Dysregulation In Schizophrenia Research Articles

Altered activation and functional connectivity of neural systems supporting cognitive control of emotion in psychosis proneness

Emotion regulation processes, such as reappraisal, are thought to operate through interactions between prefrontal emotion-control regions and subcortical emotion-generation regions such as the amygdala. Impairments in emotional processing and regulation have been reported in schizophrenia and at-risk populations. Psychometric measures may be used to detect vulnerability to schizophrenia in non-clinical samples, or psychosis proneness (PP). It has been shown that individuals with PP have a more than tenfold increased risk of developing a schizophrenia-spectrum disorder. In the present study, we used fMRI to examine the neural dynamics underlying reappraisal in such a sample. 600 undergraduate students completed the Community Assessment of Psychic Experiences Questionnaire (CAPE), positive subscale. Two groups were subsequently formed from the extremes of the distribution (total N=34). Blood-oxygenated-level-dependent activity elicited with a task involving 3 conditions was analyzed: viewing neutral pictures, viewing negative pictures, and reappraising negative pictures. Subjects reported the strength of experienced negative affect after each trial. Functional connectivity between prefrontal control regions and amygdala was investigated. At the behavioral level, both groups reported successful diminishment of experienced negative emotion. However, high psychosis-prone subjects showed stronger activation than low subjects in a number of prefrontal regions during reappraisal, relative to attending to negative pictures. The amygdala response to negative stimuli was decreased through reappraisal only in the low group. Functional connectivity analysis revealed less prefrontal-amygdala coupling in high psychosis-prone subjects. Thus, reduced cognitive control of emotion at a neural level appeared to be associated with PP. These findings extend the hypothesis of emotion dysregulation in schizophrenia to PP, and suggest that emotion regulation difficulties may be at the core of a vulnerability to psychosis.

Preliminary evidence of ubiquitin proteasome system dysregulation in schizophrenia and bipolar disorder: Convergent pathway analysis findings from two independent samples

Schizophrenia (SCZ) and bipolar disorder (BPD) are polygenic disorders with many genes contributing to their etiologies. The aim of this investigation was to search for dysregulated molecular and cellular pathways for these disorders as well as psychosis. We conducted a blood-based microarray investigation in two independent samples with SCZ and BPD from San Diego (SCZ = 13, BPD = 9, control = 8) and Taiwan (SCZ = 11, BPD = 14, control = 16). Diagnostic groups were compared to controls, and subjects with a history of psychosis [PSYCH(+): San Diego (n = 6), Taiwan (n = 14)] were compared to subjects without such history [PSYCH(-): San Diego (n = 11), Taiwan (n = 14)]. Analyses of covariance comparing mean expression levels on a gene-by-gene basis were conducted to generate the top 100 significantly dysregulated gene lists for both samples by each diagnostic group. Gene lists were imported into Ingenuity Pathway Analysis (IPA) software. Results showed the ubiquitin proteasome pathway (UPS) was listed in the top ten canonical pathways for BPD and psychosis diagnostic groups across both samples with a considerably low likelihood of a chance occurrence (P = 0.001). No overlap in dysregulated genes populating these pathways was observed between the two independent samples. Findings provide preliminary evidence of UPS dysregulation in BPD and psychosis as well as support further investigation of the UPS and other molecular and cellular pathways for potential biomarkers for SCZ, BPD, and/or psychosis.

Antipsychotic drug use is correlated with CRP40/mortalin mRNA expression in the dorsolateral prefrontal cortex of human postmortem brain specimens

Heat shock proteins act as intracellular chaperones by assisting with proper protein folding in response to various cellular stresses. In doing so, these proteins protect the cell from unwanted protein aggregation, which in turn, plays an important role in the pathogenesis of numerous disorders. Previous reports from our laboratory have described a 40 kDa catecholamine regulated heat shock-like protein (CRP40), an alternate gene product of the 70 kDa mitochondrial heat shock protein, mortalin. CRP40 shares an intimate association with dopaminergic activity, specifically as it pertains to dopamine dysregulation in schizophrenia. This study investigates human CRP40/mortalin mRNA expression within dorsolateral prefrontal cortex postmortem specimens from normal control, schizophrenic and bipolar patients obtained from the Stanley Medical Research Institute. Real-time polymerase chain reaction was carried out for all patient samples ( n = 105; n = 35 per group) in a blinded manner. No significant alterations in CRP40/mortalin mRNA expression levels were observed between control, bipolar and schizophrenic patients. However, multiple regression demonstrated a distinct positive correlation between CRP40/mortalin mRNA expression and lifetime use of antipsychotic drugs within the schizophrenic patient profile, after controlling for important confounding factors. Thus, the data suggest that human CRP40/mortalin is modulated by dopaminergic activity and may act to protect neurons from excess catecholamine activity in regions of the brain associated with psychosis.

Cortical Development and Glutamatergic Dysregulation in Schizophrenia

Brains of patients with schizophrenia (SZ) show both anatomical and functional deficits that suggest aberrant glutamate neurotransmission. Historically, many studies have addressed neurochemical changes in glutamate and its metabolites in various brain regions and cerebrospinal fluid in patients with SZ and compared them with those in normal control subjects. Alteration in molecular disposition associated with glutamate signaling has also been addressed by receptor binding assays. Although all such results are not perfectly in complete accord, an approach with 1H magnetic resonance spectroscopy (MRS) indicates more consistently that the levels of N-acetylaspartate (NAA)—a marker associated with glutamate synapses and signaling—are decreased in SZ brains, especially in the frontal cortex, temporal cortex, and thalamus ( 1 McCullumsmith R.E. Clinton S.M. Meador-Woodruff J.H. Schizophrenia as a disorder of neuroplasticity. Int Rev Neurobiol. 2004; 59: 19-45 Crossref PubMed Scopus (63) Google Scholar ). More recent genetic studies and molecular expression profiling have supported the notion of disturbed neurotransmission and synaptic connectivity ( 2 Jaaro-Peled H. Hayashi-Takagi A. Seshadri S. Kamiya A. Brandon N.J. Sawa A. Neurodevelopmental mechanisms of schizophrenia: Understanding disturbed postnatal brain maturation through neuregulin-1/ErbB4 and DISC1. Trens Neuroscienc. 2009; Google Scholar ). Genetic susceptibility factors for SZ identified through association study and cytogenetic approaches are enriched in the dendritic spine, the key postsynaptic structure, including Neuregulin-1, ErbB4, and regulator of G-protein signaling 4. Microarray analysis, an unbiased method for gene expression profiling, also provides evidence that expression of synaptic molecules is decreased in SZ. A decrease in dendritic spines is reported in SZ ( 2 Jaaro-Peled H. Hayashi-Takagi A. Seshadri S. Kamiya A. Brandon N.J. Sawa A. Neurodevelopmental mechanisms of schizophrenia: Understanding disturbed postnatal brain maturation through neuregulin-1/ErbB4 and DISC1. Trens Neuroscienc. 2009; Google Scholar , 3 Lewis D.A. Gonzalez-Burgos G. Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology. 2008; 33: 141-165 Crossref PubMed Scopus (309) Google Scholar ), consistent with these findings.

Electrocardiographical P Wave Changes After Electroconvulsive Therapy in Patients With Schizophrenia

Cardiac ventricular conduction has been studied in patients with schizophrenia who have undergone electroconvulsive therapies while they were drug-naive or drug-free or on drug regimens; however, atrial conduction has not been studied in this setting. We aimed to measure atrial and ventricular conduction changes in hospitalized patients with schizophrenia after convulsive therapy. Fifteen people with schizophrenia and 15 healthy people enrolled in the study. The participants were assessed for fasting blood glucose and electrolyte levels before the study. All patients were receiving atypical antipsychotics. The electrocardiography records were obtained before the first convulsive therapy and after the third session. The baseline P minimum duration in the patient group was significantly smaller than healthy controls. There was a significant increase in patients' P maximum duration after the third convulsive therapy session (P < 0.05). The differences in P Wave Dispersion, QTc, and QT Dispersion between baseline and after the third session in patients were not statistically significant (P > 0.05). The lower P wave duration minimum may be related to autonomic nervous system dysregulation in schizophrenia because an acute episode of the illness and/or antipsychotic drugs. In addition, we propose that electroconvulsive therapy alone or in combination with atypical antipsychotics may influence atrial conduction as evidenced by the significantly prolonged P wave maximum.

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

Emotion dysregulation in schizophrenia: Reduced amplification of emotional expression is associated with emotional blunting

A prominent emotional disturbance in schizophrenia is clinically evident in blunted affect, often observed as reduced emotional expressivity alongside the individual's report of normal or heightened emotional experience. It has been suggested that this disjunction between the experience and expression of emotion may reflect problems with the regulation of emotional expression. The present study thus set out to examine the capacity to engage in particular emotion regulatory strategies, and specifically, the ability to amplify the emotional expression of an experienced emotion (‘amplification’) or suppress the emotional expression of an experienced emotion (‘suppression’) whilst watching film clips selected to elicit amusement. Twenty nine participants with schizophrenia and 30 demographically matched non-clinical controls were asked to watch three different amusing film clips, whilst engaging in different regulatory strategies. The results indicate that participants with schizophrenia have difficulties with the amplification (but not suppression) of emotion expressive behavior. These difficulties are significantly correlated with total negative symptoms experienced, particularly emotional blunting.

Review: Glutamate and dopamine dysregulation in schizophrenia — a synthesis and selective review

The dopamine hypothesis of schizophrenia is the principal explanatory model of antipsychotic drug action. Recent discoveries extend our understanding of the neurochemistry of schizophrenia, with increasing evidence of dysfunction in glutamate and GABA as well as dopamine systems. In this review, we study the evidence for dopaminergic dysfunction in schizophrenia, drawing data from neurochemical imaging studies. We also review the NMDA receptor hypofunction hypothesis of schizophrenia as a supplementary explanatory model for the illness. We examine predictions made by the NMDA receptor hypofunction hypothesis and consider how they fit with current neurochemical findings in patients and animal models. We consider the case for glutamatergic excitotoxicity as a key process in the development and progression of schizophrenia, and suggest ways in which glutamate and dopamine dysregulation may interact in the condition.

Perinatal MK-801 treatment affects age-related changes in locomotor activity from childhood to later adulthood in rats

Neuronal degeneration underlying the pathology of schizophrenia is already present during childhood. However, most of these studies were done in adult humans or animals. The present study therefore investigated age-related changes of behavior in an innovative version of the Open Field Maze following perinatal chronic administration of the noncompetitive N-methyl- d-aspartate antagonist MK-801. The waxing and waning pattern of locomotor activity during aging with a peak around the age of 90 days was profoundly attenuated by MK-801. MK-801 further reduced locomotion and body weight in mature rats. However, it increased explorative behavior in immature rats. Therefore, the chronic perinatal administration of MK-801 seems to be a model to investigate the pathological mechanisms of psychomotor retardation and body weight dysregulation in schizophrenia.

Combined spect and MRS study of subcortical dopamine dysregulation in schizophrenia

Combined spect and MRS study of subcortical dopamine dysregulation in schizophrenia

Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: III. Retinoids.

Present antipsychotic drugs, whose clinical activity correlates with direct binding to dopamine D2 or other receptors, alleviate some of the symptoms of schizophrenia, but not all and not completely in many patients. In continuation of our overview of potential novel antipsychotic pharmacotherapy that would be based upon indirect modulation of dopamine or other neurotransmitter functioning, we focus in this article on the postulated use of retinoid analogs as novel antipsychotic agents. Several lines of evidence can be viewed as implicating retinoid dysregulation in schizophrenia, either as a causative or contributory factor. It has been proposed that using retinoid analogs to alter the downstream expression of dopamine D2 receptors might represent a novel approach to the treatment of the disease or amelioration of symptoms when used either as monotherapy or as adjunct pharmacotherapy to dopamine D2 receptor antagonists.

EEG synchronization deficits in schizophrenia spectrum disorders

Neural synchronization may have a critical role in the integration of information within and across cerebral structures. Synchronization, particularly at gamma range frequencies, is thought to be dependent on GABAergic interneurons, which may be disturbed in schizophrenia. We report that patients with schizophrenia show severe disruption of electroencephalogram (EEG) measures of neural synchronization to periodic auditory and visual stimulation. Both EEG power and phase synchronization to temporally modulated signals were affected in the beta or gamma frequency ranges. These findings are consistent with GABAergic dysregulation in schizophrenia, which disrupts neural synchronization. A deficit in neural synchronization at high firing frequencies could contribute to behavioral disturbances of perceptual and temporal integration observed in this disorder.

Drs. Kronfol and Remick Reply

Back to table of contents Previous article Next article Letter to the EditorFull AccessDrs. Kronfol and Remick ReplyZIAD KRONFOL, M.D., and DANIEL G. REMICK, M.D., ZIAD KRONFOLSearch for more papers by this author, M.D., and DANIEL G. REMICKSearch for more papers by this author, M.D., Ann Arbor, Mich.Published Online:1 Jul 2001https://doi.org/10.1176/appi.ajp.158.7.1163-aAboutSectionsView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We thank Dr. Capuron and colleagues for their interest in our article. They object to our comparison of cytokines to hormones. This comparison is not new and has often been made to underscore both the similarities and the differences in their regulation and mechanism of action (1). One major difference with regard to regulation is that cytokines are usually secreted on demand in massive amounts relative to their baseline levels, which are often undetectable. Cytokine secretion puts into motion a series of events, most of which are initiated by binding to a specific cytokine receptor, and in this regard, cytokines are similar to hormones. A significant difference between cytokines and hormones, however, is that cytokine-induced cell activation often causes the release of soluble receptors, sometimes in concentrations a hundred times higher than the specific cytokine released (2). The purpose of this tight regulation of cytokine secretion and action may be to initiate an immune and/or inflammatory response at the local level while protecting the rest of the organism from the potentially devastating effects of unchecked levels of cytokines (3). We therefore agree that differences in circulating levels of any specific cytokine between two subject groups are unlikely to provide useful information about cytokine regulation in these subjects. This was explicitly stated in our article. For this reason, we limited our review of the literature on human stress and cytokines to in vitro cytokine production by stimulated leukocytes.As to the issue of cytokine regulation in psychiatric patients, we were careful to emphasize in our article only studies in which cytokine secretion or other indices of cytokine physiology were measured directly. Indirect evidence for a possible role for cytokines in major depression—no matter how appealing—remains more in the realm of speculation and theory awaiting confirmation than as reproducible fact. Also, we think it is premature to link evidence of cytokine dysregulation in schizophrenia to brain swelling or disruption of the blood-brain barrier, since direct evidence for these observations remains slim. Last, many “omissions” referred to in the letter pertain to publications that have appeared since the submission of our manuscript. We would welcome the opportunity to add them to our overview.

482. Regulation of NR1 NMDA receptor splice variant expression in rat hippocampus

Pharmacological and neurochemical evidence implicate the NMDA subtype of glutamate receptor in the pathophysiology of schizophrenia, and alterations in NMDA receptor expression may lead to altered NMDA receptor activity. NMDA receptors are pentameric associations of subunits comprised of NR1 and NR2 subunits. NR1 subunit mRNA can be processed into eight unique splice variants containing combinations of three exons, 5, 21, and 22. These exons seem to confer unique pharmacological properties when present in the final assembled receptor. For example, exons 21 and 22 are associated with synaptic anchoring proteins, which may affect receptor insertion into the cell membrane. Therefore, the presence or absence of different exons may affect the function of NMDA receptors. Oligonucleotides specific for exons 5, 21, and 22, as well as an oligonucleotide that hybridizes to all eight splice variants, were terminally labelled with [35S]dATP and were used for both in situ and Northern hybridizations. Northern hybridization revealed that the oligonucleotide probes recognized the appropriate splice variants, and that optical density was linear with mRNA concentration. Further, we found that animals treated with either the NMDA receptor antagonist MK-801 (2–10 days) or the nonselective AMPA/kainate receptor antagonist CNQX (7 days) had increased expression of exon 21 in hippocampus, with no changes in any of the other three probes. These results suggest that there is increased insertion of exon 21 in an otherwise unchanged total pool of NR1 transcripts. Further, NR1 mRNA processing is regulatable, and is therefore a potential site of dysregulation in schizophrenia.

HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotic treatment

The authors discuss literature evidence on the possible dysfunctioning of HPA axis and the inflammatory response system (IRS) in schizophrenia in relation to a more comprehensive bio-pathogenetic hypothesis of the disorder and to the development of specific clinical patterns or ‘core’ schizophrenic symptoms, like those included in the so called negative/depressive dimension. The dysfunctions of HPA axis and IRS could be linked to some neurodevelopmental damage in relevant brain areas like hippocampus and it could involve mainly the glutamatergic pathways (e.g. NMDA receptors). Moreover, these changes could have some predictive value for response to typical antipsychotics (specifically for negative symptoms and drug resistance) in schizophrenia. Finally, the differential activity of typical versus atypical antipsychotic compounds on the basic HPA axis and IRS dysregulations in schizophrenia could account, at least partly, for the better clinical stabilization achieved in patients treated with the latter drugs compared to those receiving conventional neuroleptics.

T-cell subsets in schizophrenia: a comparison between drug-naive first episode patients and chronic schizophrenic patients

T-cell subsets (CD3+, CD4+, CD8+, NK-cells) and the CD4+/CD8+ ratio were measured in 56 schizophrenic patients admitted to hospital with an acute psychosis. Thirty-five patients with chronic schizophrenia and 21 drug-naive first episode schizophrenic patients were compared with 16 healthy controls. T-cell subsets were quantified in the acute state of the illness (day 0), after 7 days of treatment and at the time of discharge. In the acute state, schizophrenic patients showed higher CD3+ and CD4+ cells ( p=0.05) and a higher CD4/CD8 ratio ( p=0.02) than healthy controls, while NK-cells were lower ( p=0.05). In first episode patients, all T-cell alterations normalized during treatment. In the chronic group the ratio remained high, whereas the initially low number of NK-cells normalized over time. These findings, supporting immune sytem dysregulation in schizophrenia, are discussed in relation to psychopathology, the stage of illness and effects of medication.

The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia

Background: Pathology of dorsolateral prefrontal cortex and dysregulation of dopaminergic neurons have been associated with the pathophysiology of schizophrenia, but how these phenomena relate to each other in patients has not been known. It has been hypothesized that prefrontal cortical pathology might induce both diminished steady-state and exaggerated responses of dopaminergic neurons to certain stimuli (e.g., stress). We examined the relationship between a measure of prefrontal neuronal pathology and striatal dopamine activity in patients with schizophrenia and in a nonhuman primate model of abnormal prefrontal cortical development. Methods: In the patients, we studied in vivo markers of cortical neuronal pathology with NMR spectroscopic imaging and of steady-state striatal dopamine activity with radioreceptor imaging. In the monkeys, we used the same NMR technique and in vivo microdialysis. Results: Measures of N-acetyl-aspartate concentrations (NAA) in dorsolateral prefrontal cortex strongly and selectively predicted D 2 receptor availability in the striatum ( n = 14, rho = −.64, p < .01), suggesting that the greater the apparent dorsolateral prefrontal cortex pathology, the less the steady-state dopamine activity in these patients. A similar relationship between NAA measures in dorsolateral prefrontal cortex and steady-state dopamine concentrations in the striatum was found in the monkeys ( n = 5, rho = .70, p < .05). We then tested in the same monkeys the relationship of prefrontal NAA and striatal dopamine overflow following amphetamine infusion into dorsolateral prefrontal cortex. Under these conditions, the relationship was inverted, i.e., the greater the apparent dorsolateral prefrontal cortex pathology, the greater the dopamine release. Conclusions: These data demonstrate direct relationships between putative neuronal pathology in dorsolateral prefrontal cortex and striatal dopamine activity in human and nonhuman primates and implicate a mechanism for dopamine dysregulation in schizophrenia.

Kainate receptor subunit expression in old-world monkey and human brain

Although the dopamine hylx~thesis of schizophrenia has provided useful insights into this illness, various flaws in this hypothesis have become apparent, suggesting involvement of other neurotransmitter systems. Growing lines of evidence have implicated glutamate involvement in schizophrenia. It has been proposed that this illness may be associated with decreased tone of the corticostriatal glutamatergic projections, resulting in diminished activity of striatal efferents to the pallidum and thence the thalamus. The glutamate system is quite complex, with at least four distinct types of glutamate receptors defined pharmacologically, each of which is comprised of families of receptors or receptor subunits. Converging lines of evidence suggest that glutamatergic involvement in schizophrenia is most likely associated with either the NMDA or kainate classes of receptors. Accordingly, we have begun a detailed examination of the anatomy and regulation of the subunits that comprise these two receptor classes. In this study, we have determined the distributions of the mRNAs encoding the various lowand highaffinity kainate receptor subunits (e.g., gluR5-gluR7 and KA 1-2, respectively) in the brains of the human and Old-World monkey. These receptor subunits have differential distributions in the striatum and in the cortex, suggesting possible substrates for region-specific receptor expression as well as sites of potential dysregulation in schizophrenia. 259. CHARACTERIZATION OF THE RELATIONSHIP BETWEEN NEGATIVE SYMPTOMS AND COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA

Dopamine and schizophrenia—a cortically corrective perspective

The traditional dopamine hypothesis holds that excessive striatal/limbic dopamine-mediated transmission is causally related to the pathophysiology of schizophenia. However, schizophrenia is not cured by dopamine blocking drugs and is associated with relatively few replicable, direct indices of dopamine-mediated dysregulation. In comparison, the evidence supporting limbic and neocortical abnormalities in schizophrenia is robust. In light of what is known about these cortical abnormalities and about brain development and connectivity, the overall research data point to an early pathological process affecting temporal-limbic and/or prefrontal cortices which becomes clinically manifested later in life. To the extent that dopamine dysregulation may be a factor in the expression of some schizophrenic symptoms, it probably represents a secondary, ‘downstream’ effect of the cortical abnormalities. A number of possible mechanisms are described that might explain the relationship between cortical abnormalities and dopamine dysregulation in schizophrenia.

Wisconsin Card Sorting Test performance in schizophrenia: remediation of a stubborn deficit

Schizophrenic patients typically perform poorly on the Wisconsin Card Sorting Test, which is a putative index of prefrontal functioning. The authors attempted to remediate the deficits of schizophrenic patients on this measure by giving detailed instructions and monetary reinforcement. Forty-six inpatients with chronic schizophrenia and 20 control subjects with other psychiatric illnesses were given the Wisconsin Card Sorting Test under four conditions that varied in monetary reinforcement and level of instructions. The schizophrenic patients were given the Brief Psychiatric Rating Scale (BPRS) and three information processing measures (the Continuous Performance Test, Span of Apprehension, and Pin Test). Schizophrenic patients performed worse than psychiatric control subjects across most conditions. Monetary reinforcement had little effect on performance, but detailed instructions significantly improved the scores for both groups. When instructions were withdrawn and monetary reinforcement was maintained, both groups continued to show improved performance over baseline. Symptoms were not significantly associated with Wisconsin Card Sorting Test performance. One measure (the Pin Test) correlated significantly with performance on the Wisconsin Card Sorting Test. The results suggest the importance of combining motivational with instructional factors for training psychiatric patients in problem solving.