A placebo-controlled, random-assignment, parallel-group pilot study of adjunctive topiramate for patients with schizoaffective disorder, bipolar type

OBJECTIVES: This pilot study evaluated the efficacy and safety of adjunctive topiramate compared with placebo in the treatment of patients with a diagnosis of schizoaffective disorder, bipolar type (SAD-BT). METHODS: A sample of 48 adult patients with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnosis of SAD-BT (supported by the Structured Clinical Interview for DSM-IV Axis I Disorder, Patient Edition) were randomly assigned in a 2:1 ratio (favoring topiramate) to 8 weeks of double-blind treatment with topiramate (100-400 mg/day) or placebo. Patients who had achieved a > or =20% decrease from baseline in their Positive and Negative Syndrome Scale (PANSS) total scores were given the opportunity to continue for an additional 8 weeks of double-blind treatment. The dosage of the study medicine was continued unchanged from the earlier 8-week study period. At the end of the study period, the study medicine was tapered and discontinued over a 2-week period. Primary efficacy was assessed at 8 weeks using the mean change between treatment groups of the PANSS total scores in the intent-to-treat population of randomized patients. Several secondary measures were also assessed. Safety analyses included monitoring of adverse events, vital signs, electrocardiogram (ECG) and laboratory values. RESULTS: Even though both treatments reduced scores on various psychopathology rating scales, adjunctive topiramate treatment (nearly 275 mg/day) did not show increased efficacy relative to placebo on the primary outcome measure (PANSS scale) or any of the secondary outcome measures. Topiramate-treated patients lost significantly more body weight than placebo-treated patients, which led to a significant reduction in body mass index (BMI). Relative to adjunctive placebo, topiramate-treated patients experienced higher rates of paresthesia, sedation, word-finding difficulty, sleepiness, and forgetfulness, but these differences were not statistically significant. There were no clinically significant abnormalities in either the ECG or laboratory results. There were no serious adverse events in the study. Further, there was no worsening of the PANSS total scores (to > or =10% from baseline), and no significant differences between the treatments on worsening of total Montgomery-Asberg Depression Rating Scale (MADRS) scores [1/13 (7.7%) for placebo; 1/25 (4.0%) for topiramate]. CONCLUSIONS: This pilot study did not support clinical efficacy for adjunctive topiramate treatment in patients with SAD-BT. There were no major safety or tolerability issues in this study. Confirming the results of other studies, topiramate-treated patients did experience greater body weight loss and reduction in BMI.     

A double-blind, placebo-controlled trial of sibutramine for clozapine-associated weight gain

This study sought to examine the effectiveness of sibutramine, a weight loss agent, on clozapine-associated weight gain. METHOD: This was a 12-week double-blind, placebo controlled, randomized trial of sibutramine for weight loss in obese clozapine-treated schizophrenia or schizoaffective disorder subjects. RESULTS: Ten patients were enrolled into the placebo group and 11 patients into the sibutramine group. There were no significant baseline differences between the two groups on age, gender, education, ethnicity, diagnosis, weight, body mass index (BMI), and blood pressure. At week 12, there were no significant differences in changes in weight, BMI, abdominal and waist circumferences, Hba1c, fasting glucose, or cholesterol levels. CONCLUSION: Sibutramine treatment did not show significant weight loss compared with placebo in clozapine-treated patients with schizophrenia or schizoaffective disorder. Further research with a larger sample size and longer follow-up duration is warranted.     

Management of atypical antipsychotic-induced weight gain in schizophrenic patients with topiramate

Patients treated with atypical antipsychotic drugs commonly gain excess weight. Because obesity is associated with considerable morbidity and decreased life expectancy, treatment of weight gain in these patients is critical. Topiramate, a fairly new anticonvulsant, promotes bodyweight loss in healthy obese subjects, patients with bipolar disorder, and patients with eating disorder. However, there are very few reports about the efficacy of topiramate for weight management in schizophrenic patients. We present the cases of three Taiwanese patients with schizophrenia whose bodyweight increased as a result of atypical antipsychotics treatment, then was controlled by topiramate without aggravation of their psychotic symptoms.     

The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder

Objectives: Topiramate, a structurally novel anticonvulsant, is being evaluated for other neurological conditions such as migraine, neuropathic pain, and essential tremor, and also for psychiatric conditions such as bipolar disorder, bulimia, post‐traumatic stress disorder, and schizoaffective disorder, in addition to obesity. This article will focus on the use of topiramate for bipolar disorder.

Methods: The pharmacological profile of topiramate is compared to other established and putative mood stabilizers, and a rationale for its use in bipolar disorder is presented. Data from open clinical trials of topiramate for depression, mania, and rapid‐cycling bipolar disorder are summarized. Preliminary data from one pilot dose‐finding, double‐blind, random‐assignment, placebo‐controlled, 3‐week parallel group study of two doses of topiramate for acute bipolar I mania is reported. Safety data regarding topiramate was reviewed. Finally, the potential place of this agent in bipolar illness is considered.

Results: The pharmacological advantages for topiramate are low protein binding, minimal hepatic metabolism and mainly unchanged renal excretion, a 24‐h half‐life, and minimal drug interactions. Open clinical studies suggest a 50–65% response for refractory bipolar mania, and a 40–56% response for refractory bipolar depression in mainly add‐on treatment. Open clinical studies of topiramate for rapid‐cycling subjects and those for comorbid bulimia, substance abuse, post‐traumatic stress, migraine, and obesity report effectiveness. The primary efficacy endpoint data (change from baseline Y‐MRS total scores) of the placebo‐controlled, random assignment parallel group phase II dose‐finding study were not statistically significant. However, once the antidepressant‐associated manias (28 of the sample, of 97 subjects) were excluded from the controlled study, the post‐hoc analyses indicated the higher dose (512 mg/day) topiramate treatment group showed a statistically significant reduction in endpoint Y‐MRS change scores as compared to placebo (p<0.03). Adverse effects of topiramate in bipolar subjects include attention, concentration and memory problems, fatigue, sedation, transient paraesthesias, nausea, and anorexia. Some subjects experience word‐finding difficulty. Weight loss may be seen in several topiramate‐treated subjects with bipolar disorder.

Conclusions: Topiramate appears to show promise as an addition to the agents available to treat bipolar disorder. More definitive controlled data on the efficacy of topiramate in the acute and continuation phases as well as for the prophylaxis either as monotherapy or as combination treatment of bipolar disorder are ongoing, and the results are awaited.     

A randomised,placebo-controlled 52-week trial of continued quetiapine treatment in recently depressed patients with bipolar I and bipolar II disorder

Objectives. To examine the longer-term efficacy of quetiapine monotherapy in bipolar depression in a preplanned pooling of data from the EMBOLDEN I and II studies. Methods. Patients (N = 584) with bipolar I or II disorder (most recent episode: depressed) who achieved remission after 8 weeks of treatment with quetiapine (300 or 600 mg/day) were randomised to the same quetiapine dose or placebo for 26–52 weeks or until mood event recurrence. Results. The risk for recurrence of a mood event was significantly lower with quetiapine than placebo (HR 0.51 (95% CI: 0.38–0.69); P < 0.001). Quetiapine was associated with a lower risk for recurrence of depressive events (HR 0.43 (95% CI: 0.30–0.62); P < 0.001) but recurrence of manic/hypomanic events was not significantly reduced (HR 0.75 (95% CI: 0.45–1.24; P = 0.263). There was a lower risk of recurrence of mood events in bipolar I (HR 0.58 (95% CI: 0.41–0.82), P = 0.002) and bipolar II patients (HR 0.33 (95% CI: 0.18–0.60), P < 0.001). Discontinuation rates due to adverse events were 4.3, 4.0 and 1.7% for quetiapine 300 mg/day, 600 mg/day and placebo, respectively. Safety data, including changes in lipid and glucose parameters, were consistent with the recognized profile of quetiapine. Conclusions. The efficacy of quetiapine monotherapy in bipolar depression is maintained during continued treatment for 26–52 weeks. Quetiapine was generally well tolerated.     

Open adjunctive ziprasidone associated with weight loss in obese and overweight bipolar disorder patients

Objective

To assess effectiveness and tolerability of open adjunctive ziprasidone for weight loss in obese/overweight patients with bipolar disorders (BD) in diverse mood states, taking weight gain-implicated psychotropic medications.

Method

22 obese and three overweight BD patients (20 female; 10 BD-I, 14 BD-II, 1 BD-NOS) with mean ± SD baseline body mass index (BMI) of 31.8 ± 2.5 kg/m² received ZIP (mean final dose 190 ± 92 mg/day) for mean of 79.2 ± 23.2 days. Weight was assessed at six weekly and three biweekly visits. Subjects entered the study in diverse mood states. At baseline, 21 were taking second-generation antipsychotics, 7 lithium, and 1 valproate, which could be reduced/discontinued at investigators’ discretion.

Results

Weight and BMI decreased from baseline to endpoint by 4.5 ± 3.4 kg and 1.6 ± 1.2 kg/m², respectively, at weekly rates of 0.37 kg and 0.13 kg/m², respectively (all p < 0.00001). 48% of patients had at least 5% weight loss. Obesity rate decreased from 88% to 35% (p < 0.0001). Waist circumference decreased 1.6 inches (p = 0.0001). Overall, mood did not change. Patients with at least moderate baseline mood symptoms experienced significant mood improvement, despite 72% patients decreasing/discontinuing weight gain-implicated psychotropic medications. Seven patients discontinued ZIP early: 3 for weight loss inefficacy, and 1 each for viral gastroenteritis, loss of consciousness, pneumonia with hypomania, and lost to follow up.

Conclusion

Open adjunctive ziprasidone may be effective for weight loss in obese/overweight BD patients taking weight gain-implicated psychotropic medications. These preliminary data should be considered with caution due to the open uncontrolled design, small sample size, and brief duration.     

Topiramate as add-on treatment for patients with bipolar mania

Objective: Anticonvulsant agents such as carbamazepine and valproate are alternatives to lithium in treating subjects with bipolar disorder. Topiramate (Topamax®), a new antiepileptic agent, is a candidate drug for bipolar disorder. We evaluated topiramate as adjunctive treatment for bipolar patients.
Methods: Eighteen patients with DSM-IV bipolar I disorder [mania (n=12), hypomania (n=1), mixed episode (n=5), and rapid cycling (n=6)], and two subjects with schizoaffective disorder  –  bipolar type, resistant to current mood-stabilizer treatment were initiated on topiramate, 25 mg/day, increasing by 25–50 mg every 3–7 days to a target dose between 100 and 300 mg/day, as other medications were held constant for 5 weeks. The Young Mania Rating Scale (Y-MRS), Hamilton Depression Rating Scale (Ham-D), and Clinical Global Impression-Bipolar Version Scale (CGI-BP) were used to rate subjects weekly.
Results: By 5 weeks, 12 (60%) subjects were responders, i.e., 50% reduction in the Y-MRS scores and a CGI of 'much' or 'very much improved'. Three subjects were 'minimally improved', four showed no change, and one was 'minimally worse'. Six subjects had parasthesia, three experienced fatigue, and two had 'word-finding' difficulties; in all cases, side effects were transient. All patients lost weight with a mean of 9.4 lb in 5 weeks, and a significant reduction in body mass index (BMI) occurred too.
Conclusions: Topiramate appears to have efficacy for the manic and mixed phases of bipolar illness. Other preliminary data suggest antidepressant efficacy too. Among obese bipolar subjects, the weight loss potential of topiramate may be beneficial. If controlled trials confirm these initial results, topiramate may be a significant addition to the available treatments for bipolar disorder.     

A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states

Objective:  Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania.
Methods:  After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5–20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values.
Results:  Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean ± SE changes in YMRS scores were observed on day 2 with asenapine (−3.0 ± 0.4) and olanzapine (−3.4 ± 0.4) versus placebo (−1.5 ± 0.5, both p < 0.01) and were maintained until day 21 (−10.8 ± 0.8 with asenapine, −12.6 ± 0.8 with olanzapine; both p ≤ 0.0001 versus placebo, −5.5 ± 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures.
Conclusions:  These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode.     

A randomized,double‐blind,controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder

McIntyre RS, Soczynska JK, Woldeyohannes HO, Miranda A, Vaccarino A, MacQueen G, Lewis GF, Kennedy SH. A randomized, double‐blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. Bipolar Disord 2012: 14: 697–706. © 2012 John Wiley & Sons A/S. Background: Neurocognitive deficits are prevalent, persistent, and implicated as mediators of functional impairment in adults with bipolar disorder. Notwithstanding progress in the development of pharmacological treatments for various phases of bipolar disorder, no available treatment has been proven to be reliably efficacious in treating neurocognitive deficits. Emerging evidence indicates that insulin dysregulation may be pertinent to neurocognitive function. In keeping with this view, we tested the hypothesis that intranasal insulin administration would improve measures of neurocognitive performance in euthymic adults with bipolar disorder. Methods: Sixty‐two adults with bipolar I/II disorder (based on the Mini International Neuropsychiatric Interview 5.0) were randomized to adjunctive intranasal insulin 40 IU q.i.d. (n = 34) or placebo (n = 28) for eight weeks. All subjects were prospectively verified to be euthymic on the basis of a total score of ≤ 3 on the seven‐item Hamilton Depression Rating Scale (HAMD‐7) and ≤ 7 on the 11‐item Young Mania Rating Scale (YMRS) for a minimum of 28 consecutive days. Neurocognitive function and outcome was assessed with a neurocognitive battery. Results: There were no significant between‐group differences in mean age of the subjects {i.e., mean age 40 [standard deviation (SD) = 10.15] years in the insulin and 39 [SD = 10.41] in the placebo groups, respectively}. In the insulin group, n = 27 (79.4%) had bipolar I disorder, while n = 7 (21.6%) had bipolar II disorder. In the placebo group, n = 25 (89.3%) had bipolar I disorder, while n = 3 (10.7%) had bipolar II disorder. All subjects received concomitant medications; medications remained stable during study enrollment. A significant improvement versus placebo was noted with intranasal insulin therapy on executive function (i.e., Trail Making Test–Part B). Time effects were significant for most California Verbal Learning Test indices and the Process Dissociation Task–Habit Estimate, suggesting an improved performance from baseline to endpoint with no between‐group differences. Intranasal insulin was well tolerated; no subject exhibited hypoglycemia or other safety concerns. Conclusions: Adjunctive intranasal insulin administration significantly improved a single measure of executive function in bipolar disorder. We were unable to detect between‐group differences on other neurocognitive measures, with improvement noted in both groups. Subject phenotyping on the basis of pre‐existing neurocognitive deficits and/or genotype [e.g., apolipoprotein E (ApoE)] may possibly identify a more responsive subgroup.     

Pedometer walking plus motivational interviewing program for Thai schizophrenic patients with obesity or overweight: a 12-week, randomized, controlled trial

Aim: The aim of this study was to design and examine a program called the ‘pedometer walking plus motivational interviewing (PWMI) program’ in schizophrenic patients who are obese or overweight. Methods: This was a 12‐week, randomized, parallel, open‐label, controlled trial in mildly ill schizophrenic patients with a body mass index (BMI) of 23.0 kg/m² or more. Each participant in the intervention or control group was given a leaflet entitled ‘What is a healthy lifestyle?’ The 1‐week, PWMI program consisted of five 1‐h sessions of individual motivational interviewing, group education, goal‐setting, and practising of pedometer walking. The pedometers were given to the intervention group only. Weight, height, BMI and waist circumference were assessed at baseline, week 4, week 8, and week 12. The primary outcome of this trial was the changed bodyweight at week 4, week 8, and week 12. Results: Of 64 participants, 32 each were randomly allocated to intervention and control groups. All participants completed the study. Only the means of changed bodyweight at week 12 were significantly different between groups (P = 0.03). At this week, the bodyweight of the intervention group decreased significantly more than that of the control group with a mean difference of 2.21 kg (95% confidence interval of 4.12–0.29). Conclusion: Increased physical activity by pedometer walking plus individual motivational interviewing may be an effective program for the reduction of bodyweight and BMI in Thai schizophrenic patients who are obese or overweight. Its efficacy may be comparable to other cognitive/behavioral programs. Further studies in larger sample sizes are warranted.     

Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study

Marcus R, Khan A, Rollin L, Morris B, Timko K, Carson W, Sanchez R. Efficacy of aripiprazole adjunctive to lithium or valproate in the long‐term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double‐blind, randomized study.
Bipolar Disord 2011: 13: 133–144. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Listen to interview with article author Objectives: To evaluate the efficacy and safety of aripiprazole (ARI) adjunctive to lithium (Li) or valproate (Val) (ARI + Li / Val) compared with placebo (PLB) adjunctive to Li or Val (PLB + Li / Val) as maintenance therapy for patients with bipolar I disorder who had an inadequate response to Li or Val monotherapy. Methods: Patients with a current manic/mixed episode received Li or Val for at least 2 weeks. Those with an inadequate response [Young Mania Rating Scale (YMRS) total score ≥ 16 and ≤ 35% decrease from baseline at 2 weeks] received adjunctive single‐blind ARI plus mood stabilizer. Patients who achieved stability [YMRS and Montgomery–Åsberg Depression Rating Scale (MADRS) score ≤ 12] for 12 consecutive weeks were randomized to double‐blind ARI (10–30 mg/day) or PLB + Li / Val. Relapse was monitored for 52 weeks. Adverse events (AEs) were also evaluated. Results: A total of 337 patients were randomized to ARI + Li / Val (n = 168) or PLB + Li / Val (n = 169). The Kaplan–Meier relapse rate at 52 weeks was 17% with ARI + Li / Val and 29% with PLB + Li / Val. ARI + Li / Val significantly delayed time to any relapse compared with PLB + Li / Val; hazard ratio = 0.54 (95% confidence interval: 0.33–0.89; log‐rank p = 0.014). The most common AEs ≥ 5% (ARI + Li / Val versus PLB + Li / Val) were headache (13.2% versus 10.8%), weight increase (9.0% versus 6.6%), tremor (6.0% versus 2.4%), and insomnia (5.4% versus 9.6%). Conclusions: Continuation of ARI + Li / Val treatment increased the time to relapse to any mood episode compared with Li or Val monotherapy, and was relatively well tolerated during the one‐year study. These findings suggest that there is a long‐term benefit in continuing ARI adjunctive to a mood stabilizer after sustained remission is achieved.     

Risperidone in the treatment of mixed state bipolar patients: Results from a 24-week, multicenter, open-label study in Korea

Aims:  The goal of the present study was to evaluate the efficacy of risperidone combined with mood stabilizers for treating bipolar mixed state.
Methods:  The present study was a 24-week, open-label, combination, prospective investigation of the efficacy of risperidone in combination with mood stabilizers. Risperidone (1–6 mg/day) was given in combination with mood stabilizers in flexible doses according to clinical response and tolerability for 114 patients in mixed or manic episode.
Results:  Forty-four patients met our criteria for mixed state bipolar disorder and 70 met the criteria for pure mania. Mean age for the subjects was 39.0 ± 11.0 years and 55.3% were female. The combination of risperidone with mood stabilizers significantly improved the scores on the Young Mania Rating Scale (YMRS), 17-item Hamilton Rating Scale for Depression (HAMD), 18-item Brief Psychiatric Rating Scale (BPRS), Global Assessment Scale (GAS), and Clinical Global Impression Scale for use in bipolar illness Severity (CGI-BP) at 24 weeks ( P  < 0.0001). Analysis of the YMRS, BPRS, GAS, and CGI-BP scores showed significant improvement in both the manic and mixed groups. The rate of response in YMRS scores was 84.2% ( n  = 96) and the rate of YMRS remission was 77.2% ( n  = 88) at week 24 in the total population. Seventy-four patients met both YMRS ≤ 12 and HAMD ≤ 7 at week 24 (64.9%). Risperidone was well tolerated, and adverse events were mostly mild.
Conclusion:  The combination of risperidone with mood stabilizers was an effective and safe treatment for manic symptoms and coexisting depressive symptoms of bipolar disorder.     

Comparing weight gain in the year prior to treatment for overweight and obese patients with and without binge eating disorder in primary care

Objective

To examine weight change trajectories among overweight and obese patients with binge eating disorder (BED) versus without (NBO) during the year prior to seeking treatment.

Methods

Participants were 97 (75 women, 22 men) overweight and obese patients recruited for the same weight-loss treatment in primary care; 26 (27%) met DSM-5 BED criteria. Participants were assessed with the Eating Disorder Examination and completed self-report questionnaires about their weight histories and the Beck Depression Inventory-II.

Results

Participants' self-reported current weight and measured current weight were significantly correlated and did not statistically differ. Reported weight changes during the year prior to seeking treatment differed significantly by group: BED patients gained an average of 18.3 lb (8.2 kg) whereas NBO patients gained an average of 1.5 lb (0.7 kg). Among BED patients, but not NBO, weight change during the prior year was positively correlated with greater eating-disorder psychopathology, binge-eating frequency, frequency of overeating at lunch and dinner, and depression scores. For the overall group, BED status and binge-eating frequency each made independent significant contributions to predicting weight change in the past year.

Conclusion

Findings suggest BED patients are gaining considerably more weight during the year prior to treatment than NBO patients. BED treatment may interrupt a steep weight gain trajectory and prevent further weight gain for BED patients suggesting need for early intervention. Primary care physicians should screen for BED when overweight and obese patients present with rapid weight gain.     

Effects of a 10-week weight control program on obese patients with schizophrenia or schizoaffective disorder: A 12-month follow up

Aims:  Weight gain secondary to antipsychotic medication is associated with many serious conditions, including type II diabetes mellitus, hypertension, and coronary heart disease, and also with poor medication compliance. Weight control programs may be of benefit to outpatients with schizophrenia, but also raise an issue of cost-effectiveness. We aimed to evaluate the effectiveness of a 10-week weight control program for outpatients taking atypical antipsychotics for treatment of schizophrenia, and to follow up the effects of this weight control program in controlling weight gain after termination of the program.
Methods:  A total of 33 patients with schizophrenia and antipsychotic-related obesity were enrolled in a 10-week multimodal weight control program. The patients' weights were recorded at baseline, week 4, week 8, week 10 (end of the intervention), week 12, week 24, and week 48. Secondary measures included blood sugar levels, cholesterol levels, triglyceride levels, quality of life and mental health.
Results:  For those who completed the weight control program, there was a mean weight loss of 2.1 kg by the end of the intervention, 3.7 kg over 6 months, and 2.7 kg over 12 months. The mean body mass index decreased by 0.8, 1.5 and 1.1 at week 10, week 24 and week 48, respectively, all with statistical significance.
Conclusions:  The 10-week weight control program was effective in terms of weight reduction among obese patients with schizophrenia or schizoaffective disorder, and the weight reduction effect lasted for up to 6 months, and up to 12 months in some cases.