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This article describes complex, real-life issues faced by a woman with bipolar I disorder who wished to bear a healthy child while remaining psychiatrically well. The therapeutic issues include balancing treatment decisions that affect fetal and maternal risks. The authors address the importance of carefully considering the patient's history of response to medications when evaluating risks to maternal and fetal health. They discuss the role of the psychiatrist as a part of the treatment team faced with unpredictable but not unexpected complexities, such as miscarriage, abnormal or questionable prenatal screening tests, gestational diabetes, and the emergence of fetal decelerations, preterm labor, and psychiatric decompensation. The article presents and evaluates treatment decisions made in the setting of multiple obstetric and psychiatric complications that do not clearly fit published algorithms. The importance of incorporating family and social supports as an integral part of the treatment plan is emphasized. doi: 10.1176/appi.ajp.2009.09081248

Objective: The authors assessed gender differences in the proportion of clinical visits spent depressed, manic, or euthymic in patients with bipolar disorder. Method: Data were analyzed from 711 patients with bipolar I or II disorder who were followed prospectively over 7 years (13,191 visits). The main outcome measures were the presence of symptoms of depression or of hypomania or mania, measured by the Inventory of Depressive Symptomatology and the Young Mania Rating Scale. Data were analyzed using three separate repeated-measures regressions with a logistic link function to model the probability that an individual was depressed, manic, or euthymic. The models controlled for bipolar I or bipolar II diagnosis, rapid cycling, age, time in the study, comorbid anxiety disorders, and comorbid substance use disorders. Results: In approximately half of visits, patients had depressive, manic, or hypomanic symptoms. The likelihood of having depressive symptoms was significantly greater for women than for men. This was accounted for by higher rates in women of rapid cycling and anxiety disorders, each of which was associated with increased rates of depression. All patient groups showed an increase in number of euthymic visits and a decrease in number of visits with depressive and manic symptoms with increased time in study. Conclusions: Bipolar patients spend a substantial proportion of their time ill. Significant gender differences exist, with women spending a greater proportion of their visits in the depressive pole. This finding appears to be related to the corresponding differences in rates of rapid cycling and anxiety disorders.

Objective: Treatment-emergent mania can have substantial negative impact on overall mood and psychosocial stability in patients receiving treatment for bipolar depression. This study examined the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression. Method: A total of 176 adult outpatients with bipolar disorder in a 10-week trial of adjunctive antidepressant treatment for depression were categorized into three groups based on the Clinical Global Impression Scale for Bipolar Disorder: those who responded to antidepressant treatment (N-85), those who did not respond to antidepressant treatment (N=45), and those who had treatment-emergent mania or hypomania (N=46). Symptom se verity was measured with the Inventory of Depressive Symptomatology and the Young Mania Rating Scale (YMRS) at baseline and bimonthly intervals. Factor analysis was used to examine correlates of treatment-emergent mania. Results: Baseline YMRS scores were significantly different between groups. Otherwise, there were no significant between-group differences in demographic or clinical characteristics. Factor analysis showed that a subset of the YMRS items predicted treatment-emergent mania in this sample: increased motor activity, speech, and language-thought disorder. Conclusions: These data suggest that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania. A careful examination of motor activation, pressured speech, and racing thoughts is warranted before starting antidepressant treatment in bipolar depression.

Objective: Modafinil is approved by the U.S. Food and Drug Administration for improving wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift-work sleep disorder. This study was conducted to evaluate the efficacy and safety of adjunctive modafinil in bipolar depression, which is often characterized by excessive sleepiness and fatigue. Method: Eighty-five patients with bipolar depression that was inadequately responsive to a mood stabilizer with or without concomitant antidepressant therapy were randomly assigned to receive adjunctive modafinil (N=41) or placebo (N=44) for 6 weeks. The primary outcome measure was baseline-to-endpoint change in score on the Inventory of Depressive Symptoms--Clinician Rated (IDS). Results: The baseline-to-endpoint change in IDS score was significantly greater in the modafinil group (mean dose, 177 mg/day) compared with the placebo group. Improvement in depressive symptoms was significantly greater in the modafinil group by week 2, and this greater improvement was maintained at weeks 4, 5, and 6. Both the response and remission rates were significantly higher in the modafinil group (44% and 39%) compared with the placebo group (23% and 18%). During the 6-week study period, there was no difference between groups in treatment-emergent hypomania or mania (six patients in the modafinil group and five in the placebo group) or hospitalization for mania (one in each group). Conclusions: These data suggest that adjunctive modafinil at doses of 100-200 mg a day may improve depressive symptoms in patients with bipolar disorder.

Objective: The authors examined the comparative risks of switches in mood polarity into hypomania or mania during acute and continuation trials of adjunctive antidepressant treatment of bipolar depression. Method: One hundred fifty-nine patients with bipolar I disorder or bipolar II disorder participated in a total of 228 acute (10-week) randomized trials of bupropion, sertraline, or venlafaxine as an adjunct to a mood stabilizer. Patients in 87 of these trials entered continuation treatment for up to 1 year. Antidepressant response and the occurrence of subthreshold brief hypomania (emergence of brief hypomania [at least 1 but Results: Threshold switches into full-duration hypomania and mania occurred in 11.4% and 7.9%, respectively, of the acute treatment trials and in 21.8% and 14.9%, respectively, of the continuation trials. The rate of threshold switches was higher in the 169 trials in patients with bipolar I disorder (30.8%) than the 59 trials in patients with bipolar II disorder (18.6%). The ratio of threshold switches to subthreshold brief hypomanias was higher in both the acute (ratio=3.60) and continuation trials (ratio=3.75) of venlafaxine than in the acute and continuation trials of bupropion (ratios=0.85 and 1.17, respectively) and sertraline (ratios=1.67 and 1.66, respectively). In only 37 (16.2%) of the original 228 acute antidepressant trials, or in only 23.3% of the patients, was there a sustained antidepressant response in the continuation phase in the absence of a threshold switch. Conclusions: Adjunctive treatment with antidepressants in bipolar depression was associated with substantial risks of threshold switches to full-duration hypomania or mania in both acute and long-term continuation treatment. Of the three antidepressants included in the study, venlafaxine was associated with the highest relative risk of such switching and bupropion with the lowest risk.

Objective: To detect risk factors for rapid cycling in bipolar disorder, the authors compared characteristics of rapid-cycling and non-rapid-cycling patients both from a categorical and a dimensional perspective. Method: Outpatients with bipolar I disorder (N=419), bipolar II disorder (N=104), and bipolar disorder not otherwise specified (N=16) were prospectively evaluated with daily mood ratings for 1 year. Subjects were classified as having rapid cycling (defined by the DSM-IV criterion of four or more manic or depressive episodes within 1 year) or not having rapid cycling, and the two groups' demographic and retrospective and prospective illness characteristics were compared. Associated factors were also evaluated in relationship to episode frequency. Results: Patients with rapid cycling (N=206; 38.2%) significantly differed from those without rapid cycling (N-333) with respect to the following independent variables: history of childhood physical and/or sexual abuse, bipolar I disorder subtype, number of lifetime manic or depressive episodes, history of rapid cycling, and history of drug abuse. The prevalence of these characteristics increased progressively with episode frequency. The proportion of women was greater than the proportion of men only among patients with eight or more episodes per year. The average time spent manic/hypomanic increased as a function of episode frequency, but the average time spent depressed was comparable in patients with one episode and in those with more than one episode. Brief episodes were as frequent as full-duration DSM-IV-defined episodes. Conclusions: A number of heterogeneous risk factors were progressively associated with increasing episode frequency. Depression predominated in all bipolar disorder patients, but patients with rapid cycling were more likely to be characterized by manic features. The findings overall suggest that rapid cycling is a dimensional course specifier arbitrarily defined on a continuum of episode frequency.

Objective: The purpose of the study was to examine potential correlates of outcome in patients treated for bipolar disorder. Method: During a 1-year period, 258 patients with DSM-IV bipolar disorder or schizoaffective disorder were rated with the prospective NIMH-Life Chart Method, which characterizes each day in terms of the severity of manic and depressive symptoms on the basis of patients' mood-related impairment in their usual educational, social, or occupational roles. Mean ratings for the severity of mania, depression, and overall bipolar illness and the number of manic, depressive, and overall illness episodes were calculated. Potential risk factors were assessed at the start of the study, and multivariate linear regression analysis was used to determine the correlates of the six 1-year outcome measures. Results: Three of the six outcome measures were largely independent of each other and were used in the analysis. The mean rating for severity of mania was associated with comorbid substance abuse, history of more than 10 prior manic episodes, and poor occupational functioning at study entry. The mean rating for severity of depression was associated with a history of more than 10 prior depressive episodes and poor occupational functioning at study entry. The total number of overall illness episodes was associated with a positive family history of drug abuse, a history of prior rapid cycling, and poor occupational functioning. In addition, the mean rating for severity of mania and the total number of overall illness episodes were both initially associated with a history of childhood abuse, but these relationships were lost with the addition of other illness variables to the analysis. Conclusions: Clinicians who treat patients with bipolar disorder should consider a family history of drug abuse, a history of childhood abuse, prior course of illness, comorbid substance abuse, and occupational functioning in determining prognosis and setting goals for further treatment.

Objective: This study determined the placental transfer of antidepressants and their metabolites. Method: A total of 38 pregnant women taking citalopram, fluoxetine,paroxetine, or sertraline participated. Maternal and umbilical cord blood samples were obtained to determine antidepressant and metabolite concentrations. Results: Antidepressant and metabolite concentrations were detectable in 86.8% of umbilical cord samples. The mean ratios of umbilical cord to maternal serum concentrations ranged from 0.29 to 0.89. The lowest ratios were for sertraline and paroxetine; the highest were for citalopram and fluoxetine. Maternal doses of sertraline and fluoxetine correlated with umbilical cord concentrations of these medications. Conclusions: Umbilical cord concentrations of antidepressants and their metabolites were almost invariably lower than corresponding maternal concentrations. Maternal doses predicted umbilical concentrations of fluoxetine and sertraline. Mean umbilical cord to maternal serum ratios were significantly lower for sertraline than fluoxetine, suggesting that sertraline may produce less fetal medication exposure than fluoxetine near delivery.

Objective: The prevalence of lifetime alcoholabuse and/or dependence (alcoholism) in patients with bipolar disorder has been reported to be higher than in all other axis I psychiatric diagnoses. This study examined gender-specific relationships between alcoholism and bipolar illness, which have previously received little systematic study. Method: The prevalence of lifetime alcoholism in 267 outpatients enrolled in the Stanley Foundation Bipolar Network was evaluated by using the Structured Clinical Interview for DSM-IV. Alcoholism and its relationship to retrospectively assessed measures of the course of bipolar illness were evaluated by patient-rated and clinician-administered questionnaires. Results: As in the general population, more men (49%, 57 of 116) than women with bipolar disorder (29%, 44 of 151) met the criteria for lifetime alcoholism. However, the risk of having alcoholism was greater for women with bipolar disorder (odds ratio=7.35) than for men with bipolar disorder (odds ratio=2.77), compared with the general population. Alcoholism was associated with a history of polysubstance use in women with bipolar disorder and with a family history of alcoholism in men with bipolar disorder. Conclusions: This study suggests that there are gender differences in the prevalence, risk, and clinical correlates of alcoholism in bipolar illness. Although this study is limited by the retrospective assessment of illness variables, the magnitude of these gender-specific differences is substantial and warrants further prospective study.

Objective: The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial. Method: A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures. Results: The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded ([greater than or equal to] > 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale [less than or equal to] 12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment. Conclusions: The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex.

Objective: Accumulating evidence suggests a greater number of [T.sub.2] abnormalities in the brains of patients with bipolar I disorder. The authors sought to evaluate the presence of signal 'hyperintensities' in both bipolar I and II subjects and systematically review the existing literature. Method: Magnetic resonance images of the brain were obtained prospectively for 29 patients with bipolar I disorder, 26 patients with bipolar II disorder, and 20 normal comparison subjects. The presence and location of signal hyperintensities in three brain regions (periventricular white matter, subcortical gray matter, and deep white matter) were evaluated. Results: No significant differences were found between groups for the presence of subcortical gray or deep white matter hyperintensities. Periventricular hyperintensities were more common in bipolar I patients (62%) than in bipolar II patients (38%) and normal comparison subjects (30%). Within patient groups, medication use was not significantly different for those with or without the presence of white matter hyperintensities. The literature on bipolar disorder and signal hyperintensities is reviewed. A meta-analysis of the pooled data in the literature on bipolar illness and signal hyperintensities revealed that the odds of having a [T.sub.2] hyper-intensity are significantly greater for bipolar I than for normal comparison subjects. Conclusions: Having bipolar I disorder significantly increases the chance of having white matter changes in the brain. This study suggests that bipolar II patients may be more similar than bipolar I patients to comparison subjects on [T.sub.2] measures. The possible pathophysiological significance of hyperintensities is discussed.

Objectives: The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder. Method: In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score [greater than or equal to] 3 (mildly ill). Results: Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch. Conclusions: These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.

Objective: The delayed onset of therapeutic response to antidepressants remains a major problem in the treatment of depression. Among the strategies to accelerate response to treatment, the early addition of thyroid hormone to antidepressants has been suggested as a viable method. The authors performed a meta-analysis of the literature on the use of thyroid hormone supplementation to accelerate the treatment of depression to determine whether there is sufficient evidence to support the clinical efficacy of this strategy. Method: Both a computer-aided search of the National Library of Medicine MEDLINE and an intensive search by hand were conducted to identify all double-blind, placebo-controlled studies assessing the concomitant administration of thyroid hormone and antidepressant to accelerate clinical response in patients with nonrefractory depression. Results: Six studies were identified. All were conducted with triiodothyronine ([T.sub.3]) and a tricyclic antidepressant. Five of the six studies found [T.sub.3] to be significantly more effective than placebo in accelerating clinical response. The pooled, weighted effect size index was 0.58, and the average effect was highly significant. Further, the effects of [T.sub.3] acceleration were greater as the percentage of women participating in the study increased. Conclusions: This meta-analysis supports the efficacy of [T.sub.3] in accelerating clinical response to tricyclic antidepressants in patients with nonrefractory depression. Furthermore, women may be more likely than men to benefit from this intervention. (Am J Psychiatry 2001; 158:1617-1622)

Objective: Bipolar disorder often co-occurs with other axis I disorders, but little is known about the relationships between the clinical features of bipolar illness and these comorbid conditions. Therefore, the authors assessed comorbid lifetime and current axis I disorders in 288 patients with bipolar disorder and the relationships of these comorbid disorders to selected demographic and historical illness variables. Method: They evaluated 288 outpatients with bipolar I or II disorder, using structured diagnostic interviews and clinician-administered and self-rated questionnaires to determine the diagnosis of bipolar disorder, comorbid axis I disorder diagnoses, and demographic and historical illness characteristics. Results: One hundred eighty-seven (65%) of the patients with bipolar disorder also met DSM-IV criteria for at least one co-morbid lifetime axis I disorder. More patients had comorbid anxiety disorders (N=78, 42%) and substance use disorders (N=78, 42%) than had eating disorders (N=9, 5%). There were no differences in comorbidity between patients with bipolar I and bipolar II disorder. Both lifetime axis I comorbidity and current axis I co-morbidity were associated with earlier age at onset of affective symptoms and syndromal bipolar disorder. Current axis I comorbidity was associated with a history of development of both cycle acceleration and more severe episodes over time. Conclusions: Patients with bipolar disorder often have comorbid anxiety, substance use, and, to a lesser extent, eating disorders. Moreover, axis I comorbidity, especially current comorbidity, may be associated with an earlier age at onset and worsening course of bipolar illness. Further research into the prognostic and treatment response implications of axis I comorbidity in bipolar disorder is important and is in progress. (Am J Psychiatry 2001; 158:420-426)