Prevalence, predictors, and consequences of long-term refusal of antipsychotic treatment in first-episode psychosis

Studies investigating medication adherence in psychosis are limited by the need of a certain degree of medication adherence and the inclusion of mostly multiple-episode patients. By contrast, noninformed consent, epidemiological studies in first-episode psychosis (FEP) allow the assessment of an important subgroup of patients who persistently refuse antipsychotic medication and thereby never receive an adequate antipsychotic trial. The present study aims to assess the prevalence and predictors of such a "medication refusal" subgroup and its association with illness outcome.

A pharmaco-EEG study on antipsychotic drugs in healthy volunteers

RATIONALE: Both psychotropic drugs and mental disorders have typical signatures in quantitative electroencephalography (EEG). Previous studies found that some psychotropic drugs had EEG effects opposite to the EEG effects of the mental disorders treated with these drugs (key-lock principle). OBJECTIVES: We performed a placebo-controlled pharmaco-EEG study on two conventional antipsychotics (chlorpromazine and haloperidol) and four atypical antipsychotics (olanzapine, perospirone, quetiapine, and risperidone) in healthy volunteers. We investigated differences between conventional and atypical drug effects and whether the drug effects were compatible with the key-lock principle. METHODS: Fourteen subjects underwent seven EEG recording sessions, one for each drug (dosage equivalent of 1 mg haloperidol). In a time-domain analysis, we quantified the EEG by identifying clusters of transiently stable EEG topographies (microstates). Frequency-domain analysis used absolute power across electrodes and the location of the center of gravity (centroid) of the spatial distribution of power in different frequency bands. RESULTS: Perospirone increased duration of a microstate class typically shortened in schizophrenics. Haloperidol increased mean microstate duration of all classes, increased alpha 1 and beta 1 power, and tended to shift the beta 1 centroid posterior. Quetiapine decreased alpha 1 power and shifted the centroid anterior in both alpha bands. Olanzapine shifted the centroid anterior in alpha 2 and beta 1. CONCLUSIONS: The increased microstate duration under perospirone and haloperidol was opposite to effects previously reported in schizophrenic patients, suggesting a key-lock mechanism. The opposite centroid changes induced by olanzapine and quetiapine compared to haloperidol might characterize the difference between conventional and atypical antipsychotics.

Differences in the EEG profiles of early and late responders to antipsychotic treatment in first-episode, drug-naive psychotic patients

The aim of this study was to search for differences in the EEG of first-episode, drug-naive patients having a schizophrenic syndrome which presented different time courses in response to antipsychotic treatment. Thirteen patients who fulfilled DSM-IV diagnosis for schizophrenia or schizophreniform disorder participated in this study. Before beginning antipsychotic treatment, the EEG was recorded. On the same day psychopathological ratings were assessed using the ADMDP system, and again after 7 and 28 days of treatment. The resting EEG (19 leads) was subject to spectral analysis involving power values for six frequency bands. The score for the schizophrenic syndrome was used to divide the patients into two groups: those who displayed a clinically meaningful improvement of this syndrome (reduction of more than 30%) after 7 days of treatment (early responders, ER) and those who showed this improvement after 28 days (late responders. LR). Analysis of variance for repeated measures between ER, LR and their matched controls with the 19 EEG leads yielded highly significant differences for the factor group in the alpha2 and beta2 frequency band. No difference was found between the slow-wave frequency bands. Compared to controls the LR group showed significantly higher alpha2 and beta2 power and, in comparison to the ER group, significantly higher alpha2 power. There were no significant differences between the ER and the control group. These findings point to differences in brain physiology between ER and LR. The implications for diagnosis and treatment are discussed.

Early- and delayed antipsychotic response and prediction of outcome in 528 severely impaired patients with schizophrenia treated with amisulpride

'Early-onset' studies have shown that symptomatic response often occurs early and that early symptomatic response is predictive for later outcome. Limiting factors of these studies include the restriction on symptomatic outcome, the inclusion of mostly moderately ill patients, and the use of various antipsychotics.

Prediction of Psychosis by Mismatch Negativity

BACKGROUND: To develop risk-adapted prevention of psychosis, an accurate estimation of the individual risk of psychosis at a given time is needed. Inclusion of biological parameters into multilevel prediction models is thought to improve predictive accuracy of models on the basis of clinical variables. To this aim, mismatch negativity (MMN) was investigated in a sample clinically at high risk, comparing individuals with and without subsequent conversion to psychosis. METHODS: At baseline, an auditory oddball paradigm was used in 62 subjects meeting criteria of a late risk at-state who remained antipsychotic-naive throughout the study. Median follow-up period was 32 months (minimum of 24 months in nonconverters, n = 37). Repeated-measures analysis of covariance was employed to analyze the MMN recorded at frontocentral electrodes; additional comparisons with healthy controls (HC, n = 67) and first-episode schizophrenia patients (FES, n = 33) were performed. Predictive value was evaluated by a Cox regression model. RESULTS: Compared with nonconverters, duration MMN in converters (n = 25) showed significantly reduced amplitudes across the six frontocentral electrodes; the same applied in comparison with HC, but not FES, whereas the duration MMN in in nonconverters was comparable to HC and larger than in FES. A prognostic score was calculated based on a Cox regression model and stratified into two risk classes, which showed significantly different survival curves. CONCLUSIONS: Our findings demonstrate the duration MMN is significantly reduced in at-risk subjects converting to first-episode psychosis compared with nonconverters and may contribute not only to the prediction of conversion but also to a more individualized risk estimation and thus risk-adapted prevention.

Comparison of objectively measured motor behavior with ratings of the motor behavior domain of the Bern Psychopathology Scale (BPS) in schizophrenia

Motor symptoms in schizophrenia occur frequently and are relevant to diagnosis and antipsychotic therapy. To date motor symptoms are difficult to assess and their pathobiology is a widely unresolved issue. The Bern Psychopathology Scale for the assessment of system-specific psychotic symptoms (BPS) was designed to identify homogenous patient groups by focusing on three domains: language, affectivity and motor behavior. The present study aimed to validate the motor behavior domain of the BPS using wrist actigraphy. In total, 106 patients were rated with the BPS and underwent 24 h continuous actigraphy recording. The ratings of the global severity of the motor behavior domain (GSM) as well as the quantitative and the subjective items of the motor behavior domain of the BPS were significantly associated with actigraphic variables. In contrast, the qualitative items of the motor domain failed to show an association with actigraphy. Likewise, scores of the language and the affectivity domains were not related to actigraphic measures. In conclusion, we provided substantial external validity for global, quantitative and subjective ratings of the BPS motor behavior domain. Thus, the BPS is suitable to assess the dimension of quantitative motor behavior in the schizophrenia spectrum.

Insular volume abnormalities associated with different transition probabilities to psychosis

Background Although individuals vulnerable to psychosis show brain volumetric abnormalities, structural alterations underlying different probabilities for later transition are unknown. The present study addresses this issue by means of voxel-based morphometry (VBM). Method We investigated grey matter volume (GMV) abnormalities by comparing four neuroleptic-free groups: individuals with first episode of psychosis (FEP) and with at-risk mental state (ARMS), with either long-term (ARMS-LT) or short-term ARMS (ARMS-ST), compared to the healthy control (HC) group. Using three-dimensional (3D) magnetic resonance imaging (MRI), we examined 16 FEP, 31 ARMS, clinically followed up for on average 3 months (ARMS-ST, n=18) and 4.5 years (ARMS-LT, n=13), and 19 HC. Results The ARMS-ST group showed less GMV in the right and left insula compared to the ARMS-LT (Cohen's d 1.67) and FEP groups (Cohen's d 1.81) respectively. These GMV differences were correlated positively with global functioning in the whole ARMS group. Insular alterations were associated with negative symptomatology in the whole ARMS group, and also with hallucinations in the ARMS-ST and ARMS-LT subgroups. We found a significant effect of previous antipsychotic medication use on GMV abnormalities in the FEP group. Conclusions GMV abnormalities in subjects at high clinical risk for psychosis are associated with negative and positive psychotic symptoms, and global functioning. Alterations in the right insula are associated with a higher risk for transition to psychosis, and thus may be related to different transition probabilities.

Multilead quantitative electroencephalogram profile and cognitive evoked potentials (P300) in healthy subjects after a single dose of olanzapine

RATIONALE: Olanzapine is an atypical antipsychotic drug with a more favourable safety profile than typical antipsychotics with a hitherto unknown topographic quantitative electroencephalogram (QEEG) profile. OBJECTIVES: We investigated electrical brain activity (QEEG and cognitive event related potentials, ERPs) in healthy subjects who received olanzapine. METHODS: Vigilance-controlled, 19-channel EEG and ERP in an auditory odd-ball paradigm were recorded before and 3 h, 6 h and 9 h after administration of either a single dose of placebo or olanzapine (2.5 mg and 5 mg) in ten healthy subjects. QEEG was analysed by spectral analysis and evaluated in nine frequency bands. For the P300 component in the odd-ball ERP, the amplitude and latency was analysed. Statistical effects were tested using a repeated-measurement analysis of variance. RESULTS: For the interaction between time and treatment, significant effects were observed for theta, alpha-2, beta-2 and beta-4 frequency bands. The amplitude of the activity in the theta band increased most significantly 6 h after the 5-mg administration of olanzapine. A pronounced decrease of the alpha-2 activity especially 9 h after 5 mg olanzapine administration could be observed. In most beta frequency bands, and most significantly in the beta-4 band, a dose-dependent decrease of the activity beginning 6 h after drug administration was demonstrated. Topographic effects could be observed for the beta-2 band (occipital decrease) and a tendency for the alpha-2 band (frontal increase and occipital decrease), both indicating a frontal shift of brain electrical activity. There were no significant changes in P300 amplitude or latency after drug administration. Conclusion: QEEG alterations after olanzapine administration were similar to EEG effects gained by other atypical antipsychotic drugs, such as clozapine. The increase of theta activity is comparable to the frequency distribution observed for thymoleptics or antipsychotics for which treatment-emergent somnolence is commonly observed, whereas the decrease of beta activity observed after olanzapine administration is not characteristic for these drugs. There were no clear signs for an increased cerebral excitability after a single-dose administration of 2.5 mg and 5 mg olanzapine in healthy controls.

Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine

INTRODUCTION Agitation is a major problem in acute schizophrenia. Only a few studies have tested antipsychotic agents in severely agitated patients, mainly because of legal issues. Furthermore, most studies were limited to the first 24 hours. We aimed to investigate the efficacy of oral haloperidol, risperidone, and olanzapine in reducing psychotic agitation in severely agitated patients with schizophrenia or schizophreniform or schizoaffective disorder over 96 hours using a prospective, randomized, rater-blinded, controlled design within a naturalistic treatment regimen. METHODS In total, 43 severely agitated patients at acute care psychiatric units were enrolled. Participants were randomly assigned to receive either daily haloperidol 15 mg, olanzapine 20 mg, or risperidone 2 to 6 mg over 5 days. Positive and Negative Syndrome Scale psychotic agitation subscale score was the primary outcome variable. A mixed-model analysis was applied. RESULTS All drugs were effective for rapid tranquilization within 2 hours. Over 5 days, the course differed between agents (P < 0.001), but none was superior. Dropouts occurred only in the risperidone and olanzapine groups. Men responded better to treatment than did women during the initial 2 hours (P = 0.046) as well as over the 5-day course (P < 0.001). No difference between drug groups was observed regarding diazepam or biperiden use. CONCLUSIONS Oral haloperidol, risperidone, and olanzapine seem to be suitable for treating acute severe psychotic agitation in schizophrenia spectrum disorders. Response to oral antipsychotics demonstrated a gender effect with poorer outcome in women throughout the study.

Actigraphic monitoring of physical activity in clinical trials in schizophrenia

Schizophrenia is still associated with poor outcome, which is mainly related to negative symptoms, reduced physical activity and low quality of life. Physical activity can be objectively measured without distress using wrist actigraphy. The activity levels during the wake periods of the day have been informative on psychopathology and antipsychotic medication. Several studies demonstrated prominent negative symptoms to be associated with reduced activity levels with strongest correlations in chronic patients. Particularly, the avolition score is correlated with reduced activity levels. Moreover, activity levels differ between DSM-IV schizophrenia spectrum disorders and subtypes as well as between patients treated with olanzapine or risperidone. The longitudinal course of activity levels during an psychotic episode demonstrates considerable variance between subjects. During a psychotic episode patients with low activity levels at baseline experience an amelioration of negative symptoms. In contrast, patients with high activity levels at baseline have stable low negative syndrome scores. Between psychotic episodes less variance is observed. Actigraphy is easily applied in schizophrenia and allows collecting large amounts of crosssectional or longitudinal data. With larger numbers of subjects in controlled trials, continuous recording of activity would foster the detection of different outcome trajectories, which may prove as useful groups to target interventions. In clinical trials, activity monitoring may supplement and validate measures of the negative syndrome and its avolition factor or serve as an outcome marker for physical activity, which is important for metabolic issues and quality of life.

Risk of incident stroke in patients with Alzheimer disease or vascular dementia

OBJECTIVE To explore the risk of ischemic stroke, hemorrhagic stroke, or TIA in patients with Alzheimer disease (AD) or vascular dementia (VD). METHODS We conducted a follow-up study with a nested case-control analysis using the UK-based General Practice Research Database. We included patients aged 65 years and older with an incident diagnosis of AD or VD between 1998 and 2008 and a comparison group of dementia-free patients. We estimated incidence rates of ischemic stroke, hemorrhagic stroke, or TIA in patients with AD, VD, or without dementia, and we calculated odds ratios with 95% confidence intervals (CIs) of developing such an outcome in patients with AD or VD, stratified by use of antipsychotic drugs. RESULTS We followed 6,443 cases with AD, 2,302 with VD, and 9,984 dementia-free patients over time and identified 281 cases with incident ischemic stroke, 139 with hemorrhagic stroke, and 379 with TIA. The incidence rates of ischemic stroke for patients with AD, VD, or no dementia were 4.7/1,000 person-years (PYs) (95% CI 3.8-5.9), 12.8/1,000 PYs (95% CI 9.8-16.8), and 5.1/1,000 PYs (95% CI 4.3-5.9), respectively. Compared with dementia-free patients, the odds ratio of developing a TIA for patients with AD treated with atypical antipsychotic drugs was 4.5 (95% CI 2.1-9.2). CONCLUSIONS Patients with VD, but not AD, have a markedly higher risk of developing an ischemic stroke than those without dementia. In patients with AD, but not VD, use of atypical antipsychotic drugs was associated with an increased risk of TIA.

Dysfunctions of the motor system in schizophrenia

Objective: Schizophrenia patients suffer from a variety of motor symptoms, including parkinsonism, catatonia, neurological soft signs, abnormal involuntary movements and psychomotor slowing. Methods: Literature review of prevalence rates and presentation of own results. Results: Parkinsonism and abnormal involuntary movements are intrinsic to schizophrenia, but may also be evoked by antipsychotic treatment. Reduced motor activity is associated with negative symptoms, catatonia and psychomotor slowing. Furthermore, 40 % of schizophrenia patients are impaired in gesture performance, which is related to executive and basic motor function. Mild motor disturbances are found in the majority of patients, while severe dysfunctions are limited to a minority. Our neuroimaging studies suggest that hypokinesia is caused by defective cortico-subcortical motor loops in schizophrenia. Taken together, a dimensional approach to schizophrenia motor symptoms seems promising. A purely descriptive assessment of motor signs is preferred over theoryladen categorization. Using objective motor parameters allows finding neural correlates of abnormal motor behaviour. Conclusion: The motor dimension of schizophrenia is linked to distinct disturbances in the cerebral motor system. Targeted modification of the defective motor system might become a relevant treatment option in patients suffering from schizophrenia with predominant motor features.

Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized controlled study with oral haloperidol, risperidone, and olanzapine

Agitation is a major problem in acute schizophrenia. Still, only limited evidence exists on antipsychotic efficacy in severely agitated patients after the first 24 hours. We aimed to investigate the efficacy of oral haloperidol, risperidone, and olanzapine in reducing psychotic agitation in severely agitated patients with schizophrenia or schizophreniform or schizoaffective disorder over 96 hours using a prospective, randomized, rater-blinded, controlled design within a naturalistic treatment regimen. We enrolled 43 severely agitated patients at acute care psychiatric units. Participants were randomly assigned to receive either daily haloperidol 15 mg, olanzapine 20 mg, or risperidone 2 – 6 mg over 5 days. Positive and Negative Syndrome Scale psychotic agitation (PANSS-PAS) subscore was the primary outcome variable. A mixed model analyses was applied. All drugs were effective for rapid tranquillization within 2 hours. Over 5 days, the course differed between agents (p < 0.001) but none was superior. Dropouts occurred only in the risperidone and olanzapine groups. Men responded better to treatment than women during the initial 2 hours (p = 0.046) as well as over the 5 day course (p < 0.001). No difference between drug groups was observed regarding diazepam or biperiden use. Oral haloperidol, risperidone, and olanzapine seem to be suitable for treating acute severe psychotic agitation in schizophrenia spectrum disorders. We observed a gender effect with poorer outcome in women.

WHEN DOES THE TROUBLE START? OBESITY, DIABETES RISKS AND METABOLIC DISTURBANCES IN YOUNG PEOPLE WITH PSYCHOSIS

People with psychotic disorders have higher mortality rates compared to the general population. Most deaths are due to cardiovascular (CV) disease, reflecting high rates of CV risk factors such as obesity and diabetes. Treatment with antipsychotic drugs is associated with weight gain in clinical trials. However, there is little information about how these drugs affect children and young people, and how early in the course of treatment the elevation in CV risk factors begins. This information is essential in understanding the costs and benefits of these treatments in young people, and establishing preventive and early intervention services to address physical health comorbidities. This symposium reports both prospective and naturalistic data from children and adolescents treated with antipsychotic drugs. These studies demonstrate that adverse effects on cardiometabolic measures, notably BMI and insulin resistance, become apparent very soon after treatment is initiated. Further, children and adolescents appear to be even more sensitive to these effects than adults. Population-wide studies are also informative. Danish data showing that young people exposed to antipsychotics have a higher risk of diabetes, compared with young people who had a psychiatric diagnosis but were not exposed to antipsychotic drugs, will be presented. In addition, an Australian comparison between a large, nationally representative sample of people with psychosis and a general population sample shows that higher rates of obesity and other cardiometabolic abnormalities are already evident in people with psychosis by the age of 25 years. Young people living with psychosis are already disadvantaged by the demands of living with mental illness, stigma, and social factors such as unemployment and low income. The addition of obesity, diabetes and other comorbidities adds a further burden. The data presented highlights the need for careful selection of antipsychotic drugs, regular monitoring of physical health and early intervention when weight gain, glucose dysregulation, or other cardiometabolic abnormalities are detected.

Physical activity in schizophrenia is higher in the first episode than in subsequent ones

Schizophrenia is frequently associated with abnormal motor behavior, particularly hypokinesia. The course of the illness tends to deteriorate in the first years. We aimed to assess gross motor activity in patients with a first episode (n = 33) and multiple episodes (n = 115) of schizophrenia spectrum disorders using wrist actigraphy. First episode patients were younger, had higher motor activity and reduced negative symptom severity. Covarying for age, chlorpromazine equivalents, and negative symptoms, first episode patients still had higher motor activity. This was also true after excluding patients with schizophreniform disorder from the analyses. In first episode patients, but not in patients with multiple episodes, motor activity was correlated with antipsychotic dosage. In conclusion, after controlling for variables related to disorder chronicity, patients with first episodes were still more active than patients with multiple episodes. Thus, reduced motor activity is a marker of deterioration in the course of schizophrenia spectrum disorders.