Scalability of the Positive and Negative Syndrome Scale in first-episode schizophrenia assessed by Rasch models.

OBJECTIVE: Historically, assessment of the psychometric properties of the Positive and Negative Syndrome Scale (PANSS) has had several foci: (1) calculation of reliability indexes, (2) extraction of subdimensions from the scale, and (3) assessment of the validity of the total score. In this study, we aimed to examine the scalability and to assess the clinical performance of the 30-item PANSS total score as well as the scalability of a shorter version (PANSS-6) of the scale. METHODS: A composite data set of 1073 patients with first-episode schizophrenia or schizophrenia spectrum disorder was subjected to Rasch analysis of PANSS data from baseline and 4-6 weeks follow-up. RESULTS: The central tests of fit of the Rasch model failed to satisfy the statistical requirements behind item homogeneity for the PANSS-30 as well as the PANSS-6 total score. For the PANSS-30, Differential Item Functioning was pronounced both for the 7-point Likert scale rating categories and when dichotomizing the rating categories. Subsequently, the Rasch structure analysis in the context of dichotomized items was used to isolate and estimate a systematic error because of item inhomogeneity, as well as a random error. The size of the combined sources of error for the PANSS-30 total score approximated 20% which is often regarded as clinical cut-off between response versus no-response. CONCLUSION: The results demonstrate the operational consequences of a lack of statistical fit of the Rasch model and suggest that the calculated measure of uncertainty needs to be considered when using the PANSS-30 total score.

Frontal D2/3 Receptor Availability in Schizophrenia Patients Before and After Their First Antipsychotic Treatment: Relation to Cognitive Functions and Psychopathology.

BACKGROUND: We have previously reported associations between frontal D2/3 receptor binding potential positive symptoms and cognitive deficits in antipsychotic-naïve schizophrenia patients. Here, we examined the effect of dopamine D2/3 receptor blockade on cognition. Additionally, we explored the relation between frontal D2/3 receptor availability and treatment effect on positive symptoms. METHODS: Twenty-five antipsychotic-naïve first-episode schizophrenia patients were examined with the Positive and Negative Syndrome Scale, tested with the cognitive test battery Cambridge Neuropsychological Test Automated Battery, scanned with single-photon emission computerized tomography using the dopamine D2/3 receptor ligand [(123)I]epidepride, and scanned with MRI. After 3 months of treatment with either risperidone (n=13) or zuclopenthixol (n=9), 22 patients were reexamined. RESULTS: Blockade of extrastriatal dopamine D2/3 receptors was correlated with decreased attentional focus (r = -0.615, P=.003) and planning time (r = -0.436, P=.048). Moreover, baseline frontal dopamine D2/3 binding potential and positive symptom reduction correlated positively (D2/3 receptor binding potential left frontal cortex rho = 0.56, P=.003; D2/3 receptor binding potential right frontal cortex rho = 0.48, P=.016). CONCLUSIONS: Our data support the hypothesis of a negative influence of D2/3 receptor blockade on specific cognitive functions in schizophrenia. This is highly clinically relevant given the well-established association between severity of cognitive disturbances and a poor functional outcome in schizophrenia. Additionally, the findings support associations between frontal D2/3 receptor binding potential at baseline and the effect of antipsychotic treatment on positive symptoms.

Well-being and depression in individuals with subclinical hypothyroidism and thyroid autoimmunity - a general population study.

BACKGROUND: The association between subclinical hypothyroidism (SCH), with and without raised thyroid peroxidase antibodies (anti-TPO), and well-being or depression is still controversial, in spite of many studies on the topic. AIMS: In this large general population study of 8214 individuals, we aim to clarify the significance of elevated levels of anti-TPO as a marker of poor well-being and depression in euthyroid individuals and individuals with SCH. METHODS: In participants from the Danish General Suburban Population Study (GESUS), serum thyroid stimulating hormone (TSH), total triiodothyronine (tT3), free thyroxine (fT4) and anti-TPO was measured. Prevalence of poor well-being and depression was measured using the WHO-5 Well-being questionnaire and WHO MDI [Major (ICD-10) Depression Inventory] questionnaire. RESULTS: Raw score for well-being or depression overall and stratified for sex was not more significantly different in euthyroid individuals than in individuals with SCH, with or without high anti-TPO, except that euthyroid women with elevated anti-TPO had better well-being (P = 0.03) compared with euthyroid women with anti-TPO within the reference range. CONCLUSION: Elevated anti-TPO levels cannot be used as a general marker of poor well-being or depression in the general population.

Linear correlation between phenobarbital dose and concentration in alcohol withdrawal patients.

INTRODUCTION: Barbiturates are potent drugs for treatment of alcohol withdrawal symptoms, but they entail a risk of over-dosage and respiratory depression. The purpose of the present study was to investigate the correlation between phenobarbital dose and phenobarbital blood concentration in patients withdrawing from long-term alcohol intoxication. MATERIAL AND METHODS: A total of 497 patients who were hospitalized for treatment of alcohol withdrawal symptoms during an 18-month period were enrolled in the study. Phenobarbital 200 mg was administered orally every 30 or 60 minutes in response to the observed symptoms. Within the first 24 hours after admission, i.e. at 8 AM, blood was collected for determination of phenobarbital concentration, and the cumulated dose of phenobarbital at the time of the blood sampling was registered. RESULTS: The mean cumulated phenobarbital dose at the time of the blood sampling was 877 mg +/- 557 mg, while the mean plasma phenobarbital concentration was 104 micromol/l +/- 62 micromol/l. A statistically significant linear correlation between phenobarbital dose and concentration was found for both males and females as 83% and 84% of the variation in drug concentration, respectively, could be explained by the phenobarbital dose. We observed no serious complications of the phenobarbital treatment--including respiratory problems or severe sedation. DISCUSSION: The strong linear correlation between phenobarbital dose and concentration suggests that absorption of plasma phenobarbital from the gastrointestinal system is highly predictable.

Phenobarbital versus diazepam for delirium tremens--a retrospective study.

INTRODUCTION: Delirium tremens (DT) is a severe and potentially fatal condition that may occur during withdrawal from chronic alcohol intoxication. The purpose of the present study was to compare the effects and the rates of complications of phenobarbital and diazepam treatment in DT. MATERIAL AND METHODS: Data were collected retrospectively from the medical files of patients who had received DT treatment (n = 194) at two psychiatric departments located in the general Copenhagen area in the 1998-2006 period. At one department, all patients were treated with phenobarbital (n = 53), while the treatment regimen at the other department was changed from phenobarbital (n = 53) to diazepam (n = 88) in 2002. RESULTS: Length of DT and hospitalization, mortality and rate of pneumonia (26%) were not affected by treatment. A subpopulation (9%) in the diazepam group was resistant to treatment. Respiratory depression occurred in 4% of the phenobarbital and in 1% of the diazepam-treated patients. Wernicke's encephalopathy was established in 47% of the patients. CONCLUSION: Phenobarbital is a safe alternative to diazepam in the treatment of DT.

Rasch analysis of the PANSS negative subscale and exploration of negative symptom trajectories in first-episode schizophrenia - data from the OPTiMiSE trial.

The observed heterogeneity in negative symptom treatment response may be partly attributable to inadequate measurement tools or limitations in methods of analysis. Previous Item Response Theory models of the Positive and Negative Syndrome Scale (PANSS) have only examined samples of chronic patients and with mixed results. We examined the scalability of the negative subscale embedded in the PANSS and subsequently explored negative symptom trajectories across four weeks of amisulpride treatment. Data were derived from the OPTiMiSE trial comprising 446 patients with first-episode schizophrenia or schizophreniform disorder. Using the Rasch Model to examine psychometric properties of the PANSS negative subscale, we found that the composite score across items was not an adequate measure of negative symptom severity. Consequently, we chose an exploratory statistical approach involving Principal Component Analysis which yielded one significant component clustering into two significant symptom trajectories: 1) Subtle but constant decrease in negative symptom severity (N = 323; 72%), and 2) symptom instability across visits (N = 19; 4%). Explorative analytic methods as presented here may pave the way for more efficient and sensitive methods of analyzing negative symptom response in research and in clinical practice.

Extrastriatal dopamine D2/3 receptors and cortical grey matter volumes in antipsychotic-naïve schizophrenia patients before and after initial antipsychotic treatment.

OBJECTIVES: Long-term dopamine D2/3 receptor blockade, common to all antipsychotics, may underlie progressive brain volume changes observed in patients with chronic schizophrenia. In the present study, we examined associations between cortical volume changes and extrastriatal dopamine D2/3 receptor binding potentials (BPND) in first-episode schizophrenia patents at baseline and after antipsychotic treatment. METHODS: Twenty-two initially antipsychotic-naïve patients underwent magnetic resonance imaging (MRI), [123I]epidepride single-photon emission computerised tomography (SPECT), and psychopathology assessments before and after 3 months of treatment with either risperidone (N = 13) or zuclopenthixol (N = 9). Twenty healthy controls matched on age, gender and parental socioeconomic status underwent baseline MRI and SPECT. RESULTS: Neither extrastriatal D2/3 receptor BPND at baseline, nor blockade at follow-up, was related to regional cortical volume changes. In post-hoc analyses excluding three patients with cannabis use we found that higher D2/3 receptor occupancy was significantly associated with an increase in right frontal grey matter volume. CONCLUSIONS: The present data do not support an association between extrastriatal D2/3 receptor blockade and extrastriatal grey matter loss in the early phases of schizophrenia. Although inconclusive, our exclusion of patients tested positive for cannabis use speaks to keeping attention to potential confounding factors in imaging studies.

Progression in intima media thickness--the significance of hormonal biomarkers of chronic stress.

OBJECTIVE: The pathophysiological pathways from stress caused by psychosocial stress to IHD has not been dealt with very extensively. The objective of this study was to analyse the association between cortisol levels and progression in intima media thickness (IMT). METHODS AND RESULTS: In 1998 and 2002, 95 participants went through a clinical investigation including ultrasound of the artery carotis communis. Progression in IMT was analysed in relation to levels of salivary cortisol in 1998 and the average levels of salivary cortisol in 1998/2002. Further, the significance of conventional coronary risk factors, testosterone and dehydro-epiandrosterone sulphate (DHEAS) were evaluated. Among the men, only age and HDL-cholesterol (negative) were significantly correlated with progression in IMT. Among the women, awakening cortisol response was significantly correlated with progression in IMT. Testosterone and DHEAS were borderline significantly associated (negatively) with progression in IMT in both genders. CONCLUSION: Progression in atherosclerosis were determined by different risk factors in women and men. The awakening cortisol response was of great importance to IMT progression in women but not in men.

Striatal D(2/3) Binding Potential Values in Drug-Naïve First-Episode Schizophrenia Patients Correlate With Treatment Outcome.

One of best validated findings in schizophrenia research is the association between blockade of dopamine D2 receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D(2/3) receptor binding potential (BP(p)) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D(2/3) receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [(123)I]iodobenzamide ([(123)I]-IBZM) was used to examine striatal D(2/3) receptor BP(p). Patients were examined before and after 6 weeks of treatment with the D(2/3) receptor antagonist amisulpride. There was a significant negative correlation between striatal D(2/3) receptor BP(p) at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BP(p) in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BP(p) of dopamine D(2/3) receptors in antipsychotic-naïve first-episode patients with schizophrenia and treatment response. Patients with a low BP(p) have a better treatment response than patients with a high BP(p). The results further suggest that functioning may decline at high levels of dopamine receptor blockade.

The Hamilton Depression Scale (HAM-D) and the Montgomery-Åsberg Depression Scale (MADRS). A psychometric re-analysis of the European genome-based therapeutic drugs for depression study using Rasch analysis.

The objective of this re-analysis of the European Genome-Based Therapeutic Drugs for Depression Study (GENDEP) was to psychometrically test the unidimensionality of the full Montgomery Åsberg Depression Rating Scale (MADRS10) and the Hamilton Depression Scale (HAM-D17) versus their respective subscales (MADRS5 and HAM-D6) containing the core symptoms of depression severity. Rasch analysis was applied using RUMM 2030 software to assess the overall fit for unidimensionality. Neither the MADRS10 nor the HAM-D17 was found to fit the Rasch model for unidimensionality. The HAM-D6 (containing the items of depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety, and somatic general) as well as the analogue MADRS5 were tested for unidimensionality by use of the RUMM 2030 programme, and only the HAM-D6 was accepted. When testing for invariance across rating weeks or centres, the RUMM 2030 had to be supplemented with the Friedman two-way analysis of variance by ranks. The HAM-D6 but not the MADRS5 was accepted. It was therefore concluded that the HAM-D6 is a psychometrically valid outcome scale to measure change in clinical trials of antidepressants.

The Validity of the WHO-5 as an Early Screening for Apathy in an Elderly Population.

Aim. The objective of our study has been to evaluate the WHO-5 as a new early screening instrument for apathy in a group of elderly persons. Methods. The WHO-5 was compared to the Geriatric Depression Scale (GDS-15). The GDS contains five items measuring well-being and ten items measuring depression. The internal validity of the WHO-5 (total score being a sufficient statistic) was evaluated with both parametric and nonparametric item response theory models. The external validity of the WHO-5 and the GDS was evaluated by ROC using depression as index of validity. Results. The item response theory analyses confirmed that the total score of the WHO-5 is a sufficient statistic. The ROC analysis shows an adequate sensitivity (61%) and specificity (84%). The GDS(15) and its two subscales obtained low sensitivity (25-42%), but high specificity (90-98%). Conclusion. The WHO-5 was found both internally and externally valid when considering decreased positive well-being to be an early indication of apathy reflecting that the wind has begun to be taken out of the "motivation sail."

Exploring regional variation in antipsychotic coprescribing practice: a Danish questionnaire survey.

OBJECTIVE: The pharmacologic treatment of schizophrenia is characterized by excessive use of antipsychotic polypharmacy, which reflects a gap between evidence and practice. The aim of the present study was to investigate regional differences in treatment setting characteristics and in physician and nurse attitudes toward antipsychotic polypharmacy and clinical guidelines. METHOD: Cross-sectional postal questionnaire survey directed to physicians and nurses at 2 pairs of treatment settings in Denmark, characterized by low and high prevalence of antipsychotic polypharmacy, respectively. The questionnaire investigation was conducted during November 2007 to February 2008. RESULTS: Satisfactory response rates were obtained (physicians: 93%; nurses: 87%). The treatment settings with low use of antipsychotic polypharmacy were characterized by raised knowledge/awareness of local antipsychotic treatment guidelines (P = .02 for physicians; P = .01 for nurses). Among physicians, these settings were also characterized by an elevated confidence in these guidelines (P = .01), frequent local educational activities (P < .0001), and increased recent involvement in research (P = .01). Among nurses, a perception of an overwhelming work load (P = .01) and time pressure (P = .003) was significantly more prevalent in treatment settings with high rates of antipsychotic coprescribing, as was the belief in the benefit of antipsychotic polypharmacy augmentation (P = .001). CONCLUSION: Albeit no causal relationships can be inferred from this cross-sectional observational study, we recommend the furtherance of a treatment environment characterized by easily accessible clinical guidelines, frequent academic activities, and an unruffled atmosphere.