Seasonal changes in clinical status in bipolar disorder: a prospective study in 1000 STEP-BD patients.

OBJECTIVE: To investigate seasonal and regional effects on bipolar I and II patients. METHOD: The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) patients were prospectively examined for monthly change in prevalence rates of depressed and recovered clinical status over the year. General Estimating Equation modeling was used to assess the effect of season on prevalence rates. Additionally, patients were stratified by bipolar subtype and by region. RESULTS: A significantly higher prevalence rate of depression is observed in the northern sites, a significant prevalence by month effect is found only in the bipolar II patients. CONCLUSION: The prevalence of depression is greater in patients from the northern vs. southern STEP-BD sites. Seasonal peak prevalence rates of depression differ by region. Bipolar II patients were more ill year-round and demonstrated greater monthly fluctuation in prevalence rates of being ill than did bipolar I patients. We conclude that seasonal effects upon bipolar patients vary by region and bipolar subtype.

Premenstrual dysphoric disorder and psychiatric co-morbidity.

Premenstrual dysphoric disorder (PMDD) can occur co-morbidly with other axis I disorders, particularly mood and anxiety disorders. The data supporting this diagnostic dilemma are reviewed in terms of methodological comparisons between studies. The point prevalence of the co-occurrence of PMDD and other psychiatric disorders is discussed as well as implications for treatment and further study.

The electronic assessment of the longitudinal course of bipolar disorder: the ChronoRecord software.

Longitudinal studies are the optimal approach when investigating the highly variable course of bipolar disorder, but such studies are expensive, prone to reporting errors and to missing data. Automation of data collection may reduce such errors and improve data quality. The ChronoRecord, validated software that patients can install on a home computer to report mood, medications, sleep, life events, weight and menstrual data, has been designed to achieve such automation. In the trial of the ChronoRecord reported here, 80 of 96 (83 %) patients with bipolar disorder showed high acceptance of this computer-based system for self-report, entering daily recordings for a period of 3-months. This new technology, in addition to providing an accurate longitudinal record for research purposes, also facilitates on-going patient feedback and accurate study monitoring.

Bone mineral density in pre-and post-menopausal women with affective disorder treated with long-term L-thyroxine augmentation.

BACKGROUND: Augmentation with TSH-suppressive L-thyroxine (T4) has been shown to improve the course of illness in otherwise refractory affective disorders. This collaborative study investigates whether T4 augmentation for a minimum of 12 months decreases bone mineral density (BMD) in 26 pre- and post-menopausal women with affective disorder. METHODS: We measured BMD at the femoral neck, Ward's triangle, trochanter and lumbar vertebrae (L1-L4) in 13 premenopausal and 13 postmenopausal women with affective disorder using dual energy X-ray absorptiometry. BMD was expressed as g/cm(2) and as a Z-score, calculated using bone density data from the international reference population standard. RESULTS: The Z-scores for the pre- and post-menopausal women were within the reference range of the age and sex matched population standard. BMD for the composite group also did not differ either from the population standard. BMD in the lumbar spine and hip did not differ significantly between the pre- and post-menopausal groups. However, there were a relatively high number of postmenopausal patients with BMDs one S.D. lower than the population standard. LIMITATIONS: This is a cross-sectional study with a relatively small sample size. CONCLUSIONS: The study demonstrates that T4 augmentation treatment does not reduce BMD to a clinically significant degree in many women with affective disorder. However, the resilience of bone structure to T4 treatment may vary with site and menopausal status. This study underscores the need for regular assessment of BMD during adjunctive thyroid treatments for affective disorder, especially in postmenopausal women.

Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression.

OBJECTIVE: This study compared the efficacy and safety of paroxetine and imipramine with that of placebo in the treatment of bipolar depression in adult outpatients stabilized on a regimen of lithium. METHOD: In a double-blind, placebo-controlled study, 117 outpatients with DSM-III-R bipolar disorder, depressive phase, were randomly assigned to treatment with paroxetine (N=35), imipramine (N=39), or placebo (N=43) for 10 weeks. In addition to lithium monotherapy, patients may have received either carbamazepine or valproate in combination with lithium for control of manic symptoms. Patients were stratified on the basis of trough serum lithium levels determined at the screening visit (high: >0.8 meq/liter; low:

A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.

BACKGROUND: Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. METHODS: A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. RESULTS: The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. CONCLUSIONS: The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.

Lithium administration affects gene expression of thyroid hormone receptors in rat brain.

Even though lithium has received wide attention in the treatment of manic depressive illness, the mechanisms underlying its mood stabilizing effects are not understood. Lithium is known to interact with the thyroid axis and causes hypothyroidism in a subgroup of patients, which compromises its mood stabilizing effects. Since lithium was recently reported to alter thyroid hormone metabolism in the rat brain, the present study investigated whether these effects were mediated through regulation of thyroid hormone receptor (THR) gene expression. Adult male euthyroid rats were either given a diet containing 0.25% lithium or one without lithium for 14 days. Rats were sacrificed in the evening and RNA was isolated from different brain regions to quantitate the isoform specific mRNAs of THRs. Following 14 days of lithium treatment, THR alpha1 mRNA levels were increased in the cortex and decreased in hypothalamus; THR alpha2 mRNA levels were increased in the cortex and THR beta mRNA levels were decreased in the hypothalamus. No significant difference in the expression of these THR isoforms was observed in the hippocampus or cerebellum. Thus, chronic lithium treatment appeared to regulate THR gene expression in a subtype and region specific manner in the rat brain. It remains to be determined whether the observed effects of lithium on THR gene expression are related to its therapeutic efficacy in the treatment of bipolar disorder.

Telephone versus in-person clinical and health status assessment interviews in patients with bipolar disorder.

We evaluated the correspondence between in-person- and telephone interview-derived data on affective symptoms, health-related quality of life, disability days, and medication compliance in patients with bipolar disorder. Twenty-eight outpatients with DSM-III-R-documented bipolar disorder were randomly assigned to an initial in-person or telephone interview. An average of 4.0 days later, they were reassessed by the other interview method. Results indicate good to excellent agreement between telephone and in-person interviews on measures of mania (intraclass correlation coefficient (ICC) = 0.92) and depression symptoms (ICC = 0.90), suicide risk (kappa = 0.80), and alcohol use (kappa = 0.61), scores on the Medical Outcomes Study 36-item Short-Form Health Survey (ICCs = 0.66-0.92), and medication compliance (ICCs = 0.50-0.66). Measures of bed disability days (ICC = 0.34) and restricted activity days (ICC = 0.66) showed less agreement. Telephone interviews are feasible and reliable for collecting data on psychiatric and other health-related outcomes in bipolar disorder patients.

I-123 iofetamine single-photon computed emission tomography in rapid cycling bipolar disorder: a clinical study.

The regional distribution of I-123 iofetamine (IMP) in the brain of 12 patients with rapid cycling bipolar disorder was studied by single-photon computed emission tomography imaging. Patients who were either medication free (n = 4) or on lithium monotherapy (n = 8) were assessed serially in depressed/dysphoric, manic/hypomanic, or euthymic states. In 23 imaging studies, IMP images of the brain were taken on a GE Starcam system 20 min after injection of 3-4 mCi of I-123 labeled IMP. The I-123 IMP distribution in the anterior part of the temporal lobes was asymmetric in both depression/dysphoria and mania/hypomania but not in euthymia. Images taken sequentially on the same patient showed temporal lobe asymmetry in the pathological mood states that diminished or disappeared in the euthymic state. The observed changes most likely reflect an altered cerebral blood flow and changes in high-affinity IMP binding to amine receptors in the temporal lobes. This pilot study suggests the presence of a state-dependent temporal dysfunction in bipolar disorder.

Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study.

Maintenance studies in bipolar disorder have received increased attention in recent years. The interest is driven by apparent contradictions between results of early placebo-controlled trials of lithium and recent open studies, as well as interest in a new group of drugs with mood-stabilizing properties. The multiple outcome indices that require attention in prophylactic bipolar disorder studies add a dimension not present in acute studies of bipolar disorder. We present the methodology of a recently completed randomized, double-blind, placebo-controlled, parallel-group comparison of divalproex and lithium. We examine the consequences of salient design features, along with their implications for future studies. A fundamental conclusion is that such maintenance studies should be designed and executed to emphasize enrollment of patients with relatively active, severe forms of the illness. This goal is not achieved simply, as inherent features of long-term, placebo-controlled studies drive recruitment and enrollment in the direction of patients with milder forms of bipolar disorder. Attention to the frequency of both manic and depressive episodes and the severity of an index manic episode may aid in the selection of patients most suitable for studies designed to achieve adequate statistical power.

Testing definitions of dysphoric mania and hypomania: prevalence, clinical characteristics and inter-episode stability.

37 outpatients with at least one prospectively observed manic or hypomanic episode comprised a sample for comparison of five definitions of dysphoric (hypo)mania. Dysphoric symptoms were continuously rather than bimodally distributed. Prevalence of dysphoria varied from 5 to 73% depending on the definition used. Female gender was associated with dysphoria under two of the five definitions. Inter-episode stability in patients with at least two prospectively observed episodes (n = 15) was not significantly different from chance. These data do not indicate that (hypo)mania can be dichotomized on the basis of dysphoria. Advantages and disadvantages of dimensional and categorical approaches to specifying mood in mania or hypomania are discussed.

Multisite data reanalysis of the validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV.

OBJECTIVE: The validity of rapid cycling as a distinct course modifier for bipolar disorder was assessed by comparing patients with and without a history of rapid cycling (4 or more affective episodes in 12 months) on demographic, clinical, family history, and outcome variables. These data were also used to formulate operational criteria for the modifier. METHOD: Data on subjects with rapid-cycling (N = 120) and nonrapid-cycling (N = 119) bipolar disorder from four sites were pooled and analyzed by using case-control and historical cohort methods. RESULTS: The rapid-cycling group contained more women and more subjects from higher social classes than the nonrapid-cycling group. Family history did not differ between the groups. The diagnosis had predictive validity in that the rapid-cycling patients had more episodes than the nonrapid-cycling patients during prospective follow-up. The relationship between gender and episode frequency supported the validity of the cutoff point of 4-8 episodes per year. The data regarding whether patients with rapid cycling based on truncated episodes more closely resembled rapid-cycling or nonrapid-cycling patients were equivocal. Patients whose only rapid cycling was associated with antidepressants resembled spontaneously rapid-cycling patients, while the majority of spontaneously rapid-cycling patients also had periods of antidepressant-associated rapid cycling. CONCLUSIONS: The validity of rapid cycling as a distinct course modifier for bipolar disorder is supported by differences in gender, prospectively assessed outcome, and perhaps social class between rapid-cycling and nonrapid-cycling patients. The relationship of gender to episode frequency supports the cutoff of 4 or more episodes per year.

A family history study of rapid-cycling bipolar disorder.

Previous studies have yielded mixed evidence as to whether rapid-cycling bipolar disorder (four or more episodes per year) is associated with a distinctive pattern of patient characteristics and familial aggregation of affective disorder. In this study, Family History Research Diagnostic Criteria (FH-RDC) were used to interview 165 patients with rapid-cycling bipolar disorder, non-rapid-cycling bipolar disorder, or recurrent unipolar depressive disorder about the psychiatric history of 812 adult first-degree relatives. In a validity study, FH-RDC diagnoses were demonstrated to agree reasonably well with best-estimate diagnoses by two psychiatrists/psychologists, based on direct interviews with the Structured Clinical Interview for DSM-III-R. Relatives of patients with recurrent unipolar depression were less likely to have bipolar disorder and more likely to have unipolar depression than were relatives of rapid-cycling or non-rapid-cycling bipolar patients. Rapid-cycling patients were younger and more likely to be female than non-rapid-cycling patients. The relatives of rapid cyclers did not differ significantly from those of non-rapid cyclers in the prevalence of bipolar disorder, unipolar disorder, rapid-cycling bipolar disorder, or substance abuse. However, there were nonsignificant trends for the relatives of rapid-cycling bipolar patients, compared with those of non-rapid-cycling bipolar patients, to have more substance abuse and less bipolar disorder given the presence of affective disorder.

Mood and body weight in a woman with rapid cycling bipolar disorder: a case report.

To describe the relationship between mood and body weight, we analyzed 122 consecutive days of data from a 52-year-old woman with rapid cycling bipolar disorder, type II. The patient completed a daily log of self-reported mood, and weighed and recorded her weight daily. Mood and body weight were highly correlated (r = 0.60), and a decrease in mood preceded a decline in body weight by 3 days. Reports of loss of appetite on the Hamilton Depression Rating Scale also corresponded to periods of weight loss. There was a negligible difference in the patient's resting metabolic rate between a period of depression (1628 kcal/day) and of euthymia (1724 kcal/day). The association between depression and weight loss was primarily mediated by decreased food intake. Such patients should provide an excellent opportunity to study the regulation of body weight with affective illness.

Measurement of tissue lithium concentration by lithium magnetic resonance spectroscopy in patients with bipolar disorder.

Measurements of the lithium concentration in the occipital pole of the head and calf muscle of nine patients with bipolar disorder in remission were performed using in vivo lithium-7 nuclear magnetic resonance spectroscopy (7Li NMR). 7Li NMR measurements were performed on a 1-m-bore, 1.85-T, superconducting magnet supplemented with a multinuclear spectrometer, using 11.5-cm-diameter surface coils. The average lithium concentration in the occipital pole was 0.36 +/- 0.10 mEq/L, whereas in the muscle it was 0.50 +/- 0.17 mEq/L, both lower than the average serum lithium concentration (0.79 +/- 0.23 mEq/L). The average brain/serum lithium concentration ratio was 0.47 +/- 0.12 whereas the average muscle/serum lithium concentration ratio was 0.66 +/- 0.20. There was a positive correlation between the brain versus serum and brain versus muscle lithium concentrations. The hypothesis is advanced that the minimal effective concentration of brain lithium concentration for maintenance treatment of bipolar disorder is around 0.2-0.3 mEq/L.

Correlated in vivo 31P-NMR and NADH fluorometric studies on gerbil brain in graded hypoxia and hyperoxia.

Mitochondrial energy coupling in the gerbil brain was characterized by the relationship between intracellular phosphocreatine (PCr)/inorganic phosphate (Pi), phosphorylation ratio, and the mitochondrial redox state in graded hypoxia. Phosphorus-nuclear magnetic resonance (NMR) spectra of the brain and whole head were taken by surface and saddle coil, respectively. The NADH level of the brain cortex was monitored by in vivo fluororeflectometry. The PCr and Pi of the head and brain did not change between 100 and 10% O2 inhalation. PCr progressively decreased and Pi progressively increased with 6 and 4% 0% inhalation in the head. The PCr/Pi of the brain decreased by 44% at 6% fraction of inhaled oxygen (FIO2) and 57% at 4% FIO2. The ATP level did not change during hypoxia. The calculated phosphorylation ratio of the brain ([PCr] Kck[H+]/[Cr][Pi]) = ([ATP]/[ADP][Pi]) was 4.1 X 10(4) M-1 in normoxia. Hypoxia of increasing severity induced increasing NAD reduction of the brain cortex with 17% NAD reduction at 10% FIO2 when there was no change in phosphorylation ratio. The phosphorylation ratio decreased, i.e., the mitochondria failed to maintain the energy level of the brain when the magnitude of the change in NAD reduction to hypoxia was half of the total redox change between hyperoxia and anoxia. These studies demonstrated the feasibility of combined 31P-NMR and NADH fluorometry measurements on brain in vivo. The observations show similarities between the responses of mitochondrial oxidative phosphorylation to hypoxia in vivo and in vitro.

Simultaneous 31P- and 1H-nuclear magnetic resonance studies of hypoxia and ischemia in the cat brain.

The objective of this study was to evaluate simultaneous 31P/1H nuclear magnetic resonance (NMR) spectroscopy as a technique for monitoring and correlating changes in brain energy metabolism during hypoxia and ischemia. Five cats were studied with a protocol that involved 20 min of hypoxia (PaO2 20 mm), 60 min of recovery, 10 min of hypoxia with relative ischemia (bilateral carotid occlusion, PaO2 20 mm), and 60 min of recovery. Bifrontal and biparietal electrocorticograms (ECoG) were monitored continuously during the entire protocol. The results demonstrate that the degree of metabolic response is different in individual cats, but a number of quantitative relationships between metabolic parameters are consistently observed for all cats. First, there is agreement between increases in lactate and changes in intracellular pH; the observed relationship corresponds to an in vivo cerebral buffer capacity of 29 mumol/g/pH unit. Second, the delayed recovery of PCr is due to the effect of metabolic acidosis on the creatine kinase equilibrium and not to a delayed recovery of the ATP/ADP ratio. Third, the observed rate of lactate clearance from the cell is zero-order (k = 0.36 mumol/g/min) for lactate levels greater than 5 microns/g and may be composed of both lactate efflux from the cell and lactate oxidation.

Bioenergetic studies of mitochondrial oxidative phosphorylation using 31phosphorus NMR.

The relationship between phosphorylation ratio [( ATP])/[ADP][Pi], phosphocreatine (PCr)/Pi, and ATPase activity was determined for isolated rat heart mitochondria, and the use of phosphorylation ratio and/or PCr/Pi as bioenergetic indices (Chance, B., Eleff, S., Leigh, J. S., Sokolow, D., and Sapega, A. (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 6714-6718) was evaluated. Isolated rat heart mitochondria were suspended at low concentration (0.5-2.0 mg of protein/ ml) in oxygenated KCl/sucrose/4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid medium at 25 degrees C and pyruvate, malate, PCr, ATP, Pi, and Mg2+ were added. Changes in extramitochondrial phosphorus compounds were followed by 31P NMR. The ATPase activity was varied by the addition of potato apyrase. It was found that the logarithm of steady state PCr/Pi decreased linearly with increasing ATPase rate with a PCr/Pi intercept of 32.8 at 0 ATPase rate. The log phosphorylation ratio was also linearly related to the ATPase rate with an extrapolated maximum value of 6.87 at 0 ATPase rate, corresponding to a phosphorylation ratio of 7.41 X 10(6) M(-1) and a delta GATP of -16.3 kcal. The phosphorylation ratio in these experiments (for state 4 respiration) was greater by 1 or 2 orders of magnitude than previously reported for either isolated mitochondria or for whole tissue.