The relationship of akathisia with suicidality and depersonalization among patients with schizophrenia.

An association of suicidality and depersonalization with akathisia has been reported, but it is not clear whether these phenomena are specific to akathisia or are nonspecific manifestations of distress. The authors used the Barnes Akathisia Rating Scale, Brief Psychiatric Rating Scale, and Hamilton Rating Scale for Depression (Ham-D) to examine the relationships between suicidality, depersonalization, dysphoria, and akathisia in 68 patients with schizophrenia or schizophreniform disorder. Akathisia was associated with higher scores on the Ham-D ratings of suicidality, depersonalization, and agitation. In a logistic regression model, depressive mood and subjective awareness of akathisia appeared to be the only predictors of suicidality and depersonalization, respectively. These findings support the association between akathisia and both suicidality and depersonalization. However, these symptoms appear to be nonspecific responses to accompanying depressive mood and the subjective awareness of the akathisia syndrome, respectively.

Caregiver report of hallucinations and paranoid delusions in elders aged 70 or older.

This study examined the demographic, medical, and psychiatric correlates of hallucinations and paranoid delusions reported by proxy informants for 822 elders aged 70 or older. This sample comprised people who were deemed unable to complete a direct interview in a large nationwide study of aging. Marital status, trouble with vision, and cognitive impairment were associated with report of both paranoid delusions and hallucinations. Depressive symptoms and stroke were associated with hallucinations only. These results suggest that inadequate external stimulation in the elderly leads to psychotic experiences.

Unilateral vs. bilateral ultrasound in the monitoring of cerebral microemboli.

We used bilateral transcranial Doppler to monitor the number of microembolic events (ME) in the left and right middle cerebral arteries of 29 patients during cardiac surgery that required extracorporeal circulation. Based on a previously published study, we hypothesized that the commonly used method of doubling unilateral ME counts to obtain an estimated bihemispheric load would result in significant errors of estimation. In our sample, estimated bihemispheric counts were inaccurate by an average of 18% (range 0--80%). Despite this large range of error, calculation of Cronbach's alpha revealed that actual error due to unreliability (4%) was small relative to the large variation in ME counts across subjects in this patient series. These findings suggest that unilateral monitoring is sufficient when the goal is to characterize a given subject's ME load within the context of the other subjects in the sample. However, when precise ME counts are required, bilateral monitoring is essential.

The association between risk factors for tardive dyskinesia and phenylalanine-induced abnormal movements in schizophrenia.

We examined whether an oral challenge dose of the amino acid phenylalanine (a dopamine precursor) exacerbates the abnormal movements of tardive dyskinesia (TD). We also examined age, gender, treatment duration, and baseline movement severity in relation to phenylalanine-induced changes in movements. Lastly, we assessed the influence of fasting amino acid levels on phenylalanine-induced movements. In a placebo-controlled fashion, the abnormal involuntary movement scale (AIMS) was obtained on 25 patients before and after a phenylalanine challenge drink. A general linear model determined the relative effects of age, gender, treatment duration, and fasting amino acid levels on the magnitude of induced movements. Age and treatment duration did not affect phenylalanine-induced movements. Lower fasting levels of phenylalanine were associated with greater movements after controlling for age, F = 11.89, p < 0.003. The severity of abnormal movements at baseline also predicted response to phenylalanine, F = 8.62, p = 0.0079. Brain amino acid and neurotransmitter pools are influenced by changes in dietary protein, which may have implications in the development and prevention of movement disorders. This study suggests that fasting amino acid levels may predict differences in vulnerability to movements during an influx of neurotransmitter precursors, perhaps due to long-term compensatory changes in receptor sensitivity. Copyright 2001 John Wiley & Sons, Ltd.

Acute marijuana effects on rCBF and cognition: a PET study.

The effects of smoking marijuana on cognition and brain function were assessed with PET using H2(15)O. Regional cerebral blood flow (rCBF) was measured in five recreational users before and after smoking a marijuana cigarette, as they repeatedly performed an auditory attention task. Blood flow increased following smoking in a number of paralimbic brain regions (e.g. orbital frontal lobes, insula, temporal poles) and in anterior cingulate and cerebellum. Large reductions in rCBF were observed in temporal lobe regions that are sensitive to auditory attention effects. Brain regions showing increased rCBF may mediate the intoxicating and mood-related effects of smoking marijuana, whereas reduction of task-related rCBF in temporal lobe cortices may account for the impaired cognitive functions associated with acute intoxication.

Clinical features characterizing young-onset and intermediate-onset schizophrenia.

Late-onset schizophrenia has been noted to have distinct clinical characteristics. The authors compared symptom characteristics between early- and intermediate-onset patients (N = 259) to determine whether clinical features distinguished differences within younger populations. On global measures of psychotic, disorganized, and negative symptoms, early-onset patients had greater disorganized and negative symptoms but did not differ in hallucinations and delusions. The dichotomy of early vs. late onset may extend to a younger population, reflecting a more continuous influence.

Donepezil in the treatment of cognitive dysfunction associated with traumatic brain injury.

Cholinesterase inhibitors are known to enhance cognitive function among patients with dementia of the Alzheimer's type. It is quite possible that this clinical benefit may extend to other patient groups, yet this issue awaits further exploration. This study examines the use of the cholinesterase inhibitor donepezil in the treatment of patients with a history of brain injury and subsequent cognitive impairment. The sample was comprised of 53 ambulatory psychiatric patients who were receiving care for psychiatric sequelae of brain injury. In this sample, residual cognitive impairment was treated with adjunctive donepezil. This study reports the clinical assessments of this patient sample in outpatient follow-up for up to two years duration. Assessments of cognition with the Wechsler Adult Intelligence Scale-Revised and the Hooper Visual Organization Test were obtained on a subset of this sample (N = 22). Clinician assessment ratings were analyzed for the entire sample. Results indicated an improvement in full-scale IQ (t = 2.5, p = 0.02) score as well as clinician-based ratings (t = 12.2, p < 0.0001). Further research will likely delineate whether specific types of brain injuries are most responsive to cholinesterase inhibitors. These findings suggest that donepezil may enhance clinical response by complementing the medication management of other concomitant psychiatric disturbances related to brain injury.

Association between cytochrome P4502D6 (CYP2D6) genotype, antipsychotic exposure, and abnormal involuntary movement scale (AIMS) score.

Antipsychotic metabolism cosegregates with the polymorphic cytochrome P4502D6 (CYP2D6) hepatic enzyme. Approximately 5-10% of Caucasians show impaired metabolism associated with nonfunctional alleles. Genotyping determines the number of functional alleles, which is phenotypically not possible. The aim of this study was to investigate associations between CYP2D6 genotype, antipsychotic exposure, and abnormal involuntary movement scale (AIMS) score. Schizophrenic patients (DSM-IV) were genotyped for CYP2D6*1, *3, and *4 alleles by nested polymerase chain reaction. A complete history, including psychiatric symptoms, medications and AIMS score was obtained. Antipsychotic exposure was recorded in dose years [(chlorpromazine equivalents x years)/100]. A linear regression model used AIMS scores as the dependent variable. Genotype, gender, antipsychotic exposure, and interactions were independent variables. The results of the 31 patients studied showed: 20 were homozygous for the *1 allele (*1/*1) and 11 were heterozygous for the *1 allele (i.e. *1/*3 or *4). Age, sex, age of onset, treatment duration, antipsychotic exposure, and AIMS scores did not differ between groups. The interaction between dose years and genotype was significant (P < 0.0055), demonstrating that for (*1/*1) patients, the magnitude of antipsychotic exposure had a greater effect on AIMS score (slope = 0.044) compared with (*1/*3 or *4) patients (slope = 0.001). These results suggest patients with a *3 or *4 allele may have a higher risk for developing antipsychotic induced abnormal movements.

Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study.

OBJECTIVE: This study compared nortriptyline and fluoxetine with placebo in the treatment of depression and in recovery from physical and cognitive impairments after stroke. METHOD: A total of 104 patients with acute stroke enrolled between 1991 and 1997 entered a double-blind randomized study comparing nortriptyline, fluoxetine, and placebo over 12 weeks of treatment. The majority of patients were recruited from a rehabilitation hospital in Des Moines, Iowa, but other enrollment sites were also used. Both depressed and nondepressed patients were enrolled to determine whether improved recovery could be mediated by mechanisms unrelated to depression. Nortriptyline in doses of 25 mg/day gradually increased to 100 mg/day or fluoxetine in doses of 10 mg/day gradually increased to 40 mg/day or identical placebo were given over 12 weeks. Response to treatment of depression for individual patients was defined as a greater-than-50% reduction in scores on the Hamilton Rating Scale for Depression and no longer fulfilling diagnostic criteria for major or minor depression. Improved recovery for a treatment group was defined as a significantly higher mean score from baseline to end of the treatment trial, compared with patients treated with placebo, on measures of impairment in activities of daily living and levels of cognitive and social functioning. RESULTS: Nortriptyline produced a significantly higher response rate than fluoxetine or placebo in treating poststroke depression, in improving anxiety symptoms, and in improving recovery of activities of daily living as measured by the Functional Independence Measure. There was no effect of nortriptyline or fluoxetine on recovery of cognitive or social functioning among depressed or nondepressed patients. Fluoxetine in increasing doses of 10-40 mg/day led to an average weight loss of 15. 1 pounds (8% of initial body weight) over 12 weeks of treatment that was not seen with nortriptyline or placebo. CONCLUSIONS: Given the doses of medication used in this study, nortriptyline was superior to fluoxetine in the treatment of poststroke depression. Demonstrating a benefit of antidepressant treatment in recovery from stroke may require the identification of specific subgroups of patients, alternative measurement scales, or the optimal time of treatment.

Age-related changes in regional cerebral blood flow among young to mid-life adults.

Using PET with [(15)O]H2O, we examined age in relation to regional cerebral blood flow (rCBF) among young to mid-life adults. Previous work has largely contrasted rCBF between young and elderly age groups dichotomously. This study maps the continuum of normal age-related changes in rCBF from early to mid-adulthood. We obtained images from 37 healthy volunteers between 19 and 50 years of age during an eyes-closed resting baseline condition. There was a negative correlation between age and rCBF in mesial frontal cortex, involving the anterior cingulate region (r = 0.63, p<0.001). These findings reflect differences in the distribution of rCBF evident in early to mid-adulthood that may be associated with subsequent changes in memory and executive functioning in later life.

Schizophrenia.

Schizophrenia is among the most severe and debilitating of psychiatric disorders. Diagnosis is currently by criterion-based systems, including positive (eg, hallucinations and delusions) and negative (eg, avolition and alogia) symptoms. The importance of negative symptoms in the course and outcome of the illness is increasingly being studied. Current research seeks to detect causal mechanisms in schizophrenia through studies of neural connectivity and function, as well as models of genetic transmission, such as polygenic models of inheritance in genetic research. Potential genes have been identified that may confer vulnerability to the illness, perhaps in conjunction with environmental factors. Neuroimaging research with magnetic resonance imaging and positron emission tomography has investigated differences in volumes and functional dysregulation in specific neural subregions. Areas studied include the frontal and temporal cortex, the hippocampus, the thalamus, and the cerebellum. Despite these advances, treatment of symptoms and psychosocial and cognitive impairments remains only partially successful for many patients.

Quantitative in vivo measurement of gyrification in the human brain: changes associated with aging.

Clinical observation suggests that the aging process affects gyrification, with the brain appearing more 'atrophic' with increasing age. Empirical studies of tissue type indicate that gray matter volume decreases with age while cerebrospinal fluid increases. Quantitative changes in cortical surface characteristics such as sulcal and gyral shape have not been measured, however, due to difficulties in developing a method that separates abutting gyral crowns and opens up the sulci -- the 'problem of buried cortex'. We describe a quantitative method for measuring brain surface characteristics that is reliable and valid. This method is used to define the gyral and sulcal characteristics of atrophic and non-atrophic brains and to examine changes that occur with aging in a sample of 148 normal individuals from a broad age range. The shape of gyri and sulci change significantly over time, with the gyri becoming more sharply and steeply curved, while the sulci become more flattened and less curved. Cortical thickness also decreases over time. Cortical thinning progresses more rapidly in males than in females. The progression of these changes appears to be relatively stable during midlife and to begin to progress some time during the fourth decade. Measurements of sulcal and gyral shape may be useful in studying the mechanisms of both neurodevelopmental and neurodegenerative changes that occur during brain maturation and aging.

Social environment and longevity in schizophrenia.

OBJECTIVE: The role of social support as a predictor of long-term survival among patients with schizophrenia was examined. METHODS: Social histories were abstracted from the medical records of a cohort of 133 deceased schizophrenic patients admitted for inpatient treatment between 1934 and 1944. Two independent raters assessed the quantity and quality of support available in each patient's social environment. RESULTS: Cox regression analysis revealed that higher quantity of social support was significantly related to survival time (p<.05) after controlling for marital status and quality of support. The Cox model indicated that a 1-point increase in the support quantity rating was associated with a proportional 25% decrease in the hazard rate. CONCLUSIONS: The present findings suggest that social environment, specifically the quantity of social support available to the patient, may impact longevity in psychiatric populations.

Impaired glucose tolerance and abnormal movements in patients with schizophrenia.

OBJECTIVE: Diabetes mellitus has been implicated as a risk factor for tardive dyskinesia. The authors examined the association between abnormal movements and impaired glucose metabolism, which often precedes the development of overt diabetes, in patients with schizophrenia. METHOD: Twenty-one patients with DSM-IV schizophrenia receiving neuroleptic medication were given oral glucose tolerance tests involving serial glucose and insulin levels. These values were analyzed in relationship to abnormal involuntary movement ratings. RESULTS: Patients with impaired glucose tolerance had higher mean abnormal movement scores than those without glucose intolerance, but this difference was not statistically significant. There was, however, an association between the magnitude of the fasting insulin level and abnormal movements after the authors controlled for fasting glucose level. Additionally, the fasting glucose level predicted abnormal movements after the authors controlled for age. CONCLUSIONS: Hyperinsulinemia and hyperglycemia associated with insulin resistance may potentially contribute to the pathogenesis of tardive dyskinesia. Findings from this small cross-sectional study suggest a possible relationship that requires clarification through larger, longitudinal studies.

Generalized anxiety and depression. Assessment over 2 years after stroke.

The authors examined the course of anxiety up to 2 years after stroke in relation to depressive symptoms, impairment in activities of daily living (ADLs), and social functioning. One hundred forty-two patients were evaluated at 3, 6, 12, and 24 months after stroke. Anxiety was associated with greater depression severity at all follow-up visits. Depression severity was associated with impairment in ADLs at followup; association of anxiety and impairment in ADLs was present only at the intake visit, with independent effects only for women. Women reported more symptoms of both anxiety and depression during the 2-year period. Younger patients reported more anxiety symptoms, but there was no difference between age-groups in depressive symptoms. Severity of anxiety was also related to higher depression scores at initial hospitalization, but not in the remainder of the 2-year period. In summary, anxiety is associated with increased severity of depressive symptoms and greater impairment in function primarily during the acute hospitalization period. Women and younger patients also may be more vulnerable to anxiety after stroke.

Heart rate variability before and after treatment with electroconvulsive therapy.

It has been suggested that depression may be associated with decreased parasympathetic activity. Based on this work, we tested the hypothesis that treatment of depression with electroconvulsive therapy (ECT) would result in a relative increase in cardiac vagal (parasympathetic) activity. Changes in respiratory sinus arrhythmia, a marker of cardiac parasympathetic activity, were examined in nine patients with depressive episodes before and after ECT using spectral analysis. Hamilton Depression Rating Scale scores decreased significantly. In terms of the heart rate measures, RR interval tended to decrease and the amplitude of respiratory sinus arrhythmia decreased significantly following the course of ECT. This reduction in respiratory sinus arrhythmia contributed to the overall decrease in RR interval variability. Additionally, the magnitude of symptom improvement as measured by the Hamilton Scale correlated with the decrease in amplitude of the respiratory sinus arrhythmia. We report that treatment of depression with ECT was associated with a relative decrease in parasympathetic activity, in contrast to our initial hypothesis of a relative increase. This finding may not be related to the ECT per se but rather to the resolution of depression, as there was a significant correlation between the decrease in Hamilton Depression Rating Scale scores and decrease in parasympathetic activity. Further work is necessary to better understand the autonomic changes associated with depressive illness and the clinical risks and benefits associated with various treatment modalities.