Roberta S. May

Lithium Regulates Glycogen Synthase Kinase-3β in Human Peripheral Blood Mononuclear Cells: Implication in the Treatment of Bipolar Disorder

BACKGROUND Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3beta (GSK3beta). The mood stabilizer lithium inhibits GSK3beta in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3beta in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects. METHODS The PBMCs were obtained from 23 healthy control subjects, 9 bipolar subjects currently treated with lithium, and 13 lithium-free bipolar subjects. Immunoblot analyses were used to measure the inhibited, serine9-phosphorylated GSK3beta. RESULTS The level of phospho-Ser9-GSK3beta in PBMCs was regulated by agents that modified kinases and phosphatases acting on GSK3beta and was increased by in vitro lithium treatment. More important, phospho-Ser9-GSK3beta levels were eightfold higher in PBMCs from lithium-treated bipolar than healthy control subjects. CONCLUSIONS Signaling pathways regulating serine9-phosphorylation of GSK3beta can be studied in human PBMCs. Both in vitro and in vivo therapeutic lithium treatment is associated with a large increase in phospho-Ser9-GSK3beta in PBMCs. Therefore, the inhibitory serine9-phosphorylation of GSK3beta in human PBMCs may provide a biochemical marker to evaluate the association between GSK3beta inhibition and therapeutic responses to lithium treatment.

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): Recruitment and assessment methods

The Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) is a multi-site, NIMH-funded study that seeks to identify genetic polymorphisms that confer susceptibility to schizophrenia among African-Americans by linkage mapping and targeted association analyses. Because deficits in certain dimensions of cognitive ability are thought to underlie liability to schizophrenia, the project also examines cognitive abilities in individuals affected by schizophrenia and their extended family members. This article describes PAARTNERS study design, ascertainment methods and preliminary sample characteristics. We aim to recruit a sample of 1260 African-American families, all of whom have at least one proband with schizophrenia or schizoaffective disorder. The data collection protocol includes a structured Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, focused neurocognitive assessment, medical records review, and the collection of blood or buccal cells for genetic analyses. We have currently completed study procedures for 106 affected sib-pair, 457 case-parent trio and 23 multiplex families. A total of 289 probands have completed the best estimate final diagnosis process and 1153 probands and family members have been administered the computerized neuropsychological battery. This project lays the foundation for future analysis of cognitive and behavioral endophenotypes. This novel integration of diagnostic, neurocognitive and genetic data will also generate valuable information for future phenotypic and genetic studies of schizophrenia.

Delayed Sleep Timing and Symptoms in Adults With Attention-Deficit/ Hyperactivity Disorder: A Controlled Actigraphy Study

Patients with attention-deficit/hyperactivity disorder (ADHD) often exhibit disrupted sleep and circadian rhythms. Determination of whether sleep disturbance and/or circadian disruption are differentially associated with symptom severity is necessary to guide development of future treatment strategies. Therefore, we measured sleep and ADHD symptoms in participants aged 19–65 who met the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) criteria for ADHD and insomnia without psychiatric comorbidities by monitoring actigraphy and daily sleep logs for 2 wks, as well as the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), the ADHD Rating Scale (ADHD-RS), and a clinic-designed sleep behavior questionnaire. Principal components analysis identified correlated circadian- and sleep-related variables in all participants with ADHD who completed the study (n = 24). The identified components were entered into a backwards stepwise linear regression analysis, which indicated that delayed sleep timing and increased sleepiness (ESS) (but not sleep duration or sleep efficiency) significantly predicted greater severity of both hyperactive-impulsive and inattentive ADHD symptoms (p < .05 for partial regression coefficients). In addition, combined subtypes had the most impaired age-adjusted sleep quality (PSQI scores; p < .05 compared with healthy controls; n = 13), and 91.7% of them reported going to bed late due to being “not tired/too keyed up to sleep” compared with 57.2% and 50% of inattentive and symptom-controlled participants, respectively (p < .05). In conclusion, the results of this study suggest that ADHD symptom severity correlates with delayed sleep timing and daytime sleepiness, suggesting that treatment interventions aimed at advancing circadian phase may improve daytime sleepiness. In addition, ADHD adults with combined hyperactive-impulsive and inattentive symptoms have decreased sleep quality as well as the delayed sleep timing of predominately inattentive subtypes. (Author correspondence: rfargason@uab.edu)

Risperidone treatment of borderline personality disorder assessed by a borderline personality disorder-specific outcome measure: a pilot study.

To the Editors: Borderline personality disorder (BPD) has a prevalence of 1.4% and results in high rates of mortality (9%), morbidity, and comorbidity, and in disproportionately high uses of primary medical and psychiatric services. One of the most promising lines of pharmacotherapeutic research in BPD has evolved from the observed effects of low doses of neuroleptics. According to the American Psychiatric Association practice guideline, antipsychotic agents are recommended in patients with BPD who present with cognitive-perceptual symptoms, acute anger, hostility, assaultiveness, and self-injury. Placebocontrolled studies of these agents in BPD have consistently demonstrated significant symptom reduction. However, improvement in symptoms within and between the 4 behavioral dimensions of BPD (affective dysregulation, impulsivity, cognitive-perceptual impairment, and disturbed relationships) has varied among studies, even between those utilizing the same drug. This inconsistent pattern of efficacy of antipsychotic agents in BPD may be due, in part, to the treatment outcome measures used. No published study has utilized an instrument developed to evaluate treatment change in the specific symptoms and behavioral dimensions of BPD, possibly resulting in the observed inconsistency of findings and a bias in favor of type II errors. In general, condition-specific instruments seem to provide greater sensitivity to change. A self-report treatment outcome measure evaluating the symptoms and symptom domains of BPD may provide enhanced sensitivity and validity in evaluating treatment effects in this population and would complement the clinician-administered Zanarini Rating Scale for BPD (ZAN-BPD). Finally, there are conflicting results from the only 2 studies evaluating the efficacy of risperidone in BPD, a medication used off-label in patients with the disorder. Therefore, the primary objectives of this pilot study were to test the efficacy and tolerability of risperidone in subjects with BPD and to provide a preliminary evaluation of the utility of a new self-report treatment outcome measure for BPD, the Borderline Disorder Rating Scale (BDRS). Approval for this open-label trial was obtained from the University of Alabama at Birmingham (UAB) institutional review board, and written informed consent was obtained from all subjects. Female subjects were recruited from newspaper advertisements and from physicians practicing at UAB. Subjects met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for BPD (Structured Clinical Interview for DSM-IV Axis II Personality Disorders), scored 8 or higher on the Revised Diagnostic Interview for Borderlines, used an accepted means of contraception, and demonstrated an understanding of all tests and examinations used. Exclusion criteria were participation in a clinical drug trial within 1 month before study entry; currently pregnant or nursing; current diagnosis of any DSM-IVAxis I disorder (with the exception of dysthymia, posttraumatic stress disorder, generalized anxiety disorder, or substance abuse or dependence inactive for the prior 3 months); current schizotypal or antisocial personality disorder; active suicidal ideation with a plan; serious, unstable medical illnesses; use of any additional psychotropic medication during or within 4 weeks before the study, except for a maintenance dose of antidepressants; and treatment with any form of psychotherapy during the study. Comprehensive physical and psychiatric histories and examinations and laboratory studies were performed at entry into and upon completion of the study. One of the 2 primary treatment outcome measures used in the study was the BDRS, a 40-item scale developed by 4 of the authors (R.O.F., W.T.J., R.S.M., and A.S.) then at the UAB BPD Program. Four groups of 10 items each were developed to evaluate change in the 4 domains of BPD. A more complete description and a copy of the BDRS are available from the corresponding author. Further evaluation of its psychometric properties will be published elsewhere. Upon entry into the study, all subjects completed a battery of outcome measures that was readministered at the end of weeks 2, 4, 6, and 8. These included the BDRS and the second primary outcome measure, the Brief Symptom Inventory (BSI; 53 items); the State-Trait Anger Expression Inventory 2 (57 items); the Beck Depression Inventory II (26 items); the Barratt Impulsiveness Scale, 11th version (BIS-11; 30 items); the Quality of Life Enjoyment and Satisfaction Questionnaire (feelings, work, and social relations subscales); the Clinical Global Impression (CGI)—Severity and Improvement Clinician-Rated; the CGIImprovement Patient-Rated Scales; and the Social Desirability Scale. Safety and tolerability were assessed by clinicians at each visit using the treatment emergent signs and symptoms. The initial dose of risperidone for all subjects was 0.25 mg/d, given at bedtime to minimize any impairment due to somnolence. The dose was adjusted at each visit based on clinical perception of efficacy and tolerability, to a maximum dosage of 2 mg/d, a dose limit used to optimize tolerability as a result of experience in the UAB BPD Clinic. The dose was reduced at any time if, in the clinician’s judgment, adverse effects or poor tolerability indicated doing so. Letters to the Editors

Treatment of attention deficit hyperactivity disorder insomnia with blue wavelength light-blocking glasses

Correspondence: Rachel Fargason 3rd Floor Callahan Eye Foundation Hospital, 1720 University Boulevard, Birmingham, AL 35294, USA Tel +1 205 934 4301 Fax +1 205 975 9600 Email Rfargason@uab.edu Background: The aim of this study was to examine a nonmedical treatment alternative to medication in attention deficit hyperactivity disorder (ADHD) insomnia, in which blue wavelength light-blocking glasses are worn during the evening hours to counteract the phase-delaying effect of light. Outcome measures included sleep quality and midsleep time. The capacity of ADHD subjects to comply with treatment using the glasses was assessed. Methods: Daily bedtime, wake-up time, and compliance diaries were used to assess sleep quality and timing during a baseline observation week and a 2-week intervention period. The Pittsburgh Sleep Quality Index (PSQI) was administered following baseline and intervention. The intervention protocol consisted of use of blue wavelength-blocking glasses and a moderate lighting environment during evening hours. Results: Partial and variable compliance were noted, with only 14 of 22 subjects completing the study due to nonadherence with wearing the glasses and diary completion. Despite the minimum 3-hour recommendation, glasses were worn, on average, for 2.4 hours daily. Lighting was reduced for only 58.7% of the evening. Compared with baseline, the intervention resulted in significant improvement in global PSQI scores, PSQI subcomponent scores, and sleep diary measures of morning refreshment after sleep (P = 0.037) and night-time awakenings (P = 0.015). Global PSQI scores fell from 11.15 to 4.54, dropping below the cut-off score of 5 for clinical insomnia. The more phase-delayed subjects, ie, those with an initial midsleep time after 4:15 am, trended towards an earlier midsleep time by 43.2 minutes following the intervention (P = 0.073). Participants reported less anxiety following the intervention (P = 0.048). Conclusions: Despite only partial compliance with intervention instructions, subjects completing the study showed subjectively reduced anxiety and improved sleep quality on multiple measures. The more sleep-delayed subjects trended toward an earlier sleep period following use of the glasses. Blue-blocking glasses are a potential insomnia treatment for more compliant subjects with ADHD insomnia, especially those with prominent sleep delay. Larger studies of blue light-blocking glasses in more phase-delayed groups could reveal significant advances in chronotherapeutics.