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.

Heritability of functioning in families with schizophrenia in relation to neurocognition.

UNLABELLED: The role of daily functioning is an integral part of the schizophrenia (SZ) phenotype and deficits in this trait appear to be present in both affected persons and some unaffected relatives; hence we have examined its heritability in our cohort of African American schizophrenia families. There is now ample evidence that deficits in cognitive function can impact family members who are not themselves diagnosed with SZ; there is some, but less evidence that role function behaves likewise. We evaluate whether role function tends to "run in families" who were ascertained because they contain an African American proband diagnosed with SZ. METHODS: We analyzed heritability for selected traits related to daily function, employment, living situation, marital status, and Global Assessment Scale (GAS) score; modeling age, gender, along with neurocognition and diagnosis as covariates in a family based African-American sample (N=2488 individuals including 979 probands). RESULTS: Measures of role function were heritable in models including neurocognitive domains and factor analytically derived neurocognitive summary scores and demographics as covariates; the most heritable estimate was obtained from the current GAS scores (h2=0.72). Neurocognition was not a significant contributor to heritability of role function. CONCLUSIONS: Commonly assessed demographic and clinical indicators of functioning are heritable with a global rating of functioning being the most heritable. Measures of neurocognition had little impact on heritability of functioning overall. The family covariance for functioning, reflected in its heritability, supports the concept that interventions at the family level, such as evidenced-based family psychoeducation may be beneficial in schizophrenia.

Beyond the facts in schizophrenia: closing the gaps in diagnosis, pathophysiology, and treatment.

BACKGROUND: Although schizophrenia has been considered a distinct disease entity for the past century, its precise definition and etio-pathophysiology remain obscure and its treatment remains unsatisfactory. In this review, we summarize our state of knowledge about the etiology, pathophysiology, clinical features, and treatment of schizophrenia. METHODOLOGICAL ISSUES: The inadequacy of the major conceptual models of schizophrenia is a major roadblock in providing a coherent explanation for the known facts of this illness, despite these limitations and its changing definitions, the construct of schizophrenia does convey useful information: (i) patients diagnosed as having schizophrenia do have a real disease--they experience both suffering and disability; (ii) a diagnosis of schizophrenia does suggest a distinctive clinical profile--a characteristic long-term course; an admixture of positive, negative, and cognitive symptoms; (iii) a diagnosis of schizophrenia has clear treatment and prognostic implications--likelihood of benefit from antipsychotic treatment and likelihood of incomplete recovery; and (iv) schizophrenia satisfies criteria for a valid diagnostic entity better than almost any other psychiatric diagnosis. DISCUSSION: On the other hand, the concept of schizophrenia has serious shortcomings. First, it is not a single disease entity--it has multiple etiological factors and pathophysiological mechanisms but common phenotypic features. Second, its clinical manifestations are so diverse that its extreme variability has been considered by some to be a core feature. Third, its boundaries remain ill defined and not clearly demarcated from other clinical entities. CONCLUSIONS: A necessary next step is to deconstruct schizophrenia as an entity into component dimensions--endophenotypes linked to unique etiological and pathophysiological processes that may yield unique treatment targets. Innovative approaches are needed to elucidate the biological substrates of these entities because such clarity is vital for replicable research. We conclude by identifying the critical gaps in our knowledge, and unmet needs in our approaches to care, and outline steps that can move the field forward.

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.

A review of the effect of atypical antipsychotics on weight.

Controlled research trials have shown that atypical antipsychotics have important advantages over standard antipsychotics, including a broader spectrum of efficacy and improved tolerability profile, particularly with regard to neurological adverse events such as extrapyramidal symptoms (EPS). Some atypical antipsychotics, however, tend to cause significant weight gain, which may lead to poor compliance and other adverse health effects. The mechanisms involved in antipsychotic drug-related weight gain are as yet uncertain, although serotoninergic, histaminic, and adrenergic affinities have been implicated along with other metabolic mechanisms. The atypical antipsychotics vary in their propensity to cause weight change with long-term treatment. Follow-up studies show that the largest weight gains are associated with clozapine and olanzapine, and the smallest with quetiapine and ziprasidone. Risperidone is associated with modest weight changes that are not dose related. Given the equivalent efficacy of atypical antipsychotics, weight-gain profile is a legitimate factor to consider when constructing an algorithm for treatment due to the serious medical consequences of obesity.

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.

Auditory evoked potentials, clinical vs. research applications.

Evidence of abnormal auditory evoked potentials (EPs) in patients suffering from schizophrenia has been accumulating. In spite of the magnitude of the EPs in schizophrenia literature, EPs have not been found to be clinically useful thus far. In this study we attempted to replicate the findings in a large sample of schizophrenia patients, and describe how auditory EPs may be used as supplemental tests in the differential diagnostic process. Five subject groups were formed; paranoid (PAR) and disorganized/undifferentiated (disorg/undiff) schizophrenics, schizoaffective (SA), bipolar, and a normal control group. All patients were stable on medications. Subjects underwent one EP recording session. Classification and regression trees (CART) based on EP amplitudes were used to classify subjects into subgroups. The optimal Bayes classification rule that minimizes the expected misclassification cost was then constructed for various misclassification cost functions. In a standard 'Odd Ball' paradigm the N100 amplitudes were significantly decreased in the disorg/undiff group than in the bipolar or normal subjects. The P200 amplitude was smaller in the PAR, disorg/undiff and the SA groups than in the normal controls. Both the disorg/undiff and the PAR groups had significantly lower P300 amplitudes than the normal controls. Classification rules used to classify subjects into normal or ill were sensitive to the relative cost of misclassifying a subject, as well as the prior clinical probability that this subject was ill. Our data largely agree with the existing literature showing abnormally decreased N100, P200, and P300 amplitudes in schizophrenic patients, particularly the disorg/undiff patients. We conclude that whether EP measures are clinically useful depends on the clinical situation. In particular, the prior probability of the diagnosis in question being present and the cost of misclassifying the patient are critical.

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.