Weeks Of Antipsychotic Treatment Research Articles

Early striatal hypertrophy in first-episode psychosis within 3 weeks of initiating antipsychotic drug treatment

We and others have reported that patients experiencing their first episode of psychosis already have significant structural brain abnormalities. Antipsychotics seem to reverse subcortical volume deficits after months of treatment. However, the early impact of medication on brain morphology is not known. Forty-eight individuals in their first episode of psychosis underwent magnetic resonance imaging (MRI) brain scanning. Twenty-six were antipsychotic naive and 22 were newly treated with antipsychotic medication for a median period of 3 weeks. In each group, 80% of subjects received a diagnosis of schizophrenia. The two groups were balanced for age, sex, handedness, ethnicity, height, years of education, paternal socio-economic status (SES) and Positive and Negative Syndrome Scale (PANSS) score. Group differences in whole-brain grey matter were compared voxel by voxel, using Brain Activation and Morphological Mapping (BAMM) software. We also conducted testing of group differences with region-of-interest (ROI) measurements of the caudate nucleus. Relative to the untreated group, those receiving antipsychotic medication for 3-4 weeks had significantly greater grey-matter volumes in the bilateral caudate and cingulate gyri, extending to the left medial frontal gyrus. ROI analysis confirmed that, in treated patients, the right and left caudate nuclei were significantly larger by 10% (p<0.039, two-tailed) and 9% (p<0.048, two-tailed) respectively. Early striatal grey-matter enlargement may occur within the first 3-4 weeks of antipsychotic treatment. Possible reasons for putative striatal hypertrophy and its implications are discussed.

Attribution style as a factor in psychosis and symptom resolution

IntroductionAttribution (AT) style theory provides a framework for understanding the causal explanations that individuals give for their own behaviour and the behaviour of others. It has been suggested that patients with persecutory delusions excessively attribute hypothetical positive events to internal causes (self) and hypothetical negative events to external personal causes. Despite this, how AT associates with psychotic symptoms (not only persecutory delusions) and how it changes with the resolution of psychosis has never been investigated. We conducted a cross-sectional study to investigate how AT is associated with psychopathology and a longitudinal study to examine the change of AT during the first 6 weeks of antipsychotic treatment and the relationship with psychopathology improvement. Methods86 patients meeting DSM-IV criteria for schizophrenia and related psychotic disorders were included in the cross-sectional study, and 17 patients in the longitudinal study. The longitudinal group were free of antipsychotic drugs at baseline and followed for 6 weeks after being started on antipsychotic medication by their psychiatrist. We used the Internal, Personal and Situational Attributions Questionnaire (IPSAQ) as a measure of AT. ResultsPatients that tend to internalize (i.e. less self-serving bias), showed greater overall psychopathology, as measured by PANSS-Total (F(2,83)=6.59, p=0.002), with a trend toward significance for PANSS-Positive (F(2,83)=2.62 p=0.07). Longitudinally, having a low self-serving bias was associated with poorer response to antipsychotic treatment. Further, externalizing bias seems to change early on in treatment (F=9.65 df=1,15 p=0.007) and reach ceiling effects thereafter. ConclusionsAT is related to overall symptom severity, with internalizing style linked to higher global psychopathology. Antipsychotic treatment has little effect on AT, at least within 6 weeks of antipsychotic exposure, and only a modest effect is on EB which plateaus within 2 weeks. Finally, internalizing style appears associated with poorer response to antipsychotic treatment.

SERUM BDNF AND mRNA BDNF LEVELS IN SCHIZOPHRENIA

Brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the etiology of schizophrenia. There is a line of evidence that disruption of neurotrophins could play a role in the etiology of schizophrenia, and antipsychotics show their effect by altering levels of neurotrophins. The aim of this study was to evaluate the effect of antipsychotics on serum BDNF levels and their relationship with the symptoms in patients with schizophrenia. Twenty-two schizophrenia patients were enrolled in the study. The control group consisted of 22 age- and sex-matched physically and mentally healthy volunteers (7 male, 15 female). Serum BDNF levels and the positive and negative syndrome scale (PANSS) scores were recorded at baseline and after 6 weeks of treatment. Serum BDNF levels were also recorded in the control group. Schizophrenia patients who failed to meet 30% improvement in PANSS score were excluded from the study. The baseline serum BDNF levels of schizophrenia patients were lower than those of controls (t=4.56; df=21; p<0.001). There was no correlation between serum BDNF levels and PANSS scores in patients with schizophrenia (p>0.05). Although PANSS (for positive symptoms p<0.001, for negative symptoms p<0.001) and general psychopathology (t=20.9; df=22; p<0.001) scores improved significantly after 6 weeks of antipsychotic treatment; there was no change in BDNF levels in patients' serum (p>0.05). Our results support the view that BDNF would be associated with schizophrenia. However, we could not conclude that treatment with antipsychotics alters serum BDNF levels in patients with schizophrenia.

Interleukin-12 plasma levels in drug-naïve patients with a first episode of psychosis: Effects of antipsychotic drugs

An overactivation of the Th1 activity in schizophrenia had been described. Interleukin-12 (IL-12), a proinflammatory cytokine, plays a key role in the regulation of the Th1 response. The aims of this study were to investigate the effect of first and second generation antipsychotic drugs on IL-12 production during the acute phase of the illness and its association with clinical features. Participants comprised 56 drug-naïve first episode psychotic patients and 28 healthy volunteers. Patients were initially randomly assigned to risperidone ( n = 16), olanzapine ( n = 20) or haloperidol ( n = 20); subject were maintained on the same medication throughout the study. Clinical assessments were conducted at baseline and at 6 weeks. IL-12 plasma levels were assessed at baseline and after 6 weeks of antipsychotic treatment. IL-12 haplotypes were also analysed. Patients showed higher IL-12 plasma levels at baseline compared with controls, and had a significant increase in IL-12 plasma level after 6 weeks of antipsychotic treatment. No significant differences in IL-12 level increase were found among the three antipsychotic treatments. IL-12 plasma levels at week 6 were not significantly associated with the severity of psychopathology at week 6. Thus, patients with a first episode of psychosis have inflammatory-like immunological function during early phases of the illness that it is independent of the antipsychotic treatment used.

232 – Structural correlates of neurological soft signs in early schizophrenia: Preliminary results

Background: Basal ganglia volumetric increases have been reported in schizophrenic patients after early weeks of neuroleptic treatment. To validate the early effect of neuroleptics on brain plasticity, we explored the bilateral caudate nucleus volumetric differences in a prospective, longitudinal, cohort of anti-psychotic naive individuals newly diagnosed with schizophrenia. Methods: 14 patients (6 males, 8 females) hadMRI brain scans before, and after 3 weeks of antipsychotic treatment. 128 slices, contiguous, 1.2 mm thick T1 scans were used for manual (region of interest) tracing. Caudate nucleus volumes were measured “blind” to the time of the scan using MEASURE software. All measurements were performed by two raters and the inter-rater reliability between the two raters was 0.95 using left and right caudate nuclei on 10 scans. To reduce inter-rater variance, results from one rater measuring all of the MRI scans was reported. The intra-class correlation coefficient (ICC) for this rater was 0.97 for 5 scans measured 3 weeks apart. Results: We found that patients treated for a mean of 3 weeks, compared to baseline, had a total caudate volume increase of 5.4% (2 tailed pb0.001). The left caudate was increased by 3.5% (2 tailed pb0.001) and the right caudate by 7.4% (2 tailed pb0.002). Conclusions: This result provides evidence to confirm our preliminary voxel-based morphometric (VBM) analysis findings in this longitudinal cohort. Early basal ganglia volumetric increase after antipsychotic exposure suggests that drug-mediated neural plasticity occurs during clinical recovery.

Reduced Attentional Engagement Contributes to Deficits in Prefrontal Inhibitory Control in Schizophrenia

Problems with the voluntary control of behavior, such as those leading to increased antisaccade errors, are accepted as evidence of prefrontal dysfunction in schizophrenia. We previously reported that speeded prosaccade responses, i.e., shorter response latencies for automatic shifts of attention to visual targets, were associated with higher antisaccade error rates in schizophrenia. This suggests that dysregulation of automatic attentional processes may contribute to disturbances in prefrontally mediated control of voluntary behavior. Twenty-four antipsychotic-naïve schizophrenia patients and 30 healthy individuals completed three tasks: a no-gap prosaccade task in which subjects shifted gaze toward a peripheral target that appeared coincident with the disappearance of a central fixation target and separate prosaccade and antisaccade tasks in which a temporal gap or overlap of the central target offset and peripheral target onset occurred. Sixteen patients were retested after 6 weeks of antipsychotic treatment. Patients' prosaccade latencies in the no-gap task were speeded compared with healthy individuals. While patients were not atypical in the degree to which response latencies were speeded or slowed by the gap and overlap manipulations, those patients with diminished attentional engagement on the prosaccade task (i.e., reduced overlap effect) had significantly elevated antisaccade error rates. This effect persisted in patients evaluated after antipsychotic treatment. This study provides evidence that a reduced ability to engage attention may render patients more distracted by sensory inputs, thereby further compromising impaired executive control during antisaccade tasks. Thus, alterations in attentional and executive control functions can synergistically disrupt voluntary behavioral responses in schizophrenia.

Monocytic, Th1 and Th2 Cytokine Alterations in the Pathophysiology of Schizophrenia

A growing body of evidence suggests that changes in the serum levels and cellular production of various cytokines are associated with the immunological abnormalities of schizophrenia. Several studies have examined alterations in T helper type 1 (Th1) and T helper type 2 (Th2) cytokines in schizophrenia. We explored monocytic, Th1 and Th2 cytokines in 43 schizophrenia patients and 50 normal controls. The mitogen-induced production of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-4, γ-interferon (IFN-γ) and IL-2 was measured with enzyme-linked immunosorbent assays before and after antipsychotic treatment. IL-6 and TNF-α production by schizophrenic patients was significantly higher than by normal controls, while IL-2, IL-4 and IFN-γ production was significantly lower in schizophrenic patients. After 6 weeks of antipsychotic treatment, IL-6 and TNF-α production was significantly decreased, while IL-4, IFN-γ and IL-2 productions were not significantly changed. Our results suggest that increased monocytic cytokines and decreased Th1 and Th2 cytokines may be associated with the immunopathogenesis of acute psychotic schizophrenia, and that antipsychotics may play an important role in immune response by decreasing elevated monocytic cytokines.

Metabolic side effects of second generation antipsychotic agents in antipsychotic-naïve patients: One-month prospective evaluation

The present study investigated the effects of second generation antipsychotics (SGA) on the metabolism of 15 antipsychotic-naïve outpatients. Evaluations were performed at baseline and after 1 month of treatment. A significant increase in mean body mass index (BMI) and mean waist circumference was observed. These results suggest the importance of monitoring patients from the first few weeks of antipsychotic treatment.

Effects of haloperidol and risperidone on cerebrohemodynamics in drug-naive schizophrenic patients

Background Use of antipsychotics may be associated with cerebrovascular adverse events in psychotic patients. In this study, the effects of haloperidol and risperidone on the cerebral hemodynamics and the possible relationships between antipsychotics and cerebrovascular risks tendency were evaluated by Transcranial Doppler ultrasonography (TCD). Methods Twenty drug-naı¨ve schizophrenic patients and 20 normal control subjects were included. The patients were divided into haloperidol- and risperidone-treated groups and received treatment for 8 weeks double-blindly. The subjects’ cerebral blood flow mean velocities (MV) and pulsatility index (PI) were measured weekly by TCD. The Positive and Negative Syndrome Scale for schizophrenia (PANSS) was used to assess the patients’ psychopathological symptoms. Results Increased MV and decreased PI were found significantly in drug-naı¨ve schizophrenic patients than normal subjects before treatment ( p < 0.01). The decreased PI could be normalized after 8 weeks of antipsychotic treatment, while the increased MV could not. Treatment with haloperidol could significantly increase the PI than the treatment with risperidone ( p < 0.01) throughout the treatment course. The PANSS scores of both groups were significantly improved ( p < 0.05) at the endpoints of treatment. Conclusions Our findings indicate that haloperidol may affect the cerebral hemodynamics in drug-naı¨ve schizophrenics more prominently than that of risperidone via TCD monitoring.

Oxidative–antioxidative systems and their relation with serum S100 B levels in patients with schizophrenia: Effects of short term antipsychotic treatment

Oxidative stress may be a contributing factor in the etiopathophysiology of schizophrenia, which may be exacerbated by the treatment with antipsychotics with pro-oxidant properties. Increased levels of S100 B are associated with neurodegenerative disorders, including schizophrenia. The aim of the present study was to investigate the role of oxidative cell damage in the pathogenesis of schizophrenia. Forty patients who fully met the fourth Diagnostic and Statistical Manual of Mental Disorders criteria for schizophrenia and 35 healthy control subjects were included in the study. Serum S100 B level was determined to investigate brain damage. Plasma malondialdehyde (MDA) levels and susceptibility of red blood cell (RBC) to oxidation were determined to investigate the oxidative status and plasma vitamin E, vitamin C, serum total carotenoid levels and total antioxidant capacity and RBC superoxide dismutase (SOD) and whole blood glutathione peroxidase activities were measured to investigate the antioxidative defence before and after 6 weeks of antipsychotic treatment. Plasma MDA and serum S100 B levels and RBC–SOD activity were significantly higher in the schizophrenia group than those of the control group. Treatment did not modify any of the oxidative–antioxidative system parameters or serum S100 B levels. S100 B level was significantly higher in patients with negative symptoms than the patients with positive symptoms and the control subjects. S100 B levels were significantly reduced after 6 weeks of treatment in patients with negative symptoms. The results of the present study might support the oxidative cell injury hypothesis of the schizophrenia. Furthermore, the underlying mechanisms of the subgroups of schizophrenia might be different as suggested by the increased S100 B levels and its decrement after treatment in patients with negative symptoms.

Appropriate intervention strategies for weight gain induced by olanzapine: A randomized controlled study

Weight gain induced by antipsychotics is the second most frequently given reason for noncompliance with pharmacologic therapy; excessive sedative effects rank first, with extrapyramidal side effects ranking third. Frequently, weight gain leads to inconsistent pharmacologic treatment; this exposes patients to the risk of recurrent symptoms. In fact, one of the key contributors to good clinical outcomes in schizophrenic patients is compliance with pharmacologic treatment. The goals of this study were to evaluate weight gain in a group of patients treated with olanzapine, diet modifications, and moderate physical activity and to compare the findings with those from a second group of patients who were given only olanzapine treatment. For 8 wk, investigators followed 2 groups of patients suffering from schizophrenia and hypomania in bipolar disorder, according to the nosographic criteria of The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The first group (A) of 18 patients (9 female, 9 male) affected by manic episodes in bipolar disorder received olanzapine (10-20 mg/d), jogged lightly for 30 min 3 times a week, and complied with a diet that consisted of 500 kcal/d less than usual. The second group (B) of 10 patients (4 female, 6 male) with schizophrenia received only olanzapine (10-20 mg/d). All patients from both groups were weighed at the beginning of the observation period and weekly thereafter for 2 mo. After 2 mo of observation, group A showed a mean weight gain of 1.47 kg, whereas group B exhibited a mean weight gain of 3.5 kg; the difference between the 2 groups was almost 2 kg (P<.005). Group A showed a statistically significant reduction in weight gain compared with group B, clearly demonstrating the effectiveness of moderate physical activity and diet therapy in reducing weight gain in atypical antipsychotic treatment. Therefore, patient weight and body mass index must be monitored during the first weeks of antipsychotic treatment, with the goals of avoiding significant weight gain and treatment interruption.

The effect of antipsychotic treatment on Theory of Mind

Deficits in a patient's 'theory of mind' (TOM) have been proposed to lead to psychosis. However, it remains unclear whether TOM deficits constitute a trait- or a state-related deficit and whether they respond to antipsychotic treatment, and also whether the change in TOM and change in psychosis are associated. In the cross-sectional component of this study, 71 patients with psychotic disorders were included and TOM ability was measured using a hinting task in which subjects had to infer real intentions behind indirect speech. In the longitudinal study, a different cohort of 17 drug-free patients were included wherein they received antipsychotic treatment for 6 weeks and the effect on psychotic symptoms and TOM was measured every 2 weeks. Associations between TOM and psychopathology were assessed and a mixed effects model was used to investigate the rate of change over time. Positive and Negative Syndrome Scale (PANSS) total scores were significantly associated with TOM scores. The hinting task was not associated with positive symptoms but was significantly associated with negative and general symptoms. The longitudinal arm of the study showed that both PANSS positive scores and TOM improved after medication was started, particularly during the first 2 weeks of antipsychotic treatment, but these changes were not associated. The TOM response at 2 weeks of antipsychotic treatment reached similar values to those obtained in the cross-sectional sample. Although TOM and psychotic symptoms are related to each other, antipsychotic treatment impacts each independently, suggesting a dissimilar cognitive or neurobiological substrate for the two.

Lateral and Medial Hypofrontality in First-Episode Schizophrenia: Functional Activity in a Medication-Naive State and Effects of Short-Term Atypical Antipsychotic Treatment

The dorsolateral prefrontal cortex and the anterior cingulate cortex are critical components of the brain circuitry underlying executive control. The objective of this study was to investigate control-related dorsolateral prefrontal cortex functioning and conflict-related anterior cingulate cortex functioning in a group of never medicated first-episode schizophrenia patients to determine whether both regions show dysfunction at illness onset. A second objective was to assess short-term effects of atypical antipsychotic medication on dorsolateral prefrontal cortex and anterior cingulate cortex functioning. First-episode schizophrenia patients (N=23) and healthy comparison subjects (N=24) underwent event-related fMRI and performed a cognitive task designed to functionally dissociate the two regions. Four weeks after initiation of pharmacotherapy for patients, a subset of 11 patients and 16 comparison subjects underwent a repeat assessment. At baseline, patients exhibited hypoactivation in the dorsolateral prefrontal cortex and anterior cingulate cortex. After 4 weeks of antipsychotic treatment, the patients demonstrated improved functioning in the anterior cingulate cortex but not in the dorsolateral prefrontal cortex. These findings confirm the presence of dorsolateral prefrontal cortex dysfunction early in the course of schizophrenia and suggest that anterior cingulate cortex functioning may be altered at illness onset as well. Results also suggest that anterior cingulate cortex functioning may be especially sensitive to remedial antipsychotic treatment effects. These findings are consistent with an emerging literature documenting short-term benefits of atypical antipsychotic medication for the neural circuitry underlying cognitive deficits in schizophrenia.

Abnormalities in visually guided saccades suggest corticofugal dysregulation in never-treated schizophrenia

Previous studies have reported intact visually guided saccades in schizophrenia, but these are limited by potential acute and long-term pharmacological treatment effects, small sample sizes, and a failure to follow patients over time. Visually guided saccades were examined in 44 antipsychotic-naive patients experiencing their first episode of schizophrenia prior to treatment and again after 6, 26, and 52 weeks of antipsychotic treatment. Thirty-nine matched healthy individuals were followed over the same period. Before treatment, patients showed faster saccade latencies to unpredictable visual targets, suggesting reduced inhibitory regulation of brainstem saccade generators by neocortical attentional systems. Risperidone treatment reduced this deficit, suggesting a facilitation of attentional function, but haloperidol treatment did not. However, there was also a modest decline in saccade accuracy after risperidone treatment. The ability to sustain fixation of static central and peripheral targets was unimpaired before and after treatment. These findings provide evidence for impairments in neocortical attentional systems that cause reduced corticofugal regulation of brainstem systems in schizophrenia. This dysfunction appears to be minimized by the atypical antipsychotic risperidone but at the cost of a subtle reduction in saccade accuracy, possibly mediated via adverse effects on cerebellar vermis function.

Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment

Brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the etiology of schizophrenia. There is a line of evidence that disruption of neurotrophins could play a role in the etiology of schizophrenia, and antipsychotics show their effect by altering levels of neurotrophins. The aim of this study was to evaluate the effect of antipsychotics on serum BDNF levels and their relationship with the symptoms in patients with schizophrenia. Twenty-two schizophrenia patients were enrolled in the study. The control group consisted of 22 age- and sex-matched physically and mentally healthy volunteers (7 male, 15 female). Serum BDNF levels and the positive and negative syndrome scale (PANSS) scores were recorded at baseline and after 6 weeks of treatment. Serum BDNF levels were also recorded in the control group. Schizophrenia patients who failed to meet 30% improvement in PANSS score were excluded from the study. The baseline serum BDNF levels of schizophrenia patients were lower than those of controls ( t=4.56; df=21; p<0.001). There was no correlation between serum BDNF levels and PANSS scores in patients with schizophrenia ( p>0.05). Although PANSS (for positive symptoms p<0.001, for negative symptoms p<0.001) and general psychopathology ( t=20.9; df=22; p<0.001) scores improved significantly after 6 weeks of antipsychotic treatment; there was no change in BDNF levels in patients' serum ( p>0.05). Our results support the view that BDNF would be associated with schizophrenia. However, we could not conclude that treatment with antipsychotics alters serum BDNF levels in patients with schizophrenia.

Abnormal neurological signs at the onset of psychosis

Introduction: The objective of this investigation was to determine whether abnormal neurological signs (ANS) are present at the onset of psychosis, prior to the initiation of antipsychotic treatment, and to examine the effect of 6 weeks of antipsychotic treatment on these signs. Methods: We examined 29 first-episode schizophrenic patients admitted at an Army Medical Center within 10 days of psychosis onset, using the Neurological Evaluation Scale and the 18-item Brief Psychiatric Rating Scale (BPRS) and compared them to controls. Results: All of the subjects had neurological signs indicating problems in sensory integration, motor coordination, and sequencing of complex motor acts. No psychotic subject had fewer than two abnormal neurological signs. When compared to age and sex matched groups of normal controls and nonpsychotic psychiatric controls, the psychotic group had a significantly higher incidence of neurological signs. At baseline, the severity of neurological signs was associated with elevated BPRS total, positive, and negative symptom scores. The change in clinical symptoms was positively correlated with a change in neurological signs. Discussion: These findings indicate that some neurological signs are present at the onset of psychosis, and that these signs may be altered by treatment. These abnormal neurological signs reflect an underlying brain function abnormality and may be useful in differential diagnosis, prognosis, and treatment selection.

Identification of antibodies to heat shock proteins 90 kDa and 70 kDa in patients with schizophrenia

Objectives: Recent reports of antibodies to heat shock proteins 60 kDa (HSP60) and HSP70 suggested that antibodies to the heat shock protein that plays a protective role against environmental stresses in a cell might be related to the pathogenesis of schizophrenia, although the antibody to HSP90 had not yet been identified in patients with schizophrenia. In this study, we tried to elucidate the specific involvement of the autoimmunity to HSPs in the pathogenesis and development of schizophrenia. Methods: Antibodies to HSP90 and HSP70 in 90 patients with schizophrenia and in 83 normal controls were measured by enzyme-linked immunosorbent assay (ELISA) coupled with the avidin–biotin system. In the patients, the association between antibody levels and clinical variables were sought. In addition, changes in antibody levels after treatment with antipsychotic medication were investigated. Results: Eighteen (20.0%) of the 90 patients showed ‘high’ levels of antibody to HSP90 above a cutoff value, and 28 (31.1%) of those showed ‘high’ antibody levels to HSP70. On the other hand, only four (4.8%) of the normal controls showed ‘high’ HSP90 antibody levels, and one (1.2%) of these showed ‘high’ antibody level to HSP70. The distribution of elevated HSP90 antibody was significantly associated with that of elevated HSP70 antibody in the patients with schizophrenia. The patients with ‘high’ levels of antibody to HSP70 showed higher initial Brief Psychiatric Rating Scale (BPRS) scores and showed greater clinical improvement than those with ‘low’ levels, while the patients with ‘high’ levels of antibody to HSP90 did not. The frequency of patients with high levels of antibody to HSP70 was decreased significantly after 6 weeks of antipsychotic treatment, while the frequency of patients with high levels of antibody to HSP90 was not. Conclusions: Our results presented the presence of abnormal immune reactivity involving antibody to HSP90 and antibody to HSP70 in a subset of patients with schizophrenia. Differential patterns of distribution, of the association with clinical symptom severity, and of the changes of levels with treatment suggested the possibility that these two antibodies might be involved specifically in the pathogenesis of schizophrenia.

CSF thyrotropin-releasing hormone concentrations differ in patients with schizoaffective disorder from patients with schizophrenia or mood disorders

Objective: To determine if there were differences in CSF-TRH concentrations among several acute major psychiatric disorders and to investigate the effects of antipsychotic treatment on CSF-TRH levels. Method: CSF-TRH concentrations were measured in 62 psychiatric inpatients during an acute phase of illness after a drug-free period. CSF-TRH measurements were repeated in 14 of these patients after 4 weeks of antipsychotic treatment. Results: Post-hoc tests (Tukey HSD) revealed significant differences among patients with schizoaffective disorder and both schizophrenia ( P<0.03) and major depression ( P<0.01). There were no significant differences between pre and posttreatment levels of CSF-TRH in the 14 patients treated with conventional agents for 4 weeks (1.54 pg/ml vs. 1.47 pg/ml). However, patients with a reduction in CSF-TRH concentration had a significantly better symptom response measured by the Brief Psychiatric Rating Scale (BPRS) positive factor (61% in six subjects) vs. those who had an increase in posttreatment CSF-TRH (29% in eight subjects; t=2.2; d.f.=12; P<0.04). Conclusions: These results provide further evidence for a neuromodulatory role for TRH and suggest a re-examination of its behavioral effects and interactions with brain neurotransmitter systems relevant to major psychotic and mood disorders.

VBR and premorbid status in schizophrenia

Ventricular enlargement is a consistently documented abnormality in schizophrenia, seen in one third to one half of patients; ventricle-brain ratio (VBR) is the most frequently used index of ventricle enlargement. The precise timing of this abnormality in the course of schizophrenic illness and its relationship to neuropsychological dysfunction and premorbid adjustment remains unclear. We have previously shown that VBR could be used to dichotomize a sample of schizophrenics and generate hypotheses regarding premorbid ability and development: 1) childhood onset associated with poor premorbid function, low educational achievement, lower IQ, and lower VBR; and 2) later onset with relatively normal childhood function, higher academic achievement and IQ, and increased VBR. To re-examine these questions, we investigated the relationship between VBR, premorbid psychosocial and cognitive ability, and neurnpsychological function in another sample of 55 DSM-III-R schizophrenic inpatients. Each was rated on BPRS and SANS at baseline and after 4 weeks of antipsychotic treatment. VBR was determined from MRI scans via computerized planimetry. Neuropsychological testing was used to gauge current functioning and to estimate premorbid cognitive ability; the Premorbid Adjustment Scale was used to estimate premorbid psychosocial functioning. Unlike our previous study, VBR was not associated with premorbid cognitive or psychosocial functioning, decline in premorbid ability, or symptom status. Our failure to replicate our own previous findings is another example of the difficulty in obtaining consistently replicable findings in schizophrenia. In part, the discrepant findings may be related to limitations in current methods of image acquisition and analysis. More precise and comprehensive techniques such as shape analysis and image averaging may help to clarify these important issues involved in understanding the development and pathophysiology of schizophrenia.

Production of interferon-α and -γ by leukocytes from patients with schizophrenia

Production of interferon (IFN)-α and -γ by leukocytes from 34 patients with acute schizophrenia and 34 controls was measured before and after 5–6 weeks of antipsychotic treatment by using Sendai virus as IFN-α inducer and lentil lectin as inducer for IFN-γ production. The schizophrenia series included 13 first admission patients (mean duration of illness 1.1 years) and 21 re-entry patients (mean duration of illness 10.1 years). Of the total series 23 were drug-free at the time of pretreatment sampling. In all subgroups the schizophrenic patients produced less IFNs than healthy controls although the differences reached statistical significance only in the total group of schizophrenic patients with regard to production of IFN-α. The antipsychotic drug treatment did not have an effect on IFN production. The techniques used, the influence of genetic factors, and eventual clinical implications are discussed.