Non-rapid Cycling Research Articles

The efficacy and safety of lurasidone in bipolar I depression with and without rapid cycling: A pooled post-hoc analysis of two randomized, placebo-controlled trials

BackgroundThe efficacy and safety of lurasidone monotherapy in patients with bipolar I depression with or without rapid cycling has not been previously investigated. MethodsWe performed subgroup analysis (rapid cycling/non-rapid cycling) of pooled data from two 6-week, randomized, double-blind, placebo-controlled trials of lurasidone monotherapy (20–60 mg/day or 80–120 mg/day). Analyses included mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Safety assessments included the number of treatment-emergent adverse events (TEAEs) and laboratory assessments. ResultsOf 1024 patients randomized, 85 were rapid cycling. Mean change in MADRS total score in patients with non-rapid cycling and rapid cycling, respectively, was −14.8 (effect size = 0.47) and − 12.8 (effect size = 0.04) in the lurasidone 20–60 mg/day group, −14.3 (effect size = 0.41) and − 13.0 (effect size = 0.02) in the lurasidone 80–120 mg/day group and −10.6 and −13.3 in the placebo group. The most common TEAE in each subgroup was akathisia in both lurasidone groups. Treatment-emergent mania was reported only in a small number of rapid cycling and non-rapid cycling patients. LimitationsThis was a post-hoc analysis of a short-term study that excluded patients with ≥8 cycles in the past year. ConclusionsIn patients with non-rapid cycling bipolar depression, lurasidone monotherapy significantly improved depressive symptoms relative to placebo at both the 20–60 mg/day and 80–120 mg/day doses. In patients with rapid cycling, both doses of lurasidone displayed depressive symptom score reduction from baseline, but significant improvement was not observed likely due to high levels of improvement on placebo and small sample size.

Association of intron 4 VNTR polymorphism in the NOS3 gene with rapid cycling and treatment resistance in bipolar disorder: a case-control study.

To evaluate the relationship between patients' clinical parameters, especially clinical specifiers, and the intron 4 VNTR variant of the endothelial nitric oxide synthase (NOS3) gene in bipolar disorder (BD) patients. A sample of 95 patients with BD and 95 healthy volunteers were included in the case-control study. The patients consecutively admitted to the outpatient psychiatry clinic for 6 months and were evaluated with some scales for clinical parameters. In addition, PCR was used to determine the NOS3 intron 4 VNTR variant. The NOS3 genotype and allele frequency distributions of rapid cycling BD patients were significantly different from non-rapid cycling BD patients and the control groups. Furthermore, NOS3 genotype and allele frequency distributions of treatment-resistant BD patients were significantly different from treatment-responsive BD patients and the control groups. While BD patients carrying the b/b genotype and b allele had a lower risk of rapid cycling and treatment resistance, having the b/a genotype in BD patients was at higher risk in terms of rapid cycling and treatment resistance. In addition, the number of hospitalizations and the Clinical Global Impression-Improvement Scale scores of the BD group with the b/b genotype were statistically lower than the BD group with b/a and a/a genotypes. We propose that the intron 4 VNTR variant of the NOS3 gene may be associated with rapid cycling and treatment resistance in Turkish patients diagnosed with BD.

A cross-sectional study comparing some clinical features of patients with rapid cycling and non-rapid cycling bipolar disorder

Objective: Literature indicates that rapid cycling (RC) feature in bipolar disorder (BD) has been associated with worse disorder outcome and more severe disability. We aimed to investigate factors that affect or involved in vulnerability to increase rapid cycling in the previous 12 months. Methods: This is a cross-sectional study. Patients (n=380) were recruited from an outpatients clinic of a general hospital. Diagnostic interviews were performed with Structured Clinical Interview for DSM-IV Disorders (SCID-I) and SCID-II. Sociodemographic Form, Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HAM-D) were applied. RC was defined as presence four or more mood episodes in the previous 12 months. Patients were arranged as whether having rapid cycling bipolar disorder (RCBD) or not. RCBD was compared to the group of non-RCBD patients regarding the sociode-mographic and clinical data. Results: Study group showed a female preponderance (65.0%). Sixty patients (15.8%) had RC in the previous 12 months. There were statistically significant differences between two groups regarding in number of suicide attempts, family history of mood disorders, psychotic depression, number of antidepressants utilized, manic, depressive, mixed and total number of episodes. Discussion: The presence of RC in the previous 12 months was found correlated with specific clinical features closely related to worse outcome in the course of BD. Further studies are needed to clarify disease-related factors in patient groups with a standard definition of homo-geneous RCBD.

Clinical characterization of rapid cycling bipolar disorder: Association with attention deficit hyperactivity disorder

BackgroundRapid cycling (RC) bipolar disorder (BD) is associated with more disability and worse global functioning than non-rapid cycling BD (NRC) and is understudied. This study aims to investigate clinical characteristics associated to RC in a Latin-American sample and secondarily, to generate a clinical model to test the likelihood of RC in BD. Methods250 BD patients were enrolled between 2007 and 2015. All patients met DSM-IV criteria for BD type I, II or NOS. The sample was dichotomized into RC and NRC subgroups, and compared in terms of sociodemographic and clinical variables by bivariate analyses. A binary logistic regression was performed to generate a model and explain variance associated with the likelihood of presenting RC. ResultsFinal sample included 235 patients, of which forty-four (18.7%) met RC criteria. When compared to NRC, a significantly higher proportion of RC patients were female (81.4% vs. 58.9% p = 0.006), BD type II (58.1% vs. 29.7% p = 0.002), presented more manic/hypomanic episodes (43.6 ± 35.8 vs. 12.8 ± 58.9, p = 0.001), and had less psychotic symptoms (20.9% vs. 42.2%, p = 0.010). Attention deficit hyperactivity disorder (ADHD) was a significant comorbidity in RC (23.7% vs. 8.3%, p = 0.007). No differences were found in suicidality, mixed symptoms, and seasonal pattern. After logistic regression, variables significantly associated with RC were presence of ADHD (OR 4.6 [95% CI 1.54–13.93] p = 0.006) and female gender (OR 3.55 [95% CI, 1.32–9.56] p = 0.012). LimitationsIt is a cross-sectional study. ConclusionsFindings suggest that ADHD comorbidity, and female gender are risk factors for RC in BD.

Bipolar patients treated with long-acting injectable risperidone in Taiwan: A 1-year mirror-image study using a national claims database

ObjectiveBipolar disorder (BD) is burdensome for patients and healthcare systems. This study evaluated changes in concomitant medication patterns, healthcare utilization, and costs after the initiation of risperidone long-acting injection (RLAI) treatment among BD patients. Method287 BD patients receiving regular RLAI treatment for 1 year were identified from the Taiwan National Health Insurance Research database during 2007–2012. The bootstrapping procedure was performed to create 1000 samples to generate normally distributed data. The paired t-tests with a correction for multiple comparisons using Bonferroni correction were used to compare the proportion of patients of concomitant psychiatric medication and resource use and costs between pre- and post-RLAI periods. Rapid and non-rapid cycling stratification was performed based on the number of change-in-mood episodes within 1 year prior to the index date. ResultsThe mean annual dose of RLAI was 638.41mg, which was equal to an average dose of 24.6mg every 2 weeks. The prevalence of concomitant use of conventional antipsychotics, atypical antipsychotics, lithium, and antidepressants decreased from the pre-RLAI period to the post-RLAI period by 23.75%, 31.91%, 1.29%, and 7.08%, respectively. RLAI use decreased emergency room (ER) visits, hospital admissions, length of hospital stay, and non-medication costs (all P<0.0001). The cost savings with RLAI were attributed to lower hospitalization costs in spite of higher medication costs. Moreover, rapid cycling patients (n=36) demonstrated greater reduction in ER and inpatient services with RLAI than non-rapid cycling patients (n=251). LimitationsOf the patients who initiated RLAI, 15% of them who had regular treatment were included. Furthermore, data on measures of symptom severity, side effects, and hyperprolactinemia were not available. ConclusionBD patients had lower inpatient and ER utilization, and non-medication costs after using RLAI. In addition, RLAI use decreased the number of change-in-mood episodes in rapid cycling patients; which provides additional insights into the treatment of rapid cycling BD patients.

Rapid Cycling in Bipolar Disorders: Symptoms,Backgroundand Treatment Recommendations

Rapid cycling bipolar disorder is encountered frequently in clinical practice with a lifetime prevalence of up to 31 %. Besides its association with greater illness severity, increased suicide and comorbidity rates, rapid cycling bipolar disorder has been closely associated with a longer and more complicated course of disease and inadequate treatment response compared to non-rapid cycling bipolar disorder. However rapid cycling does not serve as a stable characteristic of bipolar disorder, though its prevalence increases with illness duration. Female gender, hypothyreoidism and antidepressant medications have been suggested as correlates of rapid cycling bipolar disorder; however, the interaction amongst these factors make an interpretation of their causal relations difficult. Only very few data are available from randomized clinical trials that investigated the therapeutic options of rapid cycling bipolar disorder. Based on these trials, the therapeutic outcome of lithium is similar to that of the class of anticonvulsants. Positive treatment outcome reported for atypical neuroleptics is often based on pharmaceutical company-financed, placebo-controlled RCTS. Altogether independent prospective RCTs and head-to-head comparisons are lacking that can provide sufficient information on treatment response. In addition, the role of antidepressant treatment in the course and phase acceleration of bipolar disorder remains insufficiently understood. However, in the light of present empirical evidence, the use of antidepressant medication in the treatment of rapid cycling bipolar disorder has to be looked at highly critically.

Rapid versus non-rapid cycling bipolar II depression: response to venlafaxine and lithium and hypomanic risk.

To examine the safety and effectiveness of antidepressant versus mood stabilizer monotherapy in rapid versus non-rapid cycling bipolar II disorder. Subjects ≥18 years old with bipolar II depression (n = 129) were randomized to double-blind venlafaxine or lithium carbonate monotherapy for 12 weeks. Responders (n = 59) received continuation monotherapy for six additional months. Rapid cycling did not affect frequency of response or change over time in depressive symptoms. Rapid cycling status did not affect frequency of depressive relapse or sustained treatment response. Rapid cyclers were more likely to experience hypomanic symptoms (P = 0.005) during continuation monotherapy; however, rates were similar in venlafaxine (17.6%) and lithium (42.9%) (P = 0.31). Rapid cycling status may not be associated with an increased risk of diminished response or greater depressive relapse during venlafaxine, relative to lithium monotherapy, in bipolar II subjects. Additional randomized studies are needed to confirm these findings.

Antidepressants worsen rapid-cycling course in bipolar depression: A STEP-BD randomized clinical trial

BackgroundThe use of antidepressants in rapid-cycling bipolar disorder has been controversial. We report the first randomized clinical trial with modern antidepressants on this topic. MethodsAs part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we analyzed, as an a priori secondary outcome, rapid cycling as a predictor of response in 68 patients randomized to continue vs. discontinue antidepressant treatment, after initial response for an acute major depressive episode. Outcomes assessed were percent time well and total number of episodes. All patients received standard mood stabilizers. ResultsIn those continued on antidepressants (AD), rapid cycling (RC) subjects experienced 268% (3.14/1.17) more total mood episodes/year, and 293% (1.29/0.44) more depressive episodes/year, compared with non-rapid cycling (NRC) subjects (mean difference in depressive episodes per year RC vs. NRC was 0.85±0.37 (SE), df=28, p=0.03). In the AD continuation group, RC patients also had 28.8% less time in remission than NRC patients (95% confidence intervals (9.9%, 46.5%), p=0.004). No such differences between RC and NRC subjects were seen in the AD discontinuation group (Table 1). Analyses within the rapid-cycling subgroup alone were consistent with the above comparisons between RC and NRC subjects, stratified by maintenance antidepressant treatment, though limited by sample size. ConclusionsIn an a priori analysis, despite preselection for good antidepressant response and concurrent mood stabilizer treatment, antidepressant continuation in rapid-cycling was associated with worsened maintenance outcomes, especially for depressive morbidity, vs. antidepressant discontinuation.

Anxiety Disorders and Rapid Cycling

Anxiety disorders (ADs) are common in youths with bipolar disorder (BD). We examine psychiatric comorbidity, hospitalization, and treatment in youths with versus without AD and rapid cycling (four or more cycles per year). Data from the Integrated Healthcare Information Services cohort were used and included 8129 youths (ages ≤18 years). Prevalence of AD, demographic, type of AD, hospitalization, and use of psychotropics were compared between rapid and nonrapid cycling. Overall, 51% of the youths met criteria for at least one comorbid AD; they were predominantly female and were between 12 and 17 years of age. The most common comorbid ADs were generalized ADs and separation ADs. In the patients with rapid cycling, 65.5% met criteria for comorbid AD. The BD youths with AD were more likely to have major depressive disorders and other comorbid ADs, to be given more psychotropics, and to be hospitalized for depression and medical conditions more often than were those without AD.

The effect of lisdexamfetamine dimesylate on body weight, metabolic parameters, and attention deficit hyperactivity disorder symptomatology in adults with bipolar I/II disorder

We primarily sought to determine the effect of adjunctive lisdexamfetamine dimesylate (LDX) on anthropometric and metabolic parameters. Our secondary aim was to evaluate the effect of LDX on attention deficit hyperactivity disorder (ADHD) symptom severity in adults with bipolar I/II disorder. Forty-five stable adults (i.e., non-rapid cycling, absence of clinically significant hypo/manic symptoms) with bipolar I/II disorder and comorbid ADHD were enrolled in a phase IV, 4-week, flexible dose, open-label study of adjunctive LDX. All subjects were initiated at 30 mg/day of adjunctive LDX for the first week with flexible dosing (i.e., 30-70 mg/day) between weeks 2 and 4. Of the 45 subjects enrolled, 40 received adjunctive LDX (mean dose = 60 ± 10 mg/day). A statistically significant decrease from baseline to endpoint was evident in weight (p < 0.001), body mass index (p < 0.001), fasting total cholesterol (p = 0.011), low density lipoprotein cholesterol (p = 0.044), high density lipoprotein cholesterol (p = 0.015) but not triglycerides, or blood glucose. Significant reductions were also observed in leptin (p = 0.047), but not in ghrelin, adiponectin, or resistin levels. Diastolic blood pressure and pulse increased significantly over time but on average remained within the normal range (p < 0.001). There was a significant reduction from baseline to endpoint in the total score of the ADHD Self-Report Scale. Significant improvement from baseline to endpoint was also observed in the Montgomery-Åsberg Depression Rating Scale total score as well as the Clinical Global Impression Severity and Improvement score. Short-term adjunctive LDX treatment was well tolerated by this sample of adults with stable bipolar I/II disorder. Lisdexamfetamine dimesylate offered beneficial effects on body weight, body mass index and several metabolic parameters. In addition to demonstrating short-term (i.e., 4 weeks) safety and tolerability, beneficial effects of LDX were also observed in mitigating depressive and ADHD symptom severity.

Effectiveness and Mood Conversion Rate of Short-Term Fluoxetine Monotherapy in Patients With Rapid Cycling Bipolar II Depression Versus Patients With Nonrapid Cycling Bipolar II Depression

We examined the effectiveness and mood conversion rate of fluoxetine monotherapy in patients with rapid cycling bipolar II depression versus patients with nonrapid cycling bipolar II depression. We hypothesized that there would be reduced antidepressant effectiveness and a greater mood conversion rate over time in patients with rapid cycling. Open-label fluoxetine monotherapy 10 to 80 mg daily was administered for up to 14 weeks in 42 outpatients with rapid cycling versus 124 outpatients with nonrapid cycling. Outcome measures included the change over time in depression ratings, the proportion of treatment responders and remitters, change over time in mania ratings, and frequency of syndromal and subsyndromal hypomanic episodes. There was a greater reduction in depression rating scores in the patients with rapid cycling versus those with nonrapid cycling (P = 0.04), with similar rates of response (P = 0.18) and remission (P = 0.69). Change in mean mania rating scores was similar in the patients with rapid cycling versus those with nonrapid cycling (P = 0.28). Hypomanic symptoms occurred in a similar proportion of the patients with rapid cycling versus those with nonrapid cycling (P = 0.99). Hypomanic episodes occurred in 5.4% (95% confidence interval [CI], 0.7-18.2) of the patients with rapid cycling versus 3.6% (95% CI, 1.0-8.9) of those with nonrapid cycling (P = 0.65). Subsyndromal hypomania occurred in 13.5% (95% CI, 4.5-28.8) of the patients with rapid cycling versus 9.0% (95% CI, 4.4-15.9) of those with nonrapid cycling (P = 0.43). In contrast to reports of reduced effectiveness and increased mood conversion rates in patients with rapid cycling bipolar disorder taking antidepressants, we found greater effectiveness and similar hypomania rates during fluoxetine monotherapy in the patients with rapid cycling bipolar II depression versus those with nonrapid cycling bipolar II depression.

P2RX7: Expression Responds to Sleep Deprivation and Associates with Rapid Cycling in Bipolar Disorder Type 1

ContextRapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling.ObjectivesTo assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients.DesignGene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients.ParticipantsHealthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044).Results P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10−9). The P2RX7 rs2230912 _A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45–0.49, p = 0.003–0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls.ConclusionsSleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system.

Antidepressant Discontinuation in Bipolar Depression

To assess long-term effectiveness and safety of randomized antidepressant discontinuation after acute recovery from bipolar depression. In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, conducted between 2000 and 2007, 70 patients with DSM-IV-diagnosed bipolar disorder (72.5% non-rapid cycling, 70% type I) with acute major depression, initially responding to treatment with antidepressants plus mood stabilizers, and euthymic for 2 months, were openly randomly assigned to antidepressant continuation versus discontinuation for 1-3 years. Mood stabilizers were continued in both groups. The primary outcome was mean change on the depressive subscale of the STEP-BD Clinical Monitoring Form. Antidepressant continuation trended toward less severe depressive symptoms (mean difference in DSM-IV depression criteria = -1.84 [95% CI, -0.08 to 3.77]) and mildly delayed depressive episode relapse (HR = 2.13 [1.00-4.56]), without increased manic symptoms (mean difference in DSM-IV mania criteria = +0.23 [-0.73 to 1.20]). No benefits in prevalence or severity of new depressive or manic episodes, or overall time in remission, occurred. Type II bipolar disorder did not predict enhanced antidepressant response, but rapid-cycling course predicted 3 times more depressive episodes with antidepressant continuation (rapid cycling = 1.29 vs non-rapid cycling = 0.42 episodes/year, P = .04). This first randomized discontinuation study with modern antidepressants showed no statistically significant symptomatic benefit with those agents in the long-term treatment of bipolar disorder, along with neither robust depressive episode prevention benefit nor enhanced remission rates. Trends toward mild benefits, however, were found in subjects who continued antidepressants. This study also found, similar to studies of tricyclic antidepressants, that rapid-cycling patients had worsened outcomes with modern antidepressant continuation. clinicaltrials.gov Identifier: NCT00012558.

Suicide risk in rapid cycling bipolar patients

Background Rapid-cycling (RC) is a course modifier of bipolar disorder which often implicates a poor prognosis. However, the relationship of RC with suicidal features as a marker of impairment has been understudied. Methods Three hundred and five patients ( n = 305) were included in a naturalistic, systematic prospective study in a single site setting. Patients with rapid-cycling (RC) were defined as having four or more manic, mixed or depressive episodes in the year prior to baseline assessment. The two groups were compared regarding clinical and sociodemographic variables, paying special attention to suicidal features. Statistical methods consisted of chi-square statistic for the comparison of categorical data, and Student's t test for dimensional variables normally distributed. Also, a General Linear Model was used to study the main effect of different sociodemographic and clinical variables on suicidality. All statistics were two-tailed, and significance was set at p less than 0.05. Results Fifty-five patients (18%) were classified as RC, whilst 250 (82%) were considered as nonrapid-cycling (NRC). No significative difference was found in the prevalence of RC amongst bipolar I and II patients. RC was associated with depressive onset of bipolar disorder. The number of suicide attempts was significantly higher amongst RC (RC mean 0.82 [SD 1.85] vs. NRC 0.44[SD 0.94] t = 2.09, p = 0.37). Nonetheless, no significative differences were found between RC and NRC regarding the percentage of suicide attempters. On the other hand patients that presented RC showed a marked increase of lifetime history of suicidal ideation (Chi 2 = 4.363, p = 0.039). Finally, there were not any differences between RC patients and NRC in family history of suicide. Discussion Bipolar patients with RC are more likely to attempt suicide. Intensive treatment of this marker should be considered.

Lithium: Updated Human Knowledge Using an Evidence-Based Approach

Although there has been a decrease in lithium use over several years, it is still recommended as a first-line mood stabilizer in all recent guidelines. It has been argued that many studies of lithium were conducted at a time when study design, assessment standards and the diagnostic criteria for patient selection were not as established as they presently are. However, recent placebo-controlled data from three-arm trials have demonstrated a definite efficacy of lithium in bipolar disorder. Regarding mania, recent trials of novel antimanic treatments (such as second-generation antipsychotics) that have included both placebo and lithium control groups have confirmed that lithium is effective in the treatment of moderate to severe manic episodes. The efficacy of lithium as monotherapy for acute bipolar depression is still controversial, but this therapy is recognized as a therapeutic option. For maintenance therapy, lithium is superior to placebo for the prevention of relapse or recurrence of mood episodes in bipolar I disorder patients with recent manic or hypomanic episodes. Lithium is more effective in preventing episodes of the manic/hypomanic type, including mixed episodes, than preventing depressive episodes. In rapid cycling patients, lithium improves clinical symptoms as efficiently as in nonrapid cycling persons, but is not likely to prevent recurrences. Finally, data from a number of studies suggest that lithium reduces the high suicide rates associated with mood disorders. A well designed cohort study and two independent meta-analyses are in agreement with this finding. In conclusion, most experts, and the most recent guidelines, continue to consider lithium as a keystone therapy of bipolar disorders.

Venlafaxine versus lithium monotherapy of rapid and non-rapid cycling patients with bipolar II major depressive episode: A randomized, parallel group, open-label trial

BackgroundThere is a paucity of controlled clinical data on the best initial therapy for treating patients with bipolar type II (BP II) major depressive episode (MDE). In this analysis, we examined the safety and antidepressant efficacy of short-term venlafaxine versus lithium monotherapy in rapid and non-rapid cycling patients with BP II MDE. We hypothesized that lithium would have superior efficacy to venlafaxine, with fewer syndromal and sub-syndromal hypomanic and mixed mood conversions in the rapid cycling BP II MDE patients. MethodsPatients were randomized to monotherapy with either venlafaxine 37.5–375 mg daily or lithium 300–2100 mg daily for 12 weeks. The primary outcome measure was the 28-item Hamilton Depression Rating (HAM-D 28), with embedded ‘typical’ HAM-D 17 and ‘atypical’ HAM-D 17-R symptom scores. Secondary outcomes included the Young Mania Rating Scale (YMRS), clinical global impressions severity (CGI/S) and change (CGI/C) ratings, the proportion of responders (with ≥50% reduction in baseline HAM-D score) and remitters (with a final HAM-D score ≤8), and the proportion of patients with syndromal and sub-syndromal mood conversions. ResultsForty-three patients received venlafaxine (12 rapid cycling) and 40 patients received lithium (15 rapid cycling): 48 (57.8%) were women and 69 (82.1%) were Caucasian. Thirty-three patients (39.8%) prematurely discontinued therapy: 11 for lack of efficacy, 13 for adverse events, 2 for non-compliance, and 7 who were lost to follow up. Venlafaxine produced a greater reduction in HAM-D 28 (p=0.001) and HAM-D 17 (p=0.002) scores (versus lithium) that was independent of cycling status (0.358). Venlafaxine also resulted in a higher rate of responders (p=0.021) and remitters (p=0.001) in rapid cycling patients. There was no significant difference in baseline mean YMRS scores, or mean YMRS change scores over time, between rapid and non-rapid cycling patients. Venlafaxine did not result in a higher proportion of mood conversions (versus lithium) in either the rapid or non-rapid cycling patients. LimitationsThis was a secondary analysis of rapid versus non-rapid cycling BP II MDE patients. The study was originally powered to detect differences in efficacy between treatment conditions, and was not specifically powered to detect differences in efficacy or mood conversion episodes between rapid and non-rapid cycling groups. We used a conservative life-time definition of rapid cycling (i.e., an average ≥4 affective episodes per year). We did not employ a patient-recorded daily chrono-record to identify ultra-short mood conversions. The study used a randomized, parallel group, open-label design. ConclusionThese observations from this exploratory analysis suggest that venlafaxine monotherapy may be more effective than lithium monotherapy, with a similar mood conversion rate, in rapid and non-rapid cycling patients with BP II MDE. These data support prior observations that venlafaxine monotherapy may be effective initial treatment for BP II MDE.

Electroencephalographic Cerebral Dysrhythmic Abnormalities in the Trinity of Nonepileptic General Population, Neuropsychiatric, and Neurobehavioral Disorders

Electroencephalographic Cerebral Dysrhythmic Abnormalities in the Trinity of Nonepileptic General Population, Neuropsychiatric, and Neurobehavioral Disorders

Electroencephalographic Cerebral Dysrhythmic Abnormalities in the Trinity of Nonepileptic General Population, Neuropsychiatric, and Neurobehavioral Disorders

Subclinical electroencephalographic epileptiform discharges in neurobehavioral disorders are not uncommon. The clinical significance and behavioral, diagnostic, and therapeutic implications of this EEG cerebral dysrhythmia have not been fully examined. Currently the only connotation for distinctive epileptiform electroencephalographic patterns is epileptic seizures. Given the prevailing dogma of not treating EEGs, these potential aberrations are either disregarded as irrelevant or are misattributed to indicate epilepsy. This article reappraises the literature on paroxysmal EEG dysrhythmia in normative studies of the "healthy" nonepileptic general populations, neuropsychiatry, and in neurobehavioral disorders. These EEG aberrations may be reflective of underlying morpho-functional brain abnormalities that underpin various neurobehavioral disturbances.

Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder

BackgroundThis analysis was designed to assess the efficacy and safety of aripiprazole compared with placebo in subpopulations of patients with acute manic or mixed episodes of bipolar I disorder. MethodsAcutely manic patients experiencing DSM-IV manic/mixed episodes of bipolar I disorder were pooled from two randomized, three-week, flexible-dose, double-blind, placebo-controlled trials (N=516) and stratified by disease severity (Young Mania Rating Scale, YMRS), episode type, presence or absence of psychotic features, episode frequency, age, gender, and baseline severity of depressive symptoms. Safety and treatment-emergent adverse-event analyses were also performed. ResultsAripiprazole significantly reduced mean YMRS total scores at end point compared with placebo in patients with more severe or less severe illness, with mixed or manic episodes, with or without psychotic features, or with a history of rapid or non-rapid cycling (p<0.01 for each subpopulation); in men and women (p=0.001 for both); in patients in the 18–40 and 41–55 year age groups (p≤0.001 for both); and in three subgroups stratified by baseline severity of depressive symptoms using the Montgomery-Åsberg Depression Rating Scale (p<0.05). The treatment-emergent adverse events reported in ≥5% of patients aged 18–40 years receiving aripiprazole were similar to those reported for the overall population. LimitationsThis post hoc analysis utilized pooled data from two short-term studies. ConclusionEfficacy of the second-generation antipsychotic aripiprazole was noted across a broad range of subpopulations often associated with treatment resistance in patients experiencing manic or mixed episodes of bipolar I disorder.

Early Predictors of Substantial Weight Gain in Bipolar Patients Treated with Olanzapine

To determine predictors of substantial weight gain (SWG) during treatment of bipolar disorder with olanzapine, data were pooled from 4 long-term randomized, multicenter studies in patients with bipolar mania or mixed mania (N = 948 at initiation of olanzapine). SWG was defined as gaining 5 kg or 7% of initial weight in 30 +/- 2 weeks. Logistic regression estimated odds ratios associated with early weight gain and baseline risk factors for predicting SWG. A classification system to identify patients at risk for SWG was constructed by recursive data partitioning. Baseline characteristics significantly associated with SWG included younger age, nonwhite ethnicity, lower body mass index (BMI), nonrapid cycling, and psychotic features. Weight gain of 2 or more kg in the first 3 weeks of therapy predicted SWG by 30 weeks (sensitivity = 57%; specificity = 71%). A classification system with thresholds for early weight gain, baseline BMI, and ethnicity further improved SWG predictability (sensitivity = 79%; specificity = 70%). In conclusion, patients with bipolar disorder who gained 2 to 3 kg during the first 3 weeks of treatment with olanzapine, SWG was predicted after 30 weeks of treatment. Patients with less pronounced early weight gain might still be at risk for later SWG if they have close to normal BMI (< or =27 kg/m) at treatment initiation.