Treatment-emergent Mania Research Articles

Could “triple-therapy” considered as a novel-optimal treatment model for acute bipolar depression? A prospective real-world research in China

BackgroundResults of researches of bipolar depression treatment are inconsistent and to our knowledge, no study has previously revealed an optimal treatment model for bipolar depression in the real-world through a prospective way. ObjectiveTo find out an optimal treatment model for bipolar depression in the real-world by evaluating the effect of different treatment models: monotherapy, double-therapy and triple-therapy. Designand Intervention: This 12 or 16-week, multi-center, real-world clinical study was conducted at 15 study sites (inpatient or outpatient department) in West China and a total of 573 patients completed the follow-up. During the study weeks, all researchers could choose a most proper treatment model freely basing on the evaluation of patient's symptoms and complete the follow-up according to the procedure. Main outcomes and measuresThe primary outcomes were baseline-to–endpoint change in Montgomery-Asberg Depression Rating Scale (MADRS) total score and the constituent ratio of effects. Total score change in Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI) from baseline to endpoint, treatment-emergent mania rate and severe adverse events rate were used as secondary outcomes. ResultsDuring all study weeks, all the 3 groups showed a statistically significant improvement in MARDS, YMRS and CGI (P＜0.001), but the triple-therapy group showed much more effective in significant response and response rates at endpoint than double-therapy group and monotherapy group (P＜0.001) with lower treatment-emergent mania rates (P = 0.001). At week 4, mean scores of MARDS in triple-therapy group are statistically significant lower than monotherapy group (P = 0.013) and at the endpoint, mean scores of MARDS in triple-therapy group are statistically significant lower than both double-therapy and monotherapy groups (P = 0.011). The severe adverse events rates are rare in all the 3 groups at week 4 and endpoint, and the rate of dry mouth in triple-therapy group at week 4 is statistically significant lower than the other 2 groups (P = 0.002). ConclusionsTriple-therapy is more effective in treating bipolar depression than double-therapy and monotherapy model with a lower risk of developing manic symptoms. Trial registrationChinese Clinical Trial Registry. Identifier: ChiCTR1800019064.

A Systematic Review and Meta-Analysis of Randomized Sham-Controlled Trials of Repetitive Transcranial Magnetic Stimulation for Bipolar Disorder.

Repetitive transcranial magnetic stimulation (rTMS) is effective in treating unipolar depression. However, the efficacy of rTMS in bipolar disorder (BD) is unclear. This meta-analysis aimed to examine the efficacy and tolerability of rTMS for both depressive and manic phases in BD. MEDLINE, EMBASE, PsycINFO, CENTRAL databases were searched for controlled trials on treatment of BD with rTMS. Primary outcomes included changes in depression or mania scores, response and remission rates. Secondary outcomes included quality of life and functioning assessment. We used random-effects model, Hedge's g, risk differences (RDs) and the number needed to treat (NNT). Eleven randomized sham-controlled studies were included, with a total of 345 patients with BD (bipolar depression = 257, mania = 86, mixed affective = 2). Trials of rTMS in bipolar depression (N= 8) demonstrated small but significant improvement in depression scores [standardized mean difference = 0.302, p< 0.05], compared to control group. Furthermore, rTMS brought a higher remission rate than sham-controls [RD = 0.104 ± 0.044, p< 0.05, NNT = 10; and a trend of greater response rate [RD = 0.074 ± 0.039, p= 0.06]. Results were inconclusive for effect of rTMS in mania. In both depressive and manic groups, no serious adverse events were reported. Risk of treatment-emergent mania appeared low. There was limited number of eligible primary studies, with variable randomization procedures. rTMS appears safe and effective in treating bipolar depression. More stringent RCTs are necessary for concrete conclusion about efficacy in mania.

S107. Transcranial Direct Current Stimulation for Depression and Risk of Treatment Emergent Mania: An Updated Meta-Analysis

S107. Transcranial Direct Current Stimulation for Depression and Risk of Treatment Emergent Mania: An Updated Meta-Analysis

Dosage-related nature of escitalopram treatment-emergent mania/hypomania: a case series.

ObjectiveSeveral studies have documented that treatment with various antidepressant agents can result in mood switching during major depressive episodes. Escitalopram, one of the newer selective serotonin reuptake inhibitors (SSRIs), is considered preferable due to its relatively high efficacy and acceptability. Although a few cases of escitalopram treatment-emergent mania have been reported, it remains unknown whether this effect is dose-related.MethodIn the present report, we discuss three cases of treatment-emergent mania/hypomania in patients receiving escitalopram for major depressive episodes. No patients had a family or personal history of bipolar disorder.ResultsIn all three cases, manic or hypomanic symptoms emerged within 1 month right after the dosage of escitalopram was increased to 20 mg/day. Moreover, manic episodes subsided as the dosage of escitalopram was reduced. Mood switching was not observed after the cessation of escitalopram treatment.ConclusionOur case series indicates that escitalopram may induce treatment-emergent mania/hypomania in a dose-related manner. Treatment at lower doses and with careful upward titration might be favorable in certain patients with bipolar depression and major depressive disorder in order to minimize the risk of mood switching.

Clinical and psychopathological features associated with treatment-emergent mania in bipolar-II depressed outpatients exposed to antidepressants

BackgroundTreatment-emergent affective switch (TEAS), including treatment-emergent mania (TEM), carry significant burden in the clinical management of bipolar depression, whereas the use of antidepressants raises both efficacy, safety and tolerability concerns. The present study assesses the prevalence and clinical correlates of TEM in selected sample of Bipolar Disorder (BD) Type-II (BD-II) acute depression outpatients. MethodsPost-hoc analysis of the clinical and psychopathological features associated with TEM among 91 BD-II depressed outpatients exposed to antidepressants. ResultsSecond-generation antipsychotics (SGA) (p = .005), lithium (≤ .001), cyclothymic/irritable/hyperthymic temperaments (p = ≤ .001; p = .001; p = .003, respectively), rapid-cycling (p = .005) and depressive mixed features (p = .003) differed between TEM+ cases vs. TEM− controls. Upon multinomial logistic regression, the accounted psychopathological features correctly classified as much as 88.6% of TEM+ cases (35/91 overall sample, or 38.46% of the sample), yet not statistically significantly [Exp(B) = .032; p = ns]. Specifically, lithium [B = − 2.385; p = .001], SGAs [B = − 2.354; p = .002] predicted lower rates of TEM+ in contrast to the number of lifetime previous psychiatric hospitalizations [B = 2.380; p = .002], whereas mixed features did not [B = 1.267; p = ns]. LimitationsPost-hoc analysis. Lack of systematic pharmacological history record; chance of recall bias and Berkson's biases. Permissive operational criterion for TEM. Relatively small sample size. ConclusionsCyclothymic temperament and mixed depression discriminated TEM+ between TEM− cases, although only lithium and the SGAs reliably predicted TEM+/− grouping. Larger-sampled/powered longitudinal replication studies are warranted to allow firm conclusions on the matter, ideally contributing to the identification of clear-cut sub-phenotypes of BD towards patient-tailored-pharmacotherapy.

Incidence, prevalence and clinical correlates of antidepressant-emergent mania in bipolar depression: a systematic review and meta-analysis.

Treatment-emergent mania (TEM) represents a common phenomenon inconsistently reported across primary studies, warranting further assessment. A systematic review and meta-analysis following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were conducted. Major electronic databases were searched from inception to May 2017 to assess the incidence and prevalence rates and clinical features associated with manic switch among bipolar depressed patients receiving antidepressants, using meta-regression and subgroup analysis. Overall, 10098 depressed patients with bipolar disorder (BD) across 51 studies/arms were included in the quantitative analysis. The cumulative incidence of cases (TEM+ ) among 4767 patients with BD over 15 retrospective studies was 30.9% (95% confidence interval [CI] 19.6-45.0%, I2 =97.9%). The cumulative incidence of TEM+ among 1929 patients with BD over 12 prospective open studies was 14.4% (95% CI 7.4-26.1%, I2 =93.7%). The cumulative incidence of TEM+ among 1316 patients with BD over 20 randomized controlled trials (RCTs) was 11.8% (95% CI 8.4-16.34%, I2 =73.46%). The pooled prevalence of TEM+ among 2086 patients with BD over four cross-sectional studies was 30.9% (95% CI 18.1-47.4%, I2 =95.6%). Overall, concurrent lithium therapy predicted the lowest TEM rates. Inconsistent operational definitions of TEM were recorded, and the lack of information about age, sex, co-occurring anxiety, and other clinically relevant moderators precluded further stratification of the results. Rates of TEM vary primarily depending on study setting, which is concordant with the high degree of heterogeneity of the included records. Forthcoming RCT studies should adopt consistent operational definitions of TEM and broaden the number of moderators, in order to contribute most effectively to the identification of clear-cut sub-phenotypes of BD and patient-tailored pharmacotherapy.

Calling for More Research of Medication Effects in Bipolar Disorder: Response to Ketter and Dell’Osso

Back to table of contents Previous article Next article Letters to the EditorFull AccessCalling for More Research of Medication Effects in Bipolar Disorder: Response to Ketter and Dell’OssoMikael Landén, M.D., Ph.D., Alexander Viktorin, Ph.D.Mikael LandénSearch for more papers by this author, M.D., Ph.D., Alexander ViktorinSearch for more papers by this author, Ph.D.Published Online:1 Aug 2017https://doi.org/10.1176/appi.ajp.2017.17050488rAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We thank Dr. Ketter and Dr. Dell’Osso for the interest in our study (1) published in the April 2017 issue of the Journal and for raising important questions.With respect to the issue of bipolar subtypes, individuals in our study were identified as having bipolar disorder based on a validated search algorithm (2), which required at least two inpatient or outpatient admissions with a discharge diagnosis of bipolar disorder in the Swedish National Patient Register. However, the ICD system used in this register does not reliably distinguish between bipolar I and bipolar II disorder. Therefore, all subtypes of bipolar disorder were included in the analyses. This is a limitation of the study, and more research is needed to examine if the effects observed in the study are limited to, or are more pronounced in, a specific subtype of bipolar disorder. The same limitation affected a previous study of ours (3) published in the Journal in 2014, investigating antidepressant-induced manic switch in patients with bipolar disorder. Therefore, we have read with interest the recent study by Altshuler and colleagues (4), published in the March 2017 issue of the Journal, which observed similar switch and treatment response rates in participants with bipolar II depression associated with lithium monotherapy, sertraline monotherapy, or lithium/sertraline combination therapy.Regarding the issues of dose and administration, the data used in our study include number of pills dispensed, dose per pill, and dispensation dates. Unfortunately, the mean daily dose is not available in the register. Calculating the mean daily dose would therefore need to rely on a number of assumptions regarding each individual’s pattern of consumption that may not be true for every individual. Nevertheless, we ran a new analysis on the cohort used in the study (1). Table 1 presents the distribution of methylphenidate dispensed in the different groups according to the mean dose of methylphenidate per pill dispensed in milligrams and the immediate release, slow release, or combination thereof. There were no discernible differences between the monotherapy group and the group that also received a mood stabilizer.TABLE 1. Descriptive Statistics of Methylphenidate Dispensations in the Study CohortaCharacteristicNo Mood-Stabilizing Medication (N=718)Mood-Stabilizing Medication (N=1,103)Full Sampleb (N=2,307)MeanSDMeanSDMeanSDMean dose per pill (milligrams) Immediate release14.210.617.614.715.712.9 Extended release31.116.332.813.832.114.6N%N%N%Type of release Immediate release only344.7373.4883.8 Extended release only54676.083475.61,76876.6 Combination13819.223221.045119.6aData from the study cohort used in Viktorin et al. (1). The percentages represent rounded numbers.bThe full sample includes a group of 486 subjects with uncertain stabilizer exposure who were excluded from the analyses.TABLE 1. Descriptive Statistics of Methylphenidate Dispensations in the Study CohortaEnlarge tableWe agree with Dr. Ketter and Dr. Dell’Osso that more details are needed in the extent to which stimulants and antidepressants can be safely used, not only regarding dose, medication combinations, and bipolar disorder subtypes, but also regarding interindividual variation in the form of genetic or environmental factors.From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; and the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, and the Seaver Autism Center for Research and Treatment at Mount Sinai, New York.Address correspondence to Dr. Viktorin ([email protected]).The authors’ disclosures accompany the original article.References1 Viktorin A, Rydén E, Thase ME, et al.: The risk of treatment-emergent mania with methylphenidate in bipolar disorder. Am J Psychiatry 2017; 174:341–348Link, Google Scholar2 Sellgren C, Landén M, Lichtenstein P, et al.: Validity of bipolar disorder hospital discharge diagnoses: file review and multiple register linkage in Sweden. Acta Psychiatr Scand 2011; 124:447–453Crossref, Medline, Google Scholar3 Viktorin A, Lichtenstein P, Thase ME, et al.: The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am J Psychiatry 2014; 171:1067–1073Link, Google Scholar4 Altshuler LL, Sugar CA, McElroy SL, et al.: Switch rates during acute treatment for bipolar II depression with lithium, sertraline, or the two combined: a randomized double-blind comparison. Am J Psychiatry 2017; 174:266–276Link, Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 174Issue 8 August 01, 2017Pages 804-805 Metrics KeywordsStimulantsBipolar DisorderADHDAttention Deficit Hyperactivity DisorderMethylphenidateMood DisordersPDF download History Accepted 1 June 2017 Published online 1 August 2017 Published in print 1 August 2017

A re-examination of antidepressant treatment-emergent mania in bipolar disorders: evidence of gender differences.

To explore the prevalence and clinical profile of males and females who develop antidepressant treatment-emergent mania (ATEM). From an original sample of 754 patients with BD, we identified ATEM+ cases (n = 75) and ATEM- controls (n = 135) that met stringent criteria. We specifically examined the combinations of clinical factors that best classified males and females as ATEM+ cases. Seventy-five individuals were classified as ATEM+; 87% of ATEM events occurred during antidepressant monotherapy. Regression analyses demonstrated that the presence of an alcohol and/or substance use disorder [Odds Ratio (OR) 6.37], a history of one or more suicide attempts (OR 4.19) and higher number of depressive episodes per year of illness (OR 1.71) correctly classified 73% of males. In contrast, 84% of females were correctly classified on the basis of a positive history of thyroid disorder (OR 3.23), a positive family history of BD I (OR 2.68) and depressive onset polarity (OR 2.01). Using stringent definitions of ATEM status to reduce the probability of inclusion of false-positive cases and false-negative controls, we identified for the first time that the risk profiles for the development of an ATEM differ significantly according to gender.

A critical review of trials of transcranial direct current stimulation and trigeminal nerve stimulation for depression: the issue of treatment-emergent mania.

This study is a critical review analyzing occurrence of treatment-emergent mania (TEM) related to transcranial direct current stimulation (tDCS) and trigeminal nerve stimulation (TNS). We present a systematic review of the literature on TEM related to tDCS and TNS treatment for major depressive disorder (MDD), conducted in accordance with the recommendations from Cochrane Group and the PRISMA guidelines. Our search identified few reported episodes of TEM in the literature. In fact, we found 11 trials focused on treatment of MDD (seven controlled trials of tDCS and four trials of TNS, three open label and one controlled). We highlight the need for safety assessment in clinical research settings to establish with precision and in larger samples the risks inherent to the technique under investigation. Safety assessment is of fundamental importance in clinical research. TEM is a very important safety issue in MDD trials. Further and larger controlled trials will help to clarify both the safety and the clinical effects of combinations of pharmacotherapy and tDCS or TNS in daily clinical practice.

Repetitive Transcranial Magnetic Stimulation and Treatment-emergent Mania and Hypomania: A Review of the Literature.

This review focuses on treatment-emergent mania/hypomania (TEM) associated with repetitive transcranial magnetic stimulation (rTMS). English-language studies involving possible rTMS-induced mania/hypomania published between 1966 and 2015 were retrieved through a Medline search using the search terms mania, hypomania, mixed affective state, treatment-emergent, repetitive transcranial magnetic stimulation, and rTMS. Fifteen case series and controlled studies describing TEM associated with rTMS treatment have been published involving 24 individuals, most of whom were diagnosed with either bipolar I or II disorder or major depressive disorder. rTMS has been shown to possibly induce manic or hypomanic episodes in patients with depression, who are sometimes also taking antidepressants. Both high-frequency and low-frequency rTMS with different stimulus parameters may be associated with TEM in both males and females. Given these findings, it is highly recommended that patients with bipolar disorder who are experiencing a depressive episode be prescribed a mood stabilizer and that patients diagnosed with major depressive disorder be reevaluated to consider the possibility that they might have bipolar disorder, before rTMS treatment is initiated. If TEM occurs, discontinuation of rTMS should be considered, while continuing mood-stabilizing medications. Further research is needed concerning the underlying neurobiological mechanisms and epidemiologic characteristics of TEM associated with rTMS.

Treatment of Bipolar Depression with Deep TMS: Results from a Double-Blind, Randomized, Parallel Group, Sham-Controlled Clinical Trial.

Bipolar depression (BD) is a highly prevalent condition with limited therapeutic options. Deep (H1-coil) transcranial magnetic stimulation (dTMS) is a novel TMS modality with established efficacy for unipolar depression. We conducted a randomized sham-controlled trial to evaluate the efficacy and safety of dTMS in treatment-resistant BD patients. Patients received 20 sessions of active or sham dTMS over the left dorsolateral prefrontal cortex (H1-coil, 55 18 Hz 2 s 120% MT trains). The primary outcome was changes in the 17-item Hamilton Depression Rating Scale (HDRS-17) from baseline to endpoint (week 4). Secondary outcomes were changes from baseline to the end of the follow-up phase (week 8), and response and remission rates. Safety was assessed using a dTMS adverse effects questionnaire and the Young Mania Rating Scale to assess treatment-emergent mania switch (TEMS). Out of 50 patients, 43 finished the trial. There were 2 and 5 dropouts in the sham and active groups, respectively. Active dTMS was superior to sham at end point (difference favoring dTMS=4.88; 95% CI 0.43 to 9.32, p=0.03) but not at follow-up. There was also a trend for greater response rates in the active (48%) vs sham (24%) groups (OR=2.92; 95% CI=0.87 to 9.78, p=0.08). Remission rates were not statistically different. No TEMS episodes were observed. Deep TMS is a potentially effective and well-tolerated add-on therapy in resistant bipolar depressed patients receiving adequate pharmacotherapy.

Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in acute bipolar depression: a systematic review and meta-analysis of randomised placebo-controlled trials

Although mania and hypomania define bipolar disorder, depressive episodes are more common and impairing, with few proven treatments. Adjunctive therapy with second-generation antidepressants is widely used to treat acute bipolar depression, but their efficacy and safety remain controversial. In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to Jan 31, 2016, for randomised, double-blind, placebo-controlled trials of second-generation antidepressants adjunctive to a mood stabiliser or an antipsychotic in patients with acute bipolar depression. We extracted data from published reports. The primary outcome was change in clinician-rated depressive symptom score; secondary outcomes were clinical response, clinical remission, treatment-emergent mania or hypomania, and tolerability (using dropout rates as a proxy). We used pooled random-effects models, subgroup comparisons, and meta-regression for analyses. We made subgroup comparisons on the basis of mood stabiliser or antipsychotic treatment and did meta-regression examining trial duration. This study is registered with PROSPERO, number CRD#42015016024. We identified six trials representing 1383 patients with bipolar depression. Second-generation antidepressants were associated with a small but significant improvement in clinician-rated depressive symptom score (standardised mean differences 0·165 [95% CI 0·051-0·278], p=0·004). However, clinical response and remission rates did not differ significantly between patients receiving adjunctive antidepressants and those receiving placebo (1·158 [0·840-1·597], p=0·371 for clinical response; 1·220 [0·874-1·703], p=0·243 for remission). Acute treatment was not associated with an increased risk of treatment-emergent mania or hypomania (0·926 [0·576-1·491], p=0·753), but 52 week extension periods were associated with an increase in risk (1·774 [1·018-3·091], p=0·043). Adjunctive second-generation antidepressants are associated with reduced symptoms of acute bipolar depression, but the magnitude of benefit is small because they do not increase clinical response or remission rates. However, these medications should be used only in the short term because prolonged use is associated with an increased risk of treatment-emergent mania or hypomania. None.

The Risk of Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder.

The authors sought to determine the risk of treatment-emergent mania associated with methylphenidate, used in monotherapy or with a concomitant mood-stabilizing medication, in patients with bipolar disorder. Using linked Swedish national registries, the authors identified 2,307 adults with bipolar disorder who initiated therapy with methylphenidate between 2006 and 2014. The cohort was divided into two groups: those with and those without concomitant mood-stabilizing treatment. To adjust for individual-specific confounders, including disorder severity, genetic makeup, and early environmental factors, Cox regression analyses were used, conditioning on individual to compare the rate of mania (defined as hospitalization for mania or a new dispensation of stabilizing medication) 0-3 months and 3-6 months after medication start following nontreated periods. Patients on methylphenidate monotherapy displayed an increased rate of manic episodes within 3 months of medication initiation (hazard ratio=6.7, 95% CI=2.0-22.4), with similar results for the subsequent 3 months. By contrast, for patients taking mood stabilizers, the risk of mania was lower after starting methylphenidate (hazard ratio=0.6, 95% CI=0.4-0.9). Comparable results were observed when only hospitalizations for mania were counted. No evidence was found for a positive association between methylphenidate and treatment-emergent mania among patients with bipolar disorder who were concomitantly receiving a mood-stabilizing medication. This is clinically important given that up to 20% of people with bipolar disorder suffer from comorbid ADHD. Given the markedly increased hazard ratio of mania following methylphenidate initiation in bipolar patients not taking mood stabilizers, careful assessment to rule out bipolar disorder is indicated before initiating monotherapy with psychostimulants.

Lurasidone in the treatment of bipolar depression with mixed (subsyndromal hypomanic) features: post hoc analysis of a randomized placebo-controlled trial.

Mixed (subsyndromal hypomanic) features are prevalent in patients with bipolar depression and are associated with more severe and complex illness, including increased risk for suicide attempts, higher switch to mania during antidepressant therapy, and a higher rate of recurrence. The aim of this post hoc analysis was to evaluate the efficacy and safety of lurasidone in the treatment of patients with bipolar depression presenting with mixed features. Patients with a DSM-IV-TR diagnosis of major depressive episode associated with bipolar I disorder, with or without rapid cycling, and with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20 and a Young Mania Rating Scale (YMRS) score ≤ 12 were randomly assigned to 6 weeks of double-blind, once-daily treatment with lurasidone 20-60 mg, lurasidone 80-120 mg, or placebo. The presence of mixed features was defined as a YMRS score ≥ 4 at study baseline. Efficacy analyses included change in MADRS total score from baseline to week 6 (the primary outcome in the original study, conducted between April 2009 and February 2012). At baseline, mixed features were present in 56% of patients (lurasidone, n = 182/323; placebo, n = 90/162). Treatment with lurasidone (vs placebo) was associated with significantly greater reductions in MADRS scores in the mixed features group (-15.7 vs -10.9; P = .001; week 6; mixed model for repeated measures [MMRM]; effect size, 0.48) and in the group without mixed features (-15.2 vs -10.8; P = .002; week 6; MMRM; effect size, 0.48). Rates of protocol-defined treatment-emergent hypomania or mania were similar for patients with mixed features (lurasidone, 2.2%; placebo, 3.2%) and without mixed features (lurasidone, 3.4%; placebo, 0.0%). Lurasidone was found in this post hoc analysis to be efficacious in the treatment of patients with bipolar depression who present with mixed features (assessed cross-sectionally at study baseline). No increased risk of treatment-emergent mania was observed in either group. ClinicalTrials.gov identifier: NCT00868699.

The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer.

This study examined the risk of antidepressant-induced manic switch in patients with bipolar disorder treated either with antidepressant monotherapy or with an antidepressant in conjunction with a mood stabilizer. Using Swedish national registries, the authors identified 3,240 patients with bipolar disorder who started treatment with an antidepressant and had no antidepressant treatment during the previous year. Patients were categorized into those receiving antidepressant monotherapy and those receiving an antidepressant plus a mood stabilizer. A within-individual design was used to control for confounding by disorder severity, genetic makeup, and early environmental factors. Cox regression analyses conditioned on individual were used to compare the rate of mania 0-3 months and 3-9 months after the start of antidepressant treatment with a preceding non-treatment period. Nearly 35% of the patients were treated with antidepressant monotherapy. The increased risk of treatment-emergent mania was confined to patients on antidepressant monotherapy (hazard ratio=2.83, 95% CI=1.12, 7.19). Among patients treated with a concurrent mood stabilizer, no acute change in risk of mania was observed during the 3 months after the start of antidepressant treatment (hazard ratio=0.79, 95% CI=0.54, 1.15), and a decreased risk was observed during the period 3-9 months after treatment initiation (hazard ratio=0.63, 95% CI=0.42, 0.93). In this national registry study, antidepressant monotherapy was associated with an increased risk of mania. However, no risk of mania was seen in patients receiving an antidepressant while treated with a mood stabilizer. The results highlight the importance of avoiding antidepressant monotherapy in the treatment of bipolar disorder.

Quetiapine for acute bipolar depression: a systematic review and meta-analysis.

BackgroundPrecise estimated risks and benefits of quetiapine for acute bipolar depression are needed for clinical practice.ObjectiveTo systematically review the efficacy and the tolerability of quetiapine, either as monotherapy or combination therapy, for acute bipolar depression.MethodsWe included all randomized, controlled trials (RCTs) comparing quetiapine with other treatments, including placebo, in patients with acute bipolar depression (bipolar I or II disorder, major depressive episode). Published and unpublished RCTs were identified using the Cochrane Central Register of Controlled Trials, MEDLINE®, Web of Knowledge™, CINAHL®, PsycINFO®, the EU Clinical Trials Register database, and ClinicalTrials.gov. The primary outcome was the change scores of depression rating scales.ResultsEleven RCTs (n=3,488) were included. Two of them were conducted in children and adolescents. The change in depression scores was significantly greater in the quetiapine group compared with the placebo group (mean difference, [MD] =−4.66, 95% confidence interval [CI] −5.59 to −3.73). The significant difference was observed from week 1. Compared with placebo, quetiapine had higher incidence rates of extrapyramidal side effects, sedation, somnolence, dizziness, fatigue, constipation, dry mouth, increased appetite, and weight gain but lower risks of treatment-emergent mania and headache. Quetiapine treatment was associated with significant improvement of clinical global impression, quality of life, sleep quality, anxiety, and functioning.ConclusionQuetiapine monotherapy is effective for acute bipolar depression and the prevention of mania/hypomania switching. Its common adverse effects are extrapyramidal side effects, sedation, somnolence, dizziness, fatigue, constipation, dry mouth, increased appetite, and weight gain. The lower risk of headache in quetiapine-treated patients with acute bipolar depression should be further investigated. The evidence for the use of quetiapine combined with mood stabilizers in children and adolescents with acute bipolar depression is too small to support the clinical practice.

Lithium treatment of chronic nail biting.

To the Editor: Nail biting or onychophagia has been variously described as a habit to release tension, self-mutilation behavior, or an impulse control disorder. In the DSM-5, nail biting is classified as an obsessive-compulsive and related disorder.1 Studies have found that between 28% and 33% of children between ages 7 and 10 years, 44% of adolescents, and 19%–29% of young adults engage in nail biting.2 Nail biting usually occurs in combination with other problematic body-focused repetitive behaviors such as hair pulling disorder and skin picking disorder. Nail biting in adults is underrecognized because patients often fail to seek help due to feelings of shame and embarrassment, and, consequently, the disorder has received little attention in the psychiatric literature. In most cases, nail biting seems to be only a cosmetic issue, and no treatment is required. But, in severe cases, untreated nail biting can result in a host of complications such as severe damage to the cuticles and nails, paronychia and secondary bacterial infection, dental problems, and temporomandibular dysfunction.3 Studies on drug treatment of nail biting are sparse and limited to antidepressants and N-acetylcysteine.4 We present a case of chronic, severe onychophagia comorbid with bipolar II disorder and substance use disorder and discuss the successful treatment of these disorders with lithium monotherapy. Case report. Ms A, a 28-year-old woman, was referred by her family physician for assessment and management of depression. She met DSM-5 criteria for bipolar II disorder and was noted to be in remission for substance use disorder (alcohol dependence and cocaine use). At the time of initial assessment, Ms A endorsed various symptoms of depression including thoughts of suicide. Due to concerns regarding her safety, lithium 900 mg daily was started, and the dose was optimized to achieve a serum level of 0.7 mmol/L. Within 2 months of lithium treatment, Ms A experienced remission of depression and has been symptom free for 2 years. A serendipitous finding was remission of symptoms of chronic nail biting that Ms A had struggled with since she was 12 years old. Various strategies including habit reversal training, self-monitoring, and competing response had been ineffective.5 The condition was severe because Ms A had to regularly cover the nail beds with Band-Aids to control the bleeding. Moreover, it affected her self-esteem and caused a great deal of emotional distress. The marked improvement following lithium treatment was noted by Ms A’s family and friends, who had not seen her undamaged nails in at least 15 years. Clomipramine and selective serotonin reuptake inhibitors are generally recommended in severe cases of nail biting, but the use of these drugs can cause treatment-emergent mania in individuals with bipolar disorder. Thus, the drug choice for onychophagia should be informed by the nature of the comorbid psychiatric disorder. There are reports of effectiveness of lithium in body-focused repetitive behaviors such as hair pulling disorder and skin picking disorder with comorbid bipolar disorder. It is not known if lithium is effective in patients with onychophagia in the absence of bipolar disorder. To our knowledge, this is the first reported case of lithium effectiveness in nail biting. Studies are needed to clarify the role of lithium in the management of severe nail biting in the absence of comorbid bipolar disorder.

The Sertraline vs Electrical Current Therapy for Treating Depression Clinical Study

Transcranial direct current stimulation (tDCS) trials for major depressive disorder (MDD) have shown positive but mixed results. To assess the combined safety and efficacy of tDCS vs a common pharmacological treatment (sertraline hydrochloride, 50 mg/d). Double-blind, controlled trial. Participants were randomized using a 2 × 2 factorial design to sertraline/placebo and active/sham tDCS. Outpatient, single-center academic setting in São Paulo, Brazil. One hundred twenty antidepressant-free patients with moderate to severe, nonpsychotic, unipolar MDD. Six-week treatment of 2-mA anodal left/cathodal right prefrontal tDCS (twelve 30-minute sessions: 10 consecutive sessions once daily from Monday to Friday plus 2 extra sessions every other week) and sertraline hydrochloride (50 mg/d). MAIN OUTCOME MEASURES In this intention-to-treat analysis, the primary outcome measure was the change in Montgomery-Asberg depression rating scale score at 6 weeks (end point). We considered a difference of at least 3 points to be clinically relevant. The analysis plan was previously published. Safety was measured with an adverse effects questionnaire, the young mania rating scale, and cognitive assessment. Secondary measures were rates of clinical response and remission and scores on other scales. At the main end point, there was a significant difference in Montgomery-Asberg depression rating scale scores when comparing the combined treatment group (sertraline/active tDCS) vs sertraline only (mean difference, 8.5 points; 95% CI, 2.96 to 14.03; P = .002), tDCS only (mean difference, 5.9 points; 95% CI, 0.36 to 11.43; P = .03), and placebo/sham tDCS (mean difference, 11.5 points; 95% CI, 6.03 to 17.10; P < .001). Analysis of tDCS only vs sertraline only presented comparable efficacies (mean difference, 2.6 points; 95% CI, -2.90 to 8.13; P = .35). Use of tDCS only (but not sertraline only) was superior to placebo/sham tDCS. Common adverse effects did not differ between interventions, except for skin redness on the scalp in active tDCS (P = .03). There were 7 episodes of treatment-emergent mania or hypomania, 5 occurring in the combined treatment group. In MDD, the combination of tDCS and sertraline increases the efficacy of each treatment. The efficacy and safety of tDCS and sertraline did not differ. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01033084.

Broadening bipolar diagnostic criteria: why not start with hypomania?

Broadening bipolar diagnostic criteria: why not start with hypomania?

Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression

Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression