Osama Abulseoud

Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder

OBJECTIVES Several magnetic resonance imaging studies have found changes in amygdala volumes in adults with mood disorders. The cellular basis for these changes has not been explored in detail. Specifically, it is not known whether differences in the density and/or volume of neurons or glial cells contribute to tissue volume changes seen on magnetic resonance images. METHODS Postmortem amygdala samples were obtained from the Stanley Foundation Neuropathology Consortium from subjects diagnosed with bipolar disorder (n = 10), major depressive disorder (n = 11), and schizophrenia (n = 9), and from normal controls (n = 14). Samples were first stained with glial fibrillary acidic protein (GFAP) and counter-stained with hematoxylin to ascertain neuron and glia (astrocyte) densities. RESULTS No significant differences in neuronal densities were found between groups. However, a reduction in the density of GFAP immunoreactive astrocytes was observed in the amygdala of subjects with major depressive disorder compared to the bipolar disorder, schizophrenia, and normal control postmortem samples. CONCLUSIONS A decrease in density of GFAP immunoreactive astrocytes in the amygdala of depressed subjects is consistent with prior histologic reports and might contribute to amygdala volume reductions reported in several in vivo neuroimaging studies.

Glial dysfunction in abstinent methamphetamine abusers.

Persistent neurochemical abnormalities in frontal brain structures are believed to result from methamphetamine use. We developed a localized 13C magnetic resonance spectroscopy (MRS) assay on a conventional MR scanner, to quantify selectively glial metabolic flux rate in frontal brain of normal subjects and a cohort of recovering abstinent methamphetamine abusers. Steady-state bicarbonate concentrations were similar, between 11 and 15 mmol/L in mixed gray-white matter of frontal brain of normal volunteers and recovering methamphetamine-abusing subjects (P>0.1). However, glial 13C-bicarbonate production rate from [1-13C]acetate, equating with glial tricarboxylic acid (TCA) cycle rate, was significantly reduced in frontal brain of abstinent methamphetamine-addicted women (methamphetamine 0.04 μmol/g per min (N=5) versus controls 0.11 μmol/g per min (N=5), P=0.001). This is equivalent to 36% of the normal glial TCA cycle rate. Severe reduction in glial TCA cycle rate that normally comprises 10% of total cerebral metabolic rate may impact operation of the neuronal glial glutamate cycle and result in accumulation of frontal brain glutamate, as observed in these recovering methamphetamine abusers. Although these are the first studies to define directly an abnormality in glial metabolism in human methamphetamine abuse, sequential studies using analogous 13C MRS methods may determine ‘cause and effect’ between glial failure and neuronal injury.

Metabolic Abnormalities in Abstinent Methamphetamine Dependent Subjects.

Introduction Chronic methamphetamine use results in persistent neuropsychological deficits in abstinent methamphetamine dependent (AMD) subjects. We examined the hypothesis that elevated concentration of cerebral glutamate (Glu), an excitatory neurotransmitter and neurotoxin, occurs in human AMD. Materials and Methods We examined 40 subjects, 18 of whom were AMD, abstinent more than 3 weeks and 22 were age matched controls. A Structured Clinical Interview was applied to exclude AMD with comorbid depression. We used TE-Averaged technique of MRS to uniquely identify and quantify the glutamate resonance at 2.35 ppm on a 3T clinical MR scanner. Statistics, including Bonferroni correction for multiple MRS variables were applied. Results Glu was significantly higher in frontal white matter of AMD (+19%, P = 0.01) and N-acetylaspartate (NAA), an axonal marker, was lower (-14%, P = 0.004). No significant MRS abnormalities were detected in posterior gray matter. Significant correlations were observed between NAA and Glu (P = 0.002 for AMD and P = 0.06 for controls in the posterior gray matter and P = 0.01 for controls and not significant for AMD in the frontal white matter). Conclusion Our results demonstrate a significant excess of glutamate in frontal white matter of AMD subjects and offer support for the hypothesis that methamphetamine abuse may exert its long-term neuro-toxicity via glutamate.

Improving the design of maintenance studies for bipolar disorder.

Abstract Background: In contrast to the trial design of acute mania studies, there is no standard design for bipolar maintenance studies. Over the past 15 years, the design of monotherapy maintenance studies in bipolar disorder has evolved significantly, but recent study designs continue to differ in important ways. Scope: We reviewed the design of recent controlled bipolar maintenance studies, using PubMed, from August 2006 to August 2009, examining the strengths and weaknesses of different study design features. Findings: Design differences are sufficiently important that the disparate results across maintenance studies may reflect either true differences in medication efficacy or the effects of these design differences on outcome. Design elements such as recent episode polarity, stabilization criteria, using enriched versus nonenriched samples, length of stabilization before randomization, length of experimental phase, and recurrence outcome criteria are critical factors that differ widely across studies and likely play a role in study outcome. Conclusions: As consensus for trial designs for bipolar maintenance therapy is developed, it will be easier to develop algorithms for maintenance treatment based on results from studies as opposed to clinical opinions.

The role of research in academic psychiatric departments: a case study.

ObjectiveThe authors demonstrate the role that research can play in the development of an academic department of psychiatry.MethodThe authors explore the challenges and achievements in the transition of one department from a strong clinically- and educationally-centered department to one with an equally strong research focus.ResultsThe department significantly expanded and improved its research, educational role, and contribution to its medical school.ConclusionsLeading departments of psychiatry in the United States have extremely strong research divisions. The research enterprise brings a critical academic identity to the institution and a stronger reputation and differentiates the department within the health-delivery system. However, for a department developing a research program, the frontline clinicians, staff, and students may see research as an imposition on patients and a distraction from the perceived primary mission, and they may be concerned about how they will be perceived as the institution changes its identity.

Sex and bipolar subtype association with self-reported hazardous alcohol consumption in bipolar depression

ABSTRACT Despite the high rate of co-morbid alcoholism in bipolar disorder, the relationship between mood state, sex, and alcohol consumption patterns has not been well studied. An anonymous Internet survey was conducted from August 2002 to September 2005. The survey asked participants with bipolar disorder to self-report alcohol “quantity” consumed when euthymic, manic, or depressed. Of 366 persons with bipolar disorder, significantly more males (38%) than females (23%) and bipolar II (31%) than bipolar I (16%) respondents self-reported consuming a hazardous amount of alcohol during depression. These preliminary findings suggest that hazardous drinking in bipolar depression is more common in men and in patients with bipolar II disorder. Further study is encouraged to assess whether this alcohol intake increase is a possible attempt at self-medication of mood symptoms or an independent co-morbid factor related to alcoholism.

Abstracts from the ASENT 2009 Annual Meeting March 5–7, 2009

Introduction Recent initiatives have resulted in guidelines for the assessment of cognitive function in specific clinical populations including the MATRICS consensus cognitive test battery for schizophrenia and the EMEA guideline on medicinal products for the treatment of Alzheimer s disease and other dementias. There are a number of common criteria that emerge, including assessment of cognition at the level of individual cognitive domains; validation; utility; utility as a repeated measure; and data allowing interpretation of results and understanding of the clinical relevance (i.e., normative/relationship to functional outcomes). It is apparent that such common criteria could usefully be applied to cognitive function assessment in all clinical populations. The publication of normative data is of use in the interpretation of clinical trials data. Methods Five-hundred and seventy (570) patients with newly diagnosed epilepsy, aged 12–75 years, from 21 countries within Europe, Latin America, and Australasia, not previously exposed to AEDs, were recruited to a clinical trial comparing the efficacy and safety of remacemide versus carbamazepine. Patients completed a 30 minute cognitive test battery comprised of the CDR System; Rey auditory verbal learning test; color-word Stroop test; symbol digit modalities test; Lafayette grooved pegboard; digit cancellation test; and the non-verbal matrices subtest of the Kaufman brief intelligence test. Normative data in treatment-naive patients across the studied age range were generated. Results Assessments showed a common relationship with age, with those patients in the younger adult age cohorts tending to perform better on all measures than older patients and also than the youngest age cohort patients. Conclusions These data may be useful in the analysis and interpretation of cognitive assessment data from clinical trials of AEDs and/or studies in similar patient populations. Financial disclosure This study was sponsored by AstraZeneca. None of the authors has a financial relationship with the sponsor.