Anita Riecher-Rössler

Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial

BACKGROUND Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia. METHODS We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636. FINDINGS The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%. INTERPRETATION This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.

The Psychosis High-Risk State A Comprehensive State-of-the-Art Review

CONTEXT During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. OBJECTIVE To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. DATA SOURCES Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. STUDY SELECTION AND DATA EXTRACTION Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. DATA SYNTHESIS Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. CONCLUSIONS The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.

Size of burden of schizophrenia and psychotic disorders

Schizophrenia is a severe mental disorder characterised by fundamental disturbances in thinking, perception and emotions. More than 100 years of research have not been able to fully resolve the puzzle that schizophrenia represents. Even if schizophrenia is not a very frequent disease, it is among the most burdensome and costly illnesses worldwide. It usually starts in young adulthood. Life expectancy is reduced by approximately 10 years, mostly as a consequence of suicide. Even if the course of the illness today is considered more favourable than it was originally described, it is still only a minority of those affected, who fully recover. The cumulative lifetime risk for men and women is similar, although it is higher for men in the age group younger than 40 years. According to the Global Burden of Disease Study, schizophrenia causes a high degree of disability, which accounts for 1.1% of the total DALYs (disability-adjusted life years) and 2.8% of YLDs (years lived with disability). In the World Health Report [The WHO World Health Report: new understanding, new hope, 2001. Geneva], schizophrenia is listed as the 8th leading cause of DALYs worldwide in the age group 15-44 years. In addition to the direct burden, there is considerable burden on the relatives who care for the sufferers. The treatment goals for the moment are to identify the illness as early as possible, treat the symptoms, provide skills to patients and their families, maintain the improvement over a period of time, prevent relapses and reintegrate the ill persons into the community so that they can lead as normal a life as possible.

Regional Gray Matter Volume Abnormalities in the At Risk Mental State

BACKGROUND Individuals with an At Risk Mental State (ARMS) have a very high risk of developing a psychotic disorder but the basis of this risk is unclear. We addressed this issue by studying gray matter volume in this group with magnetic resonance imaging (MRI). METHODS Thirty-five individuals with an ARMS, 25 patients with first episode schizophrenia, and 22 healthy volunteers were studied using a 1.5T MRI scanner. Twelve (34%) of the ARMS group developed schizophrenia in the 2 years subsequent to scanning. RESULTS There were significant volumetric differences between the three groups in the left insula, superior temporal gyrus, cingulate gyrus and precuneus. In these regions, the volume in the ARMS group was smaller than in volunteers but not significantly different from that in the first episode (FE) group. Direct comparison of the ARMS and control groups revealed additional areas of reduced volume in the left medial temporal cortex. Within the ARMS group, those subjects who later developed psychosis had less gray matter than subjects who did not in the right insula, inferior frontal and superior temporal gyrus. CONCLUSIONS The ARMS was associated with reductions in gray matter volume in areas that are also reduced in schizophrenia, suggesting that these are a correlate of an increased vulnerability to psychosis. Volumetric differences within the ARMS group may be related to the subsequent onset of schizophrenia in a subset of those at high risk.

Intervention in individuals at ultra high risk for psychosis : a review and future directions

OBJECTIVE Over the last 15 years, a focus on early intervention in psychotic disorders has emerged. Initially, the early psychosis movement focused on timely recognition and phase-specific treatment of first-episode psychosis. However, early psychosis researchers suspected that pushing the point of intervention even further back to the prodromal phase of psychotic disorders may result in even better outcomes. This article reviews intervention research in the ultra-high-risk phase of psychotic disorders. DATA SOURCES A literature search of intervention trials with ultra-high-risk cohorts published after 1980 was conducted on PubMed with the search terms prodrome and intervention. STUDY SELECTION All published intervention trials with ultra-high-risk cohorts. DATA SYNTHESIS The first generation of intervention trials indicated that both pharmacologic and psychological intervention strategies may be of value in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. CONCLUSIONS Further controlled intervention trials with larger sample sizes are required in order to confirm and extend these findings. We argue that the clinical staging model provides a framework for the rationale and design of such studies, with simpler, safer, and more benign interventions being better candidates for first-line treatment, while more complex and potentially harmful treatments should be reserved for those cases in which response has failed to occur. Recent evidence indicates that neuroprotective agents, such as essential fatty acids, may be a suitable form of intervention for the ultra-high-risk phase of psychotic disorders, with a positive risk-benefit balance. Ethical aspects have become more salient given the recently observed declining transition rate in ultra-high-risk samples. We outline the key questions for the next generation of ultra-high-risk intervention trials.

Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia

Motivated by the lack of knowledge of the pathophysiological processes underlying the manifestation of symptoms in schizophrenia, we have worked out a systematic search strategy. Since epidemiological distribution patterns consistently deviating from expected values provide valuable indications of causal relationships, we chose the higher age of females at first admission for schizophrenia, first reported by Kraepelin and since then confirmed in over 50 studies, as the basis for our study. This unexplained epidemiological finding was replicated on Danish and Mannheim case-register data by systematically controlling for selection and diagnostic artefacts and by testing alternative explanations at the individual stage of the study. To check whether the difference in age at first admission was determined by a difference in age at onset, a representative sample of 267 first-admitted patients with non-affective functional psychosis was examined by using an interview for the retrospective assessment of the onset of schizophrenia (IRAOS) designed for this purpose. Any of the definitions of first-ever onset applied--first sign of mental disorder, first psychotic symptom, first acute episode--led to a significant age difference of 3.2 to 4.1 years between the sexes. The distribution of onsets across the life cycle showed a later increase and a second, lower peak between the ages of 45 and 54 years among females compared with males. The lifetime risk for schizophrenia was equal for males and females. After testing the plausibility of psychosocial versus biological explanations we hypothesized that due to the effect of oestrogens the vulnerability threshold for schizophrenia is elevated in females until the menopause. Animal experiments and post mortem analyses showed that chronic oestrogen applications significantly shortened dopamine-induced behaviour and reduced D2 receptor sensitivity in the brain. The applicability of this pathophysiological mechanism to human schizophrenia was tested on acutely schizophrenic females with normal menstrual cycles. A significant negative correlation was found between measures of symptomatology and plasma oestrogen levels. The manifestation of symptoms in schizophrenia appears to be influenced by a sufficiently sensitive D2 receptor system in the brain, blocked by neuroleptics and modulated by oestrogens.

The ABC schizophrenia study: a preliminary overview of the results

Abstract The ABC Schizophrenia Study, a large-scale epidemiological and neurobiological research project commenced in 1987, initially pursued two aims: (1) to elucidate the possible causes of the sex difference in age at first admission for schizophrenia and (2) to analyse the early course of the disorder from onset until first contact and its implications for further course and outcome. First, transnational case-register data (for Denmark and Germany) were compared, second, a population-based sample of first-episode cases of schizophrenia (n = 232) were selected and third, the results obtained were compared with data from the WHO Determinants of Outcome Study by using a systematic methodology. A consistent result was a 3–4 years higher age of onset for women by any definition of onset, which was not explainable by social variables, such as differences in the male-female societal roles. A sensitivity-reducing effect of oestrogen on central D2 receptors was identified as the underlying neurobiological mechanism in animal experiments. Applicability to humans with schizophrenia was established in a controlled clinical study. A comparison of familial and sporadic cases showed that in cases with a high genetic load, the sex difference in age of onset disappeared due to a clearly reduced age of onset in women, whereas in sporadic cases it increased. To analyse early course retrospectively, a semistructured interview, IRAOS, was developed. The early stages of the disorder were reconstructed in comparison with age- and sex-matched controls from the same population of origin. The initial signs consisted mainly of negative and affective symptoms, which accumulated exponentially until the first episode, as did the later emerging positive symptoms. Social disability appeared 2–4 years before first admission on average. In early-onset cases, social course and outcome, studied prospectively over 5 years, was determined by the level of social development at onset through social stagnation. In late-onset cases, decline from initially high social statuses occurred. Socially negative illness behaviour contributed to the poor social outcome of young men. Symptomatology and other proxy variables of the disorder showed stable courses and no sex differences. Further aspects tested were the sequence of onset and the influence of substance abuse on the course of schizophrenia, primary and secondary negative symptoms, structural models and symptom clusters from onset until 5 years after first admission.

Neuroimaging predictors of transition to psychosis : a systematic review and meta-analysis

OBJECTIVES In early stage psychosis research the identification of neurobiological correlates of vulnerability to schizophrenia is an important hurdle. METHODS We systematically reviewed the neuroimaging publications on high-risk subjects with subsequent transition to psychosis (HR-T) and conducted a meta-analysis calculating the effect size Cohens d. RESULTS Out of 30 identified studies 25 met the inclusion criteria. Structural (s)MRI studies showed small to medium effect sizes of decreased prefrontal, cingulate, insular and cerebellar gray matter volume in HR-T compared to high-risk subjects without transition (HR-NT). Meta-analysis revealed relatively larger whole brain volumes in HR-T compared to HR-NT subjects (mean Cohens d 0.36, 95% CI 0.27-0. 46). Compared to HR-NT, HR-T subjects showed in functional imaging studies reduced brain activation in prefrontal cortex, reduced neuronal density, and increased membrane turnover in frontal and cingulate cortex with medium to large effect sizes. CONCLUSIONS Despite methodological differences between studies, structural and neurochemical abnormalities in prefrontal, anterior cingulate, medial temporal and cerebellar cortex might be predictive for development of psychosis within HR subjects.

Cognitive Effects of Antipsychotic Drugs in First-Episode Schizophrenia and Schizophreniform Disorder: A Randomized, Open-Label Clinical Trial (EUFEST)

OBJECTIVE Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. METHODS Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. RESULTS Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. CONCLUSION Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.

Efficacy of Using Cognitive Status in Predicting Psychosis: A 7-Year Follow-Up

BACKGROUND Despite extensive early detection research in schizophrenic psychoses, methods for identifying at-risk individuals and predicting their transition to psychosis are still unreliable. Moreover, there are sparse data on long-term prediction. We therefore investigated long-term psychosis transition in individuals with an At Risk Mental State (ARMS) and examined the relative efficacy of clinical and neuropsychological status in optimizing the prediction of transition. METHODS Sixty-four individuals with ARMS for psychosis were identified from all referrals to our early detection clinic between March 1, 2000 and February 29, 2004. Fifty-three (83%) were followed up for up to 7 (mean 5.4) years. RESULTS Twenty-one of the 53 staying in follow-up developed psychosis, corresponding to a transition rate of .34 (Kaplan-Meier estimates). Median time to transition was 10 months (range <1-55). Six of all transitions (29%) occurred only after 12 months from referral. Best transition predictors within this population were selected attenuated psychotic symptoms (suspiciousness), negative symptoms (anhedonia/asociality), and cognitive deficits (reduced speed of information processing). With these predictors in an integrated model for predicting transition to psychosis, the overall predictive accuracy was 80.9% with a sensitivity of 83.3% and a specificity of 79.3%. CONCLUSIONS Follow-up of ARMS subjects should exceed the usual 12 months. Prediction of transitions could be improved by a stronger weighting of certain early symptoms and by introducing neurocognitive tests into a stepwise risk assessment. Confirmatory research will hopefully further improve risk algorithm, including psychopathology and neuropsychological performance, for clinical application in early detection clinics.