Mood Stabilizer Monotherapy Research Articles

Prevention of Relapse and Recurrence of Bipolar Type I Depression: A Study Protocol for a Multi-site Randomized, Double-blind, Placebo-substitution Trial

Background: Bipolar (BP) I disorder affects 1.6% of the US adult population and results in estimated healthcare costs of $40 billion annually. It is characterized by a predominance of major depressive episodes interspersed with manic and hypomanic episodes. Most current practice guidelines are based upon expert consensus and generally recommend using mood stabilizer monotherapy for initial treatment of BP I depression, while avoiding antidepressants and using only mood stabilizer monotherapy for prevention of relapse and recurrence of depression. We hypothesize that long-term mood stabilizer plus antidepressant therapy will result in fewer depressive relapses and recurrences versus mood stabilizer monotherapy. Methods/design: 200 patients with BP I depression will receive initial lithium plus fluoxetine therapy for 12 weeks. Responders will be randomized to double-blind maintenance therapy with either: (i) lithium plus fluoxetine, or (ii) lithium monotherapy (following fluoxetine taper and discontinuation) for an additional 50 weeks. The primary outcome is the proportion of subjects in each condition who have a depressive relapse or recurrence during maintenance therapy. Depressive relapse or recurrence is defined as a return of moderate depressive symptoms. Discussion: We believe that evidence-based medicine will eventually support the use of concurrent antidepressant therapy for prevention of depressive relapse and recurrence in patients with BP I disorder. The paucity of modern controlled clinical trials studying the best method for preventing depressive relapse and recurrence of BP I disorder has led to contradictory practice guidelines and confusion as to the best treatment for BP I disorder. This study seeks to determine whether subjects who respond to initial mood stabilizer plus antidepressant therapy will have a superior longterm efficacy and fewer depressive relapses and recurrences if they continue therapy with maintenance mood stabilizer plus antidepressant therapy versus mood stabilizer therapy alone. Trial registration: ClinicalTrials.gov Trials Register - NCT00961961.

The utilization of psychopharmacological treatment and medication adherence among Medicaid enrolled children and adolescents with bipolar depression

BackgroundTo examine the psychotropic medication utilization and compare adherence to treatment regimens in pediatric bipolar depression patients. Methods2003–2007 MAX data from four geographically diverse states were used. According to the regimen received by the patients (6–18 years) in the first month after the index bipolar depression diagnosis, patients were categorized into six mutually exclusive groups. The month to month change of treatment regimen in each group was then assessed during the 6 month post-index bipolar depression diagnosis. Adherence to each regimen was measured as continuation of the initial regimen, switch to a new regimen, augmentation with medication from a different therapeutic category, and discontinuation of all pharmacotherapies. Repeated measure analysis was conducted to compare the trend of each adherence measure across the study groups. ResultsOf the 5,460 subjects identified, 15.39% received antipsychotic monotherapy, 9.43% received mood stabilizer monotherapy, 5.77% received antidepressant monotherapy, 26.48% received mood stabilizer–antipsychotic polytherapy, 22.51% received antidepressant polytherapy, and 19.89% received antipsychotic–mood stabilizer–antidepressant polytherapy. At the end of the follow-up period, over 50% of the 1st month polytherapy users and less than 50% of the monotherapy users were continuing their initial regimen. Repeated measure analysis using antipsychotic monotherapy as the reference group suggested differences in trend slopes (p<0.05). LimitationsIn absence of structured clinical evaluation, bipolar disorder diagnoses cannot be ascertained in this study. ConclusionsBipolar depression patients were predominantly treated with combinations of psychotropic drugs. Potentially questionable practice, such as antidepressant monotherapy was used only in a small fraction of patients. Combination regimens had better adherence as compared to monotherapies.

Investigation into the long-term metabolic effects of aripiprazole adjunctive to lithium, valproate, or lamotrigine

BackgroundBipolar I disorder (BPD) patients are often overweight or obese, and likely to have metabolic syndrome. Several medications used to treat BPD are associated with increased body weight and/or worsening metabolic parameters. MethodsMetabolic data were analyzed from two efficacy studies of aripiprazole plus the mood stabilizers, lithium/valproate (Study CN138–189), or lamotrigine (Study CN138–392), in the long-term treatment (52 weeks) of BPD. Changes in body weight, individual metabolic parameters, and incidence of metabolic syndrome were assessed. ResultsIn the lithium/valproate study, modest increases in body weight were observed at Week 52 in both groups: 1.7±0.8kg in the lithium/valproate group, and 1.6±0.7kg in the adjunctive aripiprazole group; this difference was nonsignificant. In the lamotrigine study, decreases in body weight were observed at Week 52 with lamotrigine alone (−2.2±1.0kg), whereas a modest increase was observed when combined with aripiprazole (0.4±1.0kg). In both studies, rates of metabolic syndrome at 52 weeks did not increase from baseline with aripiprazole, and median changes from baseline in individual metabolic syndrome parameters were similar with both mood stabilizer monotherapy and the addition of aripiprazole as an adjunctive therapy. LimitationsThis was a post-hoc analysis, and a low percentage of patients completed the lamotrigine study. ConclusionsAripiprazole plus a mood stabilizer has minimal impact on metabolic changes in predominantly overweight/obese BPD patients over a 52-week period. In both studies, modest mean increases in weight with the addition of aripiprazole were not accompanied by increased rates of metabolic syndrome or changes in metabolic parameters.

Prevalence of Bipolar Disorder Diagnoses and Psychotropic Drug Therapy Among Privately Insured Children and Adolescents

To estimate the treated prevalence of bipolar disorder in a privately insured population, describe the characteristics of children and adolescents receiving these diagnoses, and describe patterns of their psychotropic drug therapy. Retrospective, repeated cross-sectional study. MarketScan Commercial Claims and Encounters inpatient, outpatient, and pharmacy claims databases. A total of 22,360 children and adolescents (aged 0-17yrs) with one inpatient or two or more outpatient claims for any bipolar spectrum disorder between January 1, 2005, and December 31, 2007. Annual cross-sections were used to estimate the treated prevalence of bipolar disorder diagnoses, patient characteristics, and psychotropic drugs used 30days after a child's latest recorded bipolar disorder diagnosis within each year. The annual treated prevalence of any bipolar spectrum disorder in this privately insured population was 0.24% in 2005 and 0.26% in 2006 and 2007. Approximately 25% of diagnoses were for children younger than 13years. Approximately 30% of children had coexisting attention-deficit-hyperactivity disorder during the year. In each year, 35% of patients used no psychotropic drug therapy in the 30-day period after their most recent diagnosis. Twenty-five percent used one psychotropic drug, and 40% used two or more drugs. The most common drug regimens were antipsychotic or mood stabilizer (lithium or anticonvulsant) monotherapy and the combination of mood stabilizers and antipsychotics. Drug therapy patterns suggest that children and adolescents with bipolar diagnoses receive complex treatment regimens, often involving multiple classes of psychotropic drugs. Research on treatment combinations, particularly antipsychotic and mood stabilizer combinations, should be prioritized to better understand the safety and effectiveness of commonly prescribed treatments.

Acute treatment of mania in children and adolescents

To examine critically data concerning the efficacy and safety of acute treatments for mania in children and adolescents, in the light of considerable recent emergent evidence. We found consistent evidence favouring the use of second-generation antipsychotics (SGAs), limited evidence favouring the use of combinations of SGA with a mood stabilizer, and no evidence supporting the use of mood stabilizer monotherapy in this context. Various SGA drugs are not clearly separated in terms of efficacy, but do differ in their side-effect profiles. There are insufficient data to comment on the benefit of alternative treatments, psychological treatments and electroconvulsive therapy. The presence of common comorbidities has an inconsistent influence on clinical effectiveness. First-line treatment for mania in children and adolescents is a SGA, with combination therapies offering no clear advantage. Gaps in our knowledge remain about expected time to recovery, and when to augment or change treatment when there is lack of effect.

Efficacy of antimanic treatments in mixed states

To review the efficacy of pharmacological agents in bipolar mixed states. We conducted a PubMed search of all English-language articles involving Food and Drug Administration (FDA)-approved agents for manic/mixed states in adults with bipolar I disorder. We also included names of agents established as efficacious in acute mania/mixed states that have not received FDA approval for bipolar disorder. Bibliographies from relevant articles were also searched. The efficacy of each agent in the mixed state subpopulation was reviewed, as evidenced by change from baseline on total scores of mania [e.g., Young Mania Rating Scale (YMRS)] and depression [e.g., Montgomery-Åsberg Depression Rating Scale (MADRS)] measures. No available study is dedicated exclusively to the evaluation of mixed state populations. Although key inclusion and exclusion criteria are similar across treatment studies, mixed states have been variably defined and measured. The use of conventional manic and depressive metrics in bipolar mixed states perpetuates the unproven notion that mixed states are the consequence of coexisting depression and mania. Notwithstanding the methodological limitations, there are numerically more studies that exist for atypical antipsychotic agents than for any other class. On the basis of symptomatic improvement, recommendations for and/or strong admonishments against any established antimanic agents (e.g., lithium) cannot be made. An emergent signal supports combination treatment strategies (e.g., atypical antipsychotic plus divalproex) over mood stabilizer monotherapy (e.g., divalproex). Available evidence does not empirically support the hypothesis that conventional antipsychotics engender and/or amplify depressive symptoms in bipolar mixed states. All proven antimanic agents (including lithium), can be recommended in the treatment of mixed/dysphoric states. The totality of evidence with attention paid to the therapeutic index of each agent would suggest that atypical antipsychotics and divalproex be considered as first-line treatment, with lithium and carbamazepine as second-line. Most individuals will require combination therapy for the treatment of mixed states; variable combinations of atypical antipsychotics and conventional mood stabilizers have the most replicated evidence.

Comparison of neuropsychological effects of adjunctive risperidone or quetiapine in euthymic patients with bipolar I disorder

Although associations between antipsychotic use and neuropsychological impairment in bipolar I disorder have been observed, there is a lack of studies comparing the effects of specific agents used in this population. We compared performance between patients receiving maintenance treatment with mood stabilizer monotherapy (n=15), adjunctive risperidone (n=15) or quetiapine (n=17), and a group of demographically matched healthy controls (n=28) on tests of executive function (working memory, set shifting, and inhibition) and verbal learning. Despite having a similar clinical profile, patients being treated with risperidone showed significantly impaired working memory, set-shifting, and verbal learning (P<0.05) compared with those either on mood stabilizer monotherapy or adjunctive quetiapine. Although randomized controlled trials are required to confirm the cognitive side effects of medications prescribed for maintenance treatment of bipolar I disorder, preliminary results indicate that addition of risperidone to a mood stabilizer has a negative impact on executive function and verbal learning, an effect not shared with quetiapine.

Asenapine as Adjunctive Treatment for Acute Mania Associated With Bipolar Disorder

In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment-emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks.

Paliperidone extended-release as adjunctive therapy to lithium or valproate in the treatment of acute mania: A randomized, placebo-controlled study

Background Combination treatment with atypical antipsychotics and a mood stabilizer is often recommended for treatment of manic or mixed episodes associated with bipolar I disorder. Methods Eligible patients ( n = 300) with a Young Mania Rating Scale (YMRS) total score ≥ 20 were randomly allocated (1:1) to continue mood stabilizer monotherapy or receive flexibly-dosed paliperidone ER (3–12 mg/day) in addition (combination treatment) for 6 weeks. The primary efficacy variable was the change from baseline to endpoint in the YMRS total score. Results The mean (SD) YMRS total score at baseline was 26.7 (5.26); 33% of patients presented with a mixed (as distinct from a manic) episode and 62% were on valproate and 38% on lithium. The mean (SD) change from baseline to endpoint in the YMRS total score was not significantly different for combination treatment (− 14.3 [10.0]) compared with mood stabilizer monotherapy (− 13.2 [10.9]; p = 0.16). Combination treatment also failed to separate from mood stabilizer monotherapy for the secondary efficacy measures. The incidence of treatment-emergent adverse events was higher with combination treatment (70%) than with mood stabilizer monotherapy (54%); insomnia was the most common adverse event in both treatment groups (11%). Limitations The relatively low doses of paliperidone ER used in this study and the conduct across different countries may have contributed to its failure to differentiate combination treatment from mood stabilizer monotherapy for the primary and secondary efficacy measures. Conclusions In this study, flexibly-dosed paliperidone ER used as adjunctive therapy to mood stabilizers did not demonstrate efficacy over mood stabilizer monotherapy. No new safety signals were observed with combination treatment in this population.

Efficacy and Mood Conversion Rate of Short-Term Fluoxetine Monotherapy of Bipolar II Major Depressive Episode

As part of a long-term, relapse-prevention study of antidepressant versus mood stabilizer monotherapy of bipolar II major depressive episode, we prospectively examined the efficacy and mood conversion rate of initial fluoxetine monotherapy. We hypothesized that there would be a statistically significant reduction in depressive symptoms without a clinically meaningful increase in mood conversion symptoms. Patients received open-label fluoxetine monotherapy 10 to 80 mg daily for up to 14 weeks. Primary outcome was change over time in Hamilton Depression Rating score, with secondary outcomes including the proportion of treatment responders and remitters, change over time in Young Mania Rating Scale (YMRS) score, and frequency of mood conversion episodes. One hundred forty-eight patients had at least 1 post-baseline measurement. Mean Hamilton Depression Rating score decreased by 9.0 points (P < 0.0005). There were 88 responder patients (59.5%; 95% confidence interval [CI], 51.1%-67.4%) (P < 0.0005) and 86 remitter patients (58.1%; 95% CI, 49.7%-66.2%) (P < 0.0005). Mean time to remission was 64.4 days (95% CI, 59.1-69.7 days). Six patients (4.1%; 95% CI, 1.5%-8.6%) (P < 0.0005) had hypomania, and 29 patients (19.6%; 95% CI, 13.5%-26.9%) (P < 0.0005) had subsyndromal hypomania, which did not result in treatment discontinuation. Six patients (4.1%; 95% CI, 1.5%-8.6%) had a YMRS score of 8 or greater (P < 0.0005), and 4 patients (2.7%; 95% CI, 0.7%-6.8%) (P < 0.0005) had a YMRS score of 12 or greater at any study visit. Although design limitations constrain the interpretation of the current findings, fluoxetine monotherapy may be an effective short-term treatment of bipolar II major depressive episode with a relatively low rate of syndromal hypomanic episodes.

Healthcare Costs of Atypical Antipsychotic Use for Patients with Bipolar Disorder in a Medicaid Programme

A large body of clinical studies have demonstrated the efficacy of atypical antipsychotic use in the treatment of bipolar disorder. Facing increasing budget pressure, third-party payers, such as state Medicaid programmes in the US, are demanding better understanding of the medical costs beyond atypical antipsychotic drug costs alone in treating bipolar disorder. To examine healthcare costs associated with the atypical antipsychotic treatments for bipolar disorder from a US third-party payer perspective. This was a retrospective cohort study using an intent-to-treat approach. Using the North Carolina Medicaid claims database (August 2000 to January 2005), 3328 patients with bipolar disorder were identified who were continuously eligible for 3 months pre-initiation and 12 months post-initiation of treatment with an atypical antipsychotic (AP2) or mood stabilizer (MS). Patients were classified into three groups based on the treatment types during the first 30 days after treatment initiation: AP2 monotherapy, AP2 + MS combination therapy, and MS monotherapy. Bipolar-related and total health-related costs were examined for the 12-month period. Propensity score matching was employed to balance baseline characteristics among the three comparison groups. Generalized linear models were further employed to estimate the average treatment effect on the cost outcomes. Compared with MS monotherapy, AP2 monotherapy and AP2 + MS combination therapy incurred higher medication costs during the 12-month treatment period. Patients receiving AP2 monotherapy had significantly lower bipolar-related medical costs (-$US698; p = 0.002) [year 2004 values] than patients receiving MS monotherapy. However, the inclusion of the medication cost produced no statistically significant difference in bipolar-related total cost (p = 0.14). Similar results were observed for all health-related costs. Patients receiving AP2 + MS therapy incurred significantly higher bipolar-related total costs (+$US1659; p < 0.0001) and all health-related total costs (+$US2115; p < 0.0001) than patients receiving MS monotherapy, which was attributable largely to the higher medication cost. From a third-party payer perspective, atypical antipsychotic monotherapy generated higher drug costs but lower medical care costs, resulting in equivalent total healthcare costs over a 1-year period.

Impact of Antidepressant Continuation After Acute Positive or Partial Treatment Response for Bipolar Depression

To assess long-term outcome in bipolar disorder, subjects were prospectively followed after receiving acute treatment for bipolar depression. Eighty-three outpatients with DSM-IV bipolar depression who were enrolled between March 1996 and November 2002 and were treated in a 10-week acute double-blind antidepressant treatment trial agreed to participate in a 1-year double-blind continuation of their medication. In the acute antidepressant treatment trial, subjects were treated with a mood stabilizer plus 1 of 3 randomly assigned antidepressants. Sixty-one subjects had attained an acute positive antidepressant response (50% improvement on the Inventory for Depressive Symptomatology [IDS] or 2-point improvement on the Clinical Global Impression for Bipolar Disorder [CGI-BP]) and 22 subjects achieved only acute partial improvement at the end of the 10-week acute trial. In the blinded continuation phase immediately following the acute trial, subjects continued on the same medications and were rated monthly for up to 1 year using the IDS, CGI-BP, and the Young Mania Rating scale. At study endpoint, 42 (69%) of the 61 acute positive responders maintained positive response and 32 (53%) achieved remission. Compared to the acute positive responders, 6 (27%) of the 22 acute partial responders had achieved positive treatment response at study endpoint (p < .001). Eight acute positive responders (13%) and 5 acute partial responders (22%) developed mania. Patients who achieve a positive acute antidepressant response to 10 weeks of antidepressant treatment adjunctive to a mood stabilizer will probably maintain response with the same continued treatment. Patients who achieve only a partial acute antidepressant response are less likely to further improve when the same treatment is sustained. The switch rate into mania for patients being treated with an antidepressant adjunctive to a mood stabilizer is not higher than the reported rate for patients on mood stabilizer monotherapy.

Revised Korean medication algorithm for bipolar disorder

The rapid progress in treatments for bipolar disorder makes it necessary to revise the Korean Medication Algorithm Project for Bipolar Disorder (KMAP-BP) published in 2002. This study was performed to timely revise KMAP-BP 2002. A questionnaire comprising 37 questions and 645 treatment options was developed for surveying the opinions of Korean experts. We classified the opinions into three categories: first-, second-, and third-line treatments. Fifty-three (75.7%) of the 70 selected experts answered the questionnaire. For an acute manic episode, the combination of a mood stabilizer (MS) and an atypical antipsychotic (AAP) was the preferred first-line treatment. Most experts recommended divalproex and lithium as MSs, and olanzapine, quetiapine, and risperidone as AAPs. For moderately to severely depressed bipolar patients, MS monotherapy and a combination of an MS and an antidepressant (AD) were considered to be preferred treatments respectively. A combination of an MS and an AD was the preferred strategy in severe nonpsychotic depression. Most ADs were rated as second-line drugs. Overall, the preference for lamotrigine and AAPs was higher than in KMAP-BP 2002. The algorithm was developed mainly using consensus among experts supplemented with findings of recent clinical trials to ensure that our algorithm was both up to date and balanced. These results suggest that the medication strategies of KMAP-BP are changing rapidly, reflecting recent studies and clinical experiences.

Trends in Use of Antipsychotics and Mood Stabilizers Among Medicaid Beneficiaries With Bipolar Disorder, 2001-2004

Trends in Use of Antipsychotics and Mood Stabilizers Among Medicaid Beneficiaries With Bipolar Disorder, 2001-2004

PMH25 HEALTH CARE USE AND COSTS OF PATIENTS WITH “PURE OBSESSIVE-COMPULSIVE DISORDER” VERSUS “PURE DEPRESSION”: 9-YEAR (1997-2006), LARGE-SCALE, RETROSPECTIVE CLAIMS ANALYSIS OF FLORIDA MEDICAID ADULT ENROLLEES

A COMPARISION OF HEALTH CARE UTILIZATION AND COST OF CHILDREN ANDADOLESCENTSWITH BIPOLAR DISORDERTREATEDWITH ATYPICAL ANTIPSYCHOTIC MONOTHERAPYVERSUS MOOD STABILIZER MONOTHERAPY Jing Y, Guo JJ, Patel NC, Heaton PC, Li H, Kelton CM University of Cincinnati, Cincinnati, OH, USA, University of Georgia, Augusta, GA, USA, Bristol-Myers Squibb Company, Singapore, Singapore OBJECTIVE: To compare health care utilization and cost of children and adolescents with bipolar disorder treated with atypical antipsychotic (ATYP) versus with mood stabilizer (MS) monotherapy. METHODS: We conducted a retrospective cohort study using Pharmetrics administrative claims data from January 1, 1998 to December 31, 2002. The study population included youths (6 < AGE < 19). RESULTS: After matching on the propensity score, 486 subject pairs were retained. On average, ATYP monotherapy subjects had fewer bipolar-related office visits (p = 0.0041), but similar bipolar-related outpatient hospitalization (p = 0.084), bipolar-related days of hospitalization (p = 0.1707), and bipolar-related emergency department visits (p = 1.00). ATYP monotherapy subjects had a lower cost of bipolar-related office visits (p = 0.0246) but higher medication costs (p < 0.0001). There were no cost differences between groups for bipolar-related emergency department visits (p = 0.5477), bipolar-related outpatient hospitalization (p = 0.9817), and bipolar-related inpatient hospitalizations (p = 0.521). Total bipolar-related medical service (p = 0.6501) and general health-related medical service (p = 0.885) costs were also not significantly different between the two groups. CONCLUSION: Compared to patients with MS monotherapy, patients with ATYP monotherapy had fewer bipolar-related office visits and higher medication costs, but similar total bipolarrelated and overall medical service costs.

Comparison of Short-Term Venlafaxine Versus Lithium Monotherapy for Bipolar II Major Depressive Episode

Practice guidelines for the initial treatment of bipolar II (BP II) major depressive episode (MDE) recommend mood stabilizer (MS) monotherapy or combined MS plus antidepressant drug (AD) therapy. We hypothesized that initial AD monotherapy would be superior to MS monotherapy for BP II MDE with a low hypomanic switch rate. Bipolar II MDE patients were randomized to a 12-week open-label treatment with either venlafaxine monotherapy (n = 43) or lithium carbonate monotherapy (n = 40). The primary outcome measure was the 28-item Hamilton Depression Rating Scale (HAM-D 28). The secondary outcome measures included the Young Mania Rating Scale (YMRS), clinical global impressions severity and change ratings, and the proportion of patients classified as responder (with > or = 50% reduction in baseline HAM-D score) or as remitter (final HAM-D score, < or = 8). Thirty-four venlafaxine-treated patients (79.1%) and 15 lithium-treated patients (37.5%) completed the trial (P < 0.0005). Venlafaxine monotherapy produced a greater reduction in HAM-D 28 scores, with a difference in change of -6.57 points (95% confidence interval, -11.97 to -1.18) (P = 0.017) between treatment conditions. There was a greater proportion of venlafaxine-treated (vs lithium-treated) patients classified either as treatment responder (58.1% vs 20.0%; P < 0.0005) or as treatment remitter (44.2% vs 7.5%; P < 0.0005) for the HAM-D 28 scores. There was no significant increase in mean YMRS scores over time in the venlafaxine (vs lithium) treatment condition, and no significant increase in mean YMRS scores at any study visit compared with baseline for either treatment. Results from this study suggest that AD monotherapy with venlafaxine may be an effective initial therapy for BP II MDE with a low hypomanic switch rate.

Adjunctive Antidepressant Use and Symptomatic Recovery Among Bipolar Depressed Patients With Concomitant Manic Symptoms: Findings From the STEP-BD

Practice guidelines have advised against treating patients with antidepressants during bipolar mixed states or dysphoric manias. However, few studies have examined the outcomes of patients with co-occurring manic and depressive symptoms who are treated with antidepressants plus mood stabilizing drugs. The authors compared outcomes in patients with bipolar disorder who received a mood stabilizing agent with versus without an antidepressant for a bipolar depressive episode accompanied by > or = 2 concurrent manic symptoms. The 335 participants were drawn from the first 2,000 enrollees in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Kaplan-Meier survival curves and Cox regression models were used to compare time to recovery. General linear models examined the relationship between antidepressant use or mania symptom load at the study entry and mania or depression symptom severity at the 3-month follow-up. Adjunctive antidepressant use was associated with significantly higher mania symptom severity at the 3-month follow-up. The probability of recovery at 3 months was lower among patients with higher baseline depression severity. Antidepressant use neither hastened nor prolonged time to recovery once potential confounding factors were covaried in a Cox regression model. In bipolar depression accompanied by manic symptoms, antidepressants do not hasten time to recovery relative to treatment with mood stabilizers alone, and treatment with antidepressants may lead to greater manic symptom severity. These findings are consistent with those from the STEP-BD randomized trial for pure bipolar depression, in which adjunctive antidepressants did not yield higher recovery rates than did mood stabilizer monotherapy.

Bipolar pharmacotherapy and suicidal behavior. Part I: Lithium, divalproex and carbamazepine

Introduction The anti-suicidal benefit of lithium on suicidal behavior in bipolar disorder is well-established. Data are mixed on the effects of divalproex and carbamazepine. Methods Retrospective chart review study of 405 veterans with bipolar disorder followed for a mean of 3 years, with month by month review of clinical progress notes, and systematic assessment of current pharmacotherapy and suicide completion, attempt or hospitalization for suicidality. Comparison of suicide event rates (events/100 patient years) between mood stabilizers and during-vs-after discontinuation of mood stabilizers, with linear regression analysis for influence of potential confounding variables, and robust bootstrap confirmation analysis. Results No completed suicides occurred during or after discontinuation of monotherapy. Rates of non-lethal suicidal behavior were similar during lithium (2.49), divalproex (4.67) and carbamazepine (3.80) monotherapies. There was a sixteen fold greater, highly statistically significant non-lethal suicidal event rate after discontinuation compared with during mood stabilizer monotherapy (55.89 vs. 3.48 events/100 patient years; Chi 2 = 13.95; df = 1; p < 0.0002). On compared with off treatment differences were similar for the three different agents. Limitations Treatments were uncontrolled in this naturalistic setting, and data were analyzed retrospectively. Conclusions Lithium and the anticonvulsants may show similar benefits in protecting bipolar patients from non-lethal suicidal behavior when careful analysis of clinical data is done to confirm medication adherence/non-adherence. Findings in this study were similar to those of a previous study that applied the same methodology in a private practice setting.

Bipolar pharmacotherapy and suicidal behavior: Part 2. The impact of antidepressants

Antidepressant-induced mania and cycle acceleration is a potential risk in bipolar patients. Another serious risk of antidepressants, that of increasing suicidal behavior, has been identified in some affectively ill populations. However, there is a dearth of knowledge about the effects of antidepressants on suicidal behavior specifically in bipolar patients. Methods Retrospective chart review of 405 veterans with bipolar disorder followed for a mean of three years, with month by month systematic assessment of current pharmacotherapy and suicide completion, attempt or hospitalization for suicidality. Chi-squared comparison of (log) rates of suicidal events during mood stabilizer monotherapy, antidepressant monotherapy, and combination of mood stabilizer and antidepressant. Results Suicidal behavior event rates (per 100 patient years) were greatest during treatment with antidepressant monotherapy (25.92), least during mood stabilizer monotherapy (3.48), and intermediate during mood stabilizer + antidepressant combination treatment (9.75). These differences were statistically significant. Limitations In a clinical setting, antidepressants may have been prescribed because patients were deemed at greater risk of suicidality. Conclusions During treatment with antidepressants (even when coupled with mood stabilizers), patients with bipolar disorder have significantly higher rates of non-lethal suicidal behavior compared to those on mood stabilizers without antidepressants, and thus require careful monitoring.

Bipolar pharmacotherapy and suicidal behavior: Part 3: Impact of antipsychotics

Introduction Antipsychotics, particularly second generation agents, are widely used in bipolar disorder, but their effect on suicidal behavior in this population has not been systematically studied. Methods Retrospective chart review of 405 veterans with bipolar disorder followed for a mean of three years, with month-by-month systematic assessment of current pharmacotherapy and suicide completion, attempt or hospitalization for suicidality. Comparison of rates of suicidal events during mood stabilizer monotherapy, antipsychotic monotherapy, and combination of mood stabilizer and antipsychotic. Results Non-lethal suicide event rates were 9.4 times greater ( χ 2 = 28.29, p < .0001) during antipsychotic monotherapy and 3.5 times greater during mood stabilizer + antipsychotic ( χ 2 = 15.13, p = 0.0001) than during mood stabilizer monotherapy. Limitations Antipsychotics may have been prescribed because patients were at greater risk of suicidal behavior. First and second generation antipsychotics were not distinguished. Conclusions Treatment of bipolar patients with antipsychotics is associated with an increase in non-lethal suicidal behavior. Thus, use of antipsychotics for bipolar patients requires careful monitoring for suicidal behavior. Further studies are urgently needed to better characterize this relationship.