Christian G. Widschwendter

Cognitive impairment in schizophrenia: Clinical ratings are not a suitable alternative to neuropsychological testing

Despite the fact that cognitive impairment rated with clinical rating scales has been shown to be a poor proxy for cognitive functioning measured with a performance-based assessment battery, studies are still using this approach to predict aspects of outcome in schizophrenia. In the current study 106 outpatients with chronic schizophrenia who had been stable both from a symptomatic and a medication perspective for a period of 6 months before study inclusion were investigated to assess the relationship between a clinical rating of cognitive impairment and the actual performance on neuropsychological tests. The cognitive component of the PANSS was compared to results from a neuropsychological test battery which was selected to cover domains known to be impaired in patients with schizophrenia. Correlations of the cognitive component of the PANSS with the individual neuropsychological tests were low. They ranged between 0.19 and 0.35. None of them was sufficiently high to indicate that the cognitive component of the PANSS adequately covers the cognitive dimension measured by the respective neuropsychological test. These data clearly show that clinical assessment of cognitive deficits by the PANSS is not a viable alternative to neuropsychological testing to obtain information about cognitive functioning in schizophrenia.

Working memory and default mode network abnormalities in unaffected siblings of schizophrenia patients.

BACKGROUND Impaired working memory (WM) is a hallmark of schizophrenia. In addition to classical WM regions such as the dorsolateral prefrontal cortex (DLPFC) and the striatum, dysfunctions in the default-mode network (DMN) contribute to these WM deficits. Unaffected siblings of patients also show WM impairments. However, the nature of the functional deficits underlying these impairments is unclear, mainly because of impaired performance confounding neuroimaging results. METHODS Here, we investigated WM and DMN activity in 23 unaffected siblings of schizophrenia patients and 24 healthy volunteers using fMRI and a Sternberg WM task. WM load was determined prior to scanning to ensure 90% accuracy for all subjects. RESULTS Siblings showed hyperactivation during the encoding phase of WM in the right medial prefrontal cortex (MPFC) which is the anterior part of the DMN. No differences were found during the maintenance phase. During the retrieval phase, siblings showed hyperactivation in WM regions: DLPFC, inferior parietal cortex and the striatum. Siblings who showed hyperactivity in the MPFC during encoding showed DLPFC and striatum hyperactivation during retrieval. CONCLUSIONS Our finding of hyperactivation in WM and DMN areas indicates that siblings fail to adequately inhibit DMN activity during demanding cognitive tasks and subsequently hyperactivate WM areas. This failure may reflect dopamine hyperactivity in the striatum which prevents adequate DMN suppression needed for effective WM. This study provides support for the notion that aberrant WM and DMN activation patterns may represent candidate endophenotypes for schizophrenia.

The neural regions sustaining episodic encoding and recognition of objects

In this functional MRI experiment, encoding of objects was associated with activation in left ventrolateral prefrontal/insular and right dorsolateral prefrontal and fusiform regions as well as in the left putamen. By contrast, correct recognition of previously learned objects (R judgments) produced activation in left superior frontal, bilateral inferior frontal, and right cerebellar regions, whereas correct rejection of distractor objects (N judgments) was associated with activation in bilateral prefrontal and anterior cingulate cortices, in right parietal and cerebellar regions, in the left putamen, and in the right caudate nucleus. The R minus N comparison showed activation in the left lateral prefrontal cortex and in bilateral cingulate cortices and precunei, while the N minus R comparison did not reveal any positive signal change. These results support the view that similar regions of the frontal lobe are involved in episodic encoding and retrieval processes, and that the successful episodic retrieval of newly learned objects is mainly based on a frontoparietal network.

MEASURING ADHERENCE TO MEDICATION IN SCHIZOPHRENIA: THE RELATIONSHIP BETWEEN ATTITUDES TOWARD DRUG THERAPY AND PLASMA LEVELS OF NEW-GENERATION ANTIPSYCHOTICS

Background: Nonadherence to medication is still a major problem in the treatment of schizophrenia. The current longitudinal study investigated whether the patients’ attitudes toward treatment correlated with the ratio of observed vs expected plasma levels of antipsychotic drugs as an objective measurement of adherence. Methods: Data of patients starting monotherapy with a new-generation antipsychotic were collected 2, 4, and 12 weeks after the initiation of treatment. Next to the assessment of patients’ attitudes toward medication by means of the Drug Attitude Inventory, the ratio of the observed vs expected plasma level was calculated. Antipsychotic-induced side effects were evaluated by means of the Udvalg for Kliniske Undersogelser Side Effect Rating Scale. Results: A total of 93 patients were eligible for statistical analysis. About one-half of the ratios of observed vs expected plasma levels ranged from 0.5 to 2 and were considered normal, whereas the other ratios were considered either too low (<0.5) or too high (>2). No consistent correlation between patients’ attitude toward drug therapy and the individual ratios of observed vs expected plasma levels of medication was detected. This finding was not affected by side effects. Conclusions: Our results highlight the importance of recognizing the complex nature of adherence to medication in schizophrenia patients. Importantly, we found no consistent correlation between subjective and objective measures of medication adherence. Therefore, monitoring adherence to medication remains a challenge in clinical practice.

Prescribing Practice in Inpatients Versus Outpatients With Schizophrenia Initiating Treatment With Second-Generation Antipsychotics: A Naturalistic Follow-Up Study.

Objective The primary objective of this study was to investigate whether the choice and dosage of antipsychotic medication differ between patients with schizophrenia starting treatment in an inpatient or outpatient unit. In addition, we investigated whether the reason for the introduction of new antipsychotic medication had an impact on the treatment setting and whether the use of benzodiazepines differed between inpatients and outpatients. Method From October 1997 to September 2010, patients with a schizophrenia spectrum disorder according to the International Classification of Diseases, Tenth Revision aged between 18 and 65 years were allocated to a naturalistic drug-monitoring program when starting treatment with a second-generation antipsychotic drug. Psychopathological symptoms were rated at baseline and after 1, 2, 4, and 8 weeks of treatment using the Positive and Negative Syndrome Scale. Inpatients and outpatients were compared with regard to the use of antipsychotics and benzodiazepines. To compare different drugs, chlorpromazine and diazepam equivalents were calculated. Results Lack of efficacy and side effects were the main reasons for initiating new antipsychotic medication. Combined evaluation of all antipsychotic compounds by meta-analysis resulted in a significant effect of the treatment setting, with inpatients receiving higher doses than outpatients. In addition, inpatients were prescribed benzodiazepines more often and in higher doses than outpatients. Conclusions Both antipsychotics and benzodiazepines were prescribed at higher doses in an inpatient setting. Moreover, benzodiazepines were prescribed more frequently to inpatients. Accordingly, the treatment setting needs to be taken into consideration in treatment recommendations for schizophrenia spectrum disorders.

Bilirubin concentration correlates with positive symptoms in patients with schizophrenia.

OBJECTIVE Besides its toxic effects, bilirubin has been demonstrated to have antioxidant properties to counteract oxidative stress, which has been suggested to play a role in the pathophysiology of schizophrenia. METHODS This study investigated the potential association between changes in psychopathology measured by the Lindenmayer model of the Positive and Negative Syndrome Scale (PANSS) and changes in total plasma bilirubin concentrations. Data of patients with schizophrenia (ICD-10) starting monotherapy with a new-generation antipsychotic were analyzed at baseline (N = 52) and 2 (n = 40), 4 (n = 46), and 12 weeks (n = 30) after the initiation of treatment. Data were collected between December 1997 and October 2007 and analyzed retrospectively. RESULTS The PANSS total score decreased significantly from baseline to weeks 2, 4, and 12 of treatment (all P values ≤ .001). Total plasma bilirubin concentration also dropped significantly from baseline to week 2 (P = .015) and decreased further until week 4 (P = .013); no significant decrease was observed between baseline and week 12. Spearman rank correlation revealed a significant association of bilirubin concentration with the PANSS positive (r = 0.371, P = .007) and excitement (r = 0.322, P = .020) components at baseline. No further correlations were found. From baseline to weeks 2, 4, and 12, changes in the PANSS positive component correlated significantly with changes in plasma bilirubin concentration (all P values < .05), whereas correlations between changes in the remaining PANSS components and bilirubin were less consistent. CONCLUSIONS Assuming that positive symptoms are associated with the subjective experience of psychological distress, our findings indirectly expand the evidence on potential antioxidant properties of bilirubin in patients with schizophrenia.

Relating Spontaneously Reported Extrapyramidal Adverse Events to Movement Disorder Rating Scales

Background: While antipsychotic-induced extrapyramidal symptoms (EPS) and akathisia remain important concerns in the treatment of patients with schizophrenia, the relationship between movement disorder rating scales and spontaneously reported EPS-related adverse events (EPS-AEs) remains unexplored. Methods: Data from four randomized, placebo- and haloperidol-controlled ziprasidone trials were analyzed to examine the relationship between spontaneously reported EPS-AEs with the Simpson Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS). Categorical summaries were created for each treatment group to show the frequencies of subjects with EPS-AEs in each of the SAS and BARS categories at weeks 1, 3, and 6, and agreement between ratings was quantified by means of weighted kappa (κ). Results: In general, we found greater frequencies of EPS-AEs with increasing severity of the SAS and BARS scores. The EPS-AEs reported with a “none” SAS score ranged from 0 to 22.2%, with a “mild” SAS score from 3.3 to 29.0%, and with a “moderate” SAS score from 0 to 100%. No subjects in any treatment group reported “severe” SAS scores or corresponding EPS-AEs. Agreement between SAS scores and EPS-AEs was poor for ziprasidone and placebo (κ < 0.2) and only slightly better for haloperidol. The EPS-AEs reported with “non questionable” BARS scores ranged from 1.9 to 9.8%, with “mild moderate” BARS scores from 12.8 to 54.6%, and with “marked severe” scores from 0 to 100%. Agreement was modest for ziprasidone and placebo (κ < 0.4) and moderate for haloperidol (κ < 0.6). Conclusions: These findings may reflect either underreporting of AEs by investigators and subjects or erroneous rating scale evaluations.

Therapeutic Alliance in Patients With Schizophrenia: Introduction of a New Rating Instrument.

Objective: The quality of the patient-psychiatrist relationship can be seen as a cornerstone of adherence to medications in patients with chronic psychiatric disorders. Although therapeutic alliance in psychotherapy has been investigated broadly, it has received little attention in the context of medication adherence. The goal of this study was to develop and validate a user-friendly questionnaire for the assessment of therapeutic alliance in clinically stable outpatients with schizophrenia. Methods: The “Brief Questionnaire on Therapeutic Alliance” (BQTA) addresses both the physician and the patient, each of whom responds to 5 items that focus on important domains of the therapeutic alliance. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) and patients’ attitudes toward the illness and medication were assessed using the Drug Attitude Inventory (DAI). Results: A total of 61 patients who met ICD-10 criteria for schizophrenia spectrum disorders and their treating psychiatrists were included in the study. Overall, patients and psychiatrists gave high (ie, favorable) ratings on all BQTA items. The 5 patient-related items showed high internal consistency (Cronbach &agr;=0.77), whereas physician-related items showed slightly less internal consistency (Cronbach &agr;=0.68). The concordance between patient and physician ratings was fair, although statistically significant (&kgr;=0.33, P=0.007). Physicians’ total score on the BQTA was moderately correlated with patients’ PANSS total score and with the DAI total score and its compliance subscale, whereas patients’ total score on the BQTA did not correlate with DAI or PANSS scores. Conclusion: The BQTA was found to cover crucial aspects of the doctor-patient relationship in chronically ill individuals with schizophrenia. Further validation will shed more light on the usefulness of this questionnaire.