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.

Differential stigmatizing attitudes of healthcare professionals towards psychiatry and patients with mental health problems: something to worry about? A pilot study.

PURPOSE: This study compares stigmatizing attitudes of different healthcare professionals towards psychiatry and patients with mental health problems. METHODS: The Mental Illness Clinicians Attitude (MICA) questionnaire is used to assess stigmatizing attitudes in three groups: general practitioners (GPs, n = 55), mental healthcare professionals (MHCs, n = 67) and forensic psychiatric professionals (FPs, n = 53). RESULTS: A modest positive attitude towards psychiatry was found in the three groups (n = 176). Significant differences were found on the total MICA-score (p < 0.001). GPs scored significantly higher than the FPs and the latter scored significantly higher than the MHCs on all factors of the MICA. Most stigmatizing attitudes were found on professionals' views of health/social care field and mental illness and disclosure. Personal and work experience did not influence stigmatizing attitudes. CONCLUSIONS: Although all three groups have a relatively positive attitude using the MICA, there is room for improvement. Bias toward socially acceptable answers cannot be ruled out. Patients' view on stigmatizing attitudes of professionals may be a next step in stigma research in professionals.

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.

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.

Weight change by baseline BMI from three-year observational data: findings from the Worldwide Schizophrenia Outpatient Health Outcomes Database.

The aim was to explore weight and body mass index (BMI) changes by baseline BMI in patients completing three years of monotherapy with various first- and second-generation antipsychotics in a large cohort in a post hoc analysis of three-year observational data. Data were analyzed by antipsychotic and three baseline BMI bands: underweight/normal weight (BMI <25 kg/m²), overweight (25-30 kg/m²) and obese (>30 kg/m²). Baseline BMI was associated with subsequent weight change irrespective of the antipsychotic given. Specifically, a smaller proportion of patients gained ≥7% baseline bodyweight, and a greater proportion of patients lost ≥7% baseline bodyweight with increasing baseline BMI. For olanzapine (the antipsychotic associated with highest mean weight gain in the total drug cohort), the percentage of patients gaining ≥7% baseline weight was 45% (95% CI: 43-48) in the underweight/normal weight BMI cohort and 20% (95% CI: 15-27) in the obese BMI cohort; 7% (95% CI: 6-8) of the underweight/normal cohort and 19% (95% CI: 13-27) of the obese cohort lost ≥7% baseline weight. BMI has an association with the likelihood of weight gain or loss and should be considered in analyses of antipsychotic weight change.

Weight change from 3-year observational data: findings from the worldwide schizophrenia outpatient health outcomes database.

BACKGROUND: Weight change data from randomized clinical trials are often of limited duration and trials do not always report a full range of clinically relevant categorical end points. METHOD: We conducted a post hoc analysis of data from the observational Worldwide Schizophrenia Outpatient Health Outcomes database (2000-2005) on weight change in 4,626 patients completing 3 years of antipsychotic monotherapy with amisulpride, clozapine, olanzapine, quetiapine, risperidone, and oral and depot first-generation antipsychotics (FGAs). Reported outcomes included mean and categorical weight changes and the trajectories of different measures of weight change. RESULTS: Mean weight gain was lowest with amisulpride (1.8 kg; 95% CI, 0.2-3.3) and highest with olanzapine (4.2 kg; 95% CI, 3.9-4.5). Weight change for all antipsychotics was most rapid during the first 6 months; subsequent weight change was slower but did not plateau. All drugs showed considerable individual variation in weight change. The proportion losing ≥7% of their baseline bodyweight was highest with quetiapine (10%; 95% CI, 7%-16%) and lowest with depot FGAs (5%; 95% CI, 3%-10%). Between 7% and 15% of patients moved into an overweight or obese body mass index (kg/m2)category (≥25). CONCLUSIONS: The degree of weight gain varied between antipsychotics. All antipsychotics were associated with significant (≥7%) weight loss and gain from baseline. The mean rate of weight gain was maximal during the first 6 months but continued over 3 years without a plateau in this specific cohort. Patients should receive regular monitoring of weight throughout treatment.

Care provided by general practitioners to patients with psychotic disorders: a cohort study.

BACKGROUND: Patients suffering from psychotic disorders have an increased risk of comorbid somatic diseases such as cardiovascular disorders and diabetes mellitus. Doctor-related factors, such as unfamiliarity with these patients, as well as patient-related factors, such as cognitive disturbance and negative symptoms, contribute to suboptimal health care for these patients.General practitioners (GPs) could play a key role in diagnosing and treating this somatic comorbidity as in the Netherlands, almost all residents are registered at a general practice. This study aims to find out whether there are any differences between the levels of health care provided by GPs to patients with psychotic disorders, compared to other types of patients. METHODS: A cohort of patients with an ICPC code of psychosis and two matched control groups, one consisting of patients with other mental problems and the other one of patients without any mental problems, were followed over a period of 5 years. RESULTS: Patients with psychotic disorders (N = 734) contacted the GP practice more often than patients in the control groups. These patients, both adults (p = 0.051) and the elderly (p < 0.005), received more home visits from their GPs. In the adult group (16 to 65 years old inclusive), the number of consultations was significantly higher among both psychosis patients and the group of patients with other mental problems (p < 0.0005). The number of telephone consultations was significantly higher in both age categories, adult group (p < 0.0005), and > 65 years old (p = 0.007). With regard to chronic illnesses, elderly psychosis patients had fewer contacts related to cardiovascular diseases or chronic lung diseases. CONCLUSION: Patients with psychotic disorders contact the GP practice more frequently than other types of patients. Adult psychosis patients with diabetes mellitus, cardiovascular diseases or chronic lung diseases receive the same amount of health care for these diseases as other primary care patients. The finding that older patients with psychotic disorders are diagnosed with cardiovascular diseases and obstructive lung diseases less frequently than other types of elderly patients requires further study.

Effects of bilateral repetitive transcranial magnetic stimulation on treatment resistant auditory-verbal hallucinations in schizophrenia: a randomized controlled trial.

BACKGROUND: Neuroimaging findings implicate bilateral superior temporal regions in the genesis of auditory-verbal hallucinations (AVH). This study aimed to investigate whether 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the bilateral temporo-parietal region would lead to increased effectiveness in the management of AVH, compared to left rTMS or placebo. METHODS: 38 patients with schizophrenia (DSM-IV) and medication-resistant AVH were randomly assigned to 1 Hz rTMS treatment of the left temporo-parietal region, bilateral temporo-parietal regions, or placebo. Stimulation was conducted over 6 days, twice daily for 20 min, at 90% of the motor threshold. Effect measures included the Auditory Hallucination Rating Scale (AHRS), Positive and Negative Affect Scale (PANAS), and a score for hallucination severity obtained from the Positive and Negative Syndrome Scale (PANSS). RESULTS: All groups showed some improvement on the total AHRS. Hallucination frequency was significantly reduced in the left rTMS group only. The bilateral rTMS group demonstrated the most remarkable reduction in self-reported affective responsiveness to AVH. A modest, but significant decrease on the PANSS hallucination item was observed in the combined rTMS treatment group, whereas no change occurred in the placebo group. The left rTMS group showed a significant reduction on the general psychopathology subscale. CONCLUSION: Compared to bilateral or sham stimulation, rTMS of the left temporo-parietal region appears most effective in reducing auditory hallucinations, and additionally may have an effect on general psychopathology. Placebo effects should however not be ruled out, since sham stimulation also led to improvement on a number of AVH parameters.

Care for patients with severe mental illness: the general practitioner's role perspective.

BACKGROUND: Patients with severe mental illness (SMI) experience distress and disabilities in several aspects of life, and they have a higher risk of somatic co-morbidity. Both patients and their family members need the support of an easily accessible primary care system. The willingness of general practitioners and the impeding factors for them to participate in providing care for patients with severe mental illness in the acute and the chronic or residual phase were explored. METHODS: A questionnaire survey of a sample of Dutch general practitioners spread over the Netherlands was carried out. This comprised 20 questions on the GP's 'Opinion and Task Perspective', 19 questions on 'Treatment and Experiences', and 27 questions on 'Characteristics of the General Practitioner and the Practice Organisation'. RESULTS: 186 general practitioners distributed over urban areas (49%), urbanised rural areas (38%) and rural areas (15%) of the Netherlands participated. The findings were as follows: GPs currently considered themselves as the first contact in the acute psychotic phase. In the chronic or residual phase GPs saw their core task as to diagnose and treat somatic co-morbidity. A majority would be willing to monitor the general health of these patients as well. It appeared that GP trainers and GPs with a smaller practice setting made follow-up appointments and were willing to monitor the self-care of patients with SMI more often than GPs with larger practices.GPs also saw their role as giving support and information to the patient's family.However, they felt a need for recognition of their competencies when working with mental health care specialists. CONCLUSION: GPs were willing to participate in providing care for patients with SMI. They considered themselves responsible for psychotic emergency cases, for monitoring physical health in the chronic phase, and for supporting the relatives of psychotic patients.

Worsening of psychosis in schizophrenia is longitudinally associated with tardive dyskinesia in the European Schizophrenia Outpatient Health Outcomes study.

OBJECTIVE: The objective of the study was to examine if worsening of psychosis predicts the emergence of tardive dyskinesia (TD). METHOD: Global measures of TD and Clinical Global Impression (CGI) overall symptom severity score were rated in 4 assessments in 12 months. In a risk set free of TD at baseline, associations between TD onset and change in CGI scores were assessed using Cox proportional hazard regression. RESULTS: A total of 8,620 patients yielded 23,565 follow-up observations, 8.8% of which represented a worsening in CGI overall symptom severity relative to the previous observation, yielding an incidence of TD of 5.2%, compared with 2.7% in observations without worsening of psychopathology (rate ratio, 1.9; 95% confidence interval, 1.3-2.7). Incidence of TD was longitudinally associated with a worsening of the CGI overall symptom severity in the months preceding TD onset (adjusted hazard ratio over 6 levels of CGI score, 1.3; 95% confidence interval, 1.1-1.4). CONCLUSION: Worsening in overall psychopathology in schizophrenia is longitudinally associated with the emergence of TD as measured by CGI overall symptom severity.

How do General Practitioners experience providing care for their psychotic patients?

BACKGROUND: In primary care, GPs usually provide care for patients with chronic diseases according to professional guidelines. However, such guidelines are not available in the Netherlands for patients with recurring psychoses. It seems that the specific difficulties that GPs experience in providing care for these patients hinder the development and implementation of such guidelines. This study aims to explore the chances and problems GPs meet when providing care for patients susceptible for recurring psychoses, including schizophrenia and related disorders, bipolar disorder, and psychotic depression. METHODS: A qualitative study of focus group discussions with practising GPs in both town and rural areas. Transcripts from three focus groups with 19 GPs were analysed with the computer program 'Kwalitan'. Theoretical saturation was achieved after these three groups. RESULTS: Analysis showed that eight categories of factors influenced the GPs' care for psychotic patients: patient presentation (acute vs. chronic phase), emotional impact, expertise, professional attitude, patient related factors, patient's family, practice organization, and collaboration with psychiatric specialists. CONCLUSION: Current primary care for psychotic patients depends very much on personal characteristics of the GP and the quality of local collaboration with the Mental Health Service. A quantitative study among GPs using a questionnaire based on the eight categories mentioned above would determine the extent of the problems and limitations experienced with this type of care. From the results of this quantitative study, new realistic guidelines could be developed to improve the quality of care for psychotic patients.

Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome.

OBJECTIVE: To compare the consequences of a guided discontinuation strategy and maintenance treatment in remitted first-episode psychosis in terms of relapse rates and functional outcome. METHOD: The study was conducted in 7 mental health care organizations and the Department of Psychiatry of the University Medical Center Groningen in The Netherlands, covering a catchment area of 3.1 million inhabitants. A sample of 131 remitted first-episode patients, aged 18 to 45 years, with a DSM-IV diagnosis of schizophrenia or related psychotic disorder was included (i.e., all patients with a first psychotic episode from October 2001 through December 2002 who were willing to participate). After 6 months of positive symptom remission, they were randomly and openly assigned to the discontinuation strategy or maintenance treatment. Maintenance treatment was carried out according to American Psychiatric Association guidelines, preferably using low-dose atypical antipsychotics. The discontinuation strategy was carried out by gradual symptom-guided tapering of dosage and discontinuation if feasible. Follow-up was 18 months. Main outcome measures were relapse rates and social and vocational functioning. RESULTS: Twice as many relapses occurred with the discontinuation strategy (43% vs. 21%, p = .011). Of patients who received the strategy, approximately 20% were successfully discontinued. Recurrent symptoms caused another approximately 30% to restart antipsychotic treatment, while in the remaining patients discontinuation was not feasible at all. There were no advantages of the discontinuation strategy regarding functional outcome. CONCLUSIONS: Only a limited number of patients can be successfully discontinued. High relapse rates do not allow a discontinuation strategy to be universal practice. However, if relapse risk can be carefully managed by close monitoring, in some remitted first-episode patients a guided discontinuation strategy may offer a feasible alternative to maintenance treatment. Further research is needed to find predictors of successful discontinuation.

Evidence that early extrapyramidal symptoms predict later tardive dyskinesia: a prospective analysis of 10,000 patients in the European Schizophrenia Outpatient Health Outcomes (SOHO) study.

OBJECTIVE: This study examined whether extrapyramidal symptoms predict incidence of tardive dyskinesia 1 year later. METHOD: Simple, global measures were used to rate extrapyramidal symptoms and tardive dyskinesia in a prospective, observational health outcomes study. Baseline and 3-, 6-, and 12-month data on 9,298 patients were analyzed by using a Cox proportional-hazard model. Onset of tardive dyskinesia was examined in two groups: 1) no tardive dyskinesia at baseline (broad risk set) and 2) no tardive dyskinesia at baseline and 3 months (narrow risk set). RESULTS: Baseline extrapyramidal symptoms predicted later onset of tardive dyskinesia (broad risk set: hazard ratio=2.0, narrow risk set: hazard ratio=1.6). In analyses adjusted for age, gender, and medication exposure, this effect size was not reduced. About half of patients who developed tardive dyskinesia had earlier extrapyramidal symptoms. CONCLUSIONS: Although the association of tardive dyskinesia and extrapyramidal symptoms is significant, extrapyramidal symptoms do not robustly identify individuals at high risk for tardive dyskinesia. However, drug regimens and disease processes that increase extrapyramidal symptoms are likely to result in increased risk of tardive dyskinesia.

Tardive dyskinesia in schizophrenia is associated with prolactin-related sexual disturbances.

Tardive dyskinesia (TD) may occur in never-medicated patients with psychotic illness, indicating the existence of non-medication, possibly disease-related, causes. We tested the hypothesis that, independent of the antipsychotic-induced rise in prolactin, the incidence of TD would be associated with the incidence of prolactin-related sexual disturbances (PRSD), which would be suggestive of a common pathology involving multiple dopamine tracts. Simple, global measures of TD and PRSD (loss of libido, amenorrhea, gynaecomastia, impotence, and galactorrhea) were rated in a prospective, observational European Health Outcomes Study (SOHO). New onset of TD and new onset of PRSD at 3, 6, and 12 months was analyzed in a risk set of 4263 patients using a Cox proportional hazard model yielding adjusted hazard ratios (aHR). Incidence of TD was significantly and linearly comorbid with the incidence of PRSD in both men and women. Compared to those with no PRSD, the risk for TD was 2.0 (95% CI: 1.1, 3.7) with one PRSD, 2.4 (95% CI: 1.3, 4.5) with two PRSD, and 3.6 (95% CI: 1.1, 11.8) with three PRSD. Associations were stronger in those who only had received prolactin-sparing medications (aHR per unit PRSD increase=2.0, 95% CI: 1.2, 3.3) than in those who only had received prolactin-raising medications (aHR=1.3, 95% CI: 0.9, 1.9). In people with schizophrenia, TD and PRSD show comorbidities that are independent of antipsychotic-induced alterations in plasma prolactin. This may suggest a shared, pandopaminergic pathological mechanism associated with schizophrenia itself, rather than only a medication effect.

Effects of antipsychotic treatment on tardive dyskinesia: a 6-month evaluation of patients from the European Schizophrenia Outpatient Health Outcomes (SOHO) Study.

OBJECTIVE: To compare the incidence and persistence of tardive dyskinesia between patients diagnosed with schizophrenia (ICD-10 and/or DSM-IV) who were treated with second-generation antipsychotics and first-generation antipsychotics in routine clinical practice. METHOD: The European Schizophrenia Outpatient Health Outcomes (SOHO) study is a 3-year, prospective, observational study. Each country had a start date for patient enrollment before October 2000. All enrollment was completed by June 30, 2001. A simple, global measure of tardive dyskinesia was rated by participating clinicians. For the current analysis, data at baseline, 3 months, and 6 months were analyzed using a generalized estimating equation model. RESULTS: Second-generation antipsychotics conferred a lower risk for tardive dyskinesia at 6 months than first-generation antipsychotics (0.9% vs. 3.8%, odds ratio [OR] = 0.29, 95% confidence interval [CI] = 0.18 to 0.46). In addition, patients with tardive dyskinesia at baseline who were receiving second-generation antipsychotics were less likely than patients receiving first-generation antipsychotics to have tardive dyskinesia symptoms at 6 months (43.6% vs. 60.8%, OR = 0.50, 95% CI = 0.30 to 0.85). A sensitivity analysis suggested no bias related to pharmaceutical industry financial support. CONCLUSION: The results suggest that the relative advantage of second-generation antipsychotics in terms of lower rates of incidence and persistence of tardive dyskinesia, observed in technical randomized controlled trials, generalizes to routine clinical care.

Cognitive-behavioural therapy for refractory psychotic symptoms of schizophrenia resistant to atypical antipsychotic medication. Randomised controlled trial.

BACKGROUND: There is increasing evidence that cognitive-behavioural therapy can be an effective intervention for patients experiencing drug-refractory positive symptoms of schizophrenia. AIMS: To investigate the effects of cognitive-behavioural therapy on in-patients with treatment-refractory psychotic symptoms. METHOD: Manualised therapy was compared with supportive counselling in a randomised controlled study. Both interventions were delivered by experienced psychologists over 16 sessions of treatment. Therapy fidelity was assessed by two independent raters. Participants underwent masked assessment at baseline, after treatment and at 6 months' follow-up. Main outcome measures were the Positive and Negative Syndrome Scale and the Psychotic Symptoms Rating Scale. The analysis was by intention to treat. RESULTS: Participants receiving cognitive cognitive-behavioural therapy had improved with regard to auditory hallucinations and illness insight at the post-treatment assessment, but these findings were not maintained at follow-up. CONCLUSIONS: Cognitive-behavioural therapy showed modest short-term benefits over supportive counselling for treatment-refractory positive symptoms of schizophrenia.

Learning (potential) and social functioning in schizophrenia.

Cognitive dysfunction in schizophrenia has well-known functional consequences. The ability to learn (learning potential) may be an important mediator. This study examines the relationship between learning and functional status in schizophrenia patients before and after participation in a rehabilitation program. We reasoned that learning is a broad construct, encompassing controlled, effortful as well as automatic (learning by doing) mechanisms, called explicit and implicit learning, respectively. Both types of learning ability are important in daily life. The study included 44 medicated schizophrenia patients and 79 healthy controls. We included measures of implicit and explicit learning as well as measures of the cognitive domains for which significant relationships with functional outcome have been established: immediate and secondary verbal memory, card sorting and vigilance. Learning potential and the patient's 'learner status' were also assessed. The results show that learning, as assessed by measures of explicit and implicit learning and learning potential, was not associated with social functioning or rehabilitation outcome. The highest correlations between cognitive functioning and social functioning were found for more or less 'static' performance measures when they were assessed for a second time with or without instructions on how to do the test. Optimized cognitive performance (i.e. performance after instruction or training) seems to be a better predictor of complex domains of functioning than naive or everyday performance.