S. Kristian Hill

Neuropsychological impairments in schizophrenia and psychotic Bipolar disorder: Findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study

OBJECTIVE Familial neuropsychological deficits are well established in schizophrenia but remain less well characterized in other psychotic disorders. This study from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium 1) compares cognitive impairment in schizophrenia and bipolar disorder with psychosis, 2) tests a continuum model of cognitive dysfunction in psychotic disorders, 3) reports familiality of cognitive impairments across psychotic disorders, and 4) evaluates cognitive impairment among nonpsychotic relatives with and without cluster A personality traits. METHOD Participants included probands with schizophrenia (N=293), psychotic bipolar disorder (N=227), schizoaffective disorder (manic, N=110; depressed, N=55), their first-degree relatives (N=316, N=259, N=133, and N=64, respectively), and healthy comparison subjects (N=295). All participants completed the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery. RESULTS Cognitive impairments among psychotic probands, compared to healthy comparison subjects, were progressively greater from bipolar disorder (z=-0.77) to schizoaffective disorder (manic z=-1.08; depressed z=-1.25) to schizophrenia (z=-1.42). Profiles across subtests of the BACS were similar across disorders. Familiality of deficits was significant and comparable in schizophrenia and bipolar disorder. Of particular interest were similar levels of neuropsychological deficits in relatives with elevated cluster A personality traits across proband diagnoses. Nonpsychotic relatives of schizophrenia probands without these personality traits exhibited significant cognitive impairments, while relatives of bipolar probands did not. CONCLUSIONS Robust cognitive deficits are present and familial in schizophrenia and psychotic bipolar disorder. Severity of cognitive impairments across psychotic disorders was consistent with a continuum model, in which more prominent affective features and less enduring psychosis were associated with less cognitive impairment. Cognitive dysfunction in first-degree relatives is more closely related to psychosis-spectrum personality disorder traits in psychotic bipolar disorder than in schizophrenia.

Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naïve patients with schizophrenia

The early course of neuropsychological dysfunction in schizophrenia and the impact of treatment on these deficits need to be better specified. A sample of 45 patients with schizophrenia underwent five neuropsychological evaluations from prior to treatment with antipsychotic treatment through a 2-year follow-up period. A comparison sample of 33 matched healthy individuals underwent neuropsychological evaluations at similar time points. At baseline, a generalized deficit across cognitive domains was evident for the schizophrenia sample. After 6 weeks of treatment, patients showed modest improvements in visual memory and visual perception, but a decline in verbal memory. Verbal memory performance returned to baseline levels by the 6-month follow-up while deficits in other neuropsychological domains persisted throughout the 2-year period. Relatively static and generalized neuropsychological dysfunction, evident from illness onset, is consistent with neurodevelopmental rather than neurodegenerative models of schizophrenia.

Effect of second-generation antipsychotics on cognition: current issues and future challenges

Generalized cognitive impairments are stable deficits linked to schizophrenia and key factors associated with functional disability in the disorder. Preclinical data suggest that second-generation antipsychotics could potentially reduce cognitive impairments; however, recent large clinical trials indicate only modest cognitive benefits relative to first-generation antipsychotics. This might reflect a limited drug effect in humans, a differential drug effect due to brain alterations associated with schizophrenia, or limited sensitivity of the neuropsychological tests for evaluating cognitive outcomes. New adjunctive procognitive drugs may be needed to achieve robust cognitive and functional improvement. Drug discovery may benefit from greater utilization of translational neurocognitive biomarkers to bridge preclinical and clinical proof-of-concept studies, to optimize assay sensitivity, enhance cost efficiency, and speed progress in drug development.

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.

Impairment of verbal memory and learning in antipsychotic-naive patients with first-episode schizophrenia

BACKGROUND Verbal memory deficits are of interest in schizophrenia because of the potential relationship to functional and anatomic mesial temporal lobe pathology in this disorder. The goal of this study was to characterize the nature of verbal memory impairments in antipsychotic-naïve schizophrenic patients early in the course of illness. METHODS Neuroleptic-naïve patients with schizophrenia (n=62) and healthy individuals (n=67), matched on IQ, age, sex, and parental socioeconomic status, were administered the California Verbal Learning Test (CVLT). RESULTS Schizophrenia participants performed significantly worse than healthy individuals on measures of verbal learning, short- and long-term memory, and immediate attention. Deficits in recall were related to reduced use of organizational strategies to facilitate verbal encoding and retrieval. No group differences were found in rate of forgetting or susceptibility to proactive or retroactive interference. Memory deficits had minimal relation to positive or negative symptom severity. CONCLUSIONS Schizophrenia is characterized by significant verbal memory dysfunction early in the course of illness prior to treatment with antipsychotic medications. Deficits in consistency of learning over several trials, as well as a strong relationship between semantic organizational strategies and reduced learning capacity, implicate prefrontal dysfunction as a contributor to verbal memory deficits in schizophrenia.

Neurocognitive effects of repetitive transcranial magnetic stimulation in severe major depression.

OBJECTIVE Repetitive transcranial magnetic stimulation (rTMS) is being investigated as a potential treatment for depression. Few studies have addressed the neurocognitive effects of a course of rTMS in severely depressed patients. We evaluated neurocognitive effects of a 1-4 week course (mean 3 weeks) of rTMS using an aggressive set of parameters, in 15 severely depressed subjects. METHODS A battery of neurocognitive tests relevant to attention, working memory-executive function, objective memory and motor speed were administered to 15 subjects with treatment-resistant major depression (unipolar and bipolar), before and after a course of rTMS. Mean z scores were computed for each of 4 cognitive domains and analyzed using repeated measures multivariate analysis of covariance. Significant interactions were further clarified using univariate analysis of variance. RESULTS There was no worsening of performance on any of the cognitive domains over the baseline-post rTMS period. On the contrary, evidence of modest but statistically significant improvement in performance was noted in working memory-executive function, objective memory and fine motor speed domains over the rTMS treatment period. CONCLUSIONS There was no evidence of adverse neurocognitive changes over the baseline-post rTMS period in 15 treatment-resistant depressed subjects undergoing a 3 week (mean) trial of rTMS. Significant improvements in several domains observed over the rTMS treatment period could not be explained by improved mood. Practice effects as well as other factors potentially contributing to these findings are discussed. SIGNIFICANCE rTMS is being increasingly studied as a neurophysiological probe as well as for its potential antidepressive effects. The effects on neuronal function raise appropriate questions of safety of its use at varying stimulus parameters and durations. This study contributes to the small body of evidence of the cognitive effects of rTMS in severely depressed patients.

Neurocognitive function in pediatric bipolar disorder: 3-year follow-up shows cognitive development lagging behind healthy youths

OBJECTIVE Longitudinal follow-up of neurocognitive functioning in people with pediatric bipolar disorder (PBD) was conducted to characterize the developmental trajectory of cognitive disabilities in this disorder. METHOD Patients with PBD (n = 26) and controls (HC; n = 17; mean age 11.66 +/- 2.70 years) completed cognitive testing at baseline and then again at a 3-year follow-up. Groups were matched at baseline on age, sex, race, parental socioeconomic status, general intelligence, and single-word reading ability. The PBD group received treatment guided by a standardized medication algorithm during the 3-year period. A battery of neuropsychological tests was administered to assess attention, executive function, working memory, verbal memory, visual memory, and visuospatial perception at baseline and follow-up. RESULTS At baseline and follow-up, the patients showed deficits in all of the examined domains. At 3-year follow-up, developmental progress in executive functions and verbal memory was significantly less in the patients with PBD than in the HC. Improvement on attention, working memory, visual memory, and visuospatial perception tasks in the patients with PBD was comparable to that of the HC, but the patients with PBD remained impaired in all domains relative to the HC. CONCLUSIONS The developmental delay in some neurocognitive functioning in PBD suggests that the illness disrupts cognitive development with potential lifelong implications for reduced functional ability. Treating bipolar symptoms does not seem to prevent the lag in cognitive development. This dysmaturation may be a direct effect of the illness on brain function, or it may represent indirect consequences of psychopathology or medications on cognitive development.

Change in the relationship between anhedonia and functional deficits over a 20-year period in individuals with schizophrenia.

Although early theorists suggested that deficits in emotional experience be considered a hallmark characteristic of schizophrenia, there has been limited research, and inconsistent findings, on the relationship between anhedonia and functional capacity in individuals after the onset of schizophrenia. Stronger relationships have typically been reported for chronic samples in contrast to first episode samples, although it is not clear whether this is due to selection biases that influence recruitment in these different groups, or whether results reflect a change over the course of illness. The current longitudinal study examined the relationship between physical anhedonia and functional status in a sample of 61 individuals with schizophrenia at regular intervals over a 20-year period. Subjects were recruited into the study during an index hospitalization and completed assessments at 2-, 4.5-, 7.5-, 10-, 15-, and 20-year follow-ups. Analyses indicate that the relationship between anhedonia and impairments increases over time, although mean performance on these measures is stable across this same time period. These results suggest increasing convergence of impairments in emotional, adaptive, and cognitive capacities over time, with physical anhedonia associated with poorer outcome.

Reduced Levels of Vasopressin and Reduced Behavioral Modulation of Oxytocin in Psychotic Disorders

Oxytocin (OT) and arginine vasopressin (AVP) exert robust influence on social affiliation and specific cognitive processes in healthy individuals. Abnormalities in these neuroendocrine systems have been observed in psychotic disorders, but their relation to impairments in behavioral domains that these endocrines modulate is not well understood. We compared abnormalities of OT and AVP serum concentrations in probands with schizophrenia (n = 57), schizoaffective disorder (n = 34), and psychotic bipolar disorder (n = 75); their first-degree relatives without a history of psychosis (n = 61, 43, 91, respectively); and healthy controls (n = 66) and examined their association with emotion processing and cognition. AVP levels were lower in schizophrenia (P = .002) and bipolar probands (P = .03) and in relatives of schizophrenia probands (P = .002) compared with controls. OT levels did not differ between groups. Familiality estimates were robust for OT (h(2) = 0.79, P = 3.97e-15) and AVP (h(2) = 0.78, P = 3.93e-11). Higher levels of OT were associated with better emotion recognition (β = 0.40, P < .001) and general neuropsychological function (β = 0.26, P = .04) in healthy controls as expected but not in any proband or relative group. In schizophrenia, higher OT levels were related to greater positive symptom severity. The dissociation of OT levels and behavioral function in all proband and relative groups suggests that risk and illness factors associated with psychotic disorders are not related to reduced OT levels but to a disruption in the ability of physiological levels of OT to modulate social cognition and neuropsychological function. Decreased AVP levels may be a marker of biological vulnerability in schizophrenia because alterations were seen in probands and relatives, and familiality was high.