Psychiatry

FK506 is a macrolide immunosuppressant agent used in solid organ and bone marrow transplantation and for autoimmune disorders. FK506 is reported to have a number of neuropsychiatric side effects, including anxiety and tremor. Because FK506 was implicated in causing akathisia in a case report, we did a prospective, cross-sectional study of 25 renal transplant recipients to determine whether akathisia occurred and~or had a relationship to FK506 plasma levels. The Symptom Checklist-90-R, Hamilton Anxiety (HAM-A), and Akathisia Rating (ARS) scales were administered. Higher FK506 plasma levels correlated with higher HAM-A scores. ARS scores did not correlate with FK506 plasma levels; however, when FK506 plasma levels were divided into "high" (>>-0.9 ng/mL) and "low" (< 0.9 ng/mL) groups, total ARS and HAM-A scores were significantly higher in the "high" group. We discuss implications of these findings as well as management.

. The Maryland Psychiatric Research Center involuntary movement scale MPRC scale has been used in the evaluation of 1107 patients referred for drug-induced movement disorders. The scale has increased discrimination of body area and severity compared to other scales. Validity was examined using principal component analyses, pharmacologic response studies and associations with AIMS, global judgement and motor diagnosis. Reliability was Ž . examined using Cronbach's alpha, intraclass correlation coefficient ICC between raters and test᎐retest measurements. The prevalence of dyskinetic and parkinsonian signs at several levels of severity are reported. Total dyskinesia was strongly correlated with AIMS score, r s 0.97. Inter-rater reliability was 0.81᎐0.90 for total dyskinesia score.

Schizophrenics show severe abnormalities of working memory systems, reflected in impaired generation of mismatch negativity (MMN). Whether working memory deficits reflect impaired initial encoding, or premature decay of accurately encoded information, remains unknown . In normal subjects MMN amplitude increases with decreasing deviant probability. Thus by varying deviant probability, MMN can provide an index of initial encoding. By varying interstimulus interval (lSI) between standard stimuli, MMN can index auditory memory trace decay over time. This study examined MMN in 15 chronic schizophrenics and 17 normal controls under 4 conditions of deviant probability (25%, 10%, 5% and 2.5%) and 4 lSI conditions (250 ms, 500 ms, 1000ms and 3000 ms). If auditory working memory deficits in schizophrenia are due to abnormal initial encoding, MMN amplitude differences between groups should be maximal as deviant probability decreases. If deficitsare due to abnormal trace decay, differences should be maximal as lSI increases. Results indicated that schizophrenics showed less of the normal augmentation of MMN amplitude as deviant probability decreased but that lSI had no significant effect on MMN. This suggests that auditory working memory deficits in schizophrenics are due more to abnormal encoding than to abnormal trace decay.

The development of a new serological assay method to detect antibodies in human sera recognizing Borna disease virus (BDV) proteins and a clinical pilot study are presented. Psychiatric patients from a schizophrenia research clinic in Baltimore, Maryland, were examined for antibodies to BDV antigen with traditional indirect immunofluorescence assays (IFA) that used both single and double labeling techniques and also with a Western blot assay capable of detecting antibodies to the three BDV proteins from a human neuroblastoma cell line. Thirteen of 90 (14.4%) patients and O/20 control subjects had antibodies that recognized more than one BDV protein on the Western blot. Three patients had antibodies that recognized all three BDV proteins. Magnetic resonance imaging assessments of the volume of the putamen (with controls for total cranial volume) differentiated BDV+ from BDV-patients, and there were trend differences for bilateral amygdalae and the left amygdala-hippocampal process. We conclude that: (1) the Western blot assay is superior to IFA assays in BDV serology studies, (2) detection of antibodies to more than one BDV protein is a useful working criterion for seropositivity, (3) the 14.5 kDa BDV protein is 10 times more predictive of seropositivity than either the 38/40 kDa or the 24 kDa protein, (4) there is tentative evidence for a schizophrenia-control difference in the prevalence of anti-BDV antibodies, and (5) it is likely that there are neuroanatomicaUbehaviora1 features that differentiate seropositive from seronegative schizophrenic patients.

Several electrical neural oscillatory abnormalities have been associated with schizophrenia, although the underlying mechanisms of these oscillatory problems are unclear. Animal studies suggest that one of the key mechanisms of neural oscillations is through glutamatergic regulation; therefore, neural oscillations may provide a valuable animal-clinical interface on studying glutamatergic dysfunction in schizophrenia. To identify glutamatergic control of neural oscillation relevant to human subjects, we studied the effects of ketamine, an N-methyl-D-aspartate antagonist that can mimic some clinical aspects of schizophrenia, on auditory-evoked neural oscillations using a paired-click paradigm. This was a double-blind, placebo-controlled, crossover study of ketamine vs saline infusion on 10 healthy subjects. Clinically, infusion of ketamine in subanesthetic dose significantly increased thought disorder, withdrawal-retardation, and dissociative symptoms. Ketamine significantly augmented high-frequency oscillations (gamma band at 40-85 Hz, p ¼ 0.006) and reduced lowfrequency oscillations (delta band at 1-5 Hz, po0.001) compared with placebo. Importantly, the combined effect of increased gamma and reduced delta frequency oscillations was significantly associated with more withdrawal-retardation symptoms experienced during ketamine administration (p ¼ 0.02). Ketamine also reduced gating of the theta-alpha (5-12 Hz) range oscillation, an effect that mimics previously described deficits in schizophrenia patients and their first-degree relatives. In conclusion, acute ketamine appeared to mimic some aspects of neural oscillatory deficits in schizophrenia, and showed an opposite effect on scalp-recorded gamma vs low-frequency oscillations. These electrical oscillatory indexes of subanesthetic ketamine can be potentially used to cross-examine glutamatergic pharmacological effects in translational animal and human studies.

Context-The auditory sensory gating deficit has been considered a leading endophenotype in schizophrenia. However, the commonly used index of sensory gating, P50, has low heritability in families of people with schizophrenia, raising questions about its utility in genetic studies. We hypothesized that the sensory gating deficit may occur in a specific neuronal oscillatory frequency that reflects the underlying biological process of sensory gating. Frequency-specific sensory gating may be less complex than the P50 response, and therefore closer to direct genetic effects and thus a more valid endophenotype.

pilot study of 15 young, right-handed, male schizophrenia patients. As predicted, smaller hippocampal volume was significantly associated with poorer recall of items that were presented early in the list (reduced primary effect) for both the DSDT (r=0.59, p<0.03) and the CVLT (r=0.58, p<0.03). Neither hippocampal volume, nor the DSDT or CVLT primary effects, were significantly related to thought disorder. However, higher thought disorder was related to more intrusions during the CVLT (r=0.53, p<0.05). In summary, verbal working memory measured by the DSDT and CVLT primacy indices appears to be a functional measure of hippocampal integrity. Formal thought disorder was related to a deficit in distinguishing words that were previously presented from words that were not (intrusions). The results suggest that one aspect of list learning (primacy) is related to hippocampal volume, whereas another aspect of list learning (intrusions) was related to thought disorder. We speculate that some basic deficit in reality monitoring may be responsible for both list learning intrusions and thought disorder.

We detected anti-Borua disease virus (BDV) antibodies at a 14.4% rate in patients with schizophrenia. The hypothesis of a higher rate of BDV seropositivity in deficit syndrome was borne out in a subset of 64 patients categorized according to the Schedule for the Deficit Syndrome with 5/15 seropositive deficit and 4/49 seropositive nondeficit (p <0.05). This suggests that the antibodies and possibly a BDV-like virus are pathogenetically linked to this form of schizophrenia.

A large percentage of patients with schizophrenia are characterized by an abnormality in P50 sensory gating. This abnormality has been shown to be genetically linked to the a-7 nicotinic receptor and is transiently reversed by acute nicotine administration. These observations have led to the development of pharmacological treatments designed to improve sensory gating. However, if normalization of P50 gating abnormalities is to guide drug development, then it becomes important to delineate the clinical correlates of enhanced P50 gating. We conducted a review of all available articles through March 2005 that have examined this issue. We found that, despite the prominent role that P50 abnormalities have played in our understanding of schizophrenia, there is a relative dearth of data examining P50 clinical correlates. There is evidence suggestive of an association between P50 and measures of attention, and multiple studies have failed to document a cross-sectional or longitudinal relationship between P50 and positive, negative, or other symptoms. These results suggest that considerably more work needs to be done to understand and validate the clinical significance of this impairment.

Register has recorded all psychiatric.in-patient and .out-pa~ient contacts since 1982. Data were obtained for all patients with a diagnosis of schizophrenia (ICO 295/297) over the period 1982-1994 (n=331). Each of the 36 neighbourhoods in Maastricht (population: 120000) was assigned to one of the quartiles of degree of socio-econ0tn!c depriv~t~on. calculated through principal component analysis of municipal small area statistics on unemployment rates, individuals on social benefit. non-voters. immigrants, and broken families. The relationship between schizophrenia incidence,adjusted for age and sex, and level of neighbourhood socio-economic deprivation was examined using poisson regression.

A large percentage of patients with schizophrenia are characterized by an abnormality in P50 sensory gating. This abnormality has been shown to be genetically linked to the a-7 nicotinic receptor and is transiently reversed by acute nicotine administration. These observations have led to the development of pharmacological treatments designed to improve sensory gating. However, if normalization of P50 gating abnormalities is to guide drug development, then it becomes important to delineate the clinical correlates of enhanced P50 gating. We conducted a review of all available articles through March 2005 that have examined this issue. We found that, despite the prominent role that P50 abnormalities have played in our understanding of schizophrenia, there is a relative dearth of data examining P50 clinical correlates. There is evidence suggestive of an association between P50 and measures of attention, and multiple studies have failed to document a cross-sectional or longitudinal relationship between P50 and positive, negative, or other symptoms. These results suggest that considerably more work needs to be done to understand and validate the clinical significance of this impairment.

The brain's oscillatory activities in response to sensory input are likely signals representing different stages of sensory information processing. To understand these signals, it is critical to establish the specificity of the timing and frequency of oscillations associated with sensory and sensory-related cognitive processing. We used a simple paired auditory stimulus paradigm for sensory gating and sought to identify time- and frequency-specific oscillatory components contributing to sensory gating. Using a discrete wavelet decomposition technique we separated single-trial time-frequency components of evoked potentials elicited by the first of two stimuli. Regression analyses were then used to identify the components most relevant to the suppression of the second evoked potential response. The results suggested that beta oscillation indexed a neural process associated with the strength of sensory gating.

Serper and Harvey discuss experimental and neuropsychological research on schizophrenia and suggest their integration. They propose that such integration would offer practical and theoretical advantages. Shortcomings of these approaches and of their integration are discussed, within a broader consideration of methodological and conceptual issues in schizophrenia research. The application of experimental methods to study the relationships between brain function and behavior is suggested to be a more productive approach to the study of psychological phenomena in schizophrenia.

Schizophrenia is characterized by a substantial slowing of manual response times and by impairments in attention. However, prior research has not investigated whether attention itself is slowed in schizophrenia, and this was the goal of the present study. In Experiment 1, the N2pc component of the event-related potential waveform-an electrophysiological correlate of the focusing of attention-was recorded from 24 schizophrenia spectrum patients and 13 control subjects. Although behavioral response times were delayed by over 100 ms in the patient group, the onset latency of the N2pc component was virtually identical across groups, and no reduction in N2pc amplitude was observed in the patient group. In Experiment 2, a new cueing paradigm was developed to provide a behavioral measure of the speed of attention in 22 schizophrenia spectrum patients and 13 control subjects. We found that the average time required to allocate attention to a cued location was only 19 ms greater for the patient group than for the control group, with most patients within the range of the control subjects. Together, these experiments revealed little or no slowing of the allocation of visual-spatial attention in patients with schizophrenia. Thus, the mechanisms responsible for allocating attention to salient visual targets appear to be largely unaffected by the illness, and the well documented slowing of manual response times in schizophrenia cannot easily be explained by a slowing of attention. D

Reaction times (RTs) are substantially prolonged in schizophrenia patients, but the latency of the P3 component is not. This suggests that the RT slowing arises from impairments in a late stage of processing. To test this hypothesis, 20 schizophrenia patients and 20 control subjects were tested in a visual oddball paradigm that was modified to allow measurement of the lateralized readiness potential (LRP), an index of stimulus-response translation processes. Difference waves were used to isolate the LRP and the P3 wave. Patients and control subjects exhibited virtually identical P3 difference waves, whereas the LRP difference wave was reduced in amplitude and delayed in latency in the patients. These results indicate that, at least in simple tasks, the delayed RTs observed in schizophrenia are primarily a consequence of impairments in the response selection and preparation processes that follow perception and categorization.

Context-Nicotine administration transiently improves many neurobiological and cognitive functions in schizophrenia. It is not yet clear which nAChR subtype(s) is responsible for these seemingly pervasive nicotinic effects in schizophrenia. Objective-α4β2 is a key nAChR subtype for nicotinic actions. We investigated the effect of varenicline, a relatively specific α4β2 partial agonist/antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans. Design-double-blind, parallel, randomized, placebo controlled trial in schizophrenia patients to examine effects of varenicline on biomarkers at short-term (2 week) and long-term (8 week), using a slow titration and moderate dosing strategy for retaining α4β2 specific effect while minimizing side effects. Setting-Outpatients. Participants-69 smoking and nonsmoking patients randomized; 64 completed week 2; 59 completed week 8. Intervention(s)-varenicline. Main Outcome Measure(s)-prepulse inhibition, sensory gating, antisaccade, spatial working memory, eyetracking, processing speed, and sustained attention. Results-Moderate dose of varenicline 1) reduced P50 sensory gating deficit after a long-term (p=0.006) but not short-term treatment; significant in nonsmokers but not in smokers; 2) reduced startle reactivity (p=0.015) regardless of baseline smoking status; and 3) improved executive

The validity of previously hypothesized predictors of elapse following neuroleptic discontinuation was examined. One hundred sixty-two outpatients, with either Research Diagnotic Criteria schizophrenia or schizoaffective disorder, were discontinued from neuroleptic medication for a 28-day period or until judged to be relapsed. Pre-discontinuation neuroleptic dosage level, the severity of psychotic symptoms, and the presence of dyskinetic movements prior to neuroleptic discontinuation were the predictor variables. Of the 162 patients, 62.7% did not relapse during the study period. There were no differences in the survival rates between the patients withdrawn from oral versus depot neuroleptics. Neuroleptic dosage, but not severiO, of psychotic symptoms or dyskinetic movements, predicted relapse. These results support the hypothesis that pre-withdrawal neuroleptic dosage level predicts relapse, but fail to validate either severity of psychotic symptoms or presence of dyskbletic movements as predictors of relapse.