Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia.

Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMT gene) and SPEM. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized that DAT1 10/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects of DAT1 genotype on: Clinical diagnosis in the study sample (n = 418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n = 200; 87 schizophrenia), and DAT1 gene expression in FEF tissue obtained from postmortem brain samples (n = 32; 16 schizophrenia). DAT1 genotype was not associated with schizophrenia. DAT1 10/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first-degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study, DAT1 10/10 genotype was associated with significantly reduced DAT1 mRNA transcript in FEF tissue from healthy control donors (P < 0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulate DAT1 gene function.

Refining the predictive pursuit endophenotype in schizophrenia.

BACKGROUND: To utilize fully a schizophrenia endophenotype in gene search and subsequent neurobiological studies, it is critical that the precise underlying physiologic deficit is identified. Abnormality in smooth pursuit eye movements is one of the endophenotypes of schizophrenia. The precise nature of the abnormality is unknown. Previous work has shown a reduced predictive pursuit response to a briefly masked (i.e., invisible) moving object in schizophrenia. However, the overt awareness of target removal can confound the measurement. METHODS: This study employed a novel method that covertly stabilized the moving target image onto the fovea. The foveal stabilization was implemented after the target on a monitor had oscillated at least for one cycle and near the change of direction when the eye velocity momentarily reached zero. Thus, the subsequent pursuit eye movements were completely predictive and internally driven. Eye velocity during this foveally stabilized smooth pursuit was compared among schizophrenia patients (n = 45), their unaffected first-degree relatives (n = 42), and healthy comparison subjects (n = 22). RESULTS: Schizophrenia patients and their unaffected relatives performed similarly and both had substantially reduced predictive pursuit acceleration and velocity under the foveally stabilized condition. CONCLUSIONS: These findings show that inability to maintain internal representation of the target motion or integration of such information into a predictive response may be the specific brain deficit indexed by the smooth pursuit endophenotype in schizophrenia. Similar performance between patients and unaffected relatives suggests that the refined predictive pursuit measure may index a less complex genetic origin of the eye-tracking deficits in schizophrenia families.

Tardive dyskinesia in children treated with atypical antipsychotic medications.

Recent years have witnessed increased antipsychotic treatment of children despite limited long-term safety data in children. In this study, motor side effects associated with the use of antipsychotic drugs in children were examined in a sample of pediatric psychiatric patients. Child and adolescent psychiatric patients receiving antipsychotics (most were on atypicals) for 6 months or longer (n = 118) were compared with antipsychotic-naïve patients (n = 80) with similar age, sex ratio, and diagnoses. Only 19% of patients on antipsychotics had ever experienced psychotic symptoms. Eleven children (9%) on antipsychotics exhibited dyskinesia, when compared with 0 in the naïve group (P = 0.003, Fisher's exact test). Nine of 62 African-American children (15%) on antipsychotics exhibited dyskinesia, when compared with only 4% (2 of 52) of European-American children (P = 0.003, Fisher's exact test). Children treated with antipsychotic drugs might experience a significant risk of dyskinesia even when treated only with atypical antipsychotics. Ethnicity might also be a risk factor for dyskinesia in children. Side-effect profile of the atypical antipsychotic drugs in children may be much different than that in adults.

Lack of association between COMT gene and deficit/nondeficit schizophrenia.

BACKGROUND: The dopamine dysregulation hypothesis of schizophrenia posits that positive, negative and cognitive symptoms correlate with cortical/subcortical imbalances in dopaminergic transmission. A functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene is implicated in the pathophysiology of schizophrenia by its effect on prefrontal dopamine transmission, and its unique impact on prefrontal cognitive and behavioral phenotypes. Cognitive impairments and negative symptoms in schizophrenia have been hypothesized to be associated with hypodopaminergic states. Schizophrenia patients with the deficit syndrome are characterized by primary enduring negative symptoms, impairment on neurocognitive tasks sensitive to frontal and parietal cortical functioning, and poorer functional outcome compared to non-deficit patients. METHODS: Eighty-six schizophrenia cases that met DSM-IV criteria for schizophrenia were recruited. Additional categorization into deficit and nondeficit syndrome was performed using the Schedule for the Deficit Syndrome (SDS). A healthy comparison group (n = 50) matched to cases on age and ethnicity was recruited. Allele and genotype frequencies of the Val158Met polymorphism were compared among healthy controls, and schizophrenia cases with the deficit (n = 21), and nondeficit syndrome (n = 65). RESULTS: There was a significant difference in Val/Val genotype frequencies between schizophrenia cases (combined deficit/nondeficit) and healthy controls (p = 0.004). No significant differences in allele or genotype frequencies were observed between deficit and nondeficit cases. CONCLUSION: Results from this preliminary analysis failed to show an effect of COMT gene on deficit schizophrenia.

Evoked gamma band synchronization and the liability for schizophrenia.

OBJECTIVE: Electroencephalographic (EEG) synchronization in the gamma band is thought to represent a neuronal mechanism by which the brain integrates information processed in different cortical areas to build a coherent internal representation. Previous studies have reported abnormal gamma range ( approximately 40 Hz) synchronization in schizophrenic patients. We tested a group of first-degree relatives of schizophrenic probands who have schizophrenia spectrum personality symptoms, and a group of schizophrenic patients, to examine whether individuals with increased liability for schizophrenia have reduced gamma synchronization. METHOD: A steady-state auditory evoked potential paradigm was used to evaluate the brain's capacity to sustain 20, 30, and 40 Hz EEG synchronization in 11 relatives, 24 schizophrenic patients (11 on conventional, 13 on new generation antipsychotic medications), and 17 normal controls. RESULTS: Relatives with schizophrenic spectrum personality symptoms had reduced power at 40 Hz synchronization compared to normal controls (p=0.022). Previous findings of reduced steady-state gamma band synchronization in schizophrenic patients were not directly replicated in this study. Patients as a group did not significantly differ from controls, but patients taking new generation antipsychotics had significantly enhanced 40 Hz synchronization compared to patients taking conventional antipsychotics (p<0.001). There were no group differences in 20 or 30 Hz synchronization. CONCLUSIONS: Gamma band synchronization was found to be reduced in first-degree relatives with schizophrenia spectrum personality symptoms. Patients on new generation antipsychotic medications may exhibit enhanced gamma band synchronization.

The effects of nicotine on specific eye tracking measures in schizophrenia.

BACKGROUND: The role of neuronal nicotinic receptors in the etiology and pathophysiology of schizophrenia has been suggested by postmortem findings as well as by linkage analysis implicating chromosome 15q14, the region where the alpha-7 nicotinic receptor gene is located. In addition, drug probe studies show that acute nicotine administration reverses sensory gating and eye-tracking deficits associated with the genetic liability for schizophrenia. The purpose of the current study was to examine the effects of acute administration of nicotine on specific measures of smooth pursuit eye movements and visual attention. METHODS: Twenty nine subjects with schizophrenia (15 smokers and 14 nonsmokers), and 26 healthy comparison subjects (15 smokers and 11 nonsmokers) completed testing. The effects of 1 mg of nicotine, administered by nasal spray, on smooth pursuit initiation, pursuit maintenance, and predictive pursuit were examined. RESULTS: Nicotine significantly improved eye acceleration during smooth pursuit initiation in both smoker and nonsmoker patients but had no effects in healthy subjects. The fact that patient initiation eye acceleration in response to nicotine was significantly higher than in healthy subjects suggests that the lack of effect in healthy subjects was not due to ceiling effects. Nicotine significantly improved pursuit gain during maintenance at a target velocity of 18.7 deg/sec. There were no effects of nicotine on visually guided and memory saccades, or visual attention (d' from a continuous performance task). CONCLUSIONS: Nicotine showed differential effects in schizophrenic patients compared to healthy subjects. These effects of nicotine were unlikely the result of differences in vigilance or sustained attention, because saccadic peak velocity, a sensitive measure of vigilance, and continuous performance task measures were not affected by nicotine. These findings are not thought to be an artifact of nicotine withdrawal effects at baseline, because the abstinence period was very short, and there were similar effects of nicotine on initiation in nonsmoker patients. These findings suggest an abnormality in neuronal nicotinic system functioning in schizophrenic patients.

Neurophysiological markers of vulnerability to schizophrenia: sensitivity and specificity of specific quantitative eye movement measures.

Eye-tracking deficits in schizophrenic patients and relatives have generated interest in using eye movements to mark schizophrenia liability. Efforts to develop specific quantitative measures have provided insight into the nature of the deficit and suggested what underlying neurophysiological mechanisms are involved. This study used receiver operating characteristic curve analyses to evaluate and compare the sensitivity, specificity, and overall accuracy of predicting disease liability using single and combined specific and global quantitative measures. Results indicate that measures of predictive pursuit and leading saccades significantly increased predictive accuracy compared with traditional global measures. Combining specific measures provided greater predictive accuracy compared with single measures. Implications for the use of specific eye movement measures to define schizophrenia-related phenotypes in genetic studies are discussed.

Use of telephone screens improves efficiency of healthy subject recruitment.

Previous reports have indicated that a high percentage of those responding to advertisements for healthy controls for psychiatric research have personal or family histories of illness which would exclude them from such studies. We reviewed 1757 telephone screen interviews conducted over 14 years to determine: (1) the effectiveness of a screen for excluding unhealthy volunteers, (2) whether the reasons for exclusion changed over time, and (3) the final yield of healthy participants for psychiatric research after taking account of exclusions from telephone screens, no-shows and exclusions identified by direct interviews. Volunteers for psychiatric research, solicited by 43 newspaper advertisements in the Baltimore metropolitan area from 1989-2002, were initially screened by telephone and scheduled for in-person interviews if no exclusions were identified at the initial screen. More than half of the telephone respondents had major medical illnesses, substance abuse problems, depression, an Axis I disorder (not depression), a relative with a psychotic disorder or were otherwise deemed not eligible for face-to-face interview. Of the telephone respondents scheduled for direct interviews, 29% did not show up. However, the respondents who completed the direct interviews had a high likelihood of inclusion as non-ill controls for psychiatric research studies. Since Axis I and II interviews and family history take approximately 4-5 h per subject, the telephone screen is a cost-effective initial step in identifying healthy controls for psychiatric research.