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OBJECTIVE: Overweight/obesity, insulin resistance (IR), and other types of metabolic dysfunction are common in patients with bipolar disorder (BD); however, the pathophysiological underpinnings of metabolic dysfunction in BD are not fully understood. Family history of type 2 diabetes mellitus (FamHxDM2), which has been shown to have deleterious effects on metabolic function in the general population, may play a role in the metabolic dysfunction observed in BD.

METHODS: Using multivariate analysis of variance, the effects of BD illness and/or FamHxDM2 were examined relative to metabolic biomarkers in 103 women with BD and 36 healthy, age-matched control women.

RESULTS: As a group, women with BD had higher levels of fasting plasma insulin (FPI) and fasting plasma glucose (FPG), higher homeostatic assessment of IR (HOMA-IR) scores, body mass index (BMI), waist circumference (WC), and hip circumference (HC) compared to control women. FamHxDM2 was associated with significantly worse metabolic biomarkers among women with BD but not among healthy control women. Among women with BD, there was a significant main effect of FamHxDM2 on FPI, HOMA-IR, BMI, WC, and HC, even after controlling for type of BD illness, duration of medication exposure, and depression severity. Metabolic biomarkers were not influenced by use of weight-liable psychotropic medication (WLM), even after controlling for type of BD illness, duration of medication exposure, and depression severity.

CONCLUSIONS: Women with BD have overall worse metabolic biomarkers than age-matched control women. The use of WLM, duration of medication use, type of BD illness, and depression severity did not appear to be associated with more pronounced metabolic dysfunction. FamHxDM2 may represent a risk factor for the development of IR in women with BD. Further, focused studies of the endocrine profiles of families of BD patients are needed.

BACKGROUND: This study compared subgroups identified by cluster analysis and clinical observation by evaluating the association between the age of onset of bipolar disorder and self-reported daily mood ratings.

METHODS: Two hundred and seventy patients with bipolar disorder provided daily self-reported mood ratings for about 6 months returning 55,188 days of data. The age of onset subgroups were determined both using previously defined cutoff values based upon clinical observation (29 years), and model-based cluster analysis. Demographic characteristics were compared in the age of onset subgroups. Univariate general linear models with age of onset subgroups and other demographic variables as fixed factors and covariates were used to analyze the percent of days depressed, euthymic and hypomanic/manic.

RESULTS: Using the predetermined subgroups, demographic differences were found between the four subgroups in the diagnosis of bipolar I/II, years of illness, age and use of lamotrigine. Post-hoc pairwise comparison found that patients with an age of onset less

CONCLUSION: Age of onset subgroups arising from clinical observation may be more useful than those determined by cluster analysis.

OBJECTIVE: To assess quetiapine effectiveness in bipolar disorder (BD) patients in a clinical setting.

METHODS: We naturalistically administered open quetiapine to outpatients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form.

RESULTS: 96 patients (36 BD I, 50 BD II, 9 BD NOS, 1 Schizoaffective Bipolar Type, mean +/- SD age 42.3 +/- 13.8 years, 66.7% female) received quetiapine, combined with an average of 2.5 (in 66.7% of patients at least 2) other psychotropic medications and 0.9 non-psychotropic medications, started most often during depressive symptoms (53.1%) or euthymia (37.5%). Mean quetiapine duration and final dose were 385 days and 196 mg/day (50.0% of patients took ≤75 mg/day). Quetiapine was discontinued in 38.5% of trials, after on average 307 days, most often (in 19.8%) due to CNS adverse effects (primarily sedation). In 38.5% of trials quetiapine was continued on average 328 days with no subsequent psychotropic added. In 22.9% quetiapine was continued on average 613 days, but had subsequent psychotropic added after on average 113 days, most often for depressive symptoms. In 67 trials started at Stanford, quetiapine tended to primarily maintain euthymia and relieve depressive symptoms. In 29 trials started prior to Stanford, continuing quetiapine tended to primarily maintain euthymia and relieve mood elevation symptoms. Aside from sedation, quetiapine was generally well tolerated.

CONCLUSIONS: In bipolar disorder outpatients quetiapine had a moderate (38.5%, with 385-day mean duration) discontinuation rate, and commonly did not require subsequent additional pharmacotherapy, suggesting effectiveness in a clinical setting.

OBJECTIVE: Multiple psychotropic medications are routinely prescribed to treat bipolar disorder, creating complex medication regimens. This study investigated whether the daily number of psychotropic medications or the daily number of pills were associated with self-reported adherence with taking a mood stabilizer.

METHODS: Patients self-reported their mood and medications taken daily for about 6 months. Adherence was defined as taking at least one pill of any mood stabilizer daily. Univariate general linear models (GLMs) were used to estimate if adherence was associated with the number of daily medications and the number of pills, controlling for age. The association between mean daily dosage of mood stabilizer and adherence was also estimated using a GLM.

RESULTS: Three hundred and twelve patients (mean age 38.4 +/- 10.9 years) returned 58,106 days of data and took a mean of 3.1 +/- 1.6 psychotropic medications daily (7.0 +/- 4.2 pills). No significant association was found between either the daily number of medications or the daily number of pills and adherence. For most mood stabilizers, patients with lower adherence took a significantly smaller mean daily dosage.

CONCLUSIONS: The number of concurrent psychotropic medications may not be associated with adherence in bipolar disorder. Patients with lower adherence may be taking smaller dosages of mood stabilizers.

BACKGROUND: Psychosocial interventions may teach patients with bipolar disorder to successfully detect warning signs of relapse. These interventions often include ongoing self-monitoring of sleep. We previously reported that a change in sleep duration (sleep plus bedrest) of >3 h may indicate that a mood change is imminent. This analysis further investigated whether sleep duration, sleep onset or sleep offset was the most useful sleep/wake parameter to monitor for an oncoming mood change.

METHODS: 101 adult outpatients receiving treatment as usual recorded mood, sleep and medications every day on a home computer for a mean of 265+/-103 days. A daily time series of mood, sleep duration (sleep plus bedrest), sleep onset and sleep offset was constructed for each patient. After applying an ARIMA (0,1,1) filter, a cross correlation function was used to analyze the temporal relationship between the residuals for lags of +/-7 days.

RESULTS: Less frequent significant correlations were found between a change in either sleep onset or sleep offset and mood, than between sleep duration and mood. Patients with a significant correlation between sleep duration and mood included 86% of those with a significant correlation between sleep onset or sleep offset and mood. Mean sleep duration when euthymic was long (> or =8 h in 89% of patients, > or =9 h in 51% of patients).

LIMITATIONS: Self-reported data, naturalistic study, and computer access required.

CONCLUSIONS: Self-monitoring of sleep duration is recommended for patients with bipolar disorder. Better understanding of the long sleep duration of euthymic patients is required.

OBJECTIVE: Many researchers have analyzed seasonal variation in hospital admissions for bipolar disorder with inconsistent results. We investigated if a seasonal pattern was present in daily self-reported daily mood ratings from patients living in five climate zones in the northern and southern hemispheres. We also investigated the influence of latitude and seasonal climate variables on mood.

METHOD: 360 patients who were receiving treatment as usual recorded mood daily (59,422 total days of data). Both the percentage of days depressed and hypomanic/manic, and the episodes of depression and mania were determined. The observations were provided by patients from different geographic locations in North and South America, Europe and Australia. These data were analyzed for seasonality by climate zone using both a sinusoidal regression and the Gini index. Additionally, the influence of latitude and climate variables on mood was estimated using generalized linear models for each season and month.

RESULTS: No seasonality was found in any climate zone by either method. In spite of vastly different weather, neither latitude nor climate variables were associated with mood by season or month.

CONCLUSION: Daily self-reported mood ratings of most patients with bipolar disorder did not show a seasonal pattern. Neither climate nor latitude has a primary influence on the daily mood changes of most patients receiving medication for bipolar disorder.

OBJECTIVE: This study investigated the frequency of episodes and subsyndromal symptoms based on employment status in patients with bipolar disorder.

METHODS: Patients with bipolar disorder (n = 281) provided daily self-reported mood ratings for 5 months, returning 46,292 days of data. Data were analyzed using three employment status groups: disabled (n = 75), full-time employee or full-time student (n = 135), and other (n = 71). Demographic characteristics were compared by employment status. A univariate general linear model with employment status and other demographic variables as fixed factors and covariates was used to analyze the percent of days in episodes and percent of days with subsyndromal symptoms.

RESULTS: While there was no significant difference in the percent of days in episodes among the employment groups, disabled patients suffered subsyndromal symptoms of depression twice as frequently as those in the full-time group. Disabled patients spent 15% more days either in episodes or with subsyndromal symptoms than those in the full-time group, equivalent to about 45 extra sick days a year.

CONCLUSION: Frequent subsyndromal symptoms, especially depressive, may preclude full-time responsibilities outside the home and contribute to disability in bipolar disorder. Additional treatments to reduce the frequency of subsyndromal symptoms are needed.

OBJECTIVE: To assess lamotrigine effectiveness in bipolar disorder (BD) patients in a clinical setting.

METHOD: Open lamotrigine was naturalistically administered to outpatients at the Stanford University BD Clinic assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form.

RESULTS: One hundred and ninety-seven patients (64 BD I, 110 BD II, 21 BD NOS, 2 Schizoaffective Bipolar Type, mean+/-SD age 42.2+/-14.4 years, 62% female) had 200 trials of lamotrigine. Lamotrigine was combined with a mean of 2.1+/-1.5 other psychotropic medications, most often during euthymia or depressive symptoms. Mean lamotrigine duration was 434+/-444 days, and mean final dose was 236+/-132mg/day without valproate, and 169+/-137mg/day with valproate. Lamotrigine was discontinued in only 26.5% of trials at 255+/-242 days, most often due to inefficacy, and seldom due to adverse effects. In 31.5% of trials lamotrigine was continued 264+/-375 days with no subsequent psychotropic added. In 42.0% of trials lamotrigine was continued 674+/-479 days, but had subsequent psychotropic added at 146+/-150 days, most often for anxiety/insomnia and depressive symptoms. In 145 trials started at Stanford, lamotrigine primarily yielded relief of depressive symptoms or maintained euthymia. In 55 trials in which lamotrigine was started prior to Stanford, lamotrigine primarily maintained euthymia. Lamotrigine was generally well tolerated, with no serious rash, and only 3.5% discontinuing due to benign rash.

CONCLUSION: In a cohort of bipolar disorder outpatients commonly with comorbid conditions, and most often receiving complex combination therapy, lamotrigine had a low (26.5%, with an overall mean duration of treatment of 434 days) discontinuation rate, suggesting effectiveness in BD in a clinical setting.

OBJECTIVE: Data are emerging in bipolar disorder regarding mood across phases of the female reproductive life, yet information about mood during the menopausal transition remains limited. The menopausal transition in women without mood disorders is associated with an increase in depression. This study assesses mood course during the menopausal transition in women with bipolar disorder.

METHODS: We monitored mood episodes in 47 women with bipolar disorder ages 45-55 for 17.0+/-14.0 months with systematic treatment enhancement program for bipolar disorder (STEP-BD) standardized evaluations. Charts were additionally reviewed for menstrual status and menstrual history, as well as mood episode type, duration, frequency and history.

RESULTS: During the menopausal transition 68% of women with bipolar disorder experienced at least one depressive episode. Depression (but not mood elevation) episode frequency significantly increased during the menopausal transition compared to reported frequency during patients' reproductive years. History of pre-menstrual and or post-partum mood instability did not predict perimenopausal mood episodes.

CONCLUSIONS: Women with bipolar disorder experience a high frequency of depressive episodes during perimenopausal years and this frequency appears greater than during prior reproductive years. Prospective controlled studies are needed to better understand the course of mood episodes and to enhance the effectiveness of managing bipolar disorder during the menopausal transition.

A medline literature review of fertility and mood disorder articles published since 1980 was performed in order to critically review the literature regarding a relationship between mood disorders, fertility and infertility treatment. Previous studies suggests that mood disorders, both in the bipolar and unipolar spectrum, may be associated with decreased fertility rates. Most studies report that women seeking treatment for infertility have an increased rate of depressive symptoms and possibly major depression (none showed evaluated mood elevations). Many, but not all, studies found that depressive symptoms may decrease the success rate of fertility treatment. Treatments for infertility may independently influence mood through their effects on estrogen and progesterone, which have been shown to influence mood through their actions on serotonin. Studies are limited in scope and confounding variables are many, limiting the strength of the results. In conclusion, a range of existing studies suggests that fertility and mood disorders are related in a complex way. Future studies should use clinical interviews and standardized and validated measures to confirm the diagnosis of mood disorders and control for the variables of medication treatment, desire for children, frequency of sexual intercourse, age, FSH levels, menstrual cycle regularity in assessing an interrelationship between mood disorders and fertility.

OBJECTIVE: Patients with bipolar disorder often report depressive symptoms that do not meet the DSM-IV criteria for an episode. Using daily self-reported mood ratings, we studied how changing the length requirement to that typical of recurrent brief depression (2-4 days) would impact the number of depressed episodes.

METHOD: 203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software on a home computer (30,348 total days; mean 150 days). Episodes of depression and days of depression outside of episodes were determined. Symptom intensity (mild versus moderate or severe) was investigated within and outside of depressive episodes.

RESULTS: Decreasing the minimum duration criterion for an episode of depression to 2 days increased the number of patients with a depressed episode two and a half times (52 to 131), and quadrupled both the number of depressed episodes per patient (0.62 to 2.88) and the number of depressed episodes for all patients (125 to 584). With a 2-day episode length, 34% of days of depression remained outside an episode. The ratio of days with severe symptoms within episodes remained consistent (about 25%) in spite of decreasing the episode length to 2 days. Considering only days with severe symptoms, about 25% remained outside of episodes even with a 2-day length. None of the results distinguished bipolar I from bipolar II disorder.

LIMITATIONS: Self-reported data, computer access required, relatively short study length, no control group.

CONCLUSION: Brief depressive episodes and single days of depression outside of episodes occur frequently in both bipolar I and bipolar II disorder. Moderate or severe symptoms occur during brief episodes at a ratio similar to that for episodes that meet the DSM-IV criteria.

OBJECTIVE: Some investigators have suggested decreasing the minimum hypomania episode length criterion from 4 days, as in the DSM-IV, to 2 days. Using daily self-reported mood ratings, we studied the impact of changing the length requirement on the number of hypomanic episodes in patients with bipolar disorder.

METHOD: 203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software (30,348 total days, mean 150 days). Episodes of hypomania and days of hypomania outside of episodes were determined.

RESULTS: Decreasing the minimum duration criterion for an episode of hypomania from 4 to 2 days doubled the mean percent of days in a hypomanic episode for each patient (4% to 8%), doubled the number of patients with a hypomanic episode (44 to 96) and increased the number of hypomanic episodes for all patients about three-fold (129 to 404). With a minimum episode length of 4 days, bipolar I patients were more likely to report hypomania outside episodes than bipolar II patients (p=0.010), but with a length of 2 or 3 days there was no significant difference in the distribution of hypomania outside of episodes by diagnosis. With a 2-day length, about one-third (36%) of hypomania remained outside of an episode.

LIMITATIONS: Self-reported data, computer access, relatively short length, fewer bipolar II than bipolar I patients.

CONCLUSION: As the minimum length for an episode of hypomania decreases, there was a large increase in both the number of episodes and number of patients with episodes. One-day hypomania outside of episodes occurs frequently in both bipolar I and bipolar II disorder.

This prospective, longitudinal study compared the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. One hundred and eighty-two patients with bipolar disorder self-reported mood and psychiatric medications for 4 months using a computerized system (ChronoRecord) and returned 22,626 days of data. One hundred and four patients took antidepressants, 78 did not. Of the antidepressants taken, 95% were selective serotonin or norepinephrine reuptake inhibitors, or second-generation antidepressants. Of the patients taking an antidepressant, 91.3% were concurrently taking a mood stabilizer. The use of antidepressants did not influence the daily rate of switching from depression to mania or the rate of rapid cycling, independent of diagnosis of bipolar I or II. The primary difference in mood pattern was the time spent normal or depressed. Patients taking antidepressants frequently remained in a subsyndromal depression. In this naturalistic study using self-reported data, patients with bipolar disorder who were taking antidepressants--overwhelmingly not tricyclics and with a concurrent mood stabilizer--did not experience an increase in the rate of switches to mania or rapid cycling compared to those not taking antidepressants. Antidepressants had little impact on the mood patterns of bipolar patients taking mood stabilizers.

OBJECTIVE: To assess new treatment options for bipolar disorders.

METHOD: Controlled studies of new treatments for bipolar disorders were identified by computerized searches and reviews of scientific meeting proceedings, and were compiled by drug category.

RESULTS: Two main categories of medications, newer anticonvulsants and newer antipsychotics, are yielding emerging new treatment options for bipolar disorders. Newer anticonvulsants have diverse psychotropic profiles, and although not generally effective for acute mania, may have utility for other aspects of bipolar disorders (e.g. lamotrigine for maintenance or acute bipolar depression), or for comorbid conditions (e.g. gabapentin for anxiety or pain, topiramate for obesity, bulimia, alcohol dependence, or migraine, and zonisamide for obesity). In contrast, newer antipsychotics generally appear effective for acute mania, and some may ultimately prove effective in acute depression (e.g. olanzapine combined with fluoxetine, quetiapine) and maintenance (e.g. olanzapine).

CONCLUSION: Emerging research is yielding new treatment options for bipolar disorders and comorbid conditions.

AIMS/OBJECTIVES: To evaluate lamotrigine in a woman with a 30-year history of treatment-resistant menstrually-entrained rapid cycling bipolar II disorder with follicular phase depressive and luteal phase mood elevation symptoms.

METHODS: Lamotrigine was started at 5 mg/day and gradually increased up to 300 mg/day, while venlafaxine was tapered gradually and discontinued, and divalproex sodium 500 mg/day and levothyroxine 175 mcgm/day were continued. Daily self-reported mood ratings were obtained from the patient, using ChronoRecord software.

RESULTS: As lamotrigine was increased gradually, mood cycle amplitude attenuated. There was notable decrease in the severity and duration of depressive symptoms specifically during the follicular phase of the menstrual cycle. At the time of submission of this paper, the subject had remained euthymic for a total of 12 months.

CONCLUSION: This case suggests the potential utility of lamotrigine in treatment-resistant menstrually-related rapid cycling bipolar disorder, and raises the possibility that lamotrigine might be able to treat pathological entrainment of mood with the menstrual cycle. Both of these issues merit systematic assessment.