The role of gender in single vs married individuals with bipolar disorder.

BACKGROUND: Despite the importance of marriage as a source of social support, it has been largely neglected in studies of bipolar disorder; and differential effects on men and women have not been explored. METHODS: Data on episodes of depression, mania, and mixed states were collected for the previous 2 years from a sample of 282 bipolar individuals using the National Institute of Mental Health Life Chart Methodology. RESULTS: Effects unique to women included the following: Bipolar women were significantly more likely to be married. Married women had fewer episodes of depression during the past 2 years than never-married women, and the cumulative severity of depression was lower. There were no differences in diagnostic subtype or age of onset between married and never-married women. Among men, never-married men were more likely to have bipolar I disorder and had an earlier age of onset compared with married men. There were no differences between married and never-married men in frequency, duration, or severity of mood episodes. CONCLUSIONS: Partner selection processes as they relate to bipolar disorder may be different for men and women. The bipolar I diagnostic subtype and early age of onset were associated with a lower likelihood of being married for men, but not for women. Marriage was associated with less depression in women during a 2-year period; but marital status was not associated with disease course differences in men, suggesting that women may be more sensitive to the positive effects of social support available within a stable marital relationship.

ACNP Task Force report on SSRIs and suicidal behavior in youth.

This Task Force report by the American College of Neuropsychopharmacology evaluates the safety and efficacy of selective serotonin reuptake inhibitor (SSRIs) antidepressants for depressed youth under 18 years. The report was undertaken after regulatory agencies in the United States and United Kingdom raised concerns in 2003 about the possibility that treatment of depression in children and adolescents with SSRIs may increase the risk of suicidal thinking or suicide attempts.

Substance use disorder and other predictors of antidepressant-induced mania: a retrospective chart review.

OBJECTIVE: To determine if substance use disorder (SUD) is a predictor of antidepressant-induced mania (ADM) in bipolar disorder, correcting for confounding factors in a regression model. METHOD: 335 antidepressant trials were identified in 98 patients treated in an academic bipolar specialty clinic from 2000 to 2004. Patient charts were reviewed, and histories of SUD and ADM (primary outcome; defined as a hypomanic or manic episode within 12 weeks of beginning an antidepressant trial) were identified. Mood disorder diagnoses were made using the Structured Clinical Interview for DSM-IV mood module, and SUD diagnoses were defined using DSM-IV criteria. Potential confounding variables were also examined and included in a multivariable regression model. Concomitant mood stabilizer, antimanic, and antidepressant use was adjusted for in the regression model. RESULTS: In univariate analyses, there was no evidence of an association between ADM and past SUD. However, after adjustment for confounding variables in a multivariable regression model, there was a strong relationship (OR = 5.06, 95% CI = 1.31 to 19.64, p < .05). Other statistically significant predictors of ADM in the regression model were type II subtype of bipolar illness, female gender, and tricyclic antidepressant (TCA) use (vs. bupropion). CONCLUSIONS: Along with other factors, a history of SUD was a strong predictor of ADM. Possible underestimation of ADM in randomized clinical trials may occur due to the exclusion of subjects with SUD. Type II illness, female gender, and TCA use also appeared to be predictors of ADM, while bupropion use appeared to predict lower likelihood of ADM.

Extrapyramidal side effects with atypical neuroleptics in bipolar disorder.

OBJECTIVE: To examine, in a real-world clinical setting, the risk of extrapyramidal symptoms (EPS) with atypical neuroleptics in bipolar patients. METHODS: The authors assessed 51 individual patient trials of atypical neuroleptic agents (17 risperidone, 13 olanzapine, 11 quetiapine, 8 ziprasidone, and 2 aripiprazole) in 37 bipolar patients (type I or type II). Risk of EPS was assessed using the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, and the Simpson-Angus Scale. Mean duration of treatment was 25.5 weeks (range 3-107 weeks) and 60.8% of patients were female. RESULTS: 62.7% of trials resulted in moderate to severe EPS. EPS and discontinuation frequencies were similar between specific neuroleptic agents or between high potency (risperidone/ziprasidone/aripiprazole; 52.9%, 27/51 trials) and low potency (quetiapine/olanzapine; 47.1%, 24/51 trials) agents. In a multiple regression model adjusted for confounders, akathisia was less common with low potency agents. Younger age was associated with more akathisia. 31.4% (11/35) of trials discontinued due to side effects. 7.8% (4/51) of trials led to mild de novo tardive dyskinesia. CONCLUSIONS: Over one-half of bipolar patients experienced EPS in this real world clinical setting. This rate is much higher than the 5-15% range reported in clinical trials, suggesting potential problems with clinical trial generalizability.

Long-term lamotrigine plus lithium for bipolar disorder: One year outcome.

OBJECTIVE: To obtain pilot data in an observational setting on the use of lamotrigine plus lithium in the long-term treatment of patients with bipolar disorder, 87% of whom had failed to respond to at least one previous mood stabilizer. METHODS: Charts of 21 patients (11 females, 10 males, mean age 43.2 years) treated with the combination of lithium and lamotrigine were reviewed retrospectively for treatment response using the Clinical Global Impression-Bipolar Disorder-Improvement scale, divided into benefit for acute depressive symptoms, acute manic symptoms, and overall illness (including prophylaxis of mood episodes). Of the 21 patients, 76% were diagnosed with bipolar I disorder, and depressive symptoms were the most common acute indication for treatment (52%). Mean doses of lithium and lamotrigine were 963 mg/day and 179 mg/day, respectively, used for a mean of 55.7 weeks. RESULTS: Acute antidepressant benefit was observed in 48% of patients, acute anti-manic benefit in 14%, and overall prophylactic benefit in 29%. Side effects were observed in 38%, with cognitive problems most common (29%). 48% discontinued combination therapy, mainly due to lack of efficacy (19%) or activation of manic-like symptoms (19%). CONCLUSIONS: Among a group of largely treatment-resistant bipolar patients, the combination of lithium and lamotrigine appeared effective for acute depressive symptoms in about half of the patients, but acute anti-manic and long-term prophylactic efficacy appeared less robust.

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

BACKGROUND: The use of antidepressants in rapid-cycling bipolar disorder has been controversial. We report the first randomized clinical trial with modern antidepressants on this topic. METHODS: As 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. RESULTS: In 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. CONCLUSIONS: In 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.

Impact of formularies on clinical innovation.

It is important to consider, in light of how innovation has so often occurred, whether today's managed care environment is conducive to continued psychopharmacologic innovation. The initial step in the development of a new area in psychopharmacology has historically relied in large part on individual clinicians who pursued unconventional methods of treatment. When a set of guidelines such as a formulary (a list of drugs eligible for reimbursement compiled by a managed care organization) becomes restrictive, it decreases clinician innovation. In addition to this long-term threat to innovation, studies have found greater restrictiveness in formularies to be associated with higher health care utilization. Thus, restricted formularies that are based on a naive interpretation of "therapeutic equivalence" may slow the advance of medical science without even achieving the only goal that could possibly justify such restrictions-cost control. If innovation is to flourish, formularies must be flexible and advisory, not restrictive. Preserving the climate for innovation in health care requires the management culture to focus on the long-term impact of policies on quality and innovation as well as on the overall health cost in the system.

Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment.

Because of the great morbidity and mortality associated with bipolar disorder, long-term treatment is necessary to prevent recurrence and reduce the loss of productivity and increased medical costs associated with this illness. The agent with the most evidence of efficacy and the only U.S. Food and Drug Administration-approved medication for maintenance treatment of bipolar disorder is lithium. Lithium may cause a prophylactic response in more than two thirds of patients with bipolar disorder and reduce suicide risk by more than 8-fold. However, lithium may be more effective for patients with classical features such as fully remitting courses and typical manic symptoms than for patients with nonclassical bipolar features such as mixed states and rapid cycling. Because lithium may be toxic at only twice the therapeutic dose, physicians should consider patients' ages and medical history when prescribing this drug. Monitoring requirements; possible side effects; changes in the illness including more treatment-resistant forms; and the introduction of newer agents, which are supported by more marketing and continuing medical education programs than the essentially generic drug lithium, have contributed to the decline in lithium prescription rates in the last 15 years in the United States. However, long-term treatment with lithium continues to be effective in many patients, especially if the dose is periodically evaluated as patients experience changes in their physical health and lithium tolerance. Until newer agents have comparable evidence of efficacy, lithium will be considered a first-line long-term treatment for bipolar disorder, either as monotherapy or in combination therapy.

Rationale for using lithium in combination with other mood stabilizers in the management of bipolar disorder.

Bipolar disorder is a complex illness, and no single agent has been proven in randomized, placebo-controlled trials to effectively prevent and/or control all aspects of the illness-acute mania, rapid cycling, and breakthrough depression. However, for the most important issue, prophylaxis of episodes, lithium has more evidence of efficacy than any other agent. Like lithium, typical antipsychotics, carbamazepine, divalproex, and the atypical antipsychotic olanzapine are effective in the treatment of mania. Carbamazepine, divalproex, and olanzapine seem effective in preventing manic episodes but, like lithium, are less effective in preventing depression. Few trials have been conducted in the more difficult-to-treat characteristics of bipolar disorder, specifically, rapid cycling and break-through depression. For patients with rapid cycling, carbamazepine or divalproex therapy may improve symptoms, but only lamotrigine has been shown to reduce cycling, mostly in the bipolar II group, in a randomized, placebo-controlled study. For the treatment of depressive episodes, lithium and olanzapine have shown modest efficacy in controlled trials, and among the mood stabilizers, lamotrigine has the most robust effect. Because manic symptoms may respond best to one agent and depressive symptoms to another, combination therapy may be the optimal treatment for many patients with bipolar disorder. For example, lithium augmentation may improve overall response rates to treatment with carbamazepine or divalproex, and the lithium-lamotrigine combination should provide effective prevention of both mania and depression. Also, each mood stabilizer may be given at lower doses when given in combination, resulting in a reduced side effect burden and improved compliance.

Effect of lamotrigine on cognitive complaints in patients with bipolar I disorder.

BACKGROUND: This analysis describes the effects of bipolar I disorder on self-reported neurocognitive measures and remediation of these deficits with lamotrigine therapy. METHOD: Data were derived from 2 clinical trials designed to assess the efficacy of lamotrigine as maintenance therapy for recently manic (N = 349) or depressed (N = 966) patients (DSM-IV criteria). During the 8- to 16-week open stabilization phase, patients received lamotrigine as monotherapy or as adjunctive therapy (target dose = 200 mg/day, minimum dose = 100 mg/day) while other psychotropic drugs were discontinued. The Medical Outcomes Study Cognitive Scale (MOS-Cog) and the AB-Neurological Assessment Scale (AB-NAS) were used to measure cognitive functioning at baseline and at the end of the open-label phase. To examine the relationship between depressive and manic symptomatology, initiation of lamotrigine, and cognitive functioning, correlational analyses and analyses of covariance were conducted. RESULTS: Bipolar patients in both trials had significant cognitive impairment; however, it was much greater in index episode depressed bipolar patients compared with index episode manic patients. In both studies, substitution of lamotrigine for other psychotropic medications significantly improved the mean scores from baseline to the end of the open-label phase on the MOS-Cog and the AB-NAS (p < .0001). Among patients who took lamotrigine as monotherapy, the mean MOS-Cog score also improved significantly versus baseline (+32.2, or 81%, for depressed patients, p < .0001; and +19.9, or 35%, for manic patients, p < .0001). Mean AB-NAS scores (-19.7, or -55%, for depressed patients, p < .0001; and -7.2, or -32%, for manic patients, p = .0062) showed similar improvement. Cognitive impairment was significantly correlated with depression symptom severity based on Hamilton Rating Scale for Depression scores (p < .0001). After controlling for change in mood, age, gender, baseline score, duration of illness, and duration of use of other psychotropics, a significant improvement in cognition was observed during the open-label phase when lamotrigine was used as monotherapy/adjunctive therapy. CONCLUSION: Treatment with lamotrigine as monotherapy and as adjunctive therapy was associated with improved cognitive functioning and reduced neurocognitive side effects, regardless of index mood polarity.

Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management.

BACKGROUND: The rate of lamotrigine-associated rash in patients with mood disorders has not been well characterized. The objective of this report was to determine rash rates in clinical trials of lamotrigine in DSM-IV unipolar depression or bipolar disorder. METHOD: A retrospective analysis was conducted of rates of lamotrigine-related rash in 12 multicenter studies, including 1 open study, 7 randomized controlled acute trials, and 4 randomized controlled maintenance trials from 1996 to 2001. RESULTS: A total of 1955 patients were treated with lamotrigine in open-label settings (open-label phases preceding or following randomization and 1 stand-alone open-label study); 1198 patients received lamotrigine in controlled settings, and 1056 patients received placebo. In controlled settings, rates of benign rash were 8.3% and 6.4% in lamotrigine- and placebo-treated patients, respectively. Rates of serious rash were 0% with lamotrigine, 0.1% (N = 1) with placebo, and 0% with comparators. In the open-label setting, the overall rate of rash for lamotrigine was 13.1% (N = 257) and of serious rash, 0.1% (N = 2). One mild case of Stevens-Johnson syndrome not requiring hospitalization occurred in a patient treated with lamotrigine. There were no cases of toxic epidermal necrolysis in any setting. CONCLUSION: Serious drug eruptions associated with lamotrigine were rare. Although rash is a potentially life-threatening reaction, the risk of serious rash due to lamotrigine should be weighed against more common risks associated with untreated or undertreated bipolar depression.

Optimizing lithium treatment in bipolar disorder: a review of the literature and clinical recommendations.

While the past decade has witnessed a major proliferation of putative treatments for bipolar disorder, one medication--lithium--has proven its effectiveness through 50 years of clinical experience and scientific scrutiny. Unfortunately, because the generic compound, lithium, lacks the financial support of its newer, patented comparators, it is often neglected by clinicians who are exposed to continuing medical education (CME) and residency training programs that are heavily weighted towards the newer treatments. This article critically examines the medical literature on lithium's efficacy, anti-suicidal properties, and adverse effects. The authors present research-based recommendations for maximizing lithium's benefits and minimizing adverse effects associated with lithium in patients with bipolar disorder.

Suicide risk in bipolar disorder during treatment with lithium and divalproex.

CONTEXT: Several studies have suggested that lithium treatment reduces risk of suicide in bipolar disorder, but no research has examined suicide risk during treatment with divalproex, the most commonly prescribed mood-stabilizing drug in the United States. OBJECTIVE: To compare risk of suicide attempt and suicide death during treatment with lithium with that during treatment with divalproex. DESIGN AND SETTING: Retrospective cohort study conducted at 2 large integrated health plans in California and Washington. PATIENTS: Population-based sample of 20 638 health plan members aged 14 years or older who had at least 1 outpatient diagnosis of bipolar disorder and at least 1 filled prescription for lithium, divalproex, or carbamazepine between January 1, 1994, and December 31, 2001. Follow-up for each individual began with first qualifying prescription and ended with death, disenrollment from the health plan, or end of the study period. MAIN OUTCOME MEASURES: Suicide attempt, recorded as a hospital discharge diagnosis or an emergency department diagnosis; suicide death, recorded on death certificate. RESULTS: In both health plans, unadjusted rates were greater during treatment with divalproex than during treatment with lithium for emergency department suicide attempt (31.3 vs 10.8 per 1000 person-years; P<.001), suicide attempt resulting in hospitalization (10.5 vs 4.2 per 1000 person-years; P<.001), and suicide death (1.7 vs 0.7 per 1000 person-years; P =.04). After adjustment for age, sex, health plan, year of diagnosis, comorbid medical and psychiatric conditions, and concomitant use of other psychotropic drugs, risk of suicide death was 2.7 times higher (95% confidence interval [CI], 1.1-6.3; P =.03) during treatment with divalproex than during treatment with lithium. Corresponding hazard ratios for nonfatal attempts were 1.7 (95% CI, 1.2-2.3; P =.002) for attempts resulting in hospitalization and 1.8 (95% CI, 1.4-2.2; P<.001) for attempts diagnosed in the emergency department. CONCLUSION: Among patients treated for bipolar disorder, risk of suicide attempt and suicide death is lower during treatment with lithium than during treatment with divalproex.

Manic-depressive illness: psychodynamic features of multigenerational families.

Psychodynamic features of families with multigenerational bipolar manic-depressive illness are described. Repetitive maladaptive patterns, including avoidance of affect, unrealistic standards of conformity, absence of intimate relationships apart from family, displaced parental low self-esteem, and fears related to illness heritability, may influence the maintenance of family pathology.

Relationship of prior antidepressant exposure to long-term prospective outcome in bipolar I disorder outpatients.

OBJECTIVE: The long-term impact of prior antidepressant exposure on the subsequent course of bipolar illness remains controversial. METHOD: 139 outpatients (mean age, 42 years) with bipolar I disorder diagnosed by DSM-IV criteria had a detailed retrospective examination of their prior course of illness on the National Institute of Mental Health Life Chart Method. Number of prior antidepressant trials and total duration of antidepressant exposure were assessed. Prospective long-term response (for at least 6 months) to naturalistic treatment in the network from 1996 through 2002 was the primary outcome measure as it related to prior antidepressant exposure (and other illness variables) by logistic regression, with P < .05 used for statistical significance in this post hoc analysis. RESULTS: Greater number of antidepressant trials, but not duration of antidepressant exposure, was related to prospective nonresponse (P = .0051) whether or not antidepressants were covered by concurrent treatment with a mood stabilizer or atypical antipsychotic. Poor prospective response was also independently related to having had an anxiety disorder and 20 or more prior affective episodes. CONCLUSIONS: That the number of antidepressant trials, but not duration of antidepressant treatment, was associated with prospective nonresponse suggests that it is the repeated use of antidepressants to treat episodes of depression that is related to poor prospective response to naturalistic treatment. The direction of causality is unclear as to whether more antidepressant trials led to this increased treatment resistance or whether a difficult course of illness with more episodes and anxiety comorbidity engendered more attempts at antidepressant treatment.

Maintenance treatment study designs in bipolar disorder: do they demonstrate that atypical neuroleptics (antipsychotics) are mood stabilizers?

In this conceptual review we argue that by certifying some of the atypical neuroleptics (or, if one prefers, antipsychotics) as indicated for the 'maintenance' treatment of bipolar disorder, the US FDA has created confusion in the field. These maintenance indications are based on studies using a 'relapse prevention' design, a design that does not address whether the agents tested can prevent new episodes of illness, i.e. recurrence prevention or true prophylaxis. We found that the relapse prevention design fails to prove that these agents are mood stabilizers because patients are pre-selected to respond to the study drug for an acute mood episode (mania) and when they relapse, they do so into an episode of the same polarity (i.e. mania). We believe that this represents withdrawal into the same mood episode that patients experienced before the maintenance study began, rather than prevention of a new mood episode, as research into the natural history of bipolar disorder indicates that such new episodes typically are of the opposite polarity. Thus, the inability of neuroleptics to prevent depression in such maintenance studies reflects the general inability to prevent any new mood episode recurrence (which we believe should be defined as 6 months or longer after the index episode). If one defines a mood stabilizer, as we do, as a drug that prevents new episodes of mania and depression in monotherapy, then these studies do not show that atypical neuroleptics are mood stabilizers. Future maintenance research studies in bipolar disorder should use the prophylaxis design (i.e. without pre-selection of drug responders), rather than the relapse prevention design.

An automated Internet application to help patients with bipolar disorder track social rhythm stabilization.

This column describes a pilot study of a fully automated, Internet-based program that provides a key element of interpersonal and social rhythm therapy, a form of psychotherapy shown to be effective in the treatment of bipolar disorder when combined with mood-stabilizing medication. Participants (N=64) recorded the time they completed activities of daily living and their mood at the time of each entry. After 90 days they demonstrated a 31% increase in social rhythm stability and a small, though statistically significant, decrease in symptoms of abnormal mood. Internet-based programs can enhance access to a best practice in the management of bipolar disorder.

A randomized comparison of online and paper mood charts for people with bipolar disorder.

BACKGROUND: Longitudinal mood instability is the essential feature of bipolar disorder, however most rating scales are cross sectional in nature, and focus on acute symptoms. By contrast, the NIMH Life Chart Methodology (LCM) characterizes in detail the severity, duration, and frequency of mood episodes. Adherence to daily rating, however, tends to be low. In this study an online version of the LCM, designed to enhance adherence, was compared to the standard paper version. METHODS: Patients from a mood disorders specialty clinic were randomized to the standard LCM or an online, open-source adaptation. The online version used hypertext links embedded in a daily email as the primary rating interface. Participants rated for 90 days. The total number of days rated and the number of days with complete data were compared for the two groups. RESULTS: Forty-eight patients participated in the study. The online group rated approximately twice as many days compared to the standard group (44.3 versus 20.4, p=.029). The online group also entered complete data for a larger portion of days (55.2% versus 27.7%, p=.039). LIMITATIONS: This was a small, short-term study. The implications for longer-term rating are unclear. CONCLUSIONS: Despite the advantages of documenting mood fluctuation on a daily basis, the LCM is not commonly used, in part because ensuring adequate adherence can be resource intensive. An easily accessible online adaptation that utilizes email checking behavior can make this tool available to a wider range of patients.

Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety.

OBJECTIVE: To assess long-term effectiveness and safety of randomized antidepressant discontinuation after acute recovery from bipolar depression. METHOD: 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. RESULTS: 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). CONCLUSIONS: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00012558.