Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia.

RATIONALE: Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated. OBJECTIVES: The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment. METHODS: Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients' level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions. RESULTS: Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment. CONCLUSIONS: These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects.

Negative impact of self-stigmatization on attitude toward medication adherence in patients with psychosis.

BACKGROUND: Up to 75% of patients suffering from schizophrenia do not take their antipsychotic medication in the way it is prescribed. Nonadherence has been shown to be associated with poorer therapy outcomes, higher hospitalization rates, and increased costs for health care systems. One important contributing factor to negative attitudes toward medication adherence may be self-stigmatization. METHODS: 23 inpatients with a schizophrenia spectrum disorder, all receiving antipsychotic treatment, were assessed for attitude toward medication adherence (using the Rating of Medication Influences [ROMI] scale), subjective well-being under medication (using the Subjective Well-Being under Neuroleptics Scale), and self-stigmatization (using the Internalized Stigma of Mental Illness Inventory). Multiple linear regression analyses were used to predict attitude toward medication adherence from demographic and clinical data and level of self-stigmatization. RESULTS: Patients' gender and their level of self-stigmatization explained 29% of the variance in total attitude toward medication. Inclusion of the self-stigmatization subscore for alienation resulted in an increase of explained variance to 36%. Follow-up analyses of the ROMI pro-adherence subscale scores revealed no correlations with any assessed variables. In contrast, 70% of the variance in the ROMI nonadherence subscale scores was explained by greater alienation, higher number of experienced side effects, less subjective well-being under medication, and female gender. CONCLUSIONS: Our findings imply that reducing the extent of self-stigmatization, especially the feeling of being alienated from society, could improve a negative attitude toward medication adherence in psychosis patients. Cognitive-behavioral therapy offers a variety of therapeutic strategies that could support patients in developing a more positive self-image and in more readily accepting antipsychotic medication as a tool for reaching personal life goals.

Association of variants in DRD2 and GRM3 with motor and cognitive function in first-episode psychosis.

Similar smooth pursuit eye tracking dysfunctions are present across psychotic disorders. They include pursuit initiation and maintenance deficits that implicate different functional brain systems. This candidate gene study examined psychosis-related genotypes regulating dopamine and glutamate neurotransmission in relation to these pursuit deficits. One hundred and thirty-eight untreated first-episode patients with a psychotic disorder were genotyped for four markers in DRD2 and four markers in GRM3. The magnitude of eye movement abnormality in patients was defined in relation to performance of matched healthy controls (N = 130). Eighty three patients were followed after 6 weeks of antipsychotic treatment. At baseline, patients with a -141C deletion in DRD2 rs1799732 had slower initiation eye velocity and longer pursuit latency than CC insertion carriers. Further, GRM3 rs274622_CC carriers had poorer pursuit maintenance than T-carriers. Antipsychotic treatment resulted in prolonged pursuit latency in DRD2 rs1799732_CC insertion carriers and a decline in pursuit maintenance in GRM3 rs6465084_GG carriers. The present study demonstrates for the first time that neurophysiological measures of motor and neurocognitive deficits in patients with psychotic disorders have different associations with genes regulating dopamine and glutamate systems, respectively. Alterations in striatal D2 receptor activity through the -141C Ins/Del polymorphism could contribute to pursuit initiation deficits in psychotic disorders. Alterations in GRM3 coding for the mGluR3 protein may impair pursuit maintenance by compromising higher perceptual and cognitive processes that depend on optimal glutamate signaling in corticocortical circuits. DRD2 and GRM3 genotypes also selectively modulated the severity of adverse motor and neurocognitive changes resulting from antipsychotic treatment.

Facial emotion recognition in first-episode schizophrenia and bipolar disorder with psychosis.

Patients with schizophrenia and bipolar disorder have difficulties recognizing facial expressions of emotion. Differences in deficits between these disorders and the effects of treating acute symptoms of illness with antipsychotic medication on these deficits are not well characterized. First-episode patients with schizophrenia (n=24) and psychotic bipolar I disorder (n=16) were compared to a healthy control group (n=32) on the Penn Emotional Acuity Test. Patients were studied during an acute psychotic episode and after seven weeks of treatment with antipsychotic medication. During acute psychosis, bipolar patients showed deficits recognizing subtle facial expressions of happiness and sadness, and this deficit did not resolve with treatment. Schizophrenia patients similarly had difficulty recognizing subtle happy faces during acute illness that also did not resolve with treatment. In addition, problems recognizing subtle expressions of sadness among schizophrenia patients were apparent after treatment. Poorer emotion recognition at follow-up was related to negative symptom severity for schizophrenia patients. These findings highlight the severity and persistence of emotion recognition deficits early in the course of psychotic bipolar disorder and schizophrenia, and demonstrate an association of emotion processing deficits to negative symptoms in schizophrenia during periods of relative clinical stability.

Peripheral vasopressin but not oxytocin relates to severity of acute psychosis in women with acutely-ill untreated first-episode psychosis.

BACKGROUND: In women with chronic schizophrenia, higher levels of peripheral oxytocin have been associated with lower levels of positive but not negative symptoms. Sex-specific associations between endogenous levels of oxytocin (OT) and arginine vasopressin (AVP) with clinical symptoms and cognition in untreated early course patients have not been examined. METHOD: Clinical ratings and neuropsychological testing were performed in thirty-eight acutely ill, unmedicated first-episode schizophrenia patients (14 women, 24 men). Serum hormone assays were obtained in patients and thirty-eight demographically similar healthy controls. RESULTS: Patients demonstrated increased AVP levels compared to controls (p = 0.01). Higher AVP levels were associated with greater positive symptoms (r = 0.58, p = 0.03) and worse verbal learning (r = -0.63, p = 0.02) in female, but not male, patients. OT levels did not statistically differ between patients and controls, and were unrelated to clinical symptoms or cognition in patients. CONCLUSION: Results suggest an association of endogenous AVP with increased positive symptom severity and worse cognition in untreated female, but not male, schizophrenia patients. Findings support the role of neuroendocrine alterations in acute psychosis and the importance of examining sex-specific neuroendocrine alterations early in the course of schizophrenia.

Phenomenology of first-episode psychosis in schizophrenia, bipolar disorder, and unipolar depression: a comparative analysis.

OBJECTIVE: This study sought to identify similarities and differences in symptom characteristics at initial presentation of first psychotic episodes in schizophrenia, bipolar disorder and unipolar depression. METHODS: The Structured Interview for DSM-IV (SCID) and Positive and Negative Syndrome Scale (PANSS) were administered to consecutive admission study-eligible patients (n=101) presenting for treatment during their first acute phase of psychotic illness. Forty-nine percent of patients met diagnostic criteria for schizophrenia, 29% for psychotic bipolar disorder and 22% for unipolar depression with psychosis. The PANSS was analyzed using five-factor scoring that included Positive, Negative, Cognitive, Excitement, and Depression factors, and composite cluster scores that assessed Anergia, Thought Disturbance, and Paranoia. RESULTS: Schizophrenia and bipolar disorder patients demonstrated significantly more Positive symptoms, Thought Disturbance and Paranoia than unipolar depressed patients. Schizophrenia and unipolar depressed patients demonstrated significantly more Negative symptoms and Anergia than bipolar patients. Patients with schizophrenia reported more severe Cognitive Disorganization than patients with either bipolar disorder or uni-polar depression (p<.05). CONCLUSIONS: Findings from this study demonstrate an informative pattern of similarities and differences in the phenomenology of psychotic disorders at first illness presentation. Commonalities in symptom profiles reflect considerable symptom overlap among psychotic disorders and, thus, the importance of multidimensional differential diagnosis for these conditions. The differences across disorders in Positive and Negative symptom severity, Thought Disorder, Paranoia, and Anergia, and especially the higher level of Cognitive Disorganization seen in schizophrenia patients, point to clinically informative differences across these disorders that are relevant to clinical diagnostic practice and models of psychopathology.

Altered transfer of visual motion information to parietal association cortex in untreated first-episode psychosis: implications for pursuit eye tracking.

Visual motion processing and its use for pursuit eye movement control represent a valuable model for studying the use of sensory input for action planning. In psychotic disorders, alterations of visual motion perception have been suggested to cause pursuit eye tracking deficits. We evaluated this system in functional neuroimaging studies of untreated first-episode schizophrenia (N=24), psychotic bipolar disorder patients (N=13) and healthy controls (N=20). During a passive visual motion processing task, both patient groups showed reduced activation in the posterior parietal projection fields of motion-sensitive extrastriate area V5, but not in V5 itself. This suggests reduced bottom-up transfer of visual motion information from extrastriate cortex to perceptual systems in parietal association cortex. During active pursuit, activation was enhanced in anterior intraparietal sulcus and insula in both patient groups, and in dorsolateral prefrontal cortex and dorsomedial thalamus in schizophrenia patients. This may result from increased demands on sensorimotor systems for pursuit control due to the limited availability of perceptual motion information about target speed and tracking error. Visual motion information transfer deficits to higher-level association cortex may contribute to well-established pursuit tracking abnormalities, and perhaps to a wider array of alterations in perception and action planning in psychotic disorders.

Response suppression deficits in treatment-naïve first-episode patients with schizophrenia, psychotic bipolar disorder and psychotic major depression.

Recent evidence indicates common genetic, neurobiological, and psychopharmacological aspects of schizophrenia and psychotic affective disorders. Some similarities in neurocognitive deficits associated with these disorders have also been reported. We investigated performance on antisaccade and visually-guided saccade tasks in treatment-naïve first-episode psychosis patients (schizophrenia n=59, major depression n=15, bipolar disorder n=9), matched non-psychotic major depression patients (n=40), and matched healthy individuals (n=106). All psychosis groups displayed elevated antisaccade error rates relative to healthy individuals. Antisaccade latencies were elevated in schizophrenia, but no significant error rate or latency differences were observed among psychosis groups. For schizophrenia only, shorter visually guided saccade latencies were associated with higher antisaccade error rates. Schizophrenia was also the only group without a significant relationship between visually guided and antisaccade latencies. Reflexive saccades were unimpaired except in psychotic unipolar depression, where saccades were hypometric. As in schizophrenia, antisaccade abnormalities are present in affective psychoses, even early in the course of illness and prior to treatment. Disturbances in frontostriatal systems are believed to occur in both affective psychoses and schizophrenia, potentially causing some similar cognitive abnormalities across psychotic disorders. However, the distinct pattern of dysfunction in schizophrenia across oculomotor paradigms suggests possible unique causes of their observed oculomotor performance deficits.

A comparison of neuropsychological dysfunction in first-episode psychosis patients with unipolar depression, bipolar disorder, and schizophrenia.

The severity and profile of cognitive dysfunction in first episode schizophrenia and psychotic affective disorders were compared before and after antipsychotic treatment. Parallel recruitment of consecutively admitted study-eligible first-episode psychotic patients (30 schizophrenia, 22 bipolar with psychosis, and 21 psychotic depression) reduced confounds of acute and chronic disease/medication effects as well as differential treatment and course. Patient groups completed a neuropsychological battery and were demographically similar to healthy controls (n=41) studied in parallel. Prior to treatment, schizophrenia patients displayed significant deficits in all cognitive domains. The two psychotic affective groups were also impaired overall, generally performing intermediate between the schizophrenia and healthy comparison groups. No profile differences in neuropsychological deficits were observed across patient groups. Following 6 weeks of treatment, no patient group improved more than practice effects seen in healthy individuals, and level of performance improvement was similar for affective psychosis and schizophrenia groups. Although less severe in psychotic affective disorders, similar profiles of generalized neuropsychological deficits were observed across patient groups. Recovery of cognitive function after clinical stabilization was similar in mood disorders and schizophrenia. To the extent that these findings are generalizable, neuropsychological deficits in psychotic affective disorders, like schizophrenia, may be trait-like deficits with persistent functional implications.

Effects of risperidone on procedural learning in antipsychotic-naive first-episode schizophrenia.

Studies of procedural learning in medicated schizophrenia patients using predictive saccade paradigms have consistently demonstrated hypometric predictive responses. Findings from antipsychotic-naive schizophrenia patients indicate fewer or no deficits. This pattern of findings suggests that antipsychotic medications might adversely affect frontostriatal systems supporting procedural learning on this task. The accuracy and latency of predictive saccades were assessed in 25 antipsychotic-naive first-episode schizophrenia patients and 22 matched healthy individuals. Patients were retested after 6 weeks of treatment with risperidone. Healthy individuals were reevaluated after a similar time period. The ability to learn to time response initiation in anticipation of target appearance (target prediction) was not impaired in patients before or after treatment. In contrast, although no deficits were evident before treatment initiation, after treatment patients showed a marked decrease in the accuracy of predictive but not sensory-guided responses. The findings from pretreatment testing indicate that procedural learning is a relatively unaffected cognitive domain in antipsychotic-naive first-episode schizophrenia. Although treatment-emergent extrapyramidal symptoms were minimal, these data suggest that D2 antagonism in striatum after risperidone treatment was sufficiently robust to disrupt the generation of planned volitional behavior guided by internalized representations.

Effects of second-generation antipsychotic medication on smooth pursuit performance in antipsychotic-naive schizophrenia.

CONTEXT: Analyses of smooth pursuit eye movement parameters in patients with schizophrenia provide information about the integrity of neural networks mediating motion perception, sensorimotor transformation, and cognitive processes such as prediction. Although pursuit eye tracking deficits have been widely reported in schizophrenia, the integrity of discrete components of pursuit responses and the effect of second-generation antipsychotic medication on them are not well established. OBJECTIVE: To examine different components of smooth pursuit performance in antipsychotic-naive patients with schizophrenia before and after treatment with second-generation antipsychotic medication. DESIGN, SETTING, AND PARTICIPANTS: Thirty-three antipsychotic-naive patients with schizophrenia performed 3 different smooth pursuit paradigms designed to evaluate specific components of the pursuit response. All of the patients were retested after 6 weeks of treatment with risperidone or olanzapine. Testing was also performed with 39 matched healthy individuals. Thirteen patients and 21 healthy participants were retested after 26 and 52 weeks. MAIN OUTCOME MEASURES: Pursuit initiation, maintenance gain (ratio of eye velocity over target velocity), and frequency of catch-up saccades during pursuit maintenance. RESULTS: Prior to treatment, pursuit gain when tracking less predictable ramp targets tended to be reduced, latency of pursuit initiation was speeded, and catch-up saccade frequency was increased during predictive pursuit. After antipsychotic treatment initiation, pursuit gain decreased with ramp targets, indicating treatment-emergent impairments in sensorimotor processing. No changes were observed for predictive pursuit. Exploratory analyses in the subgroup with follow-up to 1 year revealed that these effects continued through long-term follow-up with some partial normalization at 1 year. Deficits were unrelated to drug dosage and clinical ratings. CONCLUSIONS: Impaired sensorimotor function was observed after initiation of second-generation antipsychotic medications, which may be explained by their serotonergic antagonism of brainstem sensorimotor systems. Predictive mechanisms supported by frontostriatal-cerebellar circuitry were not affected by treatment initiation and appear able to compensate for treatment-emergent sensorimotor impairments during predictive tracking.

Neurocognitive allied phenotypes for schizophrenia and bipolar disorder.

Psychiatric disorders are genetically complex and represent the end product of multiple biological and social factors. Links between genes and disorder-related abnormalities can be effectively captured via assessment of phenotypes that are both associated with genetic effects and potentially contributory to behavioral abnormalities. Identifying intermediate or allied phenotypes as a strategy for clarifying genetic contributions to disorders has been successful in other areas of medicine and is a promising strategy for identifying susceptibility genes in complex psychiatric disorders. There is growing evidence that schizophrenia and bipolar disorder, rather than being wholly distinct disorders, share genetic risk at several loci. Further, there is growing evidence of similarity in the pattern of cognitive and neurobiological deficits in these groups, which may be the result of the effects of these common genetic factors. This review was undertaken to identify patterns of performance on neurocognitive and affective tasks across probands with schizophrenia and bipolar disorder as well as unaffected family members, which warrant further investigation as potential intermediate trait markers. Available evidence indicates that measures of attention regulation, working memory, episodic memory, and emotion processing offer potential for identifying shared and illness-specific allied neurocognitive phenotypes for schizophrenia and bipolar disorder. However, very few studies have evaluated neurocognitive dimensions in bipolar probands or their unaffected relatives, and much work in this area is needed.

Reduced attentional engagement contributes to deficits in prefrontal inhibitory control in schizophrenia.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Oculomotor and neuropsychological effects of antipsychotic treatment for schizophrenia.

Cognitive enhancement has become an important target for drug therapies in schizophrenia. Treatment development in this area requires assessment approaches that are sensitive to procognitive effects of antipsychotic and adjunctive treatments. Ideally, new treatments will have translational characteristics for parallel human and animal research. Previous studies of antipsychotic effects on cognition have relied primarily on paper-and-pencil neuropsychological testing. No study has directly compared neurophysiological biomarkers and neuropsychological testing as strategies for assessing cognitive effects of antipsychotic treatment early in the course of schizophrenia. Antipsychotic-naive patients with schizophrenia were tested before treatment with risperidone and again 6 weeks later. Matched healthy participants were tested over a similar time period. Test-retest reliability, effect sizes of within-subject change, and multivariate/univariate analysis of variance were used to compare 3 neurophysiological tests (visually guided saccade, memory-guided saccade, and antisaccade) with neuropsychological tests covering 4 cognitive domains (executive function, attention, memory, and manual motor function). While both measurement approaches showed robust neurocognitive impairments in patients prior to risperidone treatment, oculomotor biomarkers were more sensitive to treatment-related effects on neurocognitive function than traditional neuropsychological measures. Further, unlike the pattern of modest generalized cognitive improvement suggested by neuropsychological measures, the oculomotor findings revealed a mixed pattern of beneficial and adverse treatment-related effects. These findings warrant further investigation regarding the utility of neurophysiological biomarkers for assessing cognitive outcomes of antipsychotic treatment in clinical trials and in early-phase drug development.

Antipsychotic drugs exacerbate impairment on a working memory task in first-episode schizophrenia.

BACKGROUND: This study sought to replicate previous findings of worsened performance on a translational spatial working memory task among antipsychotic-naïve first-episode schizophrenia patients after antipsychotic treatment and to extend these findings by examining whether changes in the allocation of covert attention contribute to this effect. METHODS: Fourteen antipsychotic-naïve schizophrenia patients performed an oculomotor delayed response task before and 6 weeks after antipsychotic treatment (risperidone n = 11; olanzapine n = 3). Fifteen matched healthy individuals were studied in parallel. RESULTS: Patients' pretreatment deficit in accurately remembering spatial locations was exacerbated by antipsychotic treatment, consistent with previous findings; however, this occurred only when covert attention was directed away from remembered locations during delay periods. CONCLUSIONS: Disruption in the allocation of covert attention might contribute to patients' decline in spatial working memory after antipsychotic treatment. Alterations in prefrontal dopaminergic systems or reduced thalamocortical drive might account for this apparent adverse cognitive effect of antipsychotic treatment.

Adverse effects of risperidone on spatial working memory in first-episode schizophrenia.

CONTEXT: Working memory impairments are a central neurocognitive feature of schizophrenia. The nature of these impairments early in the course of illness and the impact of antipsychotic drug treatment on these deficits are not well understood. The oculomotor delayed response task is a translational spatial working memory paradigm used to characterize the neurophysiologic and neurochemical aspects of working memory in the primate brain. OBJECTIVE: To examine oculomotor delayed response task performance in patients with first-episode schizophrenia before and after antipsychotic drug treatment. DESIGN, SETTING, AND PARTICIPANTS: Twenty-five antipsychotic drug-naive, acutely ill patients with first-episode schizophrenia performed an oculomotor delayed response task at baseline before any drug treatment and again after 6 weeks of risperidone treatment. Twenty-five matched healthy controls were studied in parallel. MAIN OUTCOME MEASURE: Accuracy for remembered spatial locations on an oculomotor delayed response task. RESULTS: Before treatment, patients demonstrated baseline impairment in the ability to maintain spatial location information in working memory at longer delay-period durations (8 seconds), when maintenance demands on working memory were greatest. After 6 weeks of risperidone treatment and significant clinical improvement, this pretreatment impairment worsened such that patients were uniformly impaired across all delay period durations (1-8 seconds). This occurred in the absence of any generalized adverse effect on oculomotor systems or significant extrapyramidal adverse effects. CONCLUSIONS: Deficits in the maintenance of spatial information in working memory are present early in the course of illness. Risperidone treatment exacerbated these deficits, perhaps by impairing the encoding of information into working memory. Studies with nonhuman primates performing oculomotor delayed response tasks suggest that the apparent adverse effect of risperidone might result from treatment-related changes in modulatory functions of prefrontal D1 receptor systems.

Longitudinal studies of antisaccades in antipsychotic-naive first-episode schizophrenia.

BACKGROUND: Prefrontal cortical dysfunctions, including disturbances in adaptive context-specific behavior, have been reported in neuropsychological and brain imaging studies of schizophrenia. Some data suggest that treatment with antipsychotic medications may ameliorate these deficits. METHOD: We investigated antisaccade performance in 39 antipsychotic-naive, first-episode schizophrenia patients who were re-evaluated 6 weeks after treatment initiation. A group of matched healthy subjects were examined at similar time-points. Patients and healthy individuals available for longer-term testing were re-assessed 26 and 52 weeks after initial testing. RESULTS: Before treatment, patients showed elevated rates of response suppression errors and prolonged latencies of correct antisaccades. Increased rates of antisaccade errors were associated with faster response latencies during a separate, visually guided saccade task, but only prior to treatment. Throughout the 1-year follow-up, patients progressively improved in their ability to voluntarily suppress context-inappropriate behavior. Although treatment assignment was by clinician choice, results of exploratory analyses revealed that patients treated with risperidone progressively planned and initiated correct antisaccades more quickly than patients receiving haloperidol. CONCLUSIONS: Deficits in the voluntary control of spatial attention are exaggerated during acute episodes of illness, but remain an enduring aspect of prefrontal dysfunction in schizophrenia even after treatment. During acute illness, speeded sensorimotor transformations may compound these deficits and contribute to the heightened distractibility associated with acute psychosis. Continued improvement in task performance throughout the 1-year follow-up suggests that partial normalization of prefrontal cognitive functions resulting from antipsychotic treatment may have a longer and more gradual time course than the reduction of acute psychotic symptoms.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Commentary: eye movement research with clinical populations.

The preceding set of chapters span the disciplines of neurology and psychiatry, and provide a diverse introduction to clinical eye movement research. They illustrate how oculomotor paradigms can be used to learn about acute and chronic perturbations in brain function, disturbances in brain development, disturbances in sensorimotor as well as cognitive systems, and the effects of therapeutic and illicit drugs on brain function. This commentary discusses these contributions, provides an overview of broad methodological issues involved in applying eye movement studies to psychiatric populations using the antisaccade task as an exemplar, and considers the potential of collaborations between eye movement and brain imaging researchers to advance understanding of clinical eye movement abnormalities and of what they reveal about the organization of the oculomotor system.