Antipsychotic-induced tardive dyskinesia: update on epidemiology and management.

PURPOSE OF REVIEW: To provide an update on the frequency of antipsychotic-induced tardive dyskinesia and its management in patients with schizophrenia spectrum disorders in studies published since the last systematic review in 2008. RECENT FINDINGS: Recent data about antipsychotic-induced tardive dyskinesia in patients with schizophrenia underscore the superiority of newer generation antipsychotics (21%) over first-generation antipsychotics (30%) with respect to prevalence and incidence rates. Regarding recently tested management strategies, the new vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine have been found to be effective and may be considered as first-line pharmacotherapy for tardive dyskinesia. Owing to quality issues of randomized controlled trials and/or small sample sizes, limited and conflicting evidence remains for most treatment strategies. SUMMARY: The reviewed literature reveals lower prevalence rates of antipsychotic-induced tardive dyskinesia in patients treated with newer generation compared with first-generation antipsychotics. The evidence of vesicular monoamine transporter 2 inhibitors as a first-line therapy for tardive dyskinesia is well supported by several controlled clinical trials.

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.

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.

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.

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.

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.

Attitudes of patients with schizophrenia and depression towards psychiatric research.

The success of clinical research depends heavily on patients' willingness to participate in studies. In recent years much work has been dedicated to studying the problems of conducting research in psychiatry, mainly in schizophrenia patients. In an attempt to replicate previous findings and extend results beyond schizophrenia, we interviewed patients suffering from schizophrenia or depression in a large academic centre concerning their attitudes towards psychiatric research. Ninety-five patients with a diagnosis of schizophrenia (48) or depression (47) completed the "Hamburg General Attitudes to Psychiatric Research Questionnaire" self-report instrument. Furthermore, demographic and clinical data were collected. Illness severity was evaluated using Clinical Global Impression and Global Assessment of Functioning scores. In general, patients approved of psychiatric research, and attitudes towards specific areas of research and research methods were rather positive. There were no significant differences between the two diagnostic groups regarding reasons for participation or non-participation in a clinical trial. The theoretical willingness to participate in studies was highest for studies using a questionnaire. Receiving sufficient information about a study before taking part was stated to be highly important. Our findings confirm and extend those of other groups. This should encourage psychiatrists at least in academic settings where most of this research has been done to approach patients to take part in clinical research.

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.

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.

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.

Treatment of schizophrenia patients: comparing new-generation antipsychotics to each other.

PURPOSE OF REVIEW: Although the debate on whether new antipsychotics have advantages over the old neuroleptics has recently been refueled by the first publication of the Clinical Antipsychotic Trials of Intervention Effectiveness results, one of the new challenges in the pharmacological management of schizophrenia patients is to choose among the new-generation drugs. RECENT FINDINGS: Earlier work has compared these medications primarily to traditional antipsychotics and until very recently there was little published information on the relative efficacy/safety of new-generation antipsychotics. SUMMARY: This review covers studies wherein therapeutic effects and adverse events of these drugs in schizophrenia patients were compared in head-to-head studies and that were published in 2005. Information is clearly more homogenous on the safety profile side, while the available evidence still offers little help for the clinicians' daily struggles to find the optimally effective antipsychotic for an individual schizophrenia patient.

Correlates of subjective and functional outcomes in outpatient clinic attendees with schizophrenia and schizoaffective disorder.

Outcome in schizophrenia is multidimensional and, thus, consists of clinical,humanitarian, rehabilitative and cost domains. Accordingly, recovery is conceptualized as the ability to function in the community, socially and vocationally, as well as being relatively free of disease-related psychopathology. The present cross-sectional study examined the relationship of premorbid functioning, psychopathology, insight, attitudes toward medication and side-effects, as well as sociodemographic factors with treatment outcomes in terms of quality of life (QOL) and psychosocial functioning among 60 regular attendees of a specialized schizophrenia outpatient clinic. Both insight into the illness as well as attitudes toward treatment indicated satisfactory compliance. Premorbid school and social functioning were positively correlated with actual employment status, and premorbid social functioning was further positively correlated with QOL and global functioning. Attitudes toward treatment were positively associated with global QOL, and with the patients' living situation. Both positive and negative symptoms as well as asthenia were negatively associated with QOL, while cognitive symptoms negatively influenced occupational functioning. Older patients lived independently and/or in a partnership more often, but had a lesser likelihood of competitive employment. Our observations suggest that subjective and functional outcomes in highly compliant patients are mainly predicted by psychopathological symptoms and unchangeable sociodemographic variables.