Prefrontal hypoactivation during working memory in bipolar II depression.

BACKGROUND: Patterns of abnormal neural activation have been observed during working memory tasks in bipolar I depression, yet the neural changes associated with bipolar II depression have yet to be explored. METHOD: An n-back working memory task was administered during a 3T functional magnetic resonance imaging scan in age- and gender-matched groups of 19 unmedicated, bipolar II depressed subjects and 19 healthy comparison subjects. Whole-brain and region-of-interest analyses were performed to determine regions of differential activation across memory-load conditions (0-, 1- and 2-back). RESULTS: Accuracy for all subjects decreased with higher memory load, but there was no significant group × memory load interaction. Random-effects analyses of memory load indicated that subjects with bipolar II depression exhibited significantly less activation than healthy subjects in left hemispheric regions of the middle frontal gyrus [Brodmann area (BA) 11], superior frontal gyrus (BA 10), inferior parietal lobule (BA 40), middle temporal gyrus (BA 39) and bilateral occipital regions. There was no evidence of differential activation related to increasing memory load in the dorsolateral prefrontal or anterior cingulate cortex. CONCLUSIONS: Bipolar II depression is associated with hypoactivation of the left medio-frontal and parietal cortex during working memory performance. Our findings suggest that bipolar II depression is associated with disruption of the fronto-parietal circuit that is engaged in working memory tasks, which is a finding reported across bipolar subtypes and mood states.

Myelination, oligodendrocytes, and serious mental illness.

Historically, the human brain has been conceptually segregated from the periphery and further dichotomized into gray matter (GM) and white matter (WM) based on the whitish appearance of the exceptionally high lipid content of the myelin sheaths encasing neuronal axons. These simplistic dichotomies were unfortunately extended to conceptually segregate neurons from glia, cognition from behavior, and have been codified in the separation of clinical and scientific fields into medicine, psychiatry, neurology, pathology, etc. The discrete classifications have helped obscure the importance of continual dynamic communication between all brain cell types (neurons, astrocytes, microglia, oligodendrocytes, and precursor (NG2) cells) as well as between brain and periphery through multiple signaling systems. The signaling systems range from neurotransmitters to insulin, angiotensin, and multiple kinases such a glycogen synthase kinase 3 (GSK-3) that together help integrate metabolism, inflammation, and myelination processes and orchestrate the development, plasticity, maintenance, and repair that continually optimize function of neural networks. A more comprehensive, evolution-based, systems biology approach that integrates brain, body, and environmental interactions may ultimately prove more fruitful in elucidating the complexities of human brain function. The historic focus on neurons/GM is rebalanced herein by highlighting the importance of a systems-level understanding of the interdependent age-related shifts in both central and peripheral homeostatic mechanisms that can lead to remarkably prevalent and devastating neuropsychiatric diseases. Herein we highlight the role of glia, especially the most recently evolved oligodendrocytes and the myelin they produce, in achieving and maintaining optimal brain function. The human brain undergoes exceptionally protracted and pervasive myelination (even throughout its GM) and can thus achieve and maintain the rapid conduction and synchronous timing of neural networks on which optimal function depends. The continuum of increasing myelin vulnerability resulting from the human brain's protracted myelination underlies underappreciated communalities between different disease phenotypes ranging from developmental ones such as schizophrenia (SZ) and bipolar disorder (BD) to degenerative ones such as Alzheimer's disease (AD). These shared vulnerabilities also expose significant yet underexplored opportunities for novel treatment and prevention approaches that have the potential to considerably reduce the tremendous burden of neuropsychiatric disease.

Event-related potential examination of facial affect processing in bipolar disorder and schizophrenia.

BACKGROUND: Patients with bipolar disorder exhibit consistent deficits in facial affect identification at both behavioral and neural levels. However, little is known about which stages of facial affect processing are dysfunctional. METHOD: Event-related potentials (ERPs), including amplitude and latency, were used to evaluate two stages of facial affect processing: N170 to examine structural encoding of facial features and N250 to examine decoding of facial features in 57 bipolar disorder patients, 30 schizophrenia patients and 30 healthy controls. Three conditions were administered: participants were asked to identify the emotion of a face, the gender of a face, or whether a building was one or two stories tall. RESULTS: Schizophrenia patients' emotion identification accuracy was lower than that of bipolar patients and healthy controls. N170 amplitude was significantly smaller in schizophrenia patients compared to bipolar patients and healthy controls, which did not differ from each other. Both patient groups had significantly longer N170 latency compared to healthy controls. For N250, both patient groups showed significantly smaller amplitudes compared with controls, but did not differ from each other. Bipolar patients showed longer N250 latency than healthy controls; patient groups did not differ from each other. CONCLUSIONS: Bipolar disorder patients have relatively intact structural encoding of faces (N170) but are impaired when decoding facial features for complex judgments about faces (N250 latency and amplitude), such as identifying emotion or gender.

Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.

In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.

Tranylcypromine vs. lamotrigine in the treatment of refractory bipolar depression: a failed but clinically useful study.

OBJECTIVE: To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants. METHOD: Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study. RESULTS: Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02). CONCLUSION: There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded.

Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline.

BACKGROUND: Few studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression. AIMS: To examine the relative acute effects of bupropion, sertraline and venlafaxine as adjuncts to mood stabilisers. METHOD: In a 10-week trial, participants receiving out-patient treatment for bipolar disorder (stratified for rapid cycling) were randomly treated with a flexible dose of one of the antidepressants, or their respective matching placebos, as adjuncts to mood stabilisers. RESULTS: A total of 174 adults with bipolar disorder I, II or not otherwise specified, currently in the depressed phase, were included. All three antidepressants were associated with a similar range of acute response (49-53%) and remission (34-41%). There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline. CONCLUSIONS: More caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression, especially if there is a prior history of rapid cycling.

Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression.

Supplementation of standard treatment with high-dose levothyroxine (L-T(4)) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T(4) treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [(18)F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T(4) treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T(4) treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

Relapse of depression during pregnancy following antidepressant discontinuation: a preliminary prospective study.

OBJECTIVE: Pregnancy has frequently been referred to as a time of emotional well-being for patients. However, systematic data about the risk for relapse of depression during pregnancy are sparse. METHOD: We completed a longitudinal cohort study of thirty-two (N = 32) women with histories of depression who were euthymic at conception and who either discontinued or attempted to discontinue antidepressant therapy proximate to conception. Subjects were prospectively followed across pregnancy once per trimester using structured clinical interviews. Rates of relapse and time to relapse were examined. Factors distinguishing the population with respect to risk for relapse including demographic characteristics and illness history were also examined. RESULTS: Seventy-five percent (N = 24) of patients relapsed during pregnancy. The majority of relapses (79%, N = 19) occurred in the first trimester, and relapse was more prevalent in women with histories of more chronic depression. CONCLUSIONS: Pregnancy is not "protective" with respect to risk for relapse of depression. Careful treatment planning is necessary for those women on antidepressants who plan to conceive or who become pregnant.

Relationship between prior course of illness and neuroanatomic structures in bipolar disorder: a preliminary study.

OBJECTIVE: In this preliminary study, we examined the relationships between prior course and severity of illness and size of the hippocampus, temporal lobes, and third and lateral ventricles in patients with bipolar disorder. BACKGROUND: The few studies that have investigated relationships between course of illness measures and neuroanatomic structures in patients with bipolar disorder found divergent results. METHOD: Twenty-six outpatients, who met Diagnostic and Statistical Manual, Third Edition - Revised (DSM-III-R) criteria for bipolar disorder, received a magnetic resonance imaging (MRI) scan, from which volumes of the temporal lobes, hippocampi, third ventricle, and areas of the lateral ventricles were calculated. Prior course of illness variables were determined using the NIMH Life-Chart Method and were correlated to the volumetric measures of neuroanatomic structures using multiple regression analyses. RESULTS: A longer duration of illness was paradoxically associated with a larger left temporal lobe volume whether patients with a history of substance abuse were removed from the analyses. CONCLUSIONS: Additional studies are needed to both replicate and further examine the association of prior course of illness and larger hippocampal and ventricular volumes in bipolar disorder.

Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk.

BACKGROUND: This study's goal was to characterize nursing infants' exposure to fluoxetine through breast milk and to identify variables for minimizing such exposure. METHODS: Nursing women on stable daily doses of fluoxetine were recruited into the study. Breast milk, maternal and infant serum concentrations of fluoxetine and norfluoxetine were determined with high-performance liquid chromatography. RESULTS: Nineteen nursing women one with a pair of dizygotic twins participated in the study. The women were on stable daily doses of fluoxetine (10-60 mg/day) and all but two took the medication during the last trimester of pregnancy. Fluoxetine was detectable in 30% (n = 6) of the nursing infant sera (< 1-84 ng/mL), whereas norfluoxetine was found in 85% (N = 17) (< 1-265 ng/mL). Peak breast milk concentrations occurred approximately 8 hours after maternal dosing and predicted norfluoxetine concentrations in infant serum. Maternal serum fluoxetine and norfluoxetine concentrations correlated highly with infant norfluoxetine concentrations. A daily maternal fluoxetine dosage of 20 mg or lower was significantly less likely to produce detectable concentrations of either fluoxetine or norfluoxetine in infants compared to higher daily dosages. No adverse effects were reported in any infant. CONCLUSIONS: Our findings demonstrate that maternal serum and peak breast milk concentrations of fluoxetine and norfluoxetine predict nursing infant serum norfluoxetine concentrations. In nursing women taking 20 mg/day or less of fluoxetine, infant serum concentrations were typically low.

Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature.

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(3)) and a tricyclic antidepressant. Five of the six studies found T(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(3) acceleration were greater as the percentage of women participating in the study increased. CONCLUSIONS: This meta-analysis supports the efficacy of T(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.

The Expert Consensus Guideline Series. Treatment of depression in women.

OBJECTIVES: Women constitute two-thirds of patients suffering from common depressive disorders. The treatment of depression in women is therefore a substantial public health concern. High-quality, empirical data on depressive disorders specific to women are limited. As a result, there are no comprehensive evidence-based practice guidelines on the best treatment approaches for these illnesses. We conducted a consensus survey of expert opinion on the treatment of 4 depressive conditions specific to women: premenstrual dysphoric disorder (PMDD), depression in pregnancy, postpartum depression in a mother choosing to breast-feed, and depression related to perimenopause/menopause. METHOD: After reviewing the literature and convening a work group of leading experts, we prepared a written survey covering a total of 858 treatment options in 117 specific clinical situations. Depression severity (mild to severe) was specified for most clinical situations. Treatment options included a broad range of pharmacological, psychosocial, and alternative medicine approaches. Most options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions. We identified 40 national experts, 36 (90%) of whom completed the survey. Consensus on each option was defined as a non-random distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred choice, second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations. RESULTS: The expert panel reached consensus on 76% of the options, with greater consensus in situations involving severe symptoms. For women with severe symptoms in each of the 4 central disorder areas we asked about, the first-line recommendation was for antidepressant medication combined with other modalities (generally psychotherapy), paralleling existing guidelines for severe depression in general populations. For milder symptoms in each situation, the panel was less uniform in recommending antidepressants. For the initial treatment of milder symptoms, the panel either gave equal endorsement to other treatment modalities (e.g., nutritional or psychobehavioral approaches in PMDD; hormone replacement in perimenopause) or preferred psychotherapy over medication (in conception, pregnancy, or lactation). In all milder cases, however, antidepressants were recommended as at least second-line options. Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) as a class were recommended as first-line treatment in all situations. The specific SSRIs that were preferred depended on the particular clinical situation. Tricyclic antidepressants were highly rated alternatives to SSRIs in pregnancy and lactation. CONCLUSIONS: The experts reached a high level of consensus on the appropriateness of including both antidepressant medication, specifically SSRIs, and nonpharmacological modalities in treatment plans for severe depression in 4 key clinical situations unique to women. To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data in comparing modalities with each other or in combination. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide some direction for addressing common clinical dilemmas in women. They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions.

The Stanley Foundation Bipolar Network. I. Rationale and methods.

BACKGROUND: The Stanley Foundation Bipolar Network (SFBN) was created to address the paucity of help studies in bipolar illness. AIMS: To describe the rationale and methods of the SFBN. METHOD: The SFBN includes five core sites and a number of affiliated sites that have adopted consistent methodology for continuous longitudinal monitoring of patients. Open and controlled studies are performed as patients' symptomatology dictates. RESULTS: The reliability of SFBN raters and the validity of the rating instruments have been established. More than 500 patients are in continuous daily longitudinal follow-up. More than 125 have been randomised to one of three of the newer antidepressants (bupropion, sertraline and venlafaxine) as adjuncts in a study of mood stabilizers and 93 to omega-3 fatty acids. A number of open clinical case series have been published. CONCLUSIONS: Well-characterised patients are followed in a detailed continuous longitudinal fashion in both opportunistic case series and double-blind, randomised controlled trials with reliable and validated measures.