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.

Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs.

Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q=0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.

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.

Olanzapine and haloperidol in first episode psychosis: two-year data.

Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.

Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose.

After individual determination of neuroleptic threshold (NT) doses of haloperidol, 106 patients with schizophrenia or schizoaffective disorder (Research Diagnostic Criteria) were treated openly at such doses (mean, 3.7 +/- 2.3 mg/d) for 2 weeks. Ten responding patients were discharged and unavailable for follow-up or refused subsequent randomization, and one non-responding patient refused randomization. The remaining 95 responding or nonresponding patients were then randomly assigned, double-blind, to a dosage of haloperidol two to 10 times higher (mean, 11.6 +/- 4.7 mg/d) or to a continuing NT dosage (mean, 3.4 +/- 2.3 mg/d) for another 2 weeks. Of the 58 patients exposed only to NT dosages of haloperidol, 72% clinically recovered within the 5-week trial. Higher dosages given to 47 patients did not lead to greater improvement in measures of psychosis, but did produce slightly greater declines in measures of hostility. Higher dosages did regularly lead to significant increases in distressing extrapyramidal side effects.

Dose of fluphenazine, familial expressed emotion, and outcome in schizophrenia. Results of a two-year controlled study.

Issues regarding the side effects of antipsychotic medication and the possible contribution of the environment to dose requirements led to a two-year controlled dosage study of maintenance antipsychotic medication and familial environment among recently discharged schizophrenic patients. Seventy stable patients, living in high- or low-expressed emotion (EE) households, were randomized, double blind, to receive a standard dose of fluphenazine decanoate (average, 25 mg every two weeks) or a minimal dose representing 20% of the dose prescribed (average, 3.8 mg every two weeks). No differences in relapse were observed among dose, EE, or dose and EE. Patients in the minimal dose/high-EE condition experienced more minor but aborted episodes in year 2. Side effects were fewer on the minimal dose after one year, and low-EE patients were better adjusted than high-EE patients. Over time, minimal-dose recipients were significantly more improved in their instrumental and interpersonal role performance than were standard-dose recipients.

Pharmacotherapy of impaired affect in recovering schizophrenic patients.

BACKGROUND: Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken. METHODS: In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks. RESULTS: For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression. CONCLUSION: Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature.

Clozapine-induced electroencephalogram changes as a function of clozapine serum levels.

Specific electroencephalogram (EEG) changes during clozapine therapy were prospectively studied in a cohort of 50 chronic state hospital patients with schizophrenia who were randomly assigned to one of three nonoverlapping clozapine serum level ranges (50-150 ng/mL, 200-300 ng/mL, and 350-450 ng/mL). EEGs were obtained before clozapine was instituted, and after 10 weeks of treatment. Fifty-three percent of patients showed EEG changes during the 10-week study period. We observed three seizures (6%), one in a patient on 900 mg (serum level 320 ng/mL) clozapine, and two in patients with lower clozapine serum levels (200-300 ng/mL) who had prior histories of seizures and inadequate valproate coverage. Thirteen percent of patients developed spikes with no relationship to dose or serum level of clozapine. Fifty-three percent of patients developed slowing on EEG. Compared to plasma levels below 300 ng/mL, a clozapine serum level between 350 and 450 ng/mL led to more frequent and more severe slowing. The EEG slowing correlated with observed sleepiness, although this factor was not sufficient to explain the severity of high-dose effects.

Smoking and therapeutic response to clozapine in patients with schizophrenia.

BACKGROUND: Of patients with schizophrenia, 70 to 80% smoke. Nicotine corrects certain information processing and cognitive psychomotor deficits seen in many patients with schizophrenia. Clozapine, but not conventional antipsychotics, has been shown to correct some of these deficits. METHODS: We assessed psychopathology and smoking in 70 patients with treatment refractory schizophrenia (55 smokers and 15 nonsmokers) at baseline when they were receiving conventional antipsychotics and again after they were switched to clozapine. RESULTS: Smokers showed significantly greater therapeutic response to clozapine than nonsmokers. Smokers smoked less when treated with clozapine than when treated with conventional antipsychotics. CONCLUSIONS: Certain patients with schizophrenia have contributing pathophysiologic mechanisms that respond favorably to either nicotine or clozapine.

A study of the potential confounding effects of diet, caffeine, nicotine and lorazepam on the stability of plasma and urinary homovanillic acid levels in patients with schizophrenia.

Ten men inpatients who met DSM-III-R criteria for schizophrenia participated. On five occasions at least one week apart, each subject had an intravenous line placed at 0730 after an overnight fast. On each occasion blood samples were drawn at 0800 and hourly thereafter through 1200 noon for measurement of plasma homovanillic acid (HVA). Total four-hour urine collections were obtained for measurement of urinary HVA. Subjects received five experimental conditions, in randomized sequence: no intervention, smoking one cigarette per hour, drinking one caffeinated cola per hour, lorazepam 2 mg IV push, or a high monoamine meal. Baseline (0800) plasma HVA measures showed only minor intrinsic variability. The average standard deviation in baseline plasma HVA over five occasions of measurement was low relative to the changes in HVA produced during treatment with antipsychotic medications. The high monoamine meal significantly elevated plasma HVA, with a similar trend for urinary HVA. Neither caffeine, nicotine, nor lorazepam significantly affected plasma or urinary HVA.

A pilot study of a structured interview addressing sexual function in men with schizophrenia.

Twenty physically healthy men with schizophrenia responded to a 15-item questionnaire inquiring about their usual and their present (on medications) sexual functioning. Two summary measures of present impairment (the average of items 7-13 that detail the patients' specific complaints of impairment, and item 15, the interviewer's global judgment of impairment) were significantly correlated with each other and with the differences between usual and present reported frequencies of erection and masturbation. More severe impairment on these summary measures was significantly associated with greater biological evidence of dopamine blockade (more severe extrapyramidal side effects and higher serum prolactin levels).

Diazepam for catatonia.

Intravenous diazepam rapidly relieved catatonic immobility in two schizophrenic patients, and oral diazepam maintained this therapeutic effect. Diazepam may be an immediately available and effective treatment for some patients with life-threatening catatonic disorders.

Effects of amantadine and trihexyphenidyl on memory in elderly normal volunteers.

Anticholinergic drugs impair one's ability to learn new material, even at routine clinically used doses. During the trihexyphenidyl phase of this double-blind crossover trial, elderly normal subjects complained of confusion and memory impairment and demonstrated a pattern of deficits in memory function compatible with that previously reported to result from anticholinergic drugs. The subjects neither complained of nor demonstrated memory impairment while taking amantadine, which is believed to exert its pharmacological effects upon extrapyramidal disorders via dopaminergic mechanisms and does not appear to be associated with memory impairment. Anticholinergic drugs should be avoided whenever possible in the elderly and especially in those suffering dementia.

Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges.

OBJECTIVE: This study sought to determine the relationships between serum clozapine levels and therapeutic response. METHOD: Fifty-six inpatients who met the DSM-III-R criteria for chronic schizophrenia and who had not responded to extended treatment with classical antipsychotics were randomly assigned to 12 weeks of double-blind treatment with clozapine at one of three serum level ranges: low (50-150 ng/ml), medium (200-300 ng/ml), or high (350-450 ng/ml). Baseline clinical assessments were completed before the patients' regular antipsychotic and anticholinergic drugs were discontinued. During clozapine treatment, serum levels were ascertained weekly to allow adjustment of clozapine doses so as to maintain each patient near the midpoint of his or her assigned serum level range. Clinical assessments were completed after 6 and 12 weeks of treatment. RESULTS: The analyses of the results of treatment supported the superior efficacy of the 200-300 ng/ml and 350-450 ng/ml serum clozapine level ranges over the 50-150 ng/ml range, with no advantage for 350-450 ng/ml over 200-300 ng/ml. Sleepiness increased with increasing serum levels. CONCLUSIONS: Serum clozapine levels per unit of daily dose were at the lower end of the range noted in previous reports, possibly reflecting the current study's dosing schedules of twice or three times a day, the 11- to 13-hour postdose sampling time, and the moderate doses given. Serum clozapine levels, if interpreted in relation to daily clozapine dosing schedules, postdose sampling time, and total daily dose, may help to guide dosing to provide adequate opportunities for therapeutic response and to limit certain side effects of clozapine treatment.

Use of psychopathology vignettes by patients with schizophrenia or schizoaffective disorder and by mental health professionals to judge patients' insight.

OBJECTIVE: The goal of this study was to clarify more precisely where patients with psychotic disorders and the mental health professionals who care for them disagree regarding whether the patient is ill or needs treatment. METHOD: The authors prepared brief vignettes in everyday descriptive language that provided examples of the classical positive and negative psychopathological features of schizophrenia. Fifteen men and 11 women diagnosed as having schizophrenia or schizoaffective disorder and one physician used these vignettes as a common frame of reference to rate 1) the degree to which the patients demonstrated the features described in each vignette and 2) the degree to which the features signified the presence of mental illness. RESULTS: Disagreements between the physician's and patients' ratings, indicating deficits in insight, were associated with the recognition of the presence of conceptual disorganization, avolition-apathy, and affective blunting in the patients by the physician but not the patients and with the conceptualization of hallucinatory behavior and suspiciousness as signs of mental illness by the physician but not the patients. CONCLUSIONS: The authors conclude that the failure to acknowledge conceptual disorganization, avolition-apathy, and affective blunting and the failure to view hallucinatory behavior and suspiciousness as signs of mental illness, which proved to be additive in this study, contribute to deficits in insight.

Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia.

Lesioning the ventral hippocampus of neonatal rats has been proposed as an experimental model of schizophrenia. This lesion causes a syndrome of hyperresponsivity to the stimulant effects of amphetamine, impaired grooming and disrupted social interactions, effects that emerge during adolescence, much like schizophrenia. Persisting cognitive effects of neonatal ventral hippocampal lesions were assessed in the current study, because the hippocampus is critically important for a variety of cognitive functions and cognitive impairment and because it is an important feature of schizophrenia. Spatial learning and working memory were assessed in the radial-arm maze, which is sensitive to the adverse effects of hippocampal lesions made in adults. Lesioned rats showed pronounced deficits in radial-arm maze choice accuracy that persisted throughout training. Deficits were seen during the prepubertal period as well as in adulthood. Even though the lesioned rats performed more poorly, they were significantly less sensitive to the amnestic effects of the nicotinic antagonist mecamylamine and the muscarinic antagonist scopolamine. No significant effects of nicotine or amphetamine were seen in either the lesioned or control groups. The long-lasting deficits in spatial learning and working memory resulting from neonatal ventral hippocampal lesions show that, unlike frontal cortical lesions during the same age, the effects of hippocampal lesions are not overcome during development. The resistance to the amnestic effects of nicotinic and muscarinic acetylcholine (ACh) antagonists suggests that the hippocampus is a critical site for the action of these drugs. Neonatal hippocampal lesions may provide a good model of the cognitive impairments of schizophrenia and may be useful to assess novel drug effects to counteract the cognitive deficits in schizophrenia.

A double-blind crossover comparison of antiparkinson drug therapy: amantadine versus anticholinergics in 90 normal volunteers, with an emphasis on differential effects on memory function.

Anticholinergic antiparkinson drugs administered orally at standard clinically prescribed doses impaired new memory acquisition and mood in normal volunteer subjects, based on tests of free recall, recognition memory, and time production, self-rating of memory function, and an evaluation of mood states. Elderly subjects were more severely impaired than were young adults. Amantadine did not impair new memory acquisition, and on self-report measures, it was significantly better tolerated than were anticholinergics. Among patients being treated for psychotic illness, there are two groups in which an effort to avoid anticholinergic therapy is especially worthwhile because of the severe consequences of memory dysfunction. These individuals are young neuroleptic-responsive patients who are in an early stage of their disease and elderly patients. For these two groups, amantadine should be considered as the initial mode of treatment, with low-dose anticholinergics being used for those patients who do not achieve adequate relief from extrapyramidal side effects with amantadine.

Efficacy of risperidone on positive features of schizophrenia.

Dopaminergic hyperactivity mediated via D2 receptors is implicated in the etiology of positive symptoms of schizophrenia, but selective D2 antagonists provide imperfect therapy. This article describes a subanalysis of a trial of risperidone, a combined 5-HT2A/D2 antagonist, in 513 patients with DSM-III-R chronic schizophrenia. Risperidone at 2, 6, 10, and 16 mg/day was compared with placebo and haloperidol 20 mg/day. All doses of risperidone and the 20-mg dose of haloperidol were superior to placebo (mean change from baseline on the PANSS positive and general psychopathology subscales). The 6-mg dose of risperidone also produced significantly more improvement than haloperidol 20 mg. We conclude that risperidone is an effective drug for patients with positive features of schizophrenia.

Case studies in neuropsychiaatry. II: Conversion pseudodementia.

A patient is described who experienced pseudodementia as a conversion reaction. The patient was considered to be demented originally because of the evidence for profound cognitive impairment elicited on mental state examination. Careful analysis of the patient's verbal production in unstructured situations and of her behavior inthe hospital permitted a clinical diagnosis of pseudodementia to be made, a diagnosis confirmed by response to treatment and long term follow-up. Evidence is presented to support the interpretation of her pseudodementia as a conversion reaction.

Hospitalized schizophrenic patient views about seclusion.

Twenty-six of 100 consecutively admitted schizophrenic or schizoaffective patients required seclusion during their hospital stays. Seclusion episodes usually involved involuntarily committed, severely ill patients and occurred early in their hospitalizations. The recollections of the personal seclusion experiences of 17 patients were generally factually accurate, except for a tendency to play down disruptive aggressive behavior on their part. Patients described seclusion as a painful experience associated with feelings of helplessness, fear, sadness, and anger. However, patients also stated that seclusion rooms were necessary on inpatient psychiatric units and that the rooms were used for the control of disruptive aggressive patient behaviors. This study highlights not only the need for staff to clarify for patients what behavior has led to seclusion and what behavior will lead to release, but also the need for staff to acknowledge patients' distress at the experience.