Boris Lorberg

Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation

BackgroundLithium is considered by many as the gold standard medication in the management of bipolar disorder (BD). However, the clinical response to lithium is heterogeneous, and the molecular basis for this difference in response is unknown. In the present study, we sought to determine how the peripheral blood gene expression profiles of patients with bipolar disorder (BD) changed over time following intitiation of treatment with lithium, and whether differences in those profiles over time were related to the clinical response.MethodsIllumina Sentrix Beadchip (Human-6v2) microarrays containing > 48,000 transcript probes were used to measure levels of expression of gene-expression in peripheral blood from 20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label treatment with lithium.Changes in gene-expression were compared between treatment responders (defined as a decrease in the Hamilton Depression Rating Scale of 50% or more) and non-responders. Pathway analysis was conducted using GeneGO Metacore software.Results127 genes showed a differential response in responders vs. non-responders. Pathway analysis showed that regulation of apoptosis was the most significantly affected pathway among these genes. Closer examination of the time-course of changes among BCL2 related genes showed that in lithium-responders, one month after starting treatment with lithium, several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2) were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1) and BCL2-associated agonist of cell death (BAD), were down-regulated. In contrast, in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated at the one-month time-point.ConclusionsThese results suggest that differential changes in the balance of pro- and anti- apoptotic gene-expression following treatment with lithium may explain some of the heterogeneity in clinical response in BD patients.

Increased peripheral blood expression of electron transport chain genes in bipolar depression

OBJECTIVE   To identify specific genetic pathways showing altered expression in peripheral blood of depressed subjects with bipolar disorder (BPD). METHODS   Illumina Sentrix BeadChip (Human-6v2) microarrays containing >48,000 transcript probes were used to measure levels of gene expression in peripheral blood from 20 depressed subjects with BPD and in 15 healthy control subjects. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to confirm a subset of these differences. RESULTS   A total of 1,180 genes were differentially expressed between subjects with BPD and healthy controls (fold-change >1.3, false discovery rate-corrected p < 0.05, covaried for age and sex). Of these, 559 genes were up-regulated in BPD subjects and 621 were down-regulated. Surprisingly, there was no difference between medicated (n = 11) and unmedicated (n = 9) subjects with BPD for any of these genes. Pathway analysis using GeneGo MetaCore software showed that the most significantly affected pathway was the mitochondrial electron transport chain (ETC). Of the 85 objects (genes or proteins) in this pathway, 22 were up-regulated and 2 down-regulated in subjects with BPD. qRT-PCR confirmed up-regulation of nuclear encoded ETC genes in complexes I, III, IV, and V and, in addition, demonstrated up-regulation of mitochondrially encoded genes in each of these complexes. CONCLUSION   These results suggest that increased expression of multiple components of the mitochondrial ETC may be a primary deficit in bipolar depression, rather than an effect of medication.

Levetiracetam in the Management of Bipolar Depression: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To study the efficacy of adjunctive levetiracetam therapy compared with placebo in the treatment of subjects with depression with bipolar disorder. METHOD This double-blind, placebo-controlled clinical trial randomly assigned outpatients with bipolar disorder type I and type II who were experiencing a major depressive episode (Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version criteria) to treatment with either placebo or adjunctive levetiracetam (up to 2,500 mg/d flexibly dosed) for 6 weeks. The subjects were recruited from October 2005 to June 2008. The primary efficacy measure was mean change from baseline to week 6 in the Hamilton Depression Rating Scale (21-item). Secondary efficacy assessments included the Montgomery-Åsberg Depression Rating Scale, the Beck Depression Inventory, the Clinical Global Impressions-Bipolar Version scale, the Hamilton Anxiety Rating Scale, and the Young Mania Rating Scale. RESULTS Of 42 subjects randomly assigned to placebo or drug, 32 received at least 1 postbaseline assessment and thus were included in the analysis. The mean (SD) levetiracetam daily dose at endpoint evaluation was 1,132 (425) mg/d. There was no significant difference in the mean change from baseline to week 6 in the Hamilton Depression Rating Scale scores for levetiracetam compared with placebo. There were no significant differences in any of the secondary outcome measures. CONCLUSIONS Levetiracetam adjunctive therapy was not superior to placebo in the short-term treatment of subjects with depression with bipolar disorder in the population studied. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00566150.

Lamotrigine-associated rash: to rechallenge or not to rechallenge?

The major burden of illness in bipolar disorder (BD) is in the depressive pole. Lamotrigine has been shown to be useful in the long-term prophylaxis of depressive episodes in BD. Current guidelines recommend discontinuing lamotrigine in patients who develop rash. Our objective in this paper is to review literature to identify possible predictors of serious vs. benign rash that might help guide clinical decision-making and recommend titration strategy for re-introduction of lamotrigine, if indicated. We performed a search of the literature between 1966 and July 2008 to investigate the phenomenon of lamotrigine-induced rash and rechallenge procedures. The search identified six reports, and we were able to identify another case series from reviewing the bibliography of all of the above papers. We reviewed all the papers of lamotrigine rash rechallenge that resulted from the literature search. These papers describe 44 cases of lamotrigine rechallenge. Currently, there are 39 reported cases in the literature of successful lamotrigine rechallenge after a rash and five cases with rash recurrence. There are some characteristics of the rash that can help identify serious cases from benign ones. In addition, very slow titration of lamotrigine is crucial to the reduction of rash recurrence rate. Several cases that develop benign rash on lamotrigine can be rechallenged without adverse consequences. We believe that lamotrigine rechallenge in bipolar depression is an under-utilized option in our clinical armamentarium, and further studies are needed to guide us in this area.

ADHD Symptoms and Associated Psychopathology in a Community Sample of Adolescents from the European North of Russia.

Objective: To assess the prevalence of ADHD symptoms and their relationship to psychopathology in adolescents from the European North of Russia. Method: The prevalence of ADHD symptoms is assessed by teacher reports in 536 adolescents. Internalizing and externalizing problems are assessed by teacher ratings and student self-reports. Results: Prevalence of individual ADHD symptoms ranges between 3.3% and 35%. Only 8.9% of boys and 3.6% of girls have positive ratings on six items in either inattention or hyperactivity subtype. These adolescents fare significantly worse regarding externalizing but not internalizing problems. Compared to girls with ADHD, boys with ADHD report higher levels of violent and nonviolent delinquency and are described by teachers as having more conduct problems. Possible ADHD status is associated with depressive symptoms in boys but not in girls. Conclusion: The estimates of ADHD prevalence rates obtained in this study are similar to those of other countries, suggesting the need for identification and treatment of the disorder. Evaluation of associated disruptive behavior disorders and depression, particularly in boys, is warranted. (J. of Att. Dis. 2008; 12(1) 54-63)

Pediatric psychopharmacology: Food and Drug Administration approval through the evidence lens

hen clinicians, policy makers, and consumers invoke the concept of W “Food and Drug Administration [FDA]-approved use of psychotropic medications in children,” do they all speak the same language? This article offers perspectives on the meaning of FDA approval in light of research evidence. The American Academy of Child and Adolescent Psychiatry (AACAP)’s Pediatric Psychopharmacology Initiative (PPI) created an Internet resource for clinicians based on a review of available research and FDA approval history. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework is a classification system adopted in 2007 by the World Health Organization for assessing evidence quality and making treatment recommendations. The PPI used GRADE as a guide for assessing only the quality of available evidence. Judgments on individual or relative medication efficacy were beyond the scope of its review. GRADE rating is based on type of study and estimate of effect, yielding 4 levels of quality: High (A): Several high-quality studies with consistent results; 1 large, high-quality, multicenter trial; further research is very unlikely to change our confidence in the estimate of effect. Moderate (B): One high-quality study or several studies with some limitations; further research is likely to change our confidence in the estimate of effect and may change the estimate. Low (C): At least 1 study with severe limitations; further research is very likely to change our confidence in the estimate of effect and is likely to change the estimate. Very Low (D): At least 1 study with very severe limitations; no direct research evidence; expert opinion; any estimate of effect is very uncertain.