Persistent infection with neurotropic herpes viruses and cognitive impairment.

BACKGROUND: Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens. RESULTS: PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (ß = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status. CONCLUSIONS: Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen and tetrahydroindenoindole.

OBJECTIVE: In mice and in humans, treatment with the second-generation antipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metabolic complications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet, a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by the antioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII to prevent metabolic changes in mice receiving OLZ. DESIGN AND MEASUREMENT: C57BL/6J mice received either a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg(-1) body weight), alone or with APAP (30 mg kg(-1) body weight) or THII (4.5 mg kg(-1) body weight), for 10 weeks. Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidative stress, were examined. RESULTS: OLZ treatment doubled the HF diet-induced increases in body weight and percent body fat. These increases were partially prevented by both APAP and THII, although food consumption was constant in all groups. The THII protection was associated with an increase in whole body and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HF diet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulin resistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipid peroxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation, NADPH-dependent O(2) uptake and H(2)O(2) production, which were further exacerbated by OLZ. APAP, THII and the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress in WAT. CONCLUSIONS: We conclude that both APAP and THII intervene in the development of obesity and metabolic complications associated with OLZ treatment.

Linkage analysis of schizophrenia in African-American families.

While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SIBPAL) and (2) treating only affected individuals as informative (using the program MERLIN). We also explore three definitions of affected status: narrowly defined schizophrenia; one broadened to include schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26 cM; SIBPAL p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48 cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73 cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27 cM; p from 0.0022 to 0.0000003); MERLIN results support the significance of the SIBPAL results (p=0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia.

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles.

Atypical antipsychotic drugs offer several notable benefits over typical antipsychotics, including greater improvement in negative symptoms, cognitive function, prevention of deterioration, and quality of life, and fewer extrapyramidal symptoms (EPS). However, concerns about EPS have been replaced by concerns about other side effects, such as weight gain, glucose dysregulation and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may eventually lead to clinical deterioration. Despite a greater understanding of the biochemical effects of these drugs in recent years, the pharmacological mechanisms underlying their various therapeutic properties and related side effects remain unclear. Besides dopamine D(2) receptor antagonism, a characteristic feature of all atypical antipsychotic drugs, these agents also bind to a range of non-dopaminergic targets, including serotonin, glutamate, histamine, alpha-adrenergic and muscarinic receptors. This review examines the potential contribution of different receptors to metabolic side effects associated with atypical antipsychotic treatment for all seven agents currently marketed in the United States (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and clozapine) and another agent (bifeprunox) in clinical development at the time of this publication.

The case for long-acting antipsychotic agents in the post-CATIE era.

OBJECTIVE: Long-acting antipsychotic agents were developed to promote treatment compliance in patients requiring maintenance treatment for schizophrenia. METHOD: An analysis of the impact of non-compliance on treatment outcomes in schizophrenia and the advantages and disadvantages of long-acting antipsychotics. RESULTS: Partial or total non-compliance with oral antipsychotics remains widespread and is associated with significant increases in the risk of relapse, rehospitalization, progressive brain tissue loss and further functional deterioration. Long-acting agents have the potential to address issues of all-cause discontinuation and poor compliance. The development of the first long-acting atypical antipsychotic, which appears to be effective and well tolerated, should further improve the long-term management of schizophrenia. CONCLUSION: Long-acting agents represent a valuable tool for the management of schizophrenia and merit wider use, especially in light of emerging literature regarding the neuroprotective advantages of atypical antipsychotics over conventional agents in terms of regenerating brain tissue during maintenance therapy.

Iatrogenic disorders associated with conventional vs. atypical antipsychotics.

Pharmacotherapy is an indispensable component of the management of schizophrenia and related psychotic disorders. Antipsychotic drugs are used for their efficacy in controlling the symptoms of psychosis. However, the side effects of antipsychotic drugs can have a deleterious impact on the course of the illness by inducing iatrogenic symptoms of various severity. The side effects of first-generation or conventional antipsychotic drug were often so intolerable to patients with schizophrenia that their compliance was consistently poor, leading to frequent relapse, chronicity, and impaired functioning. The second-generation (atypical) antipsychotics, introduced 40 years after the advent of the older-generation, are proving to have better outcomes in psychosis not only because of broader symptom efficacy but also because their side-effect profile is more tolerable, leading to higher compliance and fewer relapses. The authors review the side effects of the old and the new antipsychotics and conclude that the improved tolerability of the new antipsychotics is associated with greater effectiveness, not just efficacy. Differences in tolerability among the new antipsychotics are described.

Neuropsychological correlates of negative, disorganized and psychotic symptoms in schizophrenia.

Recent studies suggest that three dimensions (negative, disorganized and psychotic) categorize schizophrenic symptoms. A developing literature indicates distinct cerebral correlates of each symptom cluster, but few investigations have determined their neuropsychological correlates. In the present study, the Schedules of Negative and Positive Symptoms measured symptom severity in 62 schizophrenics, and a subsequent principal components analysis revealed three symptom dimensions. Factor scores, age and parental socio-economic status were simultaneously entered into regression equations to explain variance across a broad neuropsychological test battery. Negative symptoms were associated with deficits involving intelligence, executive function, memory, sustained-attention and sensory-motor function, whereas disorganized symptoms correlated with decreased intelligence, attention-span and sensory-motor function. Psychotic symptoms were unrelated to deficits. These data are consistent with hypotheses that these three symptom dimensions have distinct neurobehavioral correlates.

Clinical correlates of response to valproate in geriatric inpatients.

The efficacy of valproate for the management of adults with bipolar disorder has been repeatedly demonstrated in several studies. Patients with mixed states, rapid cycling, and EEG abnormalities have been shown to respond favorably to valproate. Valproate is also being increasingly used in disorders with aggressive or agitated features, such as the behavioral disorders of dementia; yet, few studies have documented the utility of valproate in geriatric patients. The need to document safe and effective pharmacologic agents to treat geriatric mood and behavioral disorders continues to increase with the growing elderly population. We conducted a retrospective study of the use of valproate in patients consecutively hospitalized over a 5-year period on a psychiatric unit. Thirty-nine patients over age 60 were identified and then categorized into non-, partial, and full responders based on Clinical Global Impression ratings. Information on diagnosis, age, valproate dose and serum concentration, psychiatric symptoms, medical comorbidity, concurrent psychotropic medications, and side effects was collected. Results suggest that responders to valproate (full or partial) over the age of 60 years were more likely to be female, younger, carry a diagnosis of bipolar disorder, and achieve higher serum valproate concentrations. Full responders had fewer psychotic symptoms but usually displayed manic symptoms. The date of this study suggests the need for controlled clinical trials to clarify the utility and clinical predictors of response to valproate in the geriatric population.

Postpartum mood disorders: clinical perspectives.

Mood disorders are common in women. A prepregnancy personal history of mood disorder (bipolar or major depression), premenstrual syndrome, or (possibly) postpartum blues places a woman at high risk for a postpartum exacerbation of symptoms. Untreated or unrecognized postpartum mood disorders can lead to serious psychologic and social consequences, in some cases even leading to suicide or infanticide. Women at risk for postpartum mood disorders need to be referred for psychiatric consultation before pregnancy and parturition. Informed, professional collaboration offers the best opportunities for prevention, as well as the earliest recognition and treatment of emergent symptoms.

Cognitive deficits distinguish patients with adolescent- and adult-onset schizophrenia.

Recent studies have shown that patients with schizophrenia who have an adolescent-symptom onset (before age 21) have a worse clinical course and greater frequency of cerebral abnormalities than those with an adult-onset (after age 25). However, little is known about the neuropsychological functioning of these groups. A comprehensive neuropsychological examination was administered to groups of patients with schizophrenia with either an adolescent- or adult symptom-onset and a healthy control group. The adolescent-onset group performed worse than the adult-onset and control groups, particularly on measures of memory and executive function. The adult-onset group also performed worse than the controls, but to a lesser extent than did the adolescent-onset group. Results are discussed with reference to hypotheses that adolescent-onset schizophrenia represents a distinct neurodevelopmental disease entity.

The volume of the entorhinal cortex in schizophrenia: a controlled MRI study.

1. The entorhinal cortex (EC), part of the limbic temporal lobe, is a critical link between the cerebral cortex and the hippocampus, and is considered one of the most important cortical "association" areas. Several postmortem abnormalities in the EC have been reported. 2. Here, the authors report the first in vivo study of the volume of the EC in schizophrenia using magnetic resonance imaging (MRI) scans. 3. The authors compared 57 schizophrenic patients and 35 healthy controls. No overall difference in the mean EC volume was found between controls and schizophrenic patients, but there was a strong trend (p = .078) for the schizophrenic females to have a large mean EC than control females and for the early onset schizophrenia group to have a smaller (EC (p = .07) than late onset schizophrenia subjects. 4. The implications of the findings are discussed.

Evoked potentials in subjects at risk for Alzheimer's disease.

Evoked potential (EP) changes accompanying dementing processes have been documented in a number of studies. However, EPs have not been studied in subjects who are at heightened risk for the development of Alzheimer's Disease (AD). Nineteen volunteers with no immediate family members with a history of AD and 33 healthy subjects with at least one first-degree relative with AD were studied. Of the 33 subjects with a positive family history of AD, the illness of the sick relative was classified as possible AD in 10 subjects, probable AD in 17 subjects, and definite (autopsy-proven) AD in 6 subjects. Mid-latency evoked potentials (P50, N100, and P200) and P300 event-related potentials were recorded in an oddball paradigm. The amplitudes of the P50 responses to the frequent stimuli and of the P300 responses were significantly higher in the subjects whose relatives had definite AD as compared with the other three groups. The amplitude of the N100 component was also larger in the same group, but the difference was only statistically significant from the group of healthy volunteers without a family history of AD. A process of increased sensitivity to incoming stimuli may be reflected in the increased P50, N100, and P300 amplitudes in the subjects at increased risk for developing AD.

The P50 evoked potential component and mismatch detection in normal volunteers: implications for the study of sensory gating.

Sensory gating is a complex, multistage, multifaceted physiological function believed to be protecting higher cortical centers from being flooded with incoming irrelevant sensory stimuli. Failure of such mechanisms is hypothesized as one of the mechanisms underlying the development of psychotic states. Attenuation of the amplitude of the P50 evoked potential component with stimulus repetition is widely used to study sensory gating. In the current study, we investigated the responsiveness of the P50 component to changes in the physical characteristics of ongoing trains of auditory stimuli. Forty normal volunteers were studied in a modified oddball paradigm. At all cerebral locations studied, P50 amplitudes were higher in response to infrequent stimuli. We postulate that the increase in P50 amplitude reflects the system's recognition of novel stimuli or "gating in" of sensory input. The ratio of the amplitude of the responses to the infrequent stimuli to those of the frequent stimuli was significantly higher for the posterior temporal regions. This finding provides further evidence that the temporal lobes may be significantly involved in sensory gating processes. Although this study only included normal subjects, the data generated contribute to the understanding of sensory gating mechanisms that may be relevant to psychotic states.

Impact of desertification on temperature trends in the Middle East.

The intense interest in desertification and climate change has stimulated detailed studies of temperature records in many areas of the world. In this investigation, the temperature records from the Middle East region are analyzed over the period 1950-1990. Results reveal a linear, statistically significant temperature increase of 0.07 °C/decade over the 41-year period. An analysis of spatial controls on these temperature changes reveals a warming effect associated with both overgrazing and the degree of human-induced desertification. The results of this study are consistent with theoretical and empirical studies predicting and demonstrating a warming signal associated with these land surface changes in the world's dryland areas.

Neuropsychological performance and CD4 levels in HIV-1 asymptomatic infection.

The performance of 68 HIV-1 seropositive asymptomatic (HIV+) subjects stratified on CD4 levels were compared with 82 HIV-1 seronegative (HIV-) subjects on a battery of neuropsychological, mood state, and perceived health status measures. The neuropsychological test battery included measures of attention, reaction time, memory, intellectual ability, psychomotor speed, frontal lobe or "executive" function, and decision time. None of the HIV+ subjects were taking antiviral agents. The groups did not differ for age, mood state, or WAIS-R Verbal and Performance IQ scores. Due to group differences for education and weekly ethanol consumption, both variables were used as covariates in multivariate analyses of variance. Relatively few differences were observed between subgroups of HIV+ patients or between these subgroups and control subjects. These data suggest that factors other than absolute levels of immunosuppression as expressed by CD4 levels alone, appear to be responsible for the deficits observed in HIV+ asymptomatic patients.

Proton magnetic resonance spectroscopy (1H MRS) of the hippocampal formation in schizophrenia: a pilot study.

BACKGROUND: Recent post-mortem and magnetic resonance imaging (MRI) studies strongly suggest a decrease in the volume of the hippocampus and other limbic temporal structures in schizophrenia. Therefore, we hypothesised that N-acetyl aspartate (NAA) which is found mainly in neurons and which can be measured by proton magnetic resonance spectroscopy (1H MRS) would be decreased in the limbic temporal region in schizophrenia. METHOD: Consenting subjects fulfilling DSM-III-R criteria for schizophrenia (n = 11) and matched healthy volunteers (n = 11) who were recruited in a tertiary university referral centre, participated in a 1H MRS brain study. Proton MRS spectra were obtained from a 12 cm3 voxel (2 x 2 x 3 cm) in the right and left hippocampus/amygdala region. A researcher blind to the source of the spectra, measured the NAA intensity in all subjects, which were then statistically compared across the two groups. RESULTS: NAA intensities were significantly reduced in the right hippocampus/amygdala region of schizophrenic patients (P = 0.038). The difference of the left side did not reach significance at the 95% confidence level. CONCLUSIONS: The findings of decreased NAA in this study suggest that there may be a decrement in neuronal number or tissue volume of the right hippocampal/amygdala region in schizophrenia. Biochemical alterations in the metabolism of NAA in schizophrenia may be an alternative explanation. The findings are consistent with other types of post-mortem and in vivo evidence for hypoplasia of the limbic temporal structures in schizophrenia, postulated to be of neurodevelopmental pathogenesis.