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Lori Lowthert,
Janine Leffert,
Aiping Lin,
Sheila Umlauf,
Kathleen Maloney,
Anjana Muralidharan, Boris Lorberg,
Shrikant Mane,
Hongyu Zhao,
Rajita Sinha,
Zubin Bhagwagar,
Robert Beech
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ABSTRACT: Lithium 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.
Illumina 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.
127 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.
These 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.
Biology of mood & anxiety disorders. 09/2012; 2(1):15.
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Robert D Beech,
Lori Lowthert,
Janine J Leffert,
Portia N Mason,
Mary M Taylor,
Sheila Umlauf,
Aiping Lin,
Ji Young Lee,
Kathleen Maloney,
Anjana Muralidharan, Boris Lorberg,
Hongyu Zhao,
Samuel S Newton,
Shrikant Mane,
C Neill Epperson,
Rajita Sinha,
Hilary Blumberg,
Zubin Bhagwagar
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ABSTRACT: To identify specific genetic pathways showing altered expression in peripheral blood of depressed subjects with bipolar disorder (BPD).
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.
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.
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.
Bipolar Disorders 12/2010; 12(8):813-24. · 5.29 Impact Factor
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ABSTRACT: We examined whether children and adolescents with bipolar disorder (BPD) "self-medicate" with cigarettes, alcohol, or other substances of abuse. One hundred and five adolescents with BPD and 98 controls were comprehensively assessed with a structured psychiatric diagnostic interview for psychopathology and the Drug Use Screening Inventory (DUSI) for self-medication. Thirteen control (mean ± standard deviation [SD]= 15.31 ± 1.18 years) and 27 BPD (15.30 ± 2.09 years) subjects endorsed use of one of the listed drugs in the DUSI Section A within the past year and were included in all analyses. BPD adolescents were more likely than nonmood disordered, substance-using controls to report starting to use their preferred drug for mood-altering effects. There were no differences between groups in motivation for use with respect to starting substances to sleep better or get high, or in continuing substances to change mood, sleep better, or get high. These data may contribute to increased prevention of substance use disorders and to the treatment of adolescent BPD. Further studies clarifying the characteristics of self-medication are necessary.
American Journal on Addictions 11/2010; 19(6):474-80. · 1.74 Impact Factor
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ABSTRACT: To study the efficacy of adjunctive levetiracetam therapy compared with placebo in the treatment of subjects with depression with bipolar disorder.
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.
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.
Levetiracetam adjunctive therapy was not superior to placebo in the short-term treatment of subjects with depression with bipolar disorder in the population studied.
The Journal of Clinical Psychiatry 10/2010; 72(6):744-50. · 5.80 Impact Factor
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ABSTRACT: 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.
The International Journal of Neuropsychopharmacology 11/2008; 12(2):257-65. · 4.58 Impact Factor
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ABSTRACT: To assess the prevalence of ADHD symptoms and their relationship to psychopathology in adolescents from the European North of Russia.
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.
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.
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.
Journal of Attention Disorders 08/2008; 12(1):54-63. · 2.45 Impact Factor
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ABSTRACT: Bipolar affective disorder is not uncommon in the elderly; prevalence rates in the United States range from 0.1% to 0.4%. However, it accounts for 10% to 25% of all geriatric patients with mood disorders and 5% of patients admitted to geropsychiatric inpatient units. These patients often present a tremendous treatment challenge to clinicians. They frequently have differing treatment needs compared with their younger counterparts because of substantial medical comorbidity and age-related variations in response to therapy. Unfortunately, the management of geriatric bipolar disorder has been relatively neglected compared with the younger population. There continues to be a scarcity of published, controlled trials in the elderly, and no treatment algorithms specific to bipolar disorder in the elderly have been devised.
The goal of this article was to review the current literature on both the pharmacologic and nonpharmacologic management of late-life bipolar disorder.
English-language articles written on the treatment of bipolar disorder in the elderly were identified. The first step in data collection involved a search for evidence-based clinical practice guidelines in the Cochrane Database of Systematic Reviews (up until the third quarter of 2006). Systematic reviews were then located in the following databases: MEDLINE (1966-September 2006), EMBASE (1980-2006 [week 36]), and PsycINFO (1967-September 2006 [week 1]). Additional use was made of these 3 databases in searching for single randomized controlled trials, meta-analyses, cohort studies, case-control studies, case series, and case reports. "Elderly," used synonymously with "geriatric," was defined as individuals aged > or =60 years. However, to take into account ambiguity in the nomenclature, the key words aged, geriatric, elderly, and older were combined with words indicating pharmacologic treatments such as pharmacotherapy; classes of medications (eg, lithium, antidepressants, antipsychotics, anticonvulsants, benzodiazepines); and names of selected individual medications (eg, lithium, valproic acid, lamotrigine, carbamazepine, oxcarbazepine, topiramate, gabapentin, zonisamide, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole). These terms were then combined with the diagnostic terms bipolar disorder, mania, hypomania, depression, or bipolar depression. Finally, the terms ECT and psychotherapy were also queried in combination with indicators for age and diagnosis. A few articles on "older adults," usually defined as individuals aged 50 to 55 years, were also included. They may allow for possible extrapolation of data to the geriatric population. Additionally, several mixed-age studies were included for similar considerations. Case reports and case series were described for their potential heuristic value.
Unfortunately, there is a considerable dearth of literature involving evidence-based clinical practice guidelines and even randomized controlled trials in elderly individuals with bipolar disorder. Available options for the treatment of bipolar disorder (including those for mania, hypomania, depression, or maintenance) in the elderly include lithium, antiepileptics, antipsychotics, benzodiazepines, antidepressants, electroconvulsive therapy (ECT), and psychotherapy.
The data for the treatment of late-life bipolar disorder are limited, but the available evidence shows efficacy for some commonly used treatments. Lithium, divalproex sodium, carbamazepine, lamotrigine, atypical antipsychotics, and antidepressants have all been found to be beneficial in the treatment of elderly patients with bipolar disorder. Although there are no specific guidelines for the treatment of these patients, monotherapy followed by combination therapy of the various classes of drugs may help with the resolution of symptoms. ECT and psychotherapy may be useful in the treatment of refractory disease. There is a need for more controlled studies in this age group before definitive treatment strategies can be enumerated.
The American Journal of Geriatric Pharmacotherapy 01/2007; 4(4):347-64. · 2.67 Impact Factor
