Daniel R. Wilson

Structural brain abnormalities in first-episode mania.

Using magnetic resonance imaging (MRI), we studied brain morphometric differences between patients with first-episode mania (n = 17) and normal control subjects (n = 16). Patients were admitted for their first psychiatric hospitalization and met DSM-III-R criteria for bipolar disorder, manic or mixed. Diagnoses were made using the Structured Clinical Interview for DSM-III-R. Patients and control subjects were matched for age, gender, height, past history of substance abuse, and handedness, although control subjects had attained higher levels of education. MRI inversion recovery coronal scans were used for measurements. Volumetric measurements were obtained for cerebral hemispheres, lateral and third ventricles, caudate, thalamus, and cingulate gyrus. Patients with first-episode mania demonstrated significantly larger third-ventricular volumes, possibly increased lateral ventricular volumes, and differences in gray/white matter distribution compared with normal control subjects. The possible pathophysiological meaning of these findings is discussed.

New-onset diabetes and ketoacidosis with atypical antipsychotics

Information from the Ohio Department of Mental Health (ODMH) database was reviewed retrospectively to identify patients at the Cincinnati center treated with an atypical antipsychotic and who had also been evaluated or treated for diabetes mellitus. Blood glucose levels, glucose tolerance, or other evaluations of diabetes had been conducted in 14 of the 126 patients treated with atypical antipsychotics. In 11 of the 14, new-onset, acute, and marked glucose intolerance developed after treatment with clozapine, olanzapine or quetiapine. Of these, six patients required insulin therapy (four only transiently) and five patients developed diabetic ketoacidosis (DKA). Also, glucose metabolism was labile in all cases, and was transient in two cases with subsequent resolution despite on-going antipsychotic therapy. Certain atypical antipsychotics may be associated with new-onset glucose intolerance, including acute diabetes and ketoacidosis. Monitoring for changes in blood glucose levels in patients taking atypical antipsychotics may be indicated. More systematic study data are clearly needed.

MRI subcortical signal hyperintensities in Mania at first hospitalization

Recently, several investigators have reported an increased frequency of subcortical signal hyperintensities detected with magnetic resonance imaging (MRI) in patients with bipolar disorder as compared to normal controls (Swayze et al 1990; Dupont et al 1987, 1990; Figiel et al 1991). The pathophysiologic significance of these neuroanatomic abnormalities has remained obscure, although it has been suggested that these lesions may be associated with the underlying pathogenetic process (Dupont et al 1987; Figiel et al 1991). However, the effects of illness chronicity (multiple episodes) and treatment on these findings is uncertain and may confound the analysis of these observations. Indeed, Dupont et al (1990) noted that those patients with signal hyperintensities on MRI had significantly more previous hospitalizations, although whether there is a relationship between treatment and subcortical signal hyperintensities is undetermined. Studying patients with bipolar disorder at the onset of the illness (prior to or very early in treatment) could control for these confounding variables and may lead to improved understanding of the pathogenesis of the disorder. If subcortical signal hyperintensities were present at the onset of the illness, then these abnormalities might have etiologic significance. With these considerations in mind, we have examined MRI scans for subcortical hypcfintcnsities from a sample of patients with first-episode mania compared to normal control subjects.

Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: A randomized, double-blind, fixed-dose study

Abstract The objective of this study was to assess the dose-response relationship of standard and higher doses of olanzapine in a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10 (n = 199), 20 (n = 200), and 40 mg/d (n = 200) for patients with schizophrenia or schizoaffective disorder and suboptimal response to current treatment. Patients meeting criteria for antipsychotic treatment resistance were excluded. Dose-response relationship was assessed by linear regression analysis with log-transformed dose (independent variable) and Positive and Negative Syndrome Scale (PANSS) total score (dependent variable). There were no significant dose group differences in patients completing the study (overall, 67.8%). All dose groups showed statistically significant improvement in PANSS total scores from baseline to end point without significant dose-response relationship (P = 0.295). Post hoc analysis of response showed significant interaction between baseline PANSS and dose (P = 0.023), indicating better response at higher doses for patients with higher baseline PANSS. There was a significant dose response for mean change in weight (P = 0.003) with significant difference between the 10- and 40-mg-dose groups (P = 0.002; 1.9 [10 mg/d], 2.3 [20 mg/d], and 3.0 kg [40 mg/d]). There was a significant dose response for change in prolactin (P < 0.001) with a significant difference between each group (−10.5 [10 mg/d], −1.7 [20 mg/d], and 4.9 ng/mL [40 mg/d]; P ≤ 0.018). Over 8 weeks, non-treatment-resistant patients with schizophrenia or schizoaffective disorder responded to all 3 doses of olanzapine, without a statistically significant dose-response relationship, suggesting that for many patients with schizophrenia or schizoaffective disorder, particularly those who are mildly or moderately ill, 10 mg/d should be the initial dose of choice.

Risperidone monotherapy for post-traumatic stress disorder related to sexual assault and domestic abuse in women

Post-traumatic stress disorder is a common, chronic, and often disabling mental illness. Selective serotonin reuptake inhibitors are the usual first-line treatment for post-traumatic stress disorder, but many patients fail to respond adequately. Thus, other treatment options, including the atypical antipsychotics such as risperidone, need to be tested. Women between the ages of 19 and 64 years with post-traumatic stress disorder were enrolled. Symptom severity was rated at baseline using the Treatment Outcomes Post-traumatic Stress Disorder Scale-8, Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression, and Clinician Administered Post-traumatic Stress Disorder Scale. After washout from other psychotropic medications, 20 participants were randomized to either risperidone or placebo. Total score on the Treatment Outcomes Post-traumatic Stress Disorder Scale-8 served as the primary outcome measure. Repeated-measures analysis of variance was followed by Newman–Keuls tests. A significant main effect exists for visits using the Treatment Outcomes Post-traumatic Stress Disorder Scale-8 raw score. For the treatment group, the difference between baseline Treatment Outcomes Post-traumatic Stress Disorder Scale-8 scores and treatment visit scores was significant beginning at visit 6 and continued through visit 11. No significant difference observed between baseline and any treatment visit for the placebo group. The Clinician Administered Post-traumatic Stress Disorder Scale, Hamilton Rating Scale for Anxiety, and Hamilton Rating Scale for Depression data revealed a similar pattern. In this small pilot study, risperidone monotherapy was more effective than placebo in the treatment of post-traumatic stress disorder.

Influence of Patient Race and Ethnicity on Clinical Assessment in Patients With Affective Disorders

CONTEXT Rates of clinical diagnoses of schizophrenia in African American individuals appear to be elevated compared with other ethnic groups in the United States, contradicting population rates derived from epidemiologic surveys. OBJECTIVE To determine whether African American individuals would continue to exhibit significantly higher rates of clinical diagnoses of schizophrenia, even after controlling for age, sex, income, site, and education, as well as the presence or absence of serious affective disorder, as determined by experts blinded to race and ethnicity. A secondary objective was to determine if a similar pattern occurred in Latino subjects. DESIGN Ethnicity-blinded and -unblinded diagnostic assessments were obtained in 241 African American individuals (mean [SD] age, 34.3 [8.1] years; 57% women), 220 non-Latino white individuals (mean [SD] age, 32.7 [8.5] years; 53% women), and 149 Latino individuals (mean [SD] age, 33.5 [8.0] years; 58% women) at 6 US sites. Logistic regression models were used to determine whether elevated rates of schizophrenia in African American individuals would persist after controlling for various confounding variables including blinded expert consensus diagnoses of serious affective illness. SETTINGS Six academic medical centers across the United States. PARTICIPANTS Six hundred ten psychiatric inpatients and outpatients. MAIN OUTCOME MEASURE Relative odds of unblinded clinical diagnoses of schizophrenia in African American compared with white individuals. RESULTS A significant ethnicity/race effect (χ(2)(2)=10.4, P=.01) was obtained when schizophrenia was narrowly defined, controlling for all other predictors. The odds ratio comparing African American with non-Latino white individuals was significant (odds ratio=2.7; 95% CI, 1.5-5.1). Similar differences between African American and white individuals occurred when schizophrenia was more broadly defined (odds ratio=2.5; 95% CI, 1.4-4.5). African American individuals did not differ significantly from white individuals in overall severity of manic and depressive symptoms but did evidence more severe psychosis. CONCLUSIONS African American individuals exhibited significantly higher rates of clinical diagnoses of schizophrenia than non-Latino white subjects, even after controlling for covariates such as serious affective disorder.

The crisis of psychiatry — insights and prospects from evolutionary theory

Darwin’s emphasis on natural selection has had a transformative influence on how biological and medical sciences are conceptualized and conducted. However, the relevance of his ideas for the understanding of psychiatric conditions is still under-appreciated. Modern understanding of disease has required appreciation of the dialectical give and take between environmental influences, life history theory imperatives, human behavioral ecology, and characteristics of adaptive processes at all levels of the individual. This has enabled a better comprehension of metabolic disturbances, cancers, auto-immune disease, inherited anemias, and vulnerability to infectious disease 1. Here we propose that a contemporary and scientifically satisfying understanding of psychiatric conditions requires adopting a similar logic of inquiry, by taking into consideration the influence of environmental contingencies and natural selection in sculpting not just brain based mechanisms and processes germane to clinical neurosciences, but also diverse characteristics of behavior. One approach to understand psychiatric disorders in an evolutionary perspective builds upon Nobel laureate Nikolaas Tinbergen’s ideas, suggesting that, for a full understanding of any given phenotypic trait, one needs to detect the development and nature of its mechanisms, construed as the “proximate causes”, and, in addition, its evolutionary (or phylogenetic) history and adaptive value 2. Studying the proximate mechanisms is standard in psychiatry and the clinical neurosciences, but the questions pertaining to the phylogeny of traits have largely been ignored. Admittedly, placing dysfunctional cognitive, emotional and behavioral processes in the context of possible adaptation is not straightforward at first sight. The clinical directive requires that “disorder” represent the appropriate focus. However, a “disorder” – by definition – is counter-intuitive in the context of adaptation. By adaptation we mean a genetically-mediated structural or behavioral trait, which when possessed, increased survival and reproductive success in the environment in which the trait evolved. Were psychiatry’s focus be placed on “traits” (i.e., cognitive processes, emotions, and behaviors), problems which are clinically relevant could more satisfactorily be understood as distorted expression of mechanisms that in earlier environments provided answers to problems of adaptive significance, but which currently interfere in light of prevailing environmental contingencies 3. Important to the understanding of a particular phenotype is the evolutionary concept of variation. Without variation, no evolution by natural selection could take place. Mainstream psychiatry has largely ignored the fact that variation is the rule, not the exception, and this creates conceptual tensions. Psychiatry conceptualizes “disorder” as a statistical deviation from a normative statistical mean, yet handles it as a category. In other words, both “normalcy” as well as “disorder” with regard to psychological or behavioral functioning are burdened with the connotation of low variation. Phenotypic variation is the result of a complex interplay of genotype and environment, including epigenetic mechanisms that are decisively shaped by experience over the individual lifespan. These issues translate to providing a clinician with a rationale for explaining why, how, and when adaptive behavior is compromised and constrained; that is, when social, cultural, or ecological conditions and circumstances pose hindrances or risks which interfere with achievement of best solutions to socio-biological problems, and which may require a modification of a strategy of coping, selection of an alternative strategy, and/or the setting of more realistic biological goals. This integrative view of psychopathology, we believe, can have profound effects on how psychiatry conceptualizes disorders, which shall be illustrated briefly in three examples.

Neuropeptides: relevance in treatment of depression and anxiety disorders.

The etiology and pathophysiology of both depression and anxiety remain unclear, but involve dysfunctional monoaminergic neurotransmission and function. The currently available antidepressant medications that work through optimizing the monoaminergic system are often limited by their lack of efficacy or their adverse effects. There is increasing evidence that some neuropeptides, including substance P, corticotropin-releasing factor, neuropeptide Y, vasopressin and galanin, may have relevance in both depression and anxiety. Integration of anatomical, physiological and clinical evidence suggests that modulation of monoaminergic transmission is the most likely mechanism by which neuropeptides may work in these disorders. These neuropeptides and their receptors may serve not only as potential therapeutic targets for treatment of depression and anxiety, but may also help enhance our understanding of the psychopathology of these two major psychiatric disorders.

Comparison of SGA Oral Medications and a Long-Acting Injectable SGA: The PROACTIVE Study

Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physicians choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials.

Child and adolescent schizophrenia: pharmacological approaches

Background: Childhood-onset schizophrenia is a serious, chronic and disabling illness that can significantly affect the quality of life of the affected individuals and their families. The affected children commonly show significant premorbid developmental impairment and social abnormalities that may provide an early clinical clue to pursue treatment. Until recent times, treatment approaches for childhood schizophrenia were derived from the adult population. However, given the unique developmental challenges in the pediatric population, this extrapolation may not hold true. Objective: This review encompasses and elaborates on the efficacy, safety and tolerability data available at present for both typical and atypical antipsychotics for treatment of childhood schizophrenia. Method: A literature search was conducted on PUBMED with special emphasis on double-blind placebo-controlled studies in childhood schizophrenia. Data from similar studies presented in recent meetings were also added to the review. Conclusions: Recent research in pediatric psychopharmacology has led to the Food and Drug Administrations approval of two atypical antipsychotics for the treatment of schizophrenia. Although data in this age group are still sparse, research in this unique population has grown over the years.