Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks

Objective: Long‐term antidepressant (AD) treatment for depression in bipolar disorder (BPD) patients is highly prevalent, but its benefits and risks remain uncertain, encouraging this meta‐analysis of available research. Method: We reviewed randomized controlled trials for BPD involving ≥6 months of treatment with AD ± mood stabilizer (MS) vs. placebo ± MS, using meta‐analyses to compare reported risks of new depression vs. mania. Results: In seven trials (350 BPD patients) involving 12 contrasts, long‐term treatments that included ADs yielded 27% lower risk of new depression vs. MS‐only or no treatment [pooled relative risk, RR = 0.73; 95% CI 0.55–0.97; number‐needed‐to‐treat (NNT) = 11], but 72% greater risk for new mania [RR = 1.72; 95% CI 1.23–2.41; number‐needed‐to‐harm (NNH) = 7]. Compared with giving an MS‐alone, adding an AD yielded neither major protection from depression (RR = 0.84; 95% CI 0.56–1.27; NNT = 16) nor substantial increase in risk of mania (RR = 1.37; 95% CI 0.81–2.33; NNH = 16). Conclusion: Long‐term adjunctive AD treatment was not superior to MS‐alone in BPD, further encouraging reliance on MSs as the cornerstone of prophylaxis.     

Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials

CONTEXT: Recommendations of treatment guidelines concerning the use of second-generation antipsychotic (SGA) agents for acute mania vary substantially across committees or working groups. Meta-analyses addressing the use of SGAs in the treatment of acute mania are lacking. OBJECTIVE: To conduct a meta-analysis of the efficacy and safety of SGAs in the treatment of acute mania. DATA SOURCES: Randomized controlled trials comparing SGAs with placebo, first-generation antipsychotic drugs, or mood stabilizers (MSs) in the treatment of acute mania were searched for in the PsiTri and MEDLINE databases (last search: May 2006). STUDY SELECTION: The abstracts, titles, and index terms of studies were searched using the following key words: aripiprazole, amisulpride, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zotepine in conjunction with mania, manic, and bipolar. DATA EXTRACTION: Data on efficacy, global dropout, dropout due to adverse events, dropout due to inefficacy, weight gain, rate of somnolence, and extrapyramidal symptoms were extracted and combined in a meta-analysis. DATA SYNTHESIS: A total of 24 studies with 6187 patients were included. The SGAs were significantly more efficacious than placebo. The analysis demonstrated that adding antipsychotic agents to MS treatment was significantly more effective than treatment with MSs alone. The SGAs displayed efficacy comparable with that of MSs. Some SGAs seemed to induce more extrapyramidal symptoms than placebo. The SGAs were also associated with higher rates of somnolence than placebo. CONCLUSION: Currently available data suggest that combining SGAs and MSs is the most efficacious treatment of acute mania.     

Metabolic effects of second‐generation antipsychotics in bipolar youth: comparison with other psychotic and nonpsychotic diagnoses

Moreno C, Merchán‐Naranjo J, Álvarez M, Baeza I, Alda JA, Martínez‐Cantarero C, Parellada M, Sánchez B, de la Serna E, Giráldez M, Arango C. Metabolic effects of second‐generation antipsychotics in bipolar youth: comparison with other psychotic and nonpsychotic diagnoses.
Bipolar Disord 2010: 12: 172–184. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Despite known metabolic effects of second‐generation antipsychotics (SGAs) on children and adolescents, comparative effects in youth with different diagnoses remain underreported. We compared differences in metabolic changes three months after starting treatment with SGAs in youth with bipolar disorder and with other psychotic and nonpsychotic disorders. Methods: Weight and metabolic differences among diagnostic groups before and three months after starting treatment with SGAs were compared in a naturalistic cohort of children and adolescents (14.9 ± 3.0 years) diagnosed with bipolar disorder (n = 31), other psychotic disorders (n = 29), and other nonpsychotic disorders (n = 30), with no (35.6%) or very little (6.6 ± 9.0 days) previous exposure to antipsychotics. Composite measurements of significant weight gain [weight increase ≥ 5% at three months or increase ≥ 0.5 in body mass index (BMI) z‐score] and ‘risk for adverse health outcome’ (≥ 95^th BMI percentile, or ≥ 85^th BMI percentile plus presence of one other obesity‐related complication) were included. SGAs (risperidone, olanzapine, and quetiapine) were prescribed in comparable proportion among groups. Results: Baseline weight and metabolic indices were not significantly different among diagnoses. Three months after starting treatment with SGAs, more than 70% patients had significant weight gain, BMI z‐score increased in all diagnostic groups (p < 0.001 for all comparisons), total cholesterol increased in the bipolar (p = 0.02) and psychotic (p = 0.01) disorder groups, low‐density lipoprotein cholesterol increased in the bipolar group (p = 0.02), and free T4 decreased in the psychotic disorder group (p = 0.05). More patients with bipolar disorder presented overweight plus ≥ 1 obesity‐related complication at follow‐up. Conclusions: There are early weight gain and metabolic changes across diagnoses in youth treated with SGAs.     

Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials

OBJECTIVE: To evaluate the efficacy and tolerability of topiramate monotherapy in adults with acute manic or mixed episodes of bipolar I disorder. METHODS: In four trials, adults hospitalized with acute mania, a diagnosis of bipolar I disorder, history of > or =1 previous manic or mixed episodes, and > or =20 Young Mania Rating Scale (YMRS) score were randomized to double-blind treatment with topiramate (target doses: 200, 400, or 600 mg/day) or placebo; two trials included an active comparator (lithium, 1500 mg/day). The core study duration in all trials was 3 weeks; three trials also had 9-week double-blind extensions. The primary efficacy variable was mean change from baseline in YMRS in the core 3-week study. RESULTS: Changes in YMRS score during 3 weeks were not significantly different for topiramate versus placebo (mean YMRS reductions, -5.1 to -8.4). Mean YMRS reductions in lithium-treated groups were significantly greater (p < or = 0.001 versus placebo and topiramate). A similar pattern was observed after 12 weeks of double-blind treatment in studies with double-blind extensions. Paresthesia, appetite decrease, dry mouth, and weight loss were more frequently associated with topiramate than with placebo. CONCLUSIONS: These studies do not support the efficacy of topiramate as monotherapy in acute mania or mixed episodes in adults with bipolar I disorder. Topiramate was not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression. Lithium was confirmed as an effective therapy in this population.     

One-year incidence rates of tardive dyskinesia in children and adolescents treated with second-generation antipsychotics: a systematic review

Objective: The aim of this study was to assess the 1-year risk of second-generation antipsychotics (SGAs) for tardive dyskinesia (TD) in children and adolescents with assumed minimal past exposure to first-generation antipsychotics. Method: We performed a systematic review and exploratory meta-analysis of long-term studies with SGAs, lasting at least 11 months and reporting on new cases of TD in patients less than 18 years old. Results:In 10 studies, 783 youth (mean age: 9.74 years, 79.2% prepubertal, 81.6% male, 78.4% white) received risperidone (n = 737, mean dose: 1.58 mg/day), quetiapine (n = 27, mean dose: 378.7 mg/day), or olanzapine (n = 19, mean dose: 10.4 mg/day) for a weighted mean of 329.6 days. Diagnoses included disruptive behavior disorders (n = 688, 87.9%), bipolar disorder (n = 52, 6.6%), schizophrenia/schizoaffective disorder (n = 26, 3.3%) and autism spectrum disorders (n = 17, 2.2%). Eight studies were open-label trials, two were retrospective chart reviews, and none included a comparator. Overall, three new cases of TD emerged during long-term treatment with SGAs of up to 3 years, resulting in crude and annualized TD rates of 0.38% (95% confidence interval, CI, 0.079-1.11) and 0.42% (95% CI, 0.087-1.24). The crude and annualized TD rates for risperidone (n = 737) were 0.27% (95% CI, 0.033-0.97) and 0.30% (95% CI, 0.037-1.10), respectively. In the two cases with information, TD resolved within weeks after antipsychotic discontinuation. Conclusions: Results across 10 studies suggest relatively low 1-year TD rates in pediatric patients treated with SGAs. However, the available data base is limited by the small sample size of studies with SGAs other than risperidone and by the use of relatively low doses, which may have obscured a potentially greater risk for TD in children and adolescents treated with higher total SGA doses and for longer durations. Large, long-term studies of various SGAs, using state-of-the art methodology, are needed before firm conclusions can be reached about the risk of TD in pediatric patients treated long-term with SGAs.     

Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis

Purpose: Evaluate the clinical comparability of new antiepileptic drugs (AEDs) in partial refractory epilepsy. Methods: Systematic review of randomized trials (RCTs) comparing a new AED (add‐on treatment) with placebo or another AED. Primary outcomes: responder (≥50% seizure reduction) and withdrawal (tolerability) rates. Pooled estimates of odds ratios (ORs) and number needed treat/harm (NNT/NNH) taking into account baseline risk were derived by random‐effects meta‐analysis. Adjusted frequentist indirect comparisons between AEDs were estimated. Key Findings: Sixty‐two placebo‐controlled (12,902 patients) and eight head‐to‐head RCTs (1,370 patients) were included. Pooled ORs for responder and withdrawal rates (vs. placebo) were 3.00 [95% confidence interval (CI) 2.63–3.41] and 1.48 (1.30–1.68), respectively. Indirect comparisons of responder rate based on relative measurements of treatment effect (ORs) favored topiramate (1.52; 1.06–2.20) in comparison to all other AEDs, whereas gabapentin (0.67; 0.46–0.97) and lacosamide (0.66; 0.48–0.92) were less efficacious, without significant heterogeneity. When analyses were based on absolute estimates (NNTs), topiramate and levetiracetam were more efficacious, whereas gabapentin and tiagabine were less efficacious. Withdrawal rate was higher with oxcarbazepine (OR 1.60; 1.12–2.29) and topiramate (OR 1.68; 1.07–2.63), and lower with gabapentin (OR 0.65; 0.42–1.00) and levetiracetam (OR 0.62; 0.43–0.89). Significance: The differences found are of relatively small magnitude to allow a definitive conclusion about which new AED(s) has superior effectiveness. This uncertainty probably reflects the limitations of conclusions based on indirect evidence. The process of pharmacologic clinical decision making in partial refractory epilepsy probably depends more on other aspects, such as individual patient characteristics and pharmacoeconomics, than on available controlled randomized evidence.     

Lack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy

PURPOSE: To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. METHODS: The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI). RESULTS: The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 microg/ml versus 8.1 microg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 microg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 microg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 microg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo. CONCLUSIONS: LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.     

Impact of obsessive‐compulsive disorder on the antimanic response to olanzapine therapy in youth with bipolar disorder

Joshi G, Mick E, Wozniak J, Geller D, Park J, Strauss S, Biederman J. Impact of obsessive‐compulsive disorder on the antimanic response to olanzapine therapy in youth with bipolar disorder.
Bipolar Disord 2010: 12: 196–204. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: To compare antimanic response to olanzapine therapy in youth with bipolar disorder (BPD) based on the status of comorbidity with obsessive‐compulsive disorder (OCD). Methods: Secondary analysis of identically designed 8‐week open‐label trials of olanzapine therapy in youth with BPD. Severity of mania assessed with the Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI) scales. Results: Of the 52 BPD subjects (mean age 8.4 ± 3.1 years) enrolled in the olanzapine trials (mean dose 8.5 ± 4.3 mg/day), 39% (n = 20) met criteria for comorbid OCD. Antimanic response in BPD subjects was significantly worse in the presence of comorbid OCD (YMRS mean reduction: ?5.9 ± 13.1 versus ?13.7 ± 18.8, p = 0.04; ≥ 30% reduction: 25% versus 63%, p = 0.008; CGI‐Improvement score ≤ 2: 25% versus 68%, p = 0.003). There was no difference in the rate of dropouts (50% versus 29%, p = 0.2) or adverse effects in BPD subjects with or without comorbid OCD. Conclusions: Less than expected antimanic response to olanzapine therapy in the presence of comorbidity with OCD suggests that OCD is an important functionally impairing psychiatric comorbidity that may impact the efficacy of antimanic agents in youth with BPD. This study is limited by its design of secondary analysis of data from trials of an uncontrolled nature. Further prospective controlled trials are warranted.     

Pharmacokinetics and safety of adjunctive topiramate in infants (1–24 months) with refractory partial‐onset seizures: A randomized,multicenter, open‐label phase 1 study

Purpose: To characterize the pharmacokinetics of adjunctive topiramate in infants (1–24 months) with refractory partial‐onset seizures (POS); also to evaluate safety and tolerability of topiramate in the dose range of 3–25 mg/kg/day. Methods: In this open‐label phase 1 study, infants (N = 55) with refractory POS receiving at least one concurrent antiepileptic drug (AED) were enrolled. Infants were stratified by age and randomly assigned to one of four topiramate target dose groups (3‐, 5‐, 15‐, or 25 mg/kg/day). Treatment was initiated at 3 mg/kg/day with titration to the target dose by weekly dose escalation. Topiramate was administered daily in two divided doses as oral liquid (5 mg/ml for infants <9 kg or those who could not tolerate solid foods) or sprinkle capsule (25 mg) formulations. Following seven consecutive days of topiramate administration at the target dose, four blood samples were collected from each infant for pharmacokinetic assessments (predose, 1–3, 4–6, and 8–10 h postdose). Key Findings: Fifty‐five infants (mean [SD] age in months: 11.4 [5.79]) with POS were enrolled, of whom 33% had seizures with or without secondary generalization. Complete pharmacokinetic profiles were obtained in 35 infants in whom mean plasma topiramate concentration–time profiles demonstrated linear pharmacokinetics (predose topiramate concentrations [C_trough] and area under the plasma concentration–time curve from time 0 through 12 h [AUC_{12 h}]) of topiramate over the dose range studied). Apparent steady state oral clearance (CL_ss/F) remained similar across all topiramate target dose groups and was independent of creatinine clearance, age, and weight. Mean values for CL_ss/F were approximately twofold greater in infants receiving concomitant enzyme‐inducing AEDs versus enzyme‐inhibiting AEDs. Topiramate was well tolerated and safety findings were consistent with previous reports in children and adults. Most common treatment emergent adverse events (≥10%) were upper respiratory tract infection, fever, vomiting, somnolence, and anorexia. Significance: In infants (1–24 months), topiramate exhibited linear steady state pharmacokinetics over the dose range 3–25 mg/kg/day, and CL_ss/F of topiramate was independent of dose. Moreover, the concomitant enzyme‐inducing AEDs doubled the clearance of topiramate. Topiramate was generally well tolerated as adjunctive therapy at doses up to 25 mg/kg/day.     

The effect of age and comedication on lamotrigine clearance, tolerability, and efficacy

Purpose: To compare pharmacokinetics, tolerability, and efficacy of lamotrigine (LTG) in older versus younger adults. Methods: We studied 686 adult outpatients seen at our center over 5 years. We compared apparent clearance (CL) of LTG in the youngest (16–36 years; n = 247) and oldest (55–92 years; n = 155) tertiles. We analyzed one‐year retention for younger and older adults newly started on LTG, frequency of adverse effects causing intolerability, and rates of specific adverse effects. We also investigated 6‐month seizure freedom. Key Findings: Median LTG CL of older adults taking LTG in monotherapy was approximately 22% lower compared to younger adults (28.8 vs. 36.5 ml/h/kg; p < 0.001). LTG CL in older adults was lower compared to younger adults in patients on polytherapy and on polytherapy without enzyme inducers or valproate. One‐year retention for LTG was comparable in older (78.1%, 121/155) and younger (72.4%, 179/247) adults. Intolerability to LTG was higher in older (34.8%) versus younger adults (24.2%; p = 0.005). Imbalance, drowsiness, and dizziness were common intolerable side effects in both groups. Older patients had higher rates of intolerability due to imbalance (16% vs. 4%), drowsiness (13% vs. 7%), and tremor (5% vs. 2%) compared with younger patients. Rates of 6‐month seizure freedom were comparable, and small numbers of each group benefited from very high levels of LTG (>15 μg/ml). Significance: LTG CL in monotherapy in older adults is approximately 20% lower than in younger adults. For a given serum LTG level, older adults are twice as likely to have significant adverse effects compared to younger adults. Older patients are more likely to experience imbalance, drowsiness, and tremor than younger patients. Younger adults tolerate LTG better than older adults, but one‐year retention is comparable. Some patients may benefit from high serum levels of LTG.     

Obesity and the three‐year longitudinal course of bipolar disorder

Goldstein BI, Liu S‐Min, Schaffer A, Sala R, Blanco C. Obesity and the three‐year longitudinal course of bipolar disorder.
Bipolar Disord 2013: 00: 000–000. © 2013 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd. Objectives: Despite substantial cross‐sectional evidence that obesity is associated with an increased medical and psychiatric burden in bipolar disorder (BD), few longitudinal studies have examined this topic. Methods: Subjects with BD (n = 1600) who completed both Wave 1 and Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions were included. Analyses examined the association between obesity at Wave 1, and the subsequent course of BD, and of psychiatric and medical comorbidities, between Wave 1 and Wave 2. Results: BD subjects with obesity (n = 506; 29.43%), compared to BD subjects without obesity (n = 1094; 70.57%) were significantly more likely to have a major depressive episode and to receive counseling for depression during follow‐up, more likely to report a lifetime suicide attempt, and less likely to develop new‐onset alcohol use disorders. These differences were no longer significant, however, after controlling for baseline demographic variables. No significant differences in new episodes or treatment of mania/hypomania were observed. After controlling for demographic variables, obese subjects remained significantly more likely to report any new‐onset medical condition [odds ratio (OR) = 2.32, 95% confidence interval (CI): 1.63–3.30], new‐onset hypertension (OR = 1.81, 95% CI: 1.16–2.82) and arthritis (OR = 1.64, 95% CI: 1.07–2.52). Obese subjects were significantly more likely to report physician‐diagnosed diabetes (OR = 6.98, 95% CI: 4.27–11.40) and hyperlipidemia (OR = 2.32, 95% CI: 1.63–3.30) (assessed in Wave 2 only). The incidence of heart attacks was doubled among obese subjects, although this difference was not statistically significant. Conclusions: The association between obesity and increased prospective depressive burden appears to be explained by baseline demographic variables. By contrast, obesity independently predicts the accumulation of medical conditions among adults with BD. Treatment of obesity could potentially mitigate the psychiatric and medical burden of BD.     

Different as night and day: Patterns of isolated seizures,clusters, and status epilepticus

Using approximations based on presumed U.S. time zones, we characterized day and nighttime seizure patterns in a patient‐reported database, Seizure Tracker. A total of 632 995 seizures (9698 patients) were classified into 4 categories: isolated seizure event (ISE), cluster without status epilepticus (CWOS), cluster including status epilepticus (CIS), and status epilepticus (SE). We used a multinomial mixed‐effects logistic regression model to calculate odds ratios (ORs) to determine night/day ratios for the difference between seizure patterns: ISE versus SE, ISE versus CWOS, ISE versus CIS, and CWOS versus CIS. Ranges of OR values were reported across cluster definitions. In adults, ISE was more likely at night compared to CWOS (OR = 1.49, 95% adjusted confidence interval [CI] = 1.36‐1.63) and to CIS (OR = 1.61, 95% adjusted CI = 1.34‐1.88). The ORs for ISE versus SE and CWOS versus SE were not significantly different regardless of cluster definition. In children, ISE was less likely at night compared to SE (OR = 0.85, 95% adjusted CI = 0.79‐0.91). ISE was more likely at night compared to CWOS (OR = 1.35, 95% adjusted CI = 1.26‐1.44) and CIS (OR = 1.65, 95% adjusted CI = 1.44‐1.86). CWOS was more likely during the night compared to CIS (OR = 1.22, 95% adjusted CI = 1.05‐1.39). With the exception of SE in children, our data suggest that more severe patterns favor daytime. This suggests distinct day/night preferences for different seizure patterns in children and adults.     

Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392)

Carlson BX, Ketter TA, Sun W, Timko K, McQuade RD, Sanchez R, Vester‐Blokland E, Marcus R. Aripiprazole in combination with lamotrigine for the long‐term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double‐blind study (CN138‐392). Bipolar Disord 2012: 14: 41–53. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: To evaluate the efficacy and safety of aripiprazole (ARI) plus lamotrigine (LTG) compared with placebo (PBO) plus LTG, for long‐term treatment in bipolar I disorder patients with a recent manic/mixed episode. Methods: After a 9–24 week stabilization phase receiving single‐blind ARI (10–30 mg/day) plus open‐label LTG (100 or 200 mg/day), patients maintaining stability (Young Mania Rating Scale/Montgomery–Åsberg Depression Rating Scale total scores ≤ 12) with ARI + LTG for eight consecutive weeks were randomized to continue on double‐blind ARI + LTG or to receive PBO + LTG, after removing ARI from ARI + LTG treatment, and followed up for 52 weeks. The primary outcome measure was time from randomization to relapse into a manic/mixed episode. Results: A total of 787 patients entered the stabilization phase, and 351 were randomized to ARI + LTG (n = 178) or PBO + LTG (n = 173). ARI + LTG yielded a numerically longer time to manic/mixed relapse than PBO + LTG, but it was not statistically significant [hazard ratio (HR) = 0.55; 95% confidence interval (CI): 0.30–1.03; p = 0.058]. The estimated relapse rates at Week 52 were 11% for ARI + LTG and 23% for PBO + LTG, yielding a number needed‐to‐treat of nine (95% CI: 5–121). The three most common adverse events were akathisia [10.8%, 6.1% for ARI + LTG and PBO + LTG, respectively; number needed‐to‐harm (NNH) = 22], insomnia (7.4%, 11.5%), and anxiety (7.4%, 3.6%). Mean weight change was 0.43 kg and ?1.81 kg, respectively (last observation carried forward, p = 0.001). Rates of ≥ 7% weight gain with ARI + LTG and PBO + LTG were 11.9% and 3.5%, respectively (NNH = 12). Conclusions: ARI + LTG delayed the time to manic/mixed relapse but did not reach statistical significance. Safety and tolerability results revealed no unexpected adverse events for ARI combination with LTG.     

Relative vs. absolute measures of benefit and risk: what’s the difference?

Citrome L. Relative vs. absolute measures of benefit and risk: what’s the difference? Objective: When appraising evidence clinicians are confronted with two types of comparisons: ratios, such as relative risk, and absolute differences, such as number needed to treat (NNT) or number needed to harm (NNH). Method: A review of the definition, calculation and interpretation of relative measures such as relative risk, odds ratio and the hazard ratio, and how they are different from absolute measures such as NNT and NNH. Results: Relative and absolute measures provide different perspectives. Ratios can be misleading and exaggerate clinical differences, but NNT can appear to trivialize the risk of potentially important adverse events. Conclusion: There is a need to understand both relative and absolute differences in order to make informed decisions.     

A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder

OBJECTIVE: To assess the efficacy of topiramate monotherapy for acute mania in children and adolescents with bipolar disorder type I. METHOD: This double-blind, placebo-controlled study was discontinued early when adult mania trials with topiramate failed to show efficacy. Efficacy end points included the Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale for Children, Children's Depression Rating Scale, Children's Global Assessment Scale, and Clinical Global Impressions-Improvement. RESULTS: Fifty-six children and adolescents (6-17 years) with a diagnosis of bipolar disorder type I received topiramate (n=29, 52%) or placebo (n=27, 48%). The only statistically significant differences in efficacy measures between treatment groups were the difference between slopes of the linear mean profiles of the YMRS (p=.003) using a post hoc repeated measures regression and the change in Brief Psychiatric Rating Scale for Children at day 28 (-14.9 versus-5.9, p=.048) using observed data. Adverse events with topiramate included decreased appetite, nausea, diarrhea, and paresthesia. CONCLUSIONS: Topiramate was well tolerated; however, the results are inconclusive because of premature termination resulting in a limited sample size. Adequately powered controlled trials are necessary to determine whether topiramate has efficacy in reducing symptoms of acute mania in children and adolescents.     

Psychosocial interventions for depression, anxiety, and quality of life in cancer survivors: meta-analyses

OBJECTIVE: The purpose of this meta-analysis was to investigate the effects of cognitive behavioral therapy (CBT) and patient education (PE) on commonly reported problems (depression, anxiety, pain, physical functioning, and quality of life (QOL)) in adult cancer survivors. METHODS: Meta analyses of randomized controlled trials of CBT and PE were conducted. MEDLINE, PSYCHINFO and the Cochrane Database were searched from 1993-2004. The effects of individual versus group interventions and short (<8 months) versus long (>8 months) term follow up are also reported. RESULTS: Fifteen studies met quality criteria. The sample size was 1,492 adult cancer survivors with an age range of 18-84. 790 were randomly assigned to intervention groups and 702 to control groups. CBT varied in duration from 4 weekly one-hour sessions to 55 weekly two-hour sessions. PE ranged from a single 20-minute session to 6 weekly one-hour sessions. Follow up ranged from 1 week to 14 months. CBT was effective for depression (ES = 1.2; 95% CI = 0.22-2.19), anxiety (ES = 1.99; 95% CI = 0.69-3.31), and QOL (ES = 0.91; 95% CI = 0.38-1.44). QOL was improved at both short and (ES = 1.45, 95% CI = .43-2.47) and long term (ES = .26; 95% CI = .06-.46) follow up. PE was not related to improved outcomes. CONCLUSIONS: CBT is related to short-term effects on depression and anxiety and both short and long term effects on QOL. Individual interventions were more effective than group. Various CBT approaches provided in an individual format can assist cancer survivors in reducing emotional distress and improving quality of life.     

Equally increased risk for metabolic syndrome in patients with bipolar disorder and schizophrenia treated with second-generation antipsychotics

Objective: Although second-generation antipsychotics (SGAs) are widely used in treating schizophrenia and bipolar disorder, their effects on dyslipidemia, glucose intolerance, metabolic syndrome (MetS), and coronary heart disease (CHD) risk are less well documented for bipolar disorder. We compared bipolar disorder and schizophrenia patients receiving SGAs to determine whether MetS prevalence is influenced by the primary psychiatric diagnosis or concomitant mood stabilizer treatment. Methods: Admission assessment of MetS criteria (abdominal obesity, fasting hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperglycemia, arterial hypertension) and the calculated 10-year CHD risk in bipolar disorder and schizophrenia patients treated with SGAs and closely matched for age, sex, and race. Results: Compared to schizophrenia patients (n = 111), those with bipolar disorder (n = 74) had lower body mass index (27.1 ± 5.3 versus 29.9 ± 8.1, p = 0.0053), were more likely treated with mood stabilizers (60.8 versus 36.0, p = 0.0009), and less likely treated with clozapine (1.3% versus 15.3%, p = 0.0017) or two antipsychotics (10.8% versus 34.2%, p = 0.0003). Despite these differences, bipolar disorder and schizophrenia patients had comparable rates of MetS (43.2% versus 45.9%, p = 0.71) and predicted CHD events (10-year risk >10%: 18.9% versus 23.4%, p = 0.47). Using ≥100 mg/dL as the adapted glucose criterion, MetS rates were 54.0% in both diagnostic groups (p = 1.0). Mood stabilizer co-treatment was not associated with MetS or its individual criteria. Conclusions: Patients with bipolar disorder and schizophrenia who are treated with SGAs have similarly high rates of MetS. These findings suggest a shared susceptibility to antipsychotic-related metabolic dysregulations that is not primarily related to psychiatric diagnosis or concomitant mood stabilizer treatment.     

Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open,randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG‐6)

Licht RW, Nielsen JN, Gram LF, Vestergaard P, Bendz H. Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6^th trial of the Danish University Antidepressant Group (DUAG‐6).
Bipolar Disord 2010: 12: 483–493. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: In industry‐generated pivotal studies, lamotrigine has been found to be superior to placebo and comparable to lithium in the maintenance treatment of bipolar I disorder. Here, we directly compared lamotrigine to lithium under conditions similar to clinical routine conditions. Methods: Adult bipolar I disorder patients with at least two episodes within the last five years and an index episode requiring treatment were randomized to lithium (n = 78; doses adjusted to obtain serum levels of 0.5–1.0 mmol/L) or to lamotrigine (n = 77; up‐titrated to 400 mg/day) as maintenance treatments. Randomization took place when clinically appropriate, and comedication was allowed within the first six months after randomization. The patients were enrolled from March 2001 to December 2005, and observations were censored December 2006, allowing a subgroup of patients to be followed for more than five years. The primary outcome measure was time to predefined endpoints indicating insufficient maintenance treatment, and the major secondary outcome measure was time to any study endpoint. Data were analyzed primarily by Cox proportional regression models. Results: For the primary outcome measure, the crude Hazard Rate Ratio (HRR) (lamotrigine relative to lithium) was 0.92 [95% confidence interval (CI): 0.60–1.40]. When the primary endpoints were broken down by polarity, the HRRs (lamotrigine relative to lithium) for mania and depression were, respectively, 1.91 (95% CI: 0.73–5.04) and 0.69 (95% CI: 0.41–1.22). There was no between‐group difference in terms of staying in study [HRR: 0.85 (95% CI: 0.61–1.19)]. Most treatment failures occurred within the first 1.5 years of treatment, and, among patients followed for at least five years, practically no patients were maintained successfully on monotherapy with either of the drugs. The lithium‐treated patients reported diarrhea, tremor, polyuria, and thirst more frequently. Two cases, probably lamotrigine‐related, of benign rash occurred. Conclusions: No differences in maintenance effectiveness between lithium and lamotrigine could be demonstrated. Lamotrigine was better tolerated than lithium, but apparently this did not influence the outcome.     

Effects of stimulus intensity on the efficacy and safety of twice‐weekly,bilateral electroconvulsive therapy (ECT) combined with antipsychotics in acute mania: a randomised controlled trial

Objectives: To examine differences in speed of improvement and remission in people with mania undergoing bilateral, brief‐pulse, twice‐weekly electroconvulsive therapy (ECT) at stimulus intensities administered just above and 2.5 times their individually titrated seizure threshold. Methods: Consecutive, eligible subjects with mania, prescribed ECT, were randomised to receive treatments at stimulus doses either just above or 2.5 times their individually titrated seizure thresholds. Main outcomes were the speed of improvement and remission as measured by the Young Mania Rating Scale (YMRS) and the Clinical Global Impressions—Improvement scale (CGI‐I) and cognitive side effects assessed by the Mini‐Mental State Exam, the Wechsler Memory Scale, and a scale for autobiographical memory. Results: A total of 24/26 subjects (92.3%) given threshold ECT and 22/24 subjects (91.7%) given suprathreshold ECT were significantly improved [CGI = 2; odds ratio (OR) = 1.1, 95% confidence interval (CI): 0.1–8.4; p = 1.0] at the end of ECT. A total of 88% of the sample had remitted [YMRS < 10; threshold 23/26 (88.5%) versus suprathreshold 21/24 (87.5%)], with no significant differences between interventions (OR = 1.1, 95% CI: 0.2– 6.0; p = 1.0). The interventions did not differ significantly in the time or number of ECT treatments required for improvement or remission. Both interventions were equally safe. Conclusions: Bilateral, twice‐weekly ECT delivered at stimulus intensities just above individually titrated seizure threshold was as effective and safe as ECT administered at stimulus intensities 2.5 times seizure threshold in rapidly resolving the symptoms of acute mania.