bipolar I or bipolar II depression and exhibited pretreatment biochemical and/or phenotypic evidence of inflammatory activation. Participants were enrolled between October 1, 2015, and April 30, 2018. Data analysis was performed from May 1 through July 31, 2018, using modified intent-to-treat analysis.InterventionsPatients were randomized to receive 3 intravenous infusions of infliximab therapy or placebo at baseline and at weeks 2 and 6 of the 12-week study.Main outcomes and measuresThe primary efficacy outcome was baseline-to-end point (ie, week-12) change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. History of childhood maltreatment, as assessed by the Childhood Trauma Questionnaire, was used for exploratory analyses as 1 of several secondary outcomes.ResultsA total of 60 participants were randomized to infliximab (n = 29 [48%]; mean [SD] age, 45.0 [11.7] years; 20 of 28 female [71%]) or to placebo (n = 31 [52%]; mean [SD] age, 46.8 [10.2] years; 26 of 30 female [87%]) across study sites. Overall baseline-to-end point change in MADRS total score was observed across treatment × time interaction (χ2 = 10.33; P = .04); reduction in symptom severity was not significant at week 12 (relative risk, 1.09; 95% CI, 0.80-1.50; df = 1; P = .60). As part of a secondary analysis, a significant treatment × time × childhood maltreatment interaction was observed in which infliximab-treated individuals with childhood history of physical abuse exhibited greater reductions in MADRS total score (χ2 = 12.20; P = .02) and higher response rates (≥50% reduction in MADRS total score) (χ2 = 4.05; P = .04).Conclusions and relevanceInfliximab did not significantly reduce depressive symptoms compared with placebo in adults with bipolar depression. Results from secondary analyses identified a subpopulation (ie, those reporting physical and/or sexual abuse) that exhibited a significant reduction in depressive symptoms with infliximab treatment compared with placebo.Trial registrationClinicalTrials.gov identifier: NCT02363738.
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