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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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Abstract
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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Review of Standard Laboratory Blood Parameters in Patients with Schizophrenia and Bipolar Disorder.
Memic-Serdarevic, A, Burnazovic-Ristic, L, Sulejmanpasic, G, Tahirovic, A, Valjevac, A, Lazovic, E
Medical archives (Sarajevo, Bosnia and Herzegovina). 2020;(5):374-380
Abstract
INTRODUCTION Symptomatic and etiopathologic heterogeneity of schizophrenia (SCH) and bipolar disorder (BD) can be adequately addressed using a dimensional approach to psychopathology, as well as interpreting physiological properties and markers as predictors of disease onset and relapse. Risk factors, genetic and environmental, are likely to modify the neurobiological processes characteristic of certain physiological processes that manifest to a greater degree of overlapping symptoms. One of the most common laboratory tests in psychiatric patients is a standard laboratory blood test. It gives us an insight into the general somatic condition of the patient. It assesses the ability to transport oxygen to tissues and carbon dioxide back to the lungs via erythrocytes (RBC) and hemoglobin (HGB) as their most important constituents, and is also an indicator of iron status and blood oxygenation. AIM: Schizophrenia (SCH) and bipolar disorder (BD) are psychiatric disorders whose complex etiology and pathogenesis are still far from known. A correlation between red blood cell abnormalities and these diseases has been recognized in some studies. One of the most common laboratory tests in psychiatric patients is a standard laboratory blood test. However, so far there is a small number of published papers that relate to the relationship between laboratory parameters of blood and the aim of this paper is to reveal more light in this subject. METHODS The research was done as an observational prospective clinical study that has evaluated different physiological and pathological parameters in patients with BD and SCH over a two-year period. A total of 159 patients with schizophrenia, 61 patients diagnosed with bipolar disorder and 82 healthy subjects participated in this study. RESULTS At baseline, BD compared to SCH patients had higher mean lymphocyte count (2,6±0,7 vs. 2,0±0,6x109; p=0,006) and haemoglobin concentration (146,8±12,2 vs. 140,2±14,7 g/L; p=0,03), and significantly lower red cell distribution width (13,6±2,2 vs. 14,7±1,8%; p=0,008). In both BD and SCH patients there was a significant number of patients with low red blood cells count and low haemoglobin concentration, and high MCH and MCHC at baseline and at 3 and 6 months of follow up. CONCLUSIONS The finding that SCH as well as BD differed from controls with respect to red blood cells, hemoglobin, lymphocytes, and average platelet count was consistent with previous findings and could be understood as a qualitative measure in the evaluation of this sample. The fact that no association with other parameters was found, as well as an association with the diagnosis, does not exclude that these associations can be found in larger samples.
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Lamotrigine compared to placebo and other agents with antidepressant activity in patients with unipolar and bipolar depression: a comprehensive meta-analysis of efficacy and safety outcomes in short-term trials.
Solmi, M, Veronese, N, Zaninotto, L, van der Loos, ML, Gao, K, Schaffer, A, Reis, C, Normann, C, Anghelescu, IG, Correll, CU
CNS spectrums. 2016;(5):403-418
Abstract
OBJECTIVES To meta-analytically summarize lamotrigine's effectiveness and safety in unipolar and bipolar depression. METHODS We conducted systematic PubMed and SCOPUS reviews (last search =10/01/2015) of randomized controlled trials comparing lamotrigine to placebo or other agents with antidepressant activity in unipolar or bipolar depression. We performed a random-effects meta-analysis of depression ratings, response, remission, and adverse effects calculating standardized mean difference (SMD) and risk ratio (RR) ±95% confidence intervals (CIs). RESULTS Eighteen studies (n=2152, duration=9.83 weeks) in patients with unipolar depression (studies=4, n=187; monotherapy vs lithium=1, augmentation of antidepressants vs placebo=3) or bipolar depression (studies=14, n=1965; monotherapy vs placebo=5, monotherapy vs lithium or olanzapine+fluoxetine=2, augmentation of antidepressants vs placebo=1, augmentation of mood stabilizers vs placebo=3, augmentation of mood stabilizers vs trancylpromine, citalopram, or inositol=3) were meta-analyzed. Lamotrigine's efficacy for depressive symptoms did not differ significantly in monotherapy vs augmentation studies (vs. placebo: p=0.98, I2=0%; vs active agents: p=0.48, I2=0%) or in unipolar vs bipolar patients (vs placebo: p=0.60, I2=0%), allowing pooling of each placebo-controlled and active-controlled trials. Lamotrigine outperformed placebo regarding depressive symptoms (studies=11, n=713 vs n=696; SMD=-0.15, 95% CI=-0.27, -0.02, p=0.02, heterogeneity: p=0.24) and response (after removing one extreme outlier; RR=1.42, 95% CI=1.13-1.78; p=0.003, heterogeneity: p=0.08). Conversely, lamotrigine did not differ regarding efficacy on depressive symptoms, response, or remission from lithium, olanzapine+fluoxetine, citalopram, or inositol (studies=6, n=306 vs n=318, p-values=0.85-0.92). Adverse effects and all-cause/specific-cause discontinuation were similar across all comparisons. CONCLUSIONS Lamotrigine was superior to placebo in improving unipolar and bipolar depressive symptoms, without causing more frequent adverse effects/discontinuations. Lamotrigine did not differ from lithium, olanzapine+fluoxetine, citalopram, or inositol.
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Effects of orally disintegrating vs regular olanzapine tablets on body weight, eating behavior, glycemic and lipid indices, and gastrointestinal hormones: a randomized, open comparison in outpatients with bipolar depression.
Bobo, WV, Epstein, RA, Shelton, RC
Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists. 2011;(3):193-201
Abstract
BACKGROUND This randomized, open-label trial aimed to compare the metabolic effects of olanzapine orally disintegrating tablets (ODT) and solid oral tablets (SOT) in bipolar depressed and mixed outpatients. METHODS Participants were openly randomized to receive olanzapine ODT (n = 13) or SOT (n = 10), 10 to 20 mg, once daily. Weight, body mass index (BMI), Food Craving Inventory (FCI), and Three-Factor Eating Questionnaire (3-FEQ) scores were assessed at baseline and at weeks 1, 2, 4, 6, and 8. Fasting glucose and lipid levels were assessed at baseline and at week 8. Insulin and leptin concentrations were measured just prior to olanzapine baseline dosing, 1 and 2 hours following administration of baseline dose, and at weeks 4 and 8. RESULTS Patients showed significant increases in weight, BMI, and leptin area under the concentration-time curve (AUC), but not in FCI or 3-FEQ scores, over 8 weeks of treatment with olanzapine ODT and SOT. However, no significant differences between olanzapine formulations (ODT vs SOT) were observed in any of the measures assessed, except for a significantly lower triglyceride concentration in the ODT group at week 8. CONCLUSIONS There was no consistent difference in metabolic profile between olanzapine ODT and SOT formulations during short-term treatment of bipolar depressed patients. Potential differences related to effects on triglyceride concentration warrant further confirmation.
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A pilot pharmacotherapy trial for depressed youths at high genetic risk for bipolarity.
Findling, RL, Lingler, J, Rowles, BM, McNamara, NK, Calabrese, JR
Journal of child and adolescent psychopharmacology. 2008;(6):615-21
Abstract
Children and adolescents who are the offspring of a bipolar parent and who first present with major depressive disorder (MDD) are at high risk for eventually developing bipolar disorder. In this report, the authors describe a group of 9 such high-risk children and adolescents with MDD, aged 7-16 years, who were randomized to receive treatment with either paroxetine monotherapy or combination paroxetine-divalproex sodium therapy. In the long-term management of depressive symptomatology in these patients, neither treatment appeared to be particularly effective. As a result, future treatment studies in this population appear to be warranted, not only due to the putative impending risk of developing bipolar disorder, but also the manifest risk of current depressive episodes.
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Olanzapine versus divalproex versus placebo in the treatment of mild to moderate mania: a randomized, 12-week, double-blind study.
Tohen, M, Vieta, E, Goodwin, GM, Sun, B, Amsterdam, JD, Banov, M, Shekhar, A, Aaronson, ST, Bardenstein, L, Grecu-Gabos, I, et al
The Journal of clinical psychiatry. 2008;(11):1776-89
Abstract
OBJECTIVE To evaluate the efficacy and safety of olanzapine, divalproex, and placebo in a randomized, double-blind trial in mild to moderate mania (DSM-IV-TR criteria). METHOD The study was conducted from October 2004 to December 2006. A total of 521 patients from private practices, hospitals, and university clinics were randomly assigned to olanzapine (5-20 mg/day), divalproex (500-2500 mg/day), or placebo for 3 weeks; those completing continued with a 9-week double-blind extension. Efficacy (mean change in Young Mania Rating Scale [YMRS] total score was the primary outcome) and safety were assessed. RESULTS After 3 weeks of treatment, olanzapine-treated (N = 215) and placebo-treated (N = 105) patients significantly differed in YMRS baseline-to-endpoint total score change (p = .034; least squares [LS] mean: -9.4 and -7.4, respectively). Such changes were not significantly different between olanzapine vs. divalproex (N = 201) or divalproex vs. placebo. After 12 weeks of treatment, olanzapine- and divalproex-treated patients significantly differed in YMRS baseline-to-endpoint changes (p = .004; LS mean: -13.3 and -10.7, respectively). Of observed cases, 35.4% (35/99; 3 weeks) to 57.1% (28/49; 12 weeks) had valproate plasma concentrations lower than the recommended valproate therapeutic range, but these patients' YMRS scores were lower than those of patients with valproate concentrations above/within range. Compared with divalproex, after 12 weeks, olanzapine-treated patients had significant increases in weight (p < .001) and in glucose (p < .001), triglyceride (p = .003), cholesterol (p = .024), uric acid (p = .027), and prolactin (p < .001) levels. Divalproex-treated patients had significant decreases in leukocytes (p = .044) and platelets (p < .001) compared with olanzapine after 12 weeks of treatment. The incidence of potentially clinically significant weight gain (≥ 7% from baseline) was higher with olanzapine than with divalproex (3-week: p = .064, 6.4% vs. 2.7%; 12-week: p = .002, 18.8% vs. 8.5%; respectively). CONCLUSION Olanzapine was significantly more efficacious than placebo but not divalproex at 3 weeks and significantly more efficacious than divalproex at 12 weeks. Olanzapine-treated patients had significantly greater increases in weight and in glucose, cholesterol, triglyceride, uric acid, and prolactin levels than divalproex-treated patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00094549.
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An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression.
Zarate, CA, Quiroz, JA, Singh, JB, Denicoff, KD, De Jesus, G, Luckenbaugh, DA, Charney, DS, Manji, HK
Biological psychiatry. 2005;(4):430-2
Abstract
BACKGROUND Preclinical and clinical evidence indicate that the glutamatergic system might play a role in the pathophysiology of mood disorders. This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in bipolar depression. METHODS This was an 8-week add-on study of riluzole in combination with lithium in acutely depressed bipolar patients aged 18 years and older. After open treatment with lithium for a minimum period of 4 weeks, subjects who continued to have a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥20 received riluzole (50-200 mg/day) for 8 weeks. RESULTS Fourteen bipolar depressed patients entered the study. The linear mixed models for total MADRS score showed a significant treatment effect. No switch into hypomania or mania was observed. Overall, riluzole was well tolerated. CONCLUSIONS Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression.
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A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder.
Zajecka, JM, Weisler, R, Sachs, G, Swann, AC, Wozniak, P, Sommerville, KW
The Journal of clinical psychiatry. 2002;(12):1148-55
Abstract
BACKGROUND This study compared the efficacy, safety, and tolerability of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. METHOD This randomized, 12-week, double-blind, parallel-group, multicenter study included DSM-IV-defined bipolar disorder type I patients hospitalized for acute mania and randomly assigned to treatment with divalproex or olanzapine. After an inpatient period of up to 21 days, subjects were followed as outpatients. Dose adjustment was permitted during the inpatient period. Efficacy was assessed using change from baseline in Mania Rating Scale (MRS) score to day 21; other efficacy measures included the Brief Psychiatric Rating Scale, the Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Part I, Severity of Illness scale. The primary safety endpoint was change from baseline in weight. Other safety and tolerability endpoints included spontaneous adverse event reporting and changes from baseline in laboratory measures and vital signs. RESULTS 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomly assigned to treatment. No significant differences between groups were found for any efficacy variable for change from baseline to day 21. Mean MRS score changes from baseline to day 21 were -14.8 for divalproex and -17.2 for olanzapine (p =.210). A significantly (p <.05) greater proportion of olanzapine-treated subjects experienced somnolence, weight gain, edema, rhinitis, and speech disorder (slurred speech); no adverse events were significantly greater in the divalproex group. A number of laboratory measures also demonstrated significant treatment differences, but the clinical significance of many of these is uncertain. Mean body weight changes were significantly greater in the olanzapine group (+ 8.8 lb [+ 4.0 kg]) than the divalproex group (+ 5.5 lb [+ 2.5 kg], p <.050). One death occurred during the study (olanzapine group, diabetic ketoacidosis). CONCLUSION No significant difference in efficacy was found between treatment groups. Divalproex was associated with a more favorable adverse event profile and significantly less weight gain than olanzapine.
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Acute antimanic efficacy and safety of oxcarbazepine in an open trial with an on-off-on design.
Hummel, B, Walden, J, Stampfer, R, Dittmann, S, Amann, B, Sterr, A, Schaefer, M, Frye, MA, Grunze, H
Bipolar disorders. 2002;(6):412-7
Abstract
RATIONALE AND OBJECTIVES Carbamazepine has shown reasonable antimanic properties, but its use has been limited because of enzyme-inducing effects. The keto-derivative oxcarbazepine (OXC) is very similar to carbamazepine, however, the metabolic pathway is different. OXC is not metabolized to the 10, 11-epoxide, which seems to be responsible for several undesirable side-effects of carbamazepine and furthermore OXC has less enzyme-inducing properties. METHODS In this non-random open label study, patients were treated with OXC for 14 days, crossed over to no OXC for 7 days, and then crossed back over to OXC for the remaining 14 days. OXC was titrated to a final dose in a range of 900-2100 mg due to individual response. Treatment success was defined as a reduction of the original Young Mania Rating Scale (YMRS) score of more than 50% at the end of study period. RESULTS Four of the 12 included patients (33%) met defined response criteria at the end of study period. Fifty percentage of the patients had to be prematurely excluded from the trial. The mean YMRS scores of the on-periods were obviously different from the off-period. Forty-two percentage of the patients experienced side-effects leading to premature discontinuation in two of 12 patients. CONCLUSION Antimanic activity of OXC was demonstrated in this pilot study only for patients with mild or moderate manic symptoms. Further studies are encouraged to clarify OXC's role as mood-stabilizer and assess whether it has a profile similar to that of carbamazepine.
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Protein kinase C and phospholipase C activity and expression of their specific isozymes is decreased and expression of MARCKS is increased in platelets of bipolar but not in unipolar patients.
Pandey, GN, Dwivedi, Y, SridharaRao, J, Ren, X, Janicak, PG, Sharma, R
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2002;(2):216-28
Abstract
Phospholipase C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide (PI) signaling system. To examine if the abnormalities observed in the PI signaling system of patients with affective disorders, reported in previous studies, are related to abnormalities in one or more of its components, we studied PKC, PI-PLC activity, the expression of their specific isozymes, and expression of myristoylated alanine-rich C-kinase substrate (MARCKS) in platelets obtained from 15 drug-free hospitalized patients with bipolar disorder and 15 with major depressive disorder (unipolar) and from 15 nonhospitalized normal control subjects. We observed a significant decrease in PI-PLC and PKC activity and the expression of selective PKC alpha, betaI, betaII, and PLC delta(1) isozymes in membrane and cytosol fraction of platelets from bipolar but not unipolar patients. On the other hand, the level of MARCKS was significantly increased in membrane and cytosol fraction of platelets from patients with bipolar but not unipolar disorders. These results suggest that alterations in PKC, PLC, and MARCKS may be involved in the pathophysiology of bipolar illness.