A randomized controlled trial of the effectiveness of handheld computers for improving everyday memory functioning in patients with memory impairments after acquired brain injury.

OBJECTIVE: To determine the effectiveness of personal digital assistant devices on achievement of memory and organization goals in patients with poor memory after acquired brain injury. DESIGN: Assessor blinded randomized controlled trial. SETTING: Specialist brain injury rehabilitation hospital (inpatients and outpatients). PARTICIPANTS: Adults with acquired brain impairments (85% traumatic brain injury; aged ≥17 years) who were assessed as having functional memory impairment on the Rivermead Behavioural Memory Test (General Memory Index). INTERVENTIONS: Training and support to use a personal digital assistant for eight weeks to compensate for memory failures by an occupational therapist. The control intervention was standard rehabilitation, including use of non-electronic memory aids. MAIN OUTCOME MEASURES: Goal Attainment Scale which assessed achievement of participants' daily memory functioning goals and caregiver perception of memory functioning; and General Frequency of Forgetting subscale of the Memory Functioning Questionnaire administered at baseline (pre-randomization) and post intervention (eight weeks later). RESULTS: Forty-two participants with memory impairment were recruited. Use of a personal digital assistant led to greater achievement of functional memory goals (mean difference 1.6 (95% confidence interval (CI) 1.0 to 2.2), P = 0.0001) and improvement on the General Frequency of Forgetting subscale (mean difference 12.5 (95% CI 2.0 to 22.9), P = 0.021). CONCLUSIONS: Occupational therapy training in the use of a handheld computer improved patients' daily memory function more than standard rehabilitation.

DRD4 VNTR polymorphism and age at onset of severe mental illnesses.

A large number of studies has investigated the hypothesis that DRD4 48 bp variable number of tandem repeat (VNTR) polymorphism is involved in the etiology of schizophrenia and bipolar disorder. However, the results are inconsistent likely due to genetic and phenotypic heterogeneity. Age at onset (AAO) is considered an important alternate phenotype for genetic investigations of psychiatric disorders. In the present study, the DRD4 VNTR 7 repeat allele (7R) was examined in 477 patients with major psychoses. Age at onset was defined as the age of first psychotic episode for schizophrenia and the age at appearance of first clinically recognized symptoms for the bipolar sample. Our results showed an interaction between sex and DRD4 genotypes among schizophrenia patients (n=203, ß=.213, p=.017). On comparing AAO between carriers and non-carriers of the 7R, we observed that females with 7R present had later onset (p=.021). The effect was not observed for males. In the sample with bipolar disorder, we observed significant association between DRD4 7R-genotype and AAO (n=274, ß=-.148, p=.012). No interaction was observed between sex and genotypic groups of the bipolar sample. The 7R was associated with early onset of the bipolar illness (p=.028). In summary, our results suggest that the 7R is associated with AAO in both schizophrenia and bipolar disorders. The effect was observed across both sexes in bipolar disorder, but specifically in females for schizophrenia.

Sex differences in hormonal responses to a social stressor in chronic major depression.

BACKGROUND: Acute depression has been associated with increased hypothalamic-pituitary-adrenal (HPA) reactivity. While chronicity of depressive illness influences symptoms, course and outcome, its effect on the HPA axis has not been extensively evaluated. The current study evaluated cortisol stress responses to a social challenge in chronic major depressive disorder (CMDD). METHODS: Cortisol stress responses to the Trier Social Stress Test (TSST) were compared in 26 participants with CMDD and 28 healthy controls using repeated measures analysis of variance (RANOVA). In addition, group differences in area under the curve (AUC) and peak percentage change in cortisol were examined. RESULTS: The RANOVA indicated a significant sex by condition interaction in cortisol responses to the social challenge. Post-hoc testing of pair-wise group differences revealed that in females, CMDD subjects had greater cortisol levels in response to the TSST than did controls. Similarly, AUC was greater in females with CMDD than in female controls. Neither of these differences was significant in males. However, male CMDD subjects exhibited a significantly decreased peak percentage change in cortisol in response to the TSST than did male controls. CONCLUSIONS: Males and females with CMDD exhibited unique differences in cortisol responses to the social challenge relative to controls. In females, CMDD subjects had greater overall secretion of cortisol whereas in males, CMDD subjects had a blunted peak response to the social stressor. Sex differences are an important consideration in future work in this population.

Seasonality and circadian preference in adult attention-deficit/hyperactivity disorder: clinical and neuropsychological correlates.

OBJECTIVE: The objective of the study was to measure both seasonal mood change and circadian preference, and their clinical and neuropsychological correlates, in adults with ADHD during the fall/winter months. METHOD: Twenty-nine adults with attention-deficit/hyperactivity disorder (ADHD) were assessed in the fall/winter season using self-report measures of ADHD, mood, seasonality, and circadian preference. Neuropsychological tests were also completed. Correlations between chronobiologic variables and clinical/neuropsychological measures were performed. RESULTS: Consistent with prior work in adult ADHD, high rates of seasonal depression were reported in this sample. Based on the morningness-eveningness questionnaire, which assesses circadian preference 11 (40.7%, N = 27) subjects were designated as evening types and only 5 (18.5%) as morning types, a distribution highly discrepant with general population studies. Later circadian preference, independent of seasonality, was strongly correlated with both self-reported symptoms of ADHD and neuropsychological deficits, including impulsive responding and poor target discrimination. None of these findings was attributable to state depression. CONCLUSIONS: In the fall/winter period, a mood-independent delay in circadian phase may contribute significantly to core pathology in many adults with ADHD. These findings establish a potential target for chronobiologic treatments such as light therapy in this complex population.

An open trial of light therapy in adult attention-deficit/hyperactivity disorder.

OBJECTIVE: In adults with attention-deficit/ hyperactivity disorder (ADHD), a delayed sleep/ activity rhythm and/or seasonal mood symptoms may contribute significantly to core pathology and disability. This study examined whether a chronobiologically based treatment, i.e., morning bright light therapy (LT), might have utility as an adjunctive treatment for adult ADHD in the fall/ winter period. METHOD: Twenty-nine adults with DSM-IV ADHD were administered a standard 3-week open trial of LT during the fall or winter months. Primary outcome measures included percentage reduction on the Brown Adult ADD Scale and the Conners' Adult ADHD Scale. Secondary measures were decrease in depression scores according to the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder version; improvements on various neuropsychological tests; and shift toward an earlier circadian preference as measured by the Horne-Ostberg Morningness-Eveningness questionnaire. Regression analyses determined which variables at baseline best predicted improvement on a given outcome measure and which variables changed in parallel with one another. The study was conducted from November 2003 through February 2004. RESULTS: Morning bright light therapy was associated with a significant decrease in both subjective and objective measures of core ADHD pathology, improved mood symptoms, and a significant phase advance in circadian preference. Multiple regression showed that the shift toward an earlier circadian preference with LT was the strongest predictor of improvement on both subjective and objective ADHD measures. Neither baseline global seasonality scores nor baseline depression scores strongly predicted LT effects on most measures of ADHD. CONCLUSION: These findings suggest that during the fall/winter period, LT may be a useful adjunct in many adults with ADHD. Strikingly, the strongest correlate of improvement in core ADHD pathology was a phase advance in circadian preference rather than alleviation of comorbid seasonal affective disorder, suggesting important clinical benefits of LT beyond the treatment of seasonal affective disorder.

A birth-season/DRD4 gene interaction predicts weight gain and obesity in women with seasonal affective disorder: A seasonal thrifty phenotype hypothesis.

We have recently described an association between the hypofunctional 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), weight gain, and obesity in women with seasonal affective disorder (SAD). In the current study, we examined whether season-of-birth might interact with the 7R allele to influence body weight regulation in SAD. In 182 female probands with SAD, we performed an analysis of covariance predicting maximum lifetime body mass index (BMI) with both the exon-3 variable number of tandem repeat polymorphism of DRD4 and season-of-birth as independent variables, and age as the covariate. The overall model was highly significant (F = 4.42, df = 8, 173, p < 0.0001) with season-of-birth predicting maximal lifetime BMI both on its own and in its interaction with the 7R allele. The latter finding was attributable to 7-repeat carriers born in the spring (N = 17), who had a mean maximal lifetime BMI of 33.7 kg/m2 (SD 8.6), compared to 26.7 kg/m2 (SD 5.4) for all other probands combined (N = 165) (F = 20.01, df = 1, 179, p < 0.0001). The lifetime rate of obesity (maximal BMI > 30 kg/m2) was also significantly higher in the 7R/spring birth group (9/17=52.9% vs 32/165=19.4%; chi2 = 9.94, df = 1, p = 0.002; odds ratio = 4.68, 95% CI = 1.67-13.07). These data may reflect a novel gene-environment interaction, during early brain development, which establishes an increased risk for obesity in women with SAD. Although the mechanism for season-of-birth effects in psychiatric disorders is unknown, a characteristic pattern of melatonin exposure during the second and third trimesters may be of particular relevance in this study population. We speculate that these data may reflect the vestigial expression of a seasonal thrifty phenotype that contributed to the positive selection of the 7R allele over the past 40,000 years.

Psychic and somatic anxiety differentially predict response to light therapy in women with seasonal affective disorder.

OBJECTIVE: To examine whether psychic and/or somatic anxiety predict responsiveness to light therapy in women with winter Seasonal Affective Disorder (SAD). DESIGN: Eighty-one women with SAD were administered a standard 10-day trial of light therapy administered for one-half hour in the early morning. Using a multiple regression model, baseline somatic and psychic anxiety item scores were used to predict percentage change scores on the 29-item SIGH-SAD post treatment. Baseline scores for weight gain, hypersomnia and the total SIGH-SAD were also included as predictor variables. RESULTS: The regression model was highly significant (F=4.63, df=5,75; p=.001; model R(2)=.236), with both psychic anxiety and somatic anxiety contributing significantly to the model. Consistent with prior work using anti-depressant medication in non-seasonal depression, psychic anxiety was positively correlated with outcome, while somatic anxiety negatively predicted outcome. CONCLUSIONS: In SAD, psychic and somatic anxiety scores at baseline appear to be independent and opposite predictors of light therapy response. These effects were independent of baseline scores for weight gain and hypersomnia, two previously established predictors of response to light. These findings may be an important consideration in the design and interpretation of light therapy studies of SAD.

The dopamine-4 receptor gene associated with binge eating and weight gain in women with seasonal affective disorder: an evolutionary perspective.

BACKGROUND: We recently described a preliminary association between the hypofunctional seven-repeat allele of the dopamine-4 receptor gene (DRD4) and increased maximal lifetime body mass index in women with seasonal affective disorder (SAD). In this study, we examined whether binge eating behavior mediated this putative association. METHODS: The study sample consisted of 131 women with winter SAD who reported increased intake of high-carbohydrate/high-fat foods during depressive episodes. We compared rates of binge eating behavior in the two genotypic groups defined by the presence or absence of the seven-repeat allele of DRD4. RESULTS: Consistent with our working hypothesis, the proportion of binge eaters was significantly greater in probands with the seven-repeat allele (18 of 46, 39.1%) than in probands without this allele (14 of 85, 16.5%) [chi(2)(1)= 8.32, p = .004; odds ratio = 3.25, 95% confidence interval 1.43, 7.41]. CONCLUSIONS: Pending replication in other samples, these results point to a genetic factor that could help in the early identification and treatment of women at higher risk for seasonal weight gain associated with binge eating behavior. At a theoretic level, the current results suggest a novel link between evolutionary models of seasonal weight gain on the one hand and the DRD4 gene on the other.