Altered emotional experiences attributed to antipsychotic medications - A potential link with estimated dopamine D2 receptor occupancy.

Altered emotional experiences in response to antipsychotics may increase the burden of disease in patients with schizophrenia. In a large cross-sectional study, patients with schizophrenia completed the Subjects Reaction to Antipsychotics questionnaire (SRA) to assess whether they attributed altered emotional experiences (flattened affect or depressive symptoms) to their antipsychotics. Association with antipsychotic D2 receptor affinity and occupancy was examined using logistic regression. We compared antipsychotic-attributed emotional experiences between patients using antipsychotic monotherapy and combination therapy. Of the 1298 included patients, 23% attributed flattened affect to their antipsychotics and 16% attributed depressive symptoms to their antipsychotics, based on the SRA. No differences were observed between antipsychotics in patients on monotherapy. We discuss that within these patients' relatively low dose range, altered emotional experiences did not appear to relate to the level of D2 receptor affinity of antipsychotic monotherapy. Patients using antipsychotic combination therapy (22%) were more likely to attribute depressive symptoms to their antipsychotics than patients using antipsychotic monotherapy (OR [95%CI]=1.443 [1.033-2.015]); possibly due to higher D2 receptor occupancies as estimated by dose equivalents.

Psychometric properties of the self-report version of the Quick Inventory of Depressive Symptoms (QIDS-SR16) questionnaire in patients with schizophrenia.

BACKGROUND: Self-report instruments for the assessment of depressive symptoms in patients with psychotic disorders are scarce. The Quick Inventory of Depressive Symptoms (QIDS-SR16) may be a useful self-report instrument, but has received little attention in this field. This paper aimed to test the psychometric properties of the QIDS-SR16 questionnaire in patients with a psychotic disorder. METHODS: Patients diagnosed with a psychotic disorder from health care institutions in The Netherlands were included in the study. Depressive symptoms were assessed with the QIDS-SR16 and the Calgary Depression Scale for Schizophrenia (CDSS). Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) and extrapyramidal symptoms (EPS) with three EPS rating scales. Spearman's correlation coefficients were used to compare the total score of the QIDS-SR16 with the total scores of the CDSS, PANSS-subscales and EPS rating scales. RESULTS: In a sample of 621 patients with psychotic disorders, the QIDS-SR16 showed good internal consistency (α = 0.87). The QIDS-SR16 correlated moderately with the CDSS (r = 0.44) and the PANSS subscale for emotional distress (r = 0.47). The QIDS-SR16 showed weak correlation with the PANSS subscale for negative symptoms (r = 0.28) and minimal correlation with EPS rating scales (r = 0.09-0.16). CONCLUSIONS: The QIDS-SR16 may reliably assess depressive symptoms in patients with psychotic disorders, but its concurrent validity with the CDSS was rather poor in this population. We would recommend developing a new self-report questionnaire for the assessment of depressive symptoms in patients with psychotic disorders.

Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis.

RATIONALE: Dose equivalents based on dopamine D2 receptor occupancy can be used to compare antipsychotics on D2 receptor-mediated (adverse) effects such as extrapyramidal symptoms and altered emotional experiences. Previous meta-analyses modeling the dose-occupancy relationship hardly addressed potential heterogeneity of the imaging data. OBJECTIVES: To model the relationship between dose and D2 receptor occupancy for a series of frequently prescribed antipsychotics while addressing the potential heterogeneity of the imaging data. METHODS: We conducted a meta-analysis on published D2 receptor occupancy data (positron emission tomography and single-photon emission computed tomography) in patients with schizophrenia treated with antipsychotics. A nonlinear mixed effects model estimated the median D2 receptor occupancy for a given antipsychotic dose. Heterogeneity between studies was investigated by incorporating study as a random effect in the model, in addition to patient- and study-specific explanatory variables. RESULTS: Included were 51 studies, describing 606 patients (mean ± SD age, 32.2 ±10.8 years; 25.7% female). The models described the dose-occupancy relationship with narrow confidence bands around the therapeutic dose range. Maximum occupancy (95% confidence interval[CI]) was estimated for haloperidol (91.9%; 95% CI, 86.1-97.8), risperidone(92.4%; 95% CI, 81.8-100), olanzapine (96.5%; 95% CI,85.8-100), clozapine (61.7%; 95% CI, 49.2-74.2), quetiapine (49.1%; 95% CI, 18.7-79.6), aripiprazole (86.9%; 95% CI, 78.2-95.7), ziprasidone (82.9%; 95% CI, 44.9-100), and amisulpride (85.0%; 95% CI, 68.5-100). Interindividual differences explained most of the variability in occupancy values, besides significant heterogeneity between studies. CONCLUSIONS: Dose-occupancy functions estimated the median level of dopamine D2 receptor occupancy for 8 frequently prescribed antipsychotics in patients with schizophrenia. These dose equivalents can be used to compare antipsychotic effects in epidemiological studies and clinical practice.

Instrumental learning: an animal model for sleep dependent memory enhancement.

The relationship between learning and sleep is multifaceted; learning influences subsequent sleep characteristics, which may in turn influence subsequent memory. Studies in humans indicate that sleep may not only prevent degradation of acquired memories, but even enhance performance without further practice. In a rodent instrumental learning task, individual differences occur in how fast rats learn to associate lever pressing with food reward. Rats habitually sleep between learning sessions, and may differ in this respect. The current study assessed if the instrumental leaning paradigm could serve as a model to study sleep-dependent memory enhancement. Male Wistar rats performed 2 sessions of instrumental learning per day for 1-3 days. Electroencephalography was recorded both before and after the sessions. Sleep deprivation (3 h) was applied between the first and second session in a subgroup of rats. Measurements comprised the number of lever presses in each session, slow wave sleep (SWS) duration, Rapid Eye Movement Sleep (REMS) duration and sleep spindles. Baseline sleep parameters were similar for fast and slow learning rats. Task-exposure increased REMS-duration. The increase in REMS-duration was observed specifically after sessions in which learning occurred, but not after a later session. Sleep deprivation during the 3h period between the initial two sessions interfered with performance enhancement, but did not prevent this in all rats. Our considered movement control protocol induced partial sleep deprivation and also interfered with performance enhancement. The classic instrumental learning task provides a practical model for animal studies on sleep-dependent memory enhancement.

A brief version of the Subjects' Response to Antipsychotics questionnaire to evaluate treatment effects.

BACKGROUND: Monitoring patients' experiences with antipsychotics may help to improve medication adherence and outcome. We aimed to develop a shorter version of a comprehensive 74-item self-report questionnaire suitable for routine monitoring of desired and undesired effects of antipsychotics. METHODS: Included were patients with psychotic disorders from seven mental health care organizations in The Netherlands, using antipsychotic medication, who completed the Subjects' Response to Antipsychotics (SRA-74). Exploratory factor analysis (EFA) and similarity analysis based on mutual information were used to identify the latent factor structure of the SRA. Items were reduced according to their metric properties and clinical relevance upon consensus by an expert panel, using a Delphi procedure of three rounds. We determined the internal consistency of the shorter version using Cronbach's alpha. RESULTS: SRA data of N=1478 patients (mean age of 40 years, 31% females) were eligible for analysis. EFA extracted thirteen factors from the SRA-74, including four factors for desired effects (e.g. recovery of psychosis, cognition and social functioning) and nine factors for undesired effects (e.g. weight gain, flattened affect and increased sleep). Based on this solution 12 items were eliminated for statistical reasons. The expert panel eliminated another 28 items with redundant content, resulting in a 34-item version. The SRA-34 includes 10 desired and 24 clinically relevant undesired effects. Both the subscales for desired and undesired effects have a Cronbach's alpha coefficient of 0.82. CONCLUSIONS: The SRA-34 can be used to evaluate desired and undesired effects of antipsychotics in routine clinical practice and research.

A systematic review of instruments to measure depressive symptoms in patients with schizophrenia.

BACKGROUND: Depressive symptoms require accurate recognition and monitoring in clinical practice of patients with schizophrenia. Depression instruments developed for use in depressed patients may not discriminate depressive symptoms from negative psychotic symptoms. OBJECTIVE: We reviewed depression instruments on their reliability and validity in patients with schizophrenia. METHODOLOGY: A systematic literature search was carried out in three electronic databases. Psychometric properties were extracted for those instruments of which reliability, divergent, concurrent and predictive validity were reported in one or more publications. RESULTS: Forty-eight publications described the reliability and validity of six depression instruments in patients with schizophrenia. The only self-report was the Beck Depression Inventory (BDI). The Brief Psychiatric Rating Scale-Depression subscale (BPRS-D), Positive and Negative Syndrome Scale-Depression subscale (PANSS-D), Hamilton Rating Scale for Depression (HAMD), Montgomery Asberg Depression Rating Scale (MADRS) and Calgary Depression Scale for Schizophrenia (CDSS) were clinician rated. All instruments were reliable for the measurement of depressive symptoms in patients with schizophrenia. The CDSS most accurately differentiated depressive symptoms from other symptoms of schizophrenia (divergent validity), correlated well with other depression instruments (concurrent validity), and was least likely to miss cases of depression or misdiagnose depression (predictive validity). CONCLUSIONS: We would recommend to use the CDSS for the measurement of depressive symptoms in research and in daily clinical practice of patients with schizophrenia. A valid self-report instrument is to be developed for the use in clinical practice.