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Effect of Sublingual Dexmedetomidine vs Placebo on Acute Agitation Associated With Bipolar Disorder: A Randomized Clinical Trial.
Preskorn, SH, Zeller, S, Citrome, L, Finman, J, Goldberg, JF, Fava, M, Kakar, R, De Vivo, M, Yocca, FD, Risinger, R
JAMA. 2022;(8):727-736
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IMPORTANCE Acute agitation is common in patients with bipolar disorder and requires urgent management to relieve distress and to prevent escalation to aggressive behavior. OBJECTIVE To 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 PARTICIPANTS Phase 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. INTERVENTIONS Participants were randomized to 3 groups: sublingual dexmedetomidine 180 μg (n = 127), sublingual dexmedetomidine 120 μg (n = 127), or placebo (n = 126). MAIN OUTCOMES AND MEASURES The 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. RESULTS Of 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 RELEVANCE Among 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 REGISTRATION ClinicalTrials.gov Identifier: NCT04276883.
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The Effect of DHA Supplementation on Cognition in Patients with Bipolar Disorder: An Exploratory Randomized Control Trial.
Ciappolino, V, DelVecchio, G, Prunas, C, Andreella, A, Finos, L, Caletti, E, Siri, F, Mazzocchi, A, Botturi, A, Turolo, S, et al
Nutrients. 2020;(3)
Abstract
Bipolar disorder (BD) is a severe mental disorder with a wide range of cognitive deficits, both in the euthymic and acute phase of the disease. Interestingly, in recent years, there has been a growing interest in investigating the impact of ω-3 polyunsaturated fatty acids on cognition in BD. In this context, the aim of this study is to evaluate the effect of docosahexaenoic acid (C22:6 ω-3, DHA) supplementation on cognitive performances in euthymic BD patients. This is an exploratory, single-centre, double-blind randomized controlled trial evaluating 12 weeks DHA supplementation (1250 mg daily) vs. a placebo (corn oil) in 31 euthymic BD patients compared to 15 healthy controls (HCs) on cognitive functions, assessed by the Brief Assessment of Cognition in Affective Disorder (BAC-A). Plasma levels of DHA were measured. After 12 weeks of treatment, no significant group differences were observed in all neuropsychological tests between the four groups, except for the emotion inhibition test, where HCs with DHA had higher scores compared to either BD with DHA (z = 3.9, p = 0.003) or BD with placebo (t = 3.7, p = 0.005). Although our results showed that DHA could be effective for ameliorating cognition in healthy subjects, future studies are still needed to clarify the impact of DHA on cognition in BD.
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Pilot study of a lifestyle intervention for bipolar disorder: Nutrition exercise wellness treatment (NEW Tx).
Sylvia, LG, Pegg, SL, Dufour, SC, Janos, JA, Bernstein, EE, Chang, WC, Hall, NE, Ellard, KK, Nierenberg, AA, Deckersbach, T
Journal of affective disorders. 2019;:278-283
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BACKGROUND Individuals with bipolar disorder (BD) are more likely than the general population to develop risk factors associated with cardiovascular disease, one of the leading causes of morbidity and mortality in this clinical population. To address this disproportionate medical burden, we developed Nutrition Exercise and Wellness Treatment (NEW Tx), a lifestyle intervention for individuals with BD. METHODS In this study, participants were randomized to NEW Tx (n = 19) or a treatment as usual waitlist (n = 19). We examine the intervention's efficacy to improve the physical and psychological outcomes of individuals with BD. Assessors were blind to participant condition throughout study duration. RESULTS The NEW Tx group reported increased weekly exercise duration and overall functioning, and decreased depression and illness severity over the study duration. However, only improvements in functioning were significantly greater in the NEW Tx group than in the control group. There were no group differences in weight loss or mood symptoms over the study duration. LIMITATIONS Limitations to this study include lack of objective measurement of exercise and a small and relatively homogeneous sample. CONCLUSIONS These data suggest that a manualized lifestyle intervention for BD may not be ideal to improve lifestyle changes in this clinical population. Further research is needed to pilot personalized approaches to creating a healthy lifestyle in BD.
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Quetiapine extended-release vs olanzapine for Japanese patients with bipolar depression: A Bayesian analysis.
Kishi, T, Ikuta, T, Matsuda, Y, Iwata, N
Neuropsychopharmacology reports. 2019;(3):256-259
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OBJECTIVE It is unknown whether there are differences in efficacy and safety between quetiapine extended-release, 300 mg/d (QUEXR300), and olanzapine, 5-20 mg/d (OLA), for Japanese patients with bipolar depression. METHODS We conducted a Bayesian analysis of data from phase 3 studies in Japan of QUEXR300 and OLA. Outcomes were remission rate (primary), response rate, improvement on the Montgomery-Åsberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale scores, discontinuation rate, and incidence of individual adverse events. We calculated the standardized mean difference (SMD) and the risk ratio (RR) and 95% credible interval (95% CrI) for continuous and dichotomous data, respectively. RESULTS There were no significant differences between QUEXR300 and OLA for any of the efficacy outcomes. QUEXR300 was associated with a higher incidence of somnolence than OLA (RR = 5.517; 95% CrI = 1.563, 19.787), while OLA was associated with greater increase body weight (SMD = -0.488; 95% CrI = -0.881, -0.089) and blood prolactin levels (SMD = -0.642; 95% CrI = -1.073, -0.213) than QUEXR300, and a greater decrease in high-density lipoprotein cholesterol levels (SMD = -0.408; 95% CrI = -0.785, -0.030) than QUEXR300. CONCLUSION Although the two drugs' efficacy did not differ, OLA increased the risk of metabolic syndrome and QUEXR300 the risk of somnolence. A large scale, long-term, head-to-head comparison study of QUEXR300 vs OLA for Japanese patients with bipolar depression is needed to confirm the results of the current study.
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A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo.
Berk, M, Turner, A, Malhi, GS, Ng, CH, Cotton, SM, Dodd, S, Samuni, Y, Tanious, M, McAulay, C, Dowling, N, et al
BMC medicine. 2019;(1):18
Abstract
BACKGROUND A phasic dysregulation of mitochondrial bioenergetics may operate in bipolar disorder, increased in mania and decreased in depression. We aimed to examine efficacy of two add-on treatments in bipolar depression: N-acetylcysteine (NAC) and NAC with a combination of nutraceutical agents that may increase mitochondrial biogenesis. METHODS A three-arm 16-week, double-blind, randomised, placebo-controlled trial, adjunctive to usual treatment, was conducted. Participants (n = 181) with bipolar disorder and current depressive symptoms were randomised to 2000 mg/day NAC (n = 59), 2000 mg/day NAC with the combination nutraceutical treatment (CT, n = 61), or placebo (n = 61). The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 16. Young Mania Rating Scale, Clinical Global Impression (CGI)-Improvement and CGI-Severity scales, Patient Global Impression scale, Social and Occupational Functioning Assessment Scale (SOFAS), Longitudinal Interval Follow-Up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT), and Quality of Life Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) were secondary outcomes. RESULTS One hundred forty-eight participants had post-randomisation data and were analysed (NAC = 52, CT = 47, Placebo = 49). No between-group differences were found for the rate of change between baseline and 16 weeks on any of the clinical and functioning variables. Improvements in MADRS, BDRS, SOFAS, and LIFE-RIFT scores from baseline to the week 20 post-discontinuation visit were significantly greater in the CT group compared to those in the placebo. At week 20, the CGI-I was significantly lower in the CT group versus placebo. Gastrointestinal symptoms were significantly greater in the NAC than in the placebo group. CONCLUSIONS These overall negative results, with no significant differences between groups detected at the primary outcome but some positive secondary signals, suggest either delayed benefit of the combination or an improvement of symptoms on withdrawal which warrants further exploration regarding the composition, mechanisms, and application of mitochondrial agents in illnesses characterised by mitochondrial dysfunction. TRIAL REGISTRATION ANZCTR ( ACTRN12612000830897 ).
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A Double-Blind, Placebo-Controlled, Pilot Study of Riluzole Monotherapy for Acute Bipolar Depression.
Park, LT, Lener, MS, Hopkins, M, Iadorola, N, Machado-Vieira, R, Ballard, E, Nugent, A, Zarate, CA
Journal of clinical psychopharmacology. 2017;(3):355-358
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BACKGROUND Glutamatergic 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. METHODS We 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. RESULTS No 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. CONCLUSIONS Although 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.
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Pragmatic replication trial of health promotion coaching for obesity in serious mental illness and maintenance of outcomes.
Bartels, SJ, Pratt, SI, Aschbrenner, KA, Barre, LK, Naslund, JA, Wolfe, R, Xie, H, McHugo, GJ, Jimenez, DE, Jue, K, et al
The American journal of psychiatry. 2015;(4):344-52
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OBJECTIVE Few studies targeting obesity in serious mental illness have reported clinically significant risk reduction, and none have been replicated in community settings or demonstrated sustained outcomes after intervention withdrawal. The authors sought to replicate positive health outcomes demonstrated in a previous randomized effectiveness study of the In SHAPE program across urban community mental health organizations serving an ethnically diverse population. METHOD Persons with serious mental illness and a body mass index (BMI) >25 receiving services in three community mental health organizations were recruited and randomly assigned either to the 12-month In SHAPE program, which included membership in a public fitness club and weekly meetings with a health promotion coach, or to fitness club membership alone. The primary outcome measures were weight and cardiorespiratory fitness (as measured with the 6-minute walk test), assessed at baseline and at 3, 6, 9, 12, and 18 months. RESULTS Participants (N=210) were ethnically diverse (46% were nonwhite), with a mean baseline BMI of 36.8 (SD=8.2). At 12 months, the In SHAPE group (N=104) had greater reduction in weight and improved fitness compared with the fitness club membership only group (N=106). Primary outcomes were maintained at 18 months. Approximately half of the In SHAPE group (51% at 12 months and 46% at 18 months) achieved clinically significant cardiovascular risk reduction (a weight loss ≥5% or an increase of >50 meters on the 6-minute walk test). CONCLUSIONS This is the first replication study confirming the effectiveness of a health coaching intervention in achieving and sustaining clinically significant reductions in cardiovascular risk for overweight and obese persons with serious mental illness.
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Melatonin decreases olanzapine induced metabolic side-effects in adolescents with bipolar disorder: a randomized double-blind placebo-controlled trial.
Mostafavi, A, Solhi, M, Mohammadi, MR, Hamedi, M, Keshavarzi, M, Akhondzadeh, S
Acta medica Iranica. 2014;(10):734-9
Abstract
Olanzapine is the frequently prescribed drug in children and adolescents with bipolar disorder, but unfortunately it has metabolic side-effects. On the other hand, in a number of melatonin studies on sleep cycle, regulation of metabolic abnormalities has been reported. Therefore, we aimed to study effects of melatonin in reducing metabolic side-effects of olanzapine in 11-17 year-old patients with bipolar disorder. Seventy-seven 11-17 year-old outpatients entered into the study after their initial diagnosis of bipolar mood disorder by a psychiatrist. After assessing inclusion and exclusion criteria, 48 patients consented to participate in the study. Of this number, 24 patients were allocated to olanzapine, lithium carbonate, and melatonin and 24 patients were allocated to olanzapine, lithium carbonate, and placebo. Young mania rating scale was performed at baseline. Before treatment initiation and at sixth and twelfth weeks after treatment, Lipid profile, Fasting Blood Sugar (FBS), Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) were measured. ANOVA with repeated measure and independent sample t-test were used for data analysis. Nineteen patients in each group completed the study and yielded data for analysis. ANOVA with repeated measure showed that FBS and Triglyceride (TG) (especially in boys) demonstrated greater increase in the placebo group compared to the melatonin group but the differences were not statistically significant. Melatonin significantly inhibited the rise in Total Cholesterol levels compared to placebo (P=0.032). Mean SBP rose more slowly in the melatonin group (1.05mmHg) compared to placebo (6.36 mmHg) (P=0.023). The trends in DBP did not show any significant pattern. Administration of melatonin along with olanzapine and lithium carbonate could significantly inhibit the rise in cholesterol level and SBP compared to placebo. The effect of melatonin on TG was more obvious in boys. Melatonin was more effective in prevention of SBP rise.
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Safety and efficacy of olanzapine in the long-term treatment of Japanese patients with bipolar I disorder, depression: an integrated analysis.
Katagiri, H, Tohen, M, McDonnell, DP, Fujikoshi, S, Case, M, Kanba, S, Takahashi, M, Gomez, JC
Psychiatry and clinical neurosciences. 2014;(7):498-505
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AIM: Safety and efficacy of long-term olanzapine treatment in Japanese patients with bipolar depression were assessed. METHODS An integrated analysis of data from two studies was performed in olanzapine-treated patients (n = 165) with bipolar depression. Study 1 was a 6-week, double-blind, global study. Patients were randomly assigned to olanzapine or placebo followed by 18 weeks of open-label treatment. Study 2 was an open-label extension of Study 1 involving only Japanese patients. Patients assigned to Pre-olanzapine and Pre-placebo in Study 1 were treated for 24 weeks (total olanzapine exposure 42 or 48 weeks) and newly recruited patients (New-olanzapine) were treated for 48 weeks. Safety outcomes included treatment-emergent adverse events and changes in metabolic parameters. Efficacy outcome was assessed with Montgomery-Åsberg Depression Rating Scale score. RESULTS Forty-three percent of patients completed the 42- or 48-week olanzapine treatment period. The most common treatment-emergent adverse event was weight increased (47.9%). Significant increases were seen in weight (3.5 kg), and in fasting glucose (3.5 mg/dL), fasting total cholesterol (8.1 mg/dL), and fasting triglycerides (35.1 mg/dL). Remission rates (Montgomery-Åsberg Depression Rating Scale total score ≤12 at any time) were 79.8% for the Pre-olanzapine group, 90.2% for the Pre-placebo group, and 85.0% for the New-olanzapine group. No patents developed mania during treatment. CONCLUSIONS Long-term use of olanzapine in a Japanese population with bipolar depression is associated with increases in weight and fasting metabolic measures, and also with improved depressive symptoms with avoidance of mania. Clinicians must carefully consider the benefits and risks of long-term therapy with olanzapine.
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Efficacy and safety of olanzapine for treatment of patients with bipolar depression: Japanese subpopulation analysis of a randomized, double-blind, placebo-controlled study.
Katagiri, H, Tohen, M, McDonnell, DP, Fujikoshi, S, Case, M, Kanba, S, Takahashi, M, Gomez, JC
BMC psychiatry. 2013;:138
Abstract
BACKGROUND The efficacy and safety of olanzapine monotherapy are evaluated in Japanese patients from a large, global study of bipolar depression. METHODS This is an analysis of Japanese patients from a 6-week, global (Japan, China, Korea, Taiwan, and the United States), randomized, double-blind, placebo-controlled, Phase 3 study of patients with a depressive episode of bipolar I disorder. The primary outcome was baseline-to-endpoint change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary outcome measures included the Clinical Global Impressions-Bipolar Version Severity of Illness Scale (CGI-BP), the 17-item Hamilton Depression Rating Scale (HAMD-17) total score, the Young Mania Rating Scale (YMRS) total score, and rates of response (≥50% baseline-to-endpoint reduction in MADRS total score), recovery, and remission. RESULTS Of the 156 Japanese patients, 104 had been allocated to olanzapine and 52 to placebo. All results are baseline-to-endpoint change. Compared to placebo, patients in the olanzapine group experienced greater improvement in the primary outcome measure, MADRS total score (-14.9 vs. -10.7; p = .01). They also had greater reductions in the following secondary measures: CGI- BP Depression (-1.41 vs. -0.89; p = .008), CGI-BP Bipolar (-1.31 vs. -0.83; p = .01), HAMD-17 (-11.7 vs. -7.9; p < .01), and YMRS (-0.32 vs. 0.34; p = .03). Differences in rates of response, recovery, and remission were not statistically significant. A greater proportion of olanzapine-treated patients reported treatment- emergent adverse events (87.5% vs. 59.6%; p < .001). Patients treated with olanzapine had greater increases in weight (p < .001) and fasting total cholesterol (p = .008); fasting triglycerides (p = .02), and fasting low-density lipoprotein (p = .01). There was a greater reduction in fasting high-density lipoprotein in olanzapine-treated patients (p = .01). Compared with placebo-group patients, more olanzapine-group patients shifted from borderline to high cholesterol (25.0% vs. 0.0%; p = .007) and had clinically significant weight gain (≥7% body weight) (20.2% vs. 1.9%; p = .001). CONCLUSIONS Results of this analysis support the efficacy and tolerability of olanzapine for the treatment of bipolar depression in Japanese patients. Results in this population were consistent with those seen in the more ethnically diverse parent study. In making treatment decisions for individual patients, clinicians should carefully consider the risks and benefits of olanzapine treatment. TRIAL REGISTRATION Clinicatrials.gov ID NCT00510146 Olanzapine Treatment of Patients with Bipolar I Disorder.