Lifetime use of psychiatric medications and cognition at 43years of age in schizophrenia in the Northern Finland Birth Cohort 1966.

BACKGROUND: Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia. METHODS: Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression. RESULTS: Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11months) before the cognitive examination was associated with better cognitive performance (P=0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P=0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition. CONCLUSIONS: Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia.

Psychometric precision in phenotype definition is a useful step in molecular genetic investigation of psychiatric disorders.

Affective disorders are highly heritable, but few genetic risk variants have been consistently replicated in molecular genetic association studies. The common method of defining psychiatric phenotypes in molecular genetic research is either a summation of symptom scores or binary threshold score representing the risk of diagnosis. Psychometric latent variable methods can improve the precision of psychiatric phenotypes, especially when the data structure is not straightforward. Using data from the British 1946 birth cohort, we compared summary scores with psychometric modeling based on the General Health Questionnaire (GHQ-28) scale for affective symptoms in an association analysis of 27 candidate genes (249 single-nucleotide polymorphisms (SNPs)). The psychometric method utilized a bi-factor model that partitioned the phenotype variances into five orthogonal latent variable factors, in accordance with the multidimensional data structure of the GHQ-28 involving somatic, social, anxiety and depression domains. Results showed that, compared with the summation approach, the affective symptoms defined by the bi-factor psychometric model had a higher number of associated SNPs of larger effect sizes. These results suggest that psychometrically defined mental health phenotypes can reflect the dimensions of complex phenotypes better than summation scores, and therefore offer a useful approach in genetic association investigations.

Lifetime affect and midlife cognitive function: prospective birth cohort study.

BACKGROUND: Recurrent affective problems are predictive of cognitive impairment, but the timing and directionality, and the nature of the cognitive impairment, are unclear. AIMS: To test prospective associations between life-course affective symptoms and cognitive function in late middle age. METHOD: A total of 1668 men and women were drawn from the Medical Research Council National Survey of Health and Development (the British 1946 birth cohort). Longitudinal affective symptoms spanning age 13-53 years served as predictors; outcomes consisted of self-reported memory problems at 60-64 years and decline in memory and information processing from age 53 to 60-64 years. RESULTS: Regression analyses revealed no clear pattern of association between longitudinal affective symptoms and decline in cognitive test scores, after adjusting for gender, childhood cognitive ability, education and midlife socioeconomic status. In contrast, affective symptoms were strongly, diffusely and independently associated with self-reported memory problems. CONCLUSIONS: Affective symptoms are more clearly associated with self-reported memory problems in late midlife than with objectively measured cognitive performance.

Response initiation in young adults at risk for psychosis in the Northern Finland 1986 Birth Cohort.

INTRODUCTION: This is one of the very few studies to investigate the specific executive function/processing speed component of response initiation in subjects at familial risk (FR) for psychosis, and the first such study in subjects at clinical risk (CR) for psychosis. METHODS: Participants (N = 177) were members of the general population-based Northern Finland 1986 Birth Cohort in the following four groups: FR for psychosis (n = 62), CR for psychosis (n = 21), psychosis (n = 25) and control subjects (n = 69). The response initiation of these groups was compared in three different tests: Semantic fluency, Stockings of Cambridge and Spatial working memory. RESULTS: The two risk groups did not differ significantly from control group, but differed from, and outperformed the psychosis group in semantic fluency response initiation. CONCLUSIONS: Response initiation deficits were not evident in a non-help seeking psychosis high-risk sample.

Personality and bipolar disorder: dissecting state and trait associations between mood and personality.

BACKGROUND: Some personality characteristics have previously been associated with an increased risk for psychiatric disorder. Longitudinal studies are required in order to tease apart temporary (state) and enduring (trait) differences in personality among individuals with bipolar disorder (BD). This study aimed to determine whether there is a characteristic personality profile in BD, and whether associations between BD and personality are best explained by state or trait effects. METHOD: A total of 2247 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder study completed the NEO Five-Factor Inventory administered at study entry, and at 1 and 2 years. RESULTS: Personality in BD was characterized by high neuroticism (N) and openness (O), and low agreeableness (A), conscientiousness (C) and extraversion (E). This profile was replicated in two independent samples, and openness was found to distinguish BD from major depressive disorder. Latent growth modeling demonstrated that manic symptoms were associated with increased E and decreased A, and depressed symptoms with higher N and lower E, A, C and O. During euthymic phases, high N and low E scores predicted a future depression-prone course. CONCLUSIONS: While there are clear state effects of mood on self-reported personality, personality variables during euthymia predict future course of illness. Personality disturbances in extraversion, neuroticism and openness may be enduring characteristics of patients with BD.

The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data.

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

The genetics of bipolar disorder.

Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.

Reinforcement and reversal learning in first-episode psychosis.

BACKGROUND: Abnormalities in reinforcement learning and reversal learning have been reported in psychosis, possibly secondary to subcortical dopamine abnormalities. METHODS: We studied simple discrimination (SD) learning and reversal learning in a sample of 119 first-episode psychosis patients from the Cambridge early psychosis service (CAMEO) and 107 control participants. We used data on reinforcement learning and reversal learning extracted from the Cambridge Neuropsychological Test Automated Battery Intradimensional-Extradimensional shift task, which measures cognitive flexibility but also involves simple reinforcement learning (SD learning) and reversal learning stages. We also gathered diagnostic information to examine whether there were any differences between patients ultimately diagnosed with schizophrenia-spectrum disorders and those diagnosed with affective psychosis. RESULTS: Psychosis patients demonstrated deficits in simple reinforcement learning (SD learning) and in reversal learning, with no differences between affective psychosis and schizophrenia-spectrum psychosis. There was a significant modest correlation between reversal errors and negative symptoms (Spearman rho = 0.3, P = .02). CONCLUSIONS: There are reinforcement learning abnormalities in first-episode psychosis, which correlate with negative symptoms, suggesting a possible role for orbitofrontal cortex and ventral striatal pathology in the pathogenesis of motivational deficits in psychosis.

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls.

The catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is hypothesized to affect executive function in patient and control populations. Studies inconsistently report better performance on the Wisconsin Card Sort Test (WCST) in individuals with one or more Met alleles. We conducted a meta-analysis of studies published until August 2006 that reported WCST perseverative errors from healthy volunteers or patients with schizophrenia-spectrum disorders. Twelve studies met inclusion criteria (total n=1910) providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d=0.29; 95% confidence interval (CI) 0.02-0.55; P=0.03), but this was not supported in the patient sample (d=-0.07; 95% CI -0.40 to 0.26; P=0.68). Post hoc analyses suggested that Val and Met alleles are codominant in their effects on cognition. Effect size was greater in studies published at an earlier date and may also be larger in non-Caucasian samples. Gender did not affect the results. There was no evidence of publication bias. We conclude that there is small but significant relationship between Val(158)Met genotype and executive function in healthy individuals but not in schizophrenia.

Cognitive reserve in neuropsychiatry.

BACKGROUND: The idea that superior cognitive function acts as a protective factor against dementia and the consequences of head injury is well established. Here we suggest the hypothesis that cognitive reserve is also important in neuropsychiatric disorders including schizophrenia, bipolar disorder and depression. METHOD: We review the history of passive and active models of reserve, and apply the concept to neuropsychiatric disorders. Schizophrenia is used as an exemplar because the effects of premorbid IQ and cognitive function in this disorder have been extensively studied. RESULTS: Cognitive reserve may impact on neuropsychiatric disorders in three ways: by affecting the risk for developing the disorder, in the expression of symptoms within disorders, and in patients' functional outcome. Cognitive failure below a certain threshold may alone, or in combination with common psychiatric symptoms, produce neuropsychiatric syndromes. CONCLUSIONS: Consideration of cognitive reserve may considerably improve our understanding of individual differences in the causes and consequences of neuropsychiatric disorders. For these reasons, the concept of cognitive reserve should be incorporated in future studies of neuropsychiatric disorder. It may be possible to enhance cognitive reserve through pharmacological or non-pharmacological means, such as education, neurocognitive activation or other treatment programmes.

Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: This study examined the effects of metoprolol on left ventricular performance, efficiency, neurohormonal activation and myocardial respiratory quotient in patients with dilated cardiomyopathy. BACKGROUND: The mechanism by which beta-adrenergic blockade improves ejection fraction in patients with dilated cardiomyopathy remains an enigma. Thus, we undertook an extensive hemodynamic evaluation of this mechanism. In addition, because animal models have shown that catecholamine exposure may increase relative fatty acid utilization, we hypothesized that antagonism of sympathetic stimulation may result in increased carbohydrate utilization. METHODS: This was a randomized, double-blind, prospective trial in which 24 men with nonischemic dilated cardiomyopathy underwent cardiac catheterization before and after 3 months of therapy with metoprolol (n = 15) or placebo (n = 9) in addition to standard therapy. Pressure-volume relations were examined using a micromanometer catheter and digital ventriculography. RESULTS: At baseline, the placebo-treated patients had somewhat more advanced left ventricular dysfunction. Ejection fraction and left ventricular performance improved only in the metoprolol-treated patients. Stroke and minute work increased without an increase in myocardial oxygen consumption, suggesting increased myocardial efficiency. Further increases in ejection fraction were seen between 3 and 6 months in the metoprolol group. The placebo group had a significant increase in ejection fraction only after crossover to metoprolol. A significant relation between the change in coronary sinus norepinephrine and myocardial respiratory quotient was seen, suggesting a possible effect of adrenergic deactivation on substrate utilization. CONCLUSIONS: These data demonstrate that in patients with cardiomyopathy, metoprolol treatment improves myocardial performance and energetics, and favorably alters substrate utilization. Beta-adrenergic blocking agents, such as metoprolol, are hemodynamically and energetically beneficial in the treatment of myocardial failure.

Discoid lupus erythematosus exacerbated by contact dermatitis.

A patient with a nickel contact dermatitis also had discoid lupus erythematosus. The dermatitis acted as a Koebner-like reaction on the cutaneous lupus, which in turn caused progressive destruction of the earlobes.

Disseminated ecthymatous herpes varicella-zoster virus infection in patients with acquired immunodeficiency syndrome.

Herpesvirus infections are among the most common and debilitating opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS), and they may have atypical clinical features. We describe the cases of three patients with AIDS in whom atypical persistent ulcerative skin lesions developed as a result of varicella-zoster virus infection. Two patients had disseminated infection without a vesicular stage; one patient had underlying asteatotic eczema. All responded well to acyclovir. One patient was treated with azidothymidine, and typical dermatomal herpes zoster subsequently developed. The profound loss of helper T cell function in AIDS may lead to multiple abnormalities in local immune response to cutaneous herpesvirus infections and may be responsible for the atypical morphology and a prolonged course.

Linear porokeratosis: treatment with the carbon dioxide laser.

A patient with a lifelong linear porokeratosis was treated with a carbon dioxide laser. The laser was successful in removing the patient's hyperkeratotic plantar lesion. No recurrence has been noted in a 6-month follow-up visit. This report demonstrates another dermatologic condition that can be treated successfully with the CO2 laser.

Multiple epitheliomata cuniculata occurring in a mutilating keratoderma.

We report on a young man with a congenital mutilating keratoderma in whom three epitheliomata cuniculata occurred during a two-year period. The clinical findings, associated disease states, and treatment of epithelioma cuniculatum (EC) are reviewed.

Lichenoid drug reactions to chlorpropamide and tolazamide.

Many medications, including gold, antimalarials, quinidine, and thiazide diuretics have been implicated in lichenoid drug reactions. Chlorpropamide and tolazamide are sulfonylurea oral hypoglycemic agents, neither of which has previously been implicated in cutaneous lichenoid reactions. We report a case of lichenoid drug reaction related to both chlorpropamide and tolazamide.

Acral lentiginous melanoma and lentigo maligna occurring in Werner's syndrome.

Werner's syndrome is an adult progeria that predisposes affected individuals to various cutaneous and internal malignant neoplasms. Herein we report on a patient with Werner's syndrome who developed two primary melanocytic tumors.