Subjective well-being, drug attitude, and changes in symptomatology in chronic schizophrenia patients starting treatment with new-generation antipsychotic medication.

BACKGROUND: Non-adherence to medication remains a major challenge in the long-term management of patients with schizophrenia. Next to lack of insight into the illness, adverse effects of antipsychotic drugs, cognitive deficits, poor therapeutic alliance, reduced quality of life, missing social support, and negative attitudes toward medication are predictors of non-adherence. This study examined potential correlations between attitudes toward antipsychotic drug therapy, subjective well-being, and symptom change in patients with chronic schizophrenia. METHODS: 30 patients with schizophrenia starting monotherapy with a new-generation antipsychotic were included into the study. The Drug Attitude Inventory (DAI) and the Subjective Well-being under Neuroleptic Treatment Scale, short form (SWN-K), were administered after 2, 4, and 12 weeks of treatment. At the same points in time and at baseline, psychopathological symptoms were rated by means of the Positive and Negative Syndrome Scale (PANSS), and functioning was assessed by means of the Global Assessment of Functioning Scale (GAF). Antipsychotic induced side effects were evaluated by using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. RESULTS: Study participants had a mean age of 37.5 ± 9.7 years, baseline symptoms were mild. The PANSS total score improved significantly from baseline to weeks 4 (p = .003) and 12 (p = .001), respectively. Neither the DAI total score nor the SWN-K total score changed significantly over the course of time. The severity of symptoms was not correlated with drug attitude at any time point but was negatively correlated with wellbeing at weeks 2 (r = -.419, p = .021) and 4 (r = -.441, p = .015). There was no significant correlation between DAI and SWN-K total scores at any time point. CONCLUSIONS: Next to showing that the DAI and the SWN-K measure different aspects of subjective experiences during antipsychotic treatment these findings emphasize the use of both instruments to optimize adherence to medication.

Why do indiviuals with schizophrenia drop out of observational clinical trials?

Randomized controlled trials (RCTs) and observational studies frequently differ with regard to study dropouts. The present naturalistic follow-up investigation aimed to shed a light on this issue by evaluating the time to and the reasons for study dropout in patients suffering from schizophrenia who started monotherapy with an oral new-generation antipsychotic. To this end, psychopathological symptoms and safety data were assessed in 194 patients who were followed up to a maximum observation period of twelve months. 9.3% of study participants completed the study. The mean time to study dropout was 2.6 ± 2.7 months with almost two thirds of patients dropping out within three months. 44.3% discontinued medication at the date of study dropout, the remainders dropped out due to withdrawal of written consent, logistic reasons, or nonappearance to the study visit ("loss to follow-up"), which were not necessarily to be equated with cessation of the antipsychotic. These findings indicate that in contrast to RCTs, dropout of observational studies is not necessarily associated with drug discontinuation. Accordingly, systematic differences between trial designs need to be considered when interpreting the results of clinical trials.

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.

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 α=0.77), whereas physician-related items showed slightly less internal consistency (Cronbach α=0.68). The concordance between patient and physician ratings was fair, although statistically significant (κ=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.

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.

Changes in psychopathology in schizophrenia patients starting treatment with new-generation antipsychotics: therapeutic drug monitoring in a naturalistic treatment setting.

Previous studies on the relationship between plasma levels of new-generation antipsychotics (NGAs) and clinical response did not account for inter- and intra-individual variability in drug levels. Therefore, the present study calculated the ratio of observed versus expected NGA plasma levels and investigated its relationship with changes in the Positive and Negative Syndrome Scale (PANSS). Data of patients starting monotherapy with a NGA were collected 2, 4, 8, and 12 weeks after initiation of treatment. Next to the assessment of changes in psychopathology (PANSS) the ratio of observed versus expected plasma level was calculated. A total number of 221 ratios were eligible for analysis. About half of them ranged from 0.5-2 and were considered "normal", whereas the others were considered either "too low" or "too high". Psychopathological symptoms improved over the course of treatment, but changes in PANSS from baseline did not correlate significantly with the ratios of observed versus expected plasma levels at any assessment. The lack of linear correlation can be explained by the fact that 92% of the observed NGA plasma levels were at ≥ 50% of the lower limit of the therapeutic reference range, i.e., within the asymptote of the logistic plasma level-effect relationship. Accordingly, our findings indicate that the great majority of patients were treated with NGA doses that led to optimal plasma levels, based on the clinical impression of the treating psychiatrist only. Thus, calculating the ratio of observed versus expected plasma level may not be necessary in a routine clinical setting.

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.

Prolactin levels and sexual adverse effects in patients with schizophrenia during antipsychotic treatment.

OBJECTIVE: Patients with schizophrenia often experience sexual dysfunction (SD), to which disorder-related factors like negative symptoms and nondisorder-related factors can theoretically contribute. Thus, we investigated the correlation of SD and serum prolactin level in patients with schizophrenia during antipsychotic treatment. METHODS: We included 39 patients with schizophrenia with a mean age of 34.6 years who were switched to second-generation antipsychotics into the study. Sexual adverse effects (via a specific scale) and serum prolactin levels were measured at baseline and week 4. RESULTS: In males, mean prolactin levels increased over 4 weeks at a trend level of significance. Although a high incidence of SD was reported at baseline, there were no statistically significant changes over the course of 4 weeks. At baseline, a positive correlation between diminished sexual desire and prolactin levels could be found in men, which was not found in women; at week 4, both male and female patients demonstrated a positive correlation between orgastic dysfunction and prolactin levels. We found significant positive correlations between changes in prolactin levels over 4 weeks and changes in orgastic dysfunction for both sexes. Regression analyses showed prolactin levels at baseline to be a predictor of diminished sexual desire in men. Change in prolactin level was found to be a predictor of change for diminished sexual desire in women and for orgastic dysfunction in both sexes. CONCLUSION: We conclude that the potential of antipsychotics to increase serum prolactin levels imposes a certain risk that patients will experience SD of varying severity.

Factors influencing the choice of new generation antipsychotic medication in the treatment of patients with schizophrenia.

OBJECTIVE: This prospective, naturalistic study investigated the factors influencing physicians' choice of antipsychotic drug therapy in the treatment of patients with schizophrenia. METHOD: 108 in- and outpatients treated at the Department of Psychiatry of the Medical University Innsbruck who started treatment with a new generation antipsychotic (except clozapine) were included. The following factors were investigated: sociodemographic and illness-related variables, pretreatment, the reasons for change of treatment (lack of efficacy, side effects, non-compliance), side effects of pretreatment and body-mass-index (BMI). RESULTS: Sociodemographic and most illness-related variables did not have an influence on the physicians' choice of medication. Risperidone was more frequently prescribed in patients with severe positive symptoms than amisulpride or quetiapine. Rigidity, orthostatic dizziness and gynecomastia during pretreatment were frequently associated with starting patients on ziprasidone. In patients with diminished sexual desire ziprasidone was preferred over olanzapine. Amisulpride was used more commonly than olanzapine if patients had experienced weight gain during pretreatment. Moreover, patients who were prescribed amisulpride had a significantly higher BMI in comparison to patients who were prescribed olanzapine. The reasons for current change of treatment, as well as the drug history (total number of antipsychotic drugs prescribed during the course of the illness) did not have an influence on the physicians' choice of antipsychotic. CONCLUSION: In summary, the data suggest that side effects have a larger influence on the choice of antipsychotic than demographic or illness-related variables, except the severity of positive symptoms.

Facial emotion recognition and its relationship to symptomatic, subjective, and functional outcomes in outpatients with chronic schizophrenia.

Outcome in schizophrenia is multidimensional and consists of clinical and psychosocial domains. Difficulties in affect recognition are a hallmark of schizophrenia, but there is little research investigating the consequences of this deficit on patients' psychosocial status. This cross-sectional study examined the relationship of facial affect recognition and treatment outcomes in terms of psychopathology, quality of life (QOL), and psychosocial functioning. We investigated 40 regular attendees of a specialized schizophrenia outpatient clinic who had been stable both from a symptomatic and a medication perspective for a minimum of 6 months and 40 healthy volunteers who were chosen to match patients in age, sex, and education. Affect recognition was positively associated with patients' level of education and negatively with increasing age. Deficits in this area corresponded to the severity of negative and affective symptoms as well as to poor work and global functioning. These findings suggest that affect recognition is an important aspect of psychosocial functioning in stable outpatients with schizophrenia.

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.

Neural substrates for episodic encoding and recognition of unfamiliar faces.

Functional MRI was used to investigate brain activation in healthy volunteers during encoding of unfamiliar faces as well as during correct recognition of newly learned faces (CR) compared to correct identification of distractor faces (CF), missed alarms (not recognizing previously presented faces, MA), and false alarms (incorrectly recognizing newly presented faces, FA). Encoding was associated with frontal, occipital/fusiform, thalamic, and cerebellar activation. CR produced activation in frontal and cerebellar regions, whereas CF activated frontal and occipitotemporal regions as well as the thalamus. In contrast, MA was associated with frontal and thalamic activation, and FA with frontal activation. The CR minus CF comparison showed left lateral prefrontal and parietal activation, while no suprathreshold positive signal changes were detected when subtracting the other conditions (CR minus MA, CR minus FA, and vice versa). These results support the view that the successful episodic retrieval of newly learned faces is based on a dorsal visual stream mechanism.

Sex differences in brain activation patterns during processing of positively and negatively valenced emotional words.

BACKGROUND: Previous studies have suggested that men and women process emotional stimuli differently. In this study, we used event-related functional magnetic resonance imaging (fMRI) to investigate gender differences in regional cerebral activity during the perception of positive or negative emotions. METHOD: The experiment comprised two emotional conditions (positively/negatively valenced words) during which fMRI data were acquired. RESULTS: Thirty-eight healthy volunteers (19 males, 19 females) were investigated. A direct comparison of brain activation between men and women revealed differential activation in the right putamen, the right superior temporal gyrus, and the left supramarginal gyrus during processing of positively valenced words versus non-words for women versus men. By contrast, during processing of negatively valenced words versus non-words, relatively greater activation was seen in the left perirhinal cortex and hippocampus for women versus men, and in the right supramarginal gyrus for men versus women. CONCLUSIONS: Our findings suggest gender-related neural responses to emotional stimuli and could contribute to the understanding of mechanisms underlying the gender disparity of neuropsychiatric diseases such as mood disorders.

Alterations of glucose metabolism during treatment with clozapine or amisulpride: results from a prospective 16-week study.

Although second-generation antipsychotics have notable benefits as compared to typical antipsychotics, their use has been associated with metabolic disturbances, such as alterations of glucose homeostasis. It is still being debated whether this is a class effect of second-generation antipsychotics. We conducted a prospective, open study comparing body weight, parameters of insulin resistance in schizophrenia patients treated with either clozapine (n = 10) or amisuLpride ( n = 12). All parameters were assessed monthly over a period of 12 to 16 weeks. Body mass index (BMI), fasting serum insulin levels and the Homeostasis Model Assessment (HOMA) index for insulin resistance increased significantly in patients treated with clozapine. None of these parameters increased significantly in patients treated with amisulpride. This study indicates that treatment with clozapine appears to have a higher risk to lead to metabolic disturbances than amisupride.

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.

Early changes of plasma lipids during treatment with atypical antipsychotics.

Metabolic side effects have been found earlier during treatment with second-generation antipsychotics. Among those disturbances serum lipids are less investigated. We conducted a prospective, open study in schizophrenia patients in order to compare body weight and serum lipids during treatment with amisulpride, ziprasidone, clozapine or olanzapine over a period of 4 weeks. Body mass index, total cholesterol and triglycerides increased in patients treated with clozapine and olanzapine whereas high-density lipoprotein cholesterol decreased in those patients. In patients treated with amisulpride or ziprasidone, we found a decrease in body mass index and total cholesterol whereas high-density lipoprotein cholesterol increased. Our results indicate that treatment with ziprasidone and amisulpride is more favourable than treatment with clozapine and olanzapine with respect to the risk to induce weight gain and hyperlipidaemia. These results are important with regard to the increased risk for cardiovascular complications in patients with schizophrenia.

Association between antipsychotic-induced elevation of liver enzymes and weight gain: a prospective study.

We conducted a prospective, open study in schizophrenia patients treated with second-generation antipsychotics in order to investigate the risk for elevation of liver enzymes and its correlation to antipsychotic-induced weight gain. Body mass index, serum transaminases, plasma serum levels of the antipsychotic used, and blood cell counts were measured weekly during the first 6 weeks of treatment and monthly thereafter. A considerable proportion of subjects showed an increase beyond normal levels of at least one of the measured transaminases. In all but one case, the elevation of liver enzymes was transient. We found a statistically significant correlation between weight gain and liver enzyme elevation. The group of patients that had gained at least 7% of the baseline body weight showed significantly higher increases of transaminases as compared with those who had gained less than 7% weight. We conclude that antipsychotic-induced elevation of liver enzymes is mostly transient and could be associated with weight gain.

Gender differences in regional cerebral activity during the perception of emotion: a functional MRI study.

Whether men activate different brain regions during various emotions compared to women or whether gender differences exist in transient emotional states has been the subject of only few studies. We used event-related functional magnetic resonance imaging (fMRI) to investigate gender differences during the perception of positive or negative emotions. The experiment comprised two emotional conditions (pleasant/unpleasant visual stimuli) during which fMRI data were acquired. Altogether, 38 healthy volunteers (19 males, 19 females) were investigated. When subtracting the activation values of men from those of women, suprathreshold positive signal changes were detected in the right posterior cingulate, the left putamen and the left cerebellum during positive mood induction, and in bilateral superior temporal gyri and cerebellar vermis during negative mood induction. The subtraction of activation values of women from those of men yielded no significant differences. Our findings suggest gender-related neural responses to emotional stimuli and could contribute to the understanding of mechanisms underlying gender-related vulnerability of the prevalence and severity of neuropsychiatric disorders.