Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Relationships among neurocognition, symptoms and functioning in patients with schizophrenia: a path-analytic approach for associations at baseline and following 24 weeks of antipsychotic drug therapy

<p>Abstract</p> <p>Background</p> <p>Neurocognitive impairment and psychiatric symptoms have been associated with deficits in psychosocial and occupational functioning in patients with schizophrenia. This post-hoc analysis evaluates the relationships among cognition, psychopathology, and psychosocial functioning in patients with schizophrenia at baseline and following sustained treatment with antipsychotic drugs.</p> <p>Methods</p> <p>Data were obtained from a clinical trial assessing the cognitive effects of selected antipsychotic drugs in patients with schizophrenia. Patients were randomly assigned to 24 weeks of treatment with olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Psychosocial functioning was assessed with the Heinrichs-Carpenter Quality of Life Scale [QLS], cognition with a standard battery of neurocognitive tests; and psychiatric symptoms with the Positive and Negative Syndrome Scale [PANSS]. A path-analytic approach was used to evaluate the effects of changes in cognitive functioning on subdomains of quality of life, and to determine whether such effects were direct or mediated via changes in psychiatric symptoms.</p> <p>Results</p> <p>At baseline, processing speed affected functioning mainly indirectly via negative symptoms. Positive symptoms also affected functioning at baseline although independent of cognition. At 24 weeks, changes in processing speed affected changes in functioning both directly and indirectly via PANSS negative subscale scores. Positive symptoms no longer contributed to the path-analytic models. Although a consistent relationship was observed between processing speed and the 3 functional domains, variation existed as to whether the paths were direct and/or indirect. Working memory and verbal memory did not significantly contribute to any of the path-analytic models studied.</p> <p>Conclusion</p> <p>Processing speed demonstrated direct and indirect effects via negative symptoms on three domains of functioning as measured by the QLS at baseline and following 24 weeks of antipsychotic treatment.</p

Treatment Outcome in Patients Receiving Assertive Community Treatment

In an observational study of severely mentally ill patients treated in assertive community treatment (ACT) teams, we investigated how treatment outcome was associated with demographic factors, clinical factors, and motivation for treatment. To determine psychosocial outcome, patients were routinely assessed using the Health of the Nation Outcome Scales (HoNOS). Trends over time were analyzed using a mixed model with repeated measures. The HoNOS total score was modeled as a function of treatment duration and patient-dependent covariates. Data comprised 637 assessments of 139 patients; mean duration of follow-up was 27.4 months (SD = 5.4). Substance abuse, higher age, problems with motivation, and lower educational level were associated with higher HoNOS total scores (i.e., worse outcome). To improve treatment outcome, we recommend better implementation of ACT, and also the implementation of additional programs targeting subgroups which seem to benefit less from ACT

Relationships Between Social Support, Social Coping and Life Events in the Relapse of Schizophrenic Patients

The vulnerability-stress model for schizophrenia posits that relapses are at least partly determined by interacting triggering and protecting psychosocial factors. This study examined social support and general coping style in 42 consecutively admitted DSM:III schizophrenic patients, who were followed prospectively for up to four years. In a second part of the study, a subgroup of the patients were interviewed using the Life Event and Difficulty Schedule 9 months after discharge or at relapse. Patients contented with low social integration had a higher relapse rate over four years than patients lacking of social provisions, but wanting more. We found an excess of life events three weeks before relapse compared to events reported in the non-relapsing group. Suggesting a buffering effect of social factors, time between life event and relapse was significantly extended among patients with a high availability of attachment and a coping strategy characterised of active support seeking

Electrodermal activity and social network as predictors of outcome of episodes in schizophrenia

The predictive value of electrodermal activity and social network was examined among 48 consecutively admitted schizophrenic patients. The patients were followed from an initial admission, through hospital stay, discharge, follow-up (M = 31 months), and possible relapse. Outcome variables were the length of stay in the hospital at the key episode and time to relapse, defined as a marked exacerbation or return of schizophrenic symptoms requiring inpatient or expansion of outpatient treatment. Multivariate analyses showed that a psychosocial variable, the availability of attachment, was the only independent predictor of length of stay in the hospital. Age at admission was a strong predictor of time to relapse. Age interacted with both outcome and electrodermal activity, and young electrodermal nonresponders were found to have the shortest time to relapse. At the 1-year follow-up, a main relapse effect was found for patients with a low skin conductance level

Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism

Humans express at least seven alcohol dehydrogenase (ADH) isoforms that are encoded by ADH gene cluster (ADH7–ADH1C–ADH1B–ADH1A–ADH6–ADH4–ADH5) at chromosome 4. ADHs are key catabolic enzymes for retinol and ethanol. The functional ADH variants (mostly rare) have been implicated in alcoholism risk. In addition to catalyzing the oxidation of retinol and ethanol, ADHs may be involved in the metabolic pathways of several neurotransmitters that are implicated in the neurobiology of neuropsychiatric disorders. In the present study, we comprehensively examined the associations between common ADH variants [minor allele frequency (MAF) >0.05] and 11 neuropsychiatric and neurological disorders. A total of 50,063 subjects in 25 independent cohorts were analyzed. The entire ADH gene cluster was imputed across these 25 cohorts using the same reference panels. Association analyses were conducted, adjusting for multiple comparisons. We found 28 and 15 single nucleotide polymorphisms (SNPs), respectively, that were significantly associated with schizophrenia in African-Americans and autism in European-Americans after correction by false discovery rate (FDR) (q <0.05); and 19 and 6 SNPs, respectively, that were significantly associated with these two disorders after region-wide correction by SNPSpD (8.9 × 10(−5) ≤ p ≤ 0.0003 and 2.4 × 10(−5) ≤ p ≤ 0.0003, respectively). No variants were significantly associated with the other nine neuropsychiatric disorders, including alcohol dependence. We concluded that common ADH variants conferred risk for both schizophrenia in African-Americans and autism in European-Americans

The revolving door phenomenon revisited: time to readmission in 17'415 patients with 37'697 hospitalisations at a German hospital

Objective: Despite the recurring nature of the disease process in many psychiatric patients, individual careers and time to readmission rarely have been analysed by statistical models that incorporate sequence and velocity of recurrent hospitalisations. This study aims at comparing four statistical models specifically designed for recurrent event history analysis and evaluating the potential impact of predictor variables from different sources (patient, treatment process, social environment). Method: The so called Andersen-Gil counting process model, two variants of the conditional models of Prentice, Williams, and Peterson (gap time model, conditional probability model), and the so called frailty model were applied to a dataset of 17’415 patients observed during a 12 years period starting from 1996 and leading to 37’697 psychiatric hospitalisations. Potential prognostic factors stem from a standardized patient documentation form. Results: Estimated regression coefficients over different models were highly similar, but the frailty model best represented the sequentiality of individual treatment careers and differing velocities of disease progression. It also avoided otherwise likely misinterpretations of the impact of gender, partnership, historical time and length of stay. A widespread notion of psychiatric diseases as inevitably chronic and worsening could be rejected. Time in community was found to increase over historical time for all patients. Most important protective factors beyond diagnosis were employment, partnership, and sheltered living situation. Risky conditions were urban living and a concurrent substance use disorder. Conclusion: Prognostic factors for course of diseases should be determined only by statistical models capable of adequately incorporating the recurrent nature of psychiatric illnesses