Margret S.H. Harris

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.

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.

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.

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.

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.

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.

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.

Sensorimotor Transformation Deficits for Smooth Pursuit in First-Episode Affective Psychoses and Schizophrenia

BACKGROUND Smooth pursuit deficits are an intermediate phenotype for schizophrenia that may result from disturbances in visual motion perception, sensorimotor transformation, predictive mechanisms, or alterations in basic oculomotor control. Which of these components are the primary causes of smooth pursuit impairments and whether they are impaired similarly across psychotic disorders remain to be established. METHODS First-episode psychotic patients with bipolar disorder (n = 34), unipolar depression (n = 24), or schizophrenia (n = 77) and matched healthy participants (n = 130) performed three smooth pursuit tasks designed to evaluate different components of pursuit tracking. RESULTS On ramp tasks, maintenance pursuit velocity was reduced in all three patients groups with psychotic bipolar patients exhibiting the most severe impairments. Open loop pursuit velocity was reduced in psychotic bipolar and schizophrenia patients. Motion perception during pursuit initiation, as indicated by the accuracy of saccades to moving targets, was not impaired in any patient group. Analyses in 138 participants followed for 6 weeks, during which patients were treated and psychotic symptom severity decreased, and no significant change in performance in any group was revealed. CONCLUSIONS Sensorimotor transformation deficits in all patient groups suggest a common alteration in frontostriatal networks that dynamically regulate gain control of pursuit responses using sensory input and feedback about performance. Predictive mechanisms appear to be sufficiently intact to compensate for this deficit across psychotic disorders. The absence of significant changes after acute treatment and symptom reduction suggests that these deficits appear to be stable over time.