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Objectives: The aim of this study was to describe atypical dyskinesias (AtypDs) occurring during treatment with antipsychotic drugs (APDs). AtypDs are dyskinesias showing either an unusual temporal relationship between onset of treatment and start of the adverse drug reaction (ADR) or an unusual presentation of clinical symptoms., Methods: Data on the utilisation of APDs and reports of severe APD-induced AtypDs were collected using data from the observational pharmacovigilance programme - 'Arzneimittelsicherheit in der Psychiatrie (English: drug safety in psychiatry)' (AMSP) - from 1993 to 2016., Results: A total of 495,615 patients were monitored, of which 333,175 were treated with APDs. Sixty-seven cases (0.020%) of severe AtypDs under treatment with APDs were registered. The diagnoses of schizophrenic disorders as well as organic mental disorders were related to significantly higher rates of AtypDs. Second-generation antipsychotic drugs (SGAs) showed slightly higher rates of AtypDs (0.024%) than high-potency (0.011%) or low-potency first-generation antipsychotic drugs (FGAs; 0.006%). In 41 cases (61.2%), two or more drugs were found to cause AtypDs., Conclusions: Our study indicates that AtypDs are rare ADRs. SGAs may have a higher risk for the occurrence of AtypDs than FGAs. Clinicians should be aware of this ADR and patients should be monitored and examined carefully.

Objectives: Drug-induced liver injury (DILI) has been associated with various antipsychotic drugs (APDs). Comparative studies between individual APDs are largely not available., Methods: Antipsychotic drug utilisation data and reports of severe antipsychotic DILI were assessed by using data from an observational pharmacovigilance programme-Arzneimittelsicherheit in der Psychiatrie (AMSP)-during the period 1993-2016., Results: Of the 333,175 patients treated with APDs, a total of 246 (0.07%) events of severe DILI were identified. Phenothiazines were associated with significantly higher rates of severe DILI (0.03%, 95% CI = 0.02-0.04) than thioxanthenes (0.01%, 95% CI = 0.00-0.02) or butyrophenones (0.01%, 95% CI = 0.00-0.01). Among individual drugs, olanzapine (0.12%, 95% CI = 0.10-0.16), perazine (0.09%, 95% CI = 0.05-0.15) and clozapine (0.09%, 95% CI = 0.10-0.12 ranked highest. In 78 cases (31.7%), combination therapies with antipsychotic and antidepressant drugs or with two or more APDs were considered responsible. Male sex and a diagnosis of mania were associated with significantly higher rates of severe DILI while older patients (≥65 years old) were significantly less often affected., Conclusions: In the present analysis of a representative psychiatric inpatient cohort, olanzapine, perazine, and clozapine were the most common individual APDs associated with severe DILI.

Data on drug prescription for outpatients with major depressive disorder (MDD) suggest women are more likely to be treated with psychotropic drugs, while data on sex differences regarding pharmacological treatment of psychiatric inpatients are currently not available. Drug utilization data from the program "Drug Safety in Psychiatry" (German: Arzneimittelsicherheit in der Psychiatrie, AMSP) of 44,418 psychiatric inpatients with MDD were analyzed for sex differences between 2001 and 2017. Sex differences were analyzed using relative risks (RR) and 95% confidence intervals (95% CI). Time trends were analyzed by comparing the first (2001-2003) with the last time period (2015-2017). In general, men and women were equally likely to use psychotropic drugs. Monotherapy was more common in men. Women were more likely to utilize ≥ 4 psychotropic drugs. Antidepressant drugs (ADDs) were the most prescribed drug class. Men had a higher utilization of noradrenergic and specific serotonergic antidepressants (RR 1.15; 95% CI 1.12-1.19), especially mirtazapine (RR 1.16; 95% CI 1.12-1.19), but also of other ADDs such as bupropion (RR 1.50; 95% CI 1.35-1.68). Males had a slightly higher utilization of second-generation antipsychotic drugs (RR 1.06; 95% CI 1.03-1.09) and were less often treated with low-potency first-generation antipsychotic drugs (RR 0.86; 95% CI 0.83-0.90). Tranquilizing (e.g., benzodiazepines; RR 0.89; 95% CI 0.86-0.92) and hypnotic drugs (e.g., Z-drugs; RR 0.85; 95% CI 0.81-0.89) were less utilized in the treatment of male patients. Not all sex differences were stable over time. More sex differences were detectable in 2015-2017 than in 2001-2003. Findings suggest that certain psychotropic drugs are preferred in the treatment of men vs. women, however, sex differences found in this study are not as large as in ambulatory settings. To make evidence-based sex-specific recommendations in the treatment of MDD, differences in drug response and tolerability need to be further researched.

Background: This study addresses the question of whether psychosocial functioning measured by the Personal and Social Performance (PSP) Scale is related to various psychopathological measures in a cohort of patients with schizophrenia., Methods: The 'Neuroleptic Strategy Study' (NeSSy) performed at 14 German hospitals between 2010 and 2013 compared two treatment strategies instead of individual drugs. Secondary end-points were the two PSP scales as well as measures of quality of life (SF-36) and the Positive and Negative Syndrome Scale (PANSS)., Results: 149 patients were randomised. There was no difference between the two treatment strategies (first-generation versus second-generation antipsychotics) with regard to the PSP. There were differences in doctors' assessments regarding psychosocial functioning compared with patients' own assessments. Furthermore, there were relationships between the PSP and quality of life, level of skills (ICF), and severity of disease (PANSS), level of sexual activities and poor well-being under antipsychotic medication but not with cognitive changes., Conclusions: The findings on psychosocial functioning of patients with schizophrenia related to severity and skill level could be confirmed. Further findings were the correlation between psychosocial functioning and quality of life, well-being under treatment, and sexuality what emphasizes the substantial importance of a reduced psychosocial functioning.

Aim of the study was to examine the course of schizophrenia patients within 2 years after discharge. Within a multicenter study of the German Competence Network on Schizophrenia, patients suffering from a schizophrenia spectrum disorder were examined regarding their psychopathological improvement, tolerability, and the treatment regime applied during hospitalization and a 2-year follow-up period. Response, remission, the level of everyday functioning, and relapse were furthermore evaluated during the follow-up period using established definitions for these outcome domains. The psychopharmacological treatment was specifically evaluated in terms of a potential association with relapse. 149 patients were available for analysis, with 65% of the patients being in response, 52% in symptomatic remission, and 64% having a satisfiable everyday functioning 2 years after their discharge from hospital. Despite these favorable outcome rates, 63% of the patients suffered from a relapse within the 2-year follow-up period with 86% of these patients being rehospitalized. Discharge non-responder and non-remitter were twice as likely to relapse during follow-up. A significant decrease of side-effects was observed with negligible rates of extrapyramidal side-effects, sedation, and weight gain during follow-up. Patients receiving treatment with atypical antipsychotics were found to have the lowest risk to relapse (p < 0.0001). The results highlight the natural and unsteady course of schizophrenia in most patients underlining the need to develop more specific treatment strategies ensuring ongoing stability and preventing relapse.

Background: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy)., Methods: An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties., Results: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being., Conclusions: Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.

Cognitive impairment represents a core feature of schizophrenia. Uncertainty about demonstrable benefits of available antipsychotics on cognition remains an important clinical question relevant to patients' quality of life. The aim of our multi-center, randomized, double-blind "Neuroleptic Strategy Study" (NeSSy) was to compare the effectiveness of selected antipsychotics, conventionally classified as second- (SGAs) (haloperidol, flupentixol) and first generation antipsychotics (FGAs) (aripiprazole, olanzapine, quetiapine), on quality of life in schizophrenia. The effects on cognitive deficits represented a secondary outcome. We used an innovative double randomization for assignment of treatment group, and followed the patients with a neurocognitive test-battery upon six and 24 weeks of treatment. Psychopathology and quality of life were assessed using CGI, PANSS and SF-36. Assessment of cognitive performance was conducted in 114 of the 136 randomized patients. The SGA group (N = 62) showed beneficial effects of small to moderate effect size on cognition during the initial six weeks of treatment (executive functions, verbal fluency) and at 24 weeks (executive functions, working memory). In contrast, the FGA group (N = 52) showed moderately improved executive function, but a decline in verbal fluency at six weeks, with significant declines of moderate to large effect size in executive function, verbal learning and memory, and verbal fluency at 24 weeks. Our study indicates that SGAs present an advantage over FGAs regarding cognitive function during a medium-term treatment for schizophrenia. The results further emphasize a distinction between progression to detrimental effects of FGAs with prolonged treatment in contrast to more persistent cognitive benefits with SGA treatment., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Background: Whether or not second-generation antipsychotics (SGAs) represent an advantage over first-generation antipsychotics (FGAs) in the treatment of schizophrenia is not certain. Effectiveness studies published in the past 10 years have not unequivocally confirmed the superiority of SGAs over FGAs. We aimed to compare quality of life in patients with schizophrenia on an FGA strategy with those on an SGA strategy., Methods: In the multicentre, randomised, double-blind Neuroleptic Strategy Study (NeSSy), we recruited participants (aged 18-65 years) with schizophrenia (ICD-10: F20.X) who required treatment initiation or a change in treatment, from 14 psychiatric university hospitals and state hospitals in Germany. Double randomisation allowed for restricted selection of a treatment within each antipsychotic drug group (FGA or SGA) for an individual patient: first, patients were assigned with a random number table to two of six possible drug pairs, each pair consisting of an FGA (haloperidol [3-6 mg] or flupentixol [6-12 mg]) given orally and an SGA (aripiprazole [10-20 mg], olanzapine [10-20 mg], or quetiapine [400-800 mg]) given orally, and the investigator then selected which pair was best suited to the patient; a second, double-blind random assignment allocated either the FGA or the SGA from the investigator-chosen pair to the patient. Treatment duration was 24 weeks. Primary outcomes were change from baseline to week 24 in quality of life (SF-36) and clinical global impression (CGI-I), analysed in all randomly assigned patients who received at least one dose of the study drug. Safety was assessed in a safety set, consisting of all randomly assigned patients who received at least one dose of the study drug, coinciding with the set of the efficacy analyses. The study is registered with ClinicalTrials.gov, number NCT01164059; German Clinical Trials Register, number DRKS00000304; WHO ICTRP, number U1111-1112-9727; and EudraCT, number 2009-010966-47., Findings: Between April 1, 2010, and May 31, 2013, 149 patients were randomly assigned, 69 to FGA treatment and 80 to SGA treatment. 136 patients received at least one dose of study drug (63 in the FGA group, 73 in the SGA group). Mean area under the curve (AUC) values of SF-36 were significantly higher in the SGA group than in the FGA group (85·1 [SD 14·7] vs 79·7 [17·3], p=0·0112). Mean AUC values for CGI-I scores decreased in both groups, but were not significantly different between the two groups (3·39 [SD 0·89] in the FGA group vs 3·26 [0·92] in the SGA group, p=0·3423). 30 (48%) of 63 patients given FGAs had at least one adverse event compared with 42 (57%) of 73 patients given an SGA (p=0·3019); the most common were nervous system disorders (18 [60%] of 30 in the FGA group vs 19 [45%] of 42 in the SGA group) and psychiatric disorders (ten [33%] vs 16 [38%]). One patient died after cessation of study drug (olanzapine), most likely as a result of an illicit drug overdose. The increase in body-mass index (BMI) was significantly higher in the SGA group than in the FGA group (p=0·0021 at week 6 and p=0·0041 at week 24)., Interpretation: Improvement of patient-reported quality of life was significantly higher in patients with schizophrenia given SGAs than in those given FGAs, when treatment selection was individualised. This advantage, however, has to be weighed against the potential metabolic adverse effects of some SGAs., Funding: German Federal Ministry of Education and Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The 'gold standard' for clinical studies is a randomised controlled trial usually comparing specific treatments. If the scientific study expands to strategy comparison with each strategy including various treatments, the research problems are increasingly complicated. The strategy debate in the psychiatric community is the starting point for the development of our new design. It is widely accepted that second-generation antipsychotics are the therapy of choice in the treatment of schizophrenia. However, their general superiority over first-generation antipsychotics could not be demonstrated in recent randomised controlled trials. Furthermore, we are becoming increasingly aware that the experimental conditions of randomised controlled trials, as in the European First Episode Schizophrenia Trial and Clinical Antipsychotic Trials of Intervention Effectiveness Phase 1 studies, may be inappropriate for psychiatric treatments. The high heterogeneity in the patient population produces discrepancies between daily clinical perception and randomised controlled trials results. The patient-oriented approach in the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study reflects everyday clinical practice. The results, however, are highly dependent on the physicians' preferences. The goal of the design described here is to take an intermediate path between randomised controlled trials and clinical studies such as Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, combining the advantages of both study types., Methods: The idea is to randomise two treatment pairs each consisting of one first-generation antipsychotic and one second-generation antipsychotic in a first step and subsequently, to involve the investigators in deciding for a pair most appropriate to the patients' needs and then to randomise the allocation to one drug (first-generation antipsychotic or second-generation antipsychotic) of that chosen pair. This idea was first implemented in the clinical trial, the Neuroleptic Strategy Study, with a randomised design comparing efficacy and safety of two different strategies: either to use first-generation antipsychotics (haloperidol and flupentixol) or second-generation antipsychotics (olanzapine, aripiprazole and quetiapine) in patients suffering from schizophrenia., Results: In the course of the Neuroleptic Strategy Study, feasibility of this design was demonstrated. All aspects of the new design were implemented: randomisation process, documentation of responses from investigators as well as patients and drug logistic experience. In implementing the design, furthermore, we could investigate its theoretical properties. The physicians' preferences for specific drugs used for the respective patients were analysed., Conclusion: The idea of patient-oriented randomisation can be generalised. In light of the heterogeneity and complexity of patient-drug interaction, this design should prove particularly useful., (© The Author(s) 2016.)

The aim of this study was to investigate the characteristics and treatment patterns of older antipsychotic (AP) users in Germany. We carried out a cohort study in the German Pharmacoepidemiological Research Database and identified new AP users aged at least 65 years between 2005 and 2011. Possible indications, comedication, and information on persistence and adherence, concurrent multiple use, and switch of APs were assessed. Overall, 298,847 individuals were included in the cohort. Almost 70% entered the cohort with a typical antipsychotic (TAP). Melperone (23.4%) was used most frequently, followed by promethazine (18.3%), sulpiride (11.0%), and risperidone (10.3%). AP users had a low prevalence of schizophrenia and bipolar disorders in contrast to dementia. Initiators of atypical antipsychotics had more treatment episodes compared with TAPs (median 3 vs. 2), but lower median persistence (14 vs. 22 days). Persistence was also lower in patients with, rather than without, dementia. The overall percentage of concurrent multiple use and switch to other APs was low with 5.6%, but higher in patients with, rather than without, dementia. In conclusion, APs were used for a broad range of indications, mostly other than schizophrenia and bipolar disorders. Low persistence and a high number of treatment episodes suggest frequent 'as-needed' treatment, especially in dementia patients.

This study compares the first-generation antipsychotic (FGA) flupentixol to haloperidol and common second-generation antipsychotics (SGAs) as to drug utilization and severe adverse drug reactions (ADRs) in clinical treatment of schizophrenia inpatients using data from the drug safety program Arzneimittelsicherheit in der Psychiatrie (AMSP). AMSP drug utilization and reported ADR data were analyzed. Type and frequency of severe ADRs attributed to flupentixol were compared with haloperidol, clozapine, olanzapine, quetiapine, risperidone and amisulpride in a total of 56,861 schizophrenia inpatients exposed to these drugs. In spite of increasing prescription of SGAs, flupentixol was consistently used in schizophrenic inpatients (about 5 %) over time. Reporting rates of severe ADR ranged from 0.38 to 1.20 % for the individual antipsychotics (drugs imputed alone); flupentixol ranked lowest. The type of ADR differed considerably; as to severe EPMS, flupentixol (0.27 %), such as risperidone (0.28 %), held an intermediate position between haloperidol/amisulpride (0.55/0.52 %) and olanzapine/quetiapine (<0.1 %). The study is a heuristic approach, not a confirmatory test. Flupentixol has a stable place in the treatment of schizophrenia in spite of the introduction of different SGAs. Comparative ADR profiles suggest an intermediate position between FGAs and SGAs for flupentixol in clinical practice.

Background: To date, research has identified distinct antipsychotic response trajectories yet focussing on data from randomized-controlled trials (RCTs). Therefore, the heterogeneity of response in "real-world" schizophrenia patients is still unknown., Methods: Antipsychotic response was evaluated in 399 patients suffering from a schizophrenia spectrum disorder within a naturalistic multicenter study of the Competence Network on Schizophrenia using latent class regression. Baseline and illness-related variables were compared between the different trajectory classes as well as currently proposed outcome definitions (early improvement, response, remission) using univariate tests. In order to predict the trajectory group membership classification and regression tree analysis were furthermore performed., Results: Five distinct trajectories of antipsychotic response were identified: Class 1 (15%) showing an early and considerable improvement, Class 2 (14%) incorporating patients with the greatest response to treatment, Class 3 (34%) again showing an early improvement to treatment yet with a slightly lower degree of improvement, Class 4 (22%) featuring patients gradually responding to treatment, and Class 5 (15%) with the poorest antipsychotic response. Fewer depressive symptoms at admission, better functioning, a shorter duration of illness and less previous hospitalizations were found to be significant predictors of good response. No considerable differences were found comparing the present results to the previous trajectory analyses deriving from RCTs., Conclusion: Our results underline the heterogeneous course of response independent of the study or treatment design suggesting that the diversity in schizophrenia response and outcome is determined primarily by different pathophysiological underpinnings., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Relapse and its predictors were examined among patients with schizophrenia in the year after hospital discharge., Methods: The sample included 200 patients with schizophrenia participating in a German multicenter study. Relapse was defined as a worsening of psychopathological symptoms or rehospitalization in the year after hospital discharge. Predictors examined were variables related to course of illness and to response and remission at discharge., Results: Fifty-two percent of participants had a relapse. Patients whose symptoms were not in remission at discharge were more likely to have a relapse, as were those who had more severe symptoms and more side effects at discharge. Those who experienced a relapse were less likely to be taking a second-generation antipsychotic at discharge, less likely to have a positive attitude toward treatment adherence, and less likely to be employed., Conclusions: The high rate of relapse among patients with schizophrenia highlights the need to improve current treatment strategies.

Background: To examine the influencing factors and predictors of early improvement in schizophrenia patients., Methods: 370 patients suffering from a schizophrenia spectrum disorder were examined within a naturalistic multicenter study. Early improvement was defined as a ≥30% PANSS total score reduction within the first two treatment weeks, response as a ≥50% improvement of the PANSS total score from admission to discharge and remission according to the consensus remission criteria. Baseline and course-related variables such as positive, negative and depressive symptoms, side effects, functioning and subjective well-being were examined regarding their explanatory value for early improvement., Results: 46% of the patients were identified to be early improvers. Of these, 77% became treatment responder at discharge and 74% achieved the consensus remission criteria. Amongst others, early improvers were significantly more often first-episode patients (p = 0.009), with a significantly shorter duration of current episode (p = 0.024) and a shorter duration of the illness (p = 0.0094). A higher PANSS positive subscore (p = 0.0089), a higher score in the Strauss-Carpenter-Prognostic Scale (SCPS) (p < 0.0001), less extrapyramidal side effects (p = 0.0004) at admission and the development of less extrapyramidal side effects within the first two treatment weeks (p = 0.0013) as well as a duration of current episode of ≤6 months (p = 0.0373) were identified to be significant predictors of early improvement., Conclusion: Early improvement is associated with less illness chronicity and seems to be independent of the type of antipsychotic and the antipsychotic dosage applied. The SCPS was found to be a valuable tool to detect early improvers already at the initiation of antipsychotic treatment., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The aim of this naturalistic observational study was to investigate EEG alterations in patients under olanzapine treatment with a special regard to olanzapine dose and plasma concentration. Twenty-two in-patients of a psychiatric university ward with the monodiagnosis of paranoid schizophrenia (ICD-10: F20.0), who received a monotherapy of olanzapine were included in this study. All patients had a normal alpha-EEG before drug therapy, and did not suffer from brain-organic dysfunctions, as verified by clinical examination and cMRI scans. EEG and olanzapine plasma levels were determined under steady-state conditions (between 18 and 22 days after begin of treatment). In 9 patients (40.9%), pathological EEG changes (one with spike-waves) consecutive to olanzapine treatment were observed. The dose of olanzapine was significantly higher in patients with changes of the EEG than in patients without changes (24.4 mg/day (SD: 8.1) vs. 12.7 mg/day (SD: 4.8); T = -4.3, df = 21, P < 0.001). In patients with EEG changes, the blood plasma concentration of olanzapine (45.6 μg/l (SD: 30.9) vs. 26.3 μg/l (SD: 21.6) tended to be also higher. The sensitivity of olanzapine dosage to predict EEG changes was 66.7%, the specificity 100% (Youden-index: 0.67). EEG abnormalities during olanzapine treatment are common. These are significantly dose dependent. Thus, EEG control recordings should be mandatory during olanzapine treatment with special emphasis on dosages exceeding 20 mg per day, although keeping in mind that EEGs have only a limited predictive power regarding future epileptic seizures.

Background: The aim of this paper is to apply the proposed consensus remission criteria to an acutely ill inpatient sample at admission and evaluate their adaptability in this patient population and pharmaceutical trials., Methods: The Remission in Schizophrenia Working Group's consensus criteria were applied to 272 acutely ill schizophrenia patients. Patients were examined using the PANSS, HAMD, UKU and SWN-K total scales at admission as well as the GAF, SOFAS and the Strauss-Carpenter Prognostic Scale. Sociodemographic and clinical baseline variables were assessed using a standardized documentation system., Results: 33 patients (12%) fulfilled the symptom severity component of the proposed remission criteria already at baseline. Almost no significant differences were found when comparing patients with achieved and failed symptom severity component that would explain the hospitalization of the patients with achieved criteria despite their apparently mild psychopathological symptoms. The only explainable difference was that patients with an achieved symptom severity component had received significantly more antipsychotics and had suffered from significantly more life events before admission., Conclusion: The present results raise the question whether the symptom severity threshold is adequate to identify patients in remission when applied in clinical trials., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To describe the course of positive and negative symptoms during inpatient treatment and examine remission and response rates under routine clinical care conditions., Methods: Two hundred and eighty inpatients with schizophrenia (DSM-IV criteria) were assessed with the Positive and Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the symptom-severity component of the consensus criteria (Remission in Schizophrenia Working Group) as a rating of three or less in the relevant PANSS items at discharge, and response as a reduction of at least 20% in the PANSS total score from admission to discharge., Results: The mean duration of inpatient treatment was 54.8 days. Of the total sample, 78.5% achieved the criteria for response and 44.6% those for remission. Mean PANSS total scores decreased from 72.4 at admission to 52.5 at discharge (p<0.001). A reduction in PANSS total scores was found from visit to visit, up to week 8. The most pronounced decline was observed within the first two weeks of treatment., Conclusion: Response rates were comparable to those found in efficacy studies, and remission rates were slightly higher. This may be explained by differences in the selection and the treatment of patients. Nevertheless, the findings might indicate that a complex naturalistic treatment approach is beneficial in terms of effectiveness., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Second-generation atypical antipsychotics such as clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride and ariprazole offer the potential to reduce the significant health care resource demands in the treatment of schizophrenia through improved levels of initial clinical response and reduced levels of long-term acute relapse. However, the optimal sequencing of these drugs remains unclear. To consider this issue from a health economic viewpoint a decision model approach was used comparing healthcare costs and clinical outcomes when treating patients with alternative sequences of atypical antipsychotic treatment. Treated patients were assumed to be in a current acute episode with at least a 10-year history of disease and to be naive to previous atypical treatments. Treatment strategies were based on either first-line olanzapine or risperidone with switching to the alternative drug as second-line treatment following an inadequate clinical response to first-line drug therapy. Clinical response data were derived from a pivotal published comparative study of both olanzapine and risperidone. Published data on the long-term use of antipsychotic drugs where used wherever possible to populate the model for relapse rates during the maintenance phase. Health care resource data were defined for Germany based on expert clinical opinion. A treatment strategy of first-line olanzapine was shown to be cost saving over a 1-year period, with additional clinical benefits in the form of avoided relapses. The model suggests that over the first year of treatment a strategy of first-line olanzapine is associated with lower risk of additional relapse (0.33 fewer acute relapses per 100 patients per year) and with cost savings (euro 35,306 per 100 patients per year). There is a need for longer term direct in-trial comparisons of atypical antipsychotics to confirm these indicative results.

Rationale: Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis is an important aspect of the pathophysiology of major depression and schizophrenia. Despite the usefulness of atypical antipsychotics in the treatment of depression and their positive influence on cognitive functioning possibly related to their impact on cortisol, little is known about their effect on HPA axis function., Objective: Therefore, this double-blind, placebo-controlled, randomized cross-over study investigated the influence of the atypical antipsychotics quetiapine and olanzapine in comparison with haloperidol and placebo on plasma adrenocorticotropic hormone (ACTH), cortisol, and prolactin levels. Eleven healthy male volunteers were studied during four sessions one week apart, orally receiving placebo, quetiapine (50 mg), olanzapine (5 mg), or haloperidol (3 mg). Blood samples were taken at hourly intervals from 0900 until 1700 hours. For ACTH, cortisol, and prolactin a significant effect of treatment condition (p < or = 0.005; p < or = 0.035; p < or = 0.0001, respectively) for area under the curve (AUC) was found. In comparison to placebo, quetiapine and olanzapine significantly reduced ACTH (p < or = 0.002; p < or = 0.05, respectively) and cortisol (p < or = 0.005; p < or = 0.03, respectively). No effect of haloperidol on AUC of ACTH or cortisol levels was observed. In comparison with placebo, haloperidol (p < or = 0.0001) and olanzapine (p < or = 0.0001) elevated AUC of prolactin plasma levels, whereas no significant effect was observed for quetiapine as a main effect of treatment condition. The atypical antipsychotics' strong influence on HPA-function with pronounced ACTH and cortisol lowering is possibly related to the atypicals' blockade of serotonergic receptors, but blockade of adrenergic or histaminergic receptors may play a role as well. The observed HPA-axis down-regulation may be clinically important for the atypicals' effects on depressive symptomatology and cognitive functioning.

Aims: To determine the influence of the atypical antipsychotic ziprasidone on cortisol excretion., Methods: In a double-blind, placebo-controlled, randomized cross-over design 11 healthy male subjects were studied twice for 2 consecutive nights (N1, undisturbed sleep conditions; N2, exposure to acoustic stress) 5 days apart. Placebo or ziprasidone 40 mg was administered orally 2 h before bedtime on N1 and N2. Urine was collected during three fractionated collection periods (evening; night; morning) for the later determination of cortisol concentrations by standard radioimmunoassays., Results: Ziprasidone decreased the total amount of cortisol excreted by 4.9 (95% CI 3.3, 6.5) microg during N1 and by 10.8 (95% CI 5.7, 15.8) microg during N2 (P < 0.002). This effect was still detectable in the morning (P < 0.02), with decreases of 5.8 (95% CI -2.8, 14.4) microg after N1 and by 12.1 (95% CI 2.8, 21.4) microg after N2. The effect subsided in the evening. A significant intervention-condition interaction (P < 0.02), was found. The significant increase in cortisol excretion during acoustic stress observed with placebo was absent after treatment with ziprasidone., Conclusions: The significant decrease in nocturnal cortisol excretion following ziprasidone reflects a decreased activity of the HPA-axis in healthy subjects. This effect may be an important contributor to the mode of action of ziprasidone in different patient populations, particularly in the treatment of depression and in cognitive impairment in schizophrenia.

Objective: Efficacy of atypical antipsychotic in acute schizophrenic episodes is still in debate. This study evaluated treatment practices over 7 years of initial treatment with oral risperidone in acutely exacerbated patients with schizophrenia and in a subgroup of highly agitated, tense, and aggressive patients. Additionally, the study investigated the efficacy and tolerability of risperidone in routine clinical practice., Methods: In a prospective, multicenter, observational trial from 1996 to 2002, patients with schizophrenia experiencing acute symptom exacerbations were treated with risperidone within 24 hours of inpatient admission. Patients with a total score of > or =15 points on the agitation subscale of the Positive and Negative Syndrome Scale (PANSS) were defined as highly agitated. Efficacy measures were carried out with a modified PANSS, the Clinical Global Impression (CGI) and the Brief Psychiatric Rating Scale (BPRS)., Results: A total of 1625 patients were evaluated. Despite prescription of decreasing risperidone dosages over 7 years, efficacy was maintained and tolerability improved significantly. Significant symptom relief occurred in all patients and was more pronounced in the subgroup of highly agitated patients (n = 256; P < 0.001 for PANSS, BPRS, and CGI). At Week 6, the mean daily dosage of risperidone was 4.8 mg in the highly agitated patients and 4.7 mg in the remaining patients, and more than 55% of all patients were receiving risperidone as monotherapy., Conclusions: Prescribing patterns with risperidone in patients with acutely exacerbated schizophrenia, including highly agitated patients, changed with the experience gained with this compound. In routine clinical practice in this indication, risperidone was found to be effective and well tolerated.

Objective: Ziprasidone, an atypical antipsychotic, is a potent dopamine (D(2)) and serotonin (5-HT(2A/C)) receptor blocker, has agonistic properties at the 5-HT(1A) receptor, and blocks serotonin and norepinephrine reuptake. These transmitter systems are closely related to the regulation of sleep., Method: The aim of this double-blind, placebo-controlled, randomized, crossover study was to investigate the effects of ziprasidone on polysomnographic sleep structure and subjective sleep quality. Twelve healthy male subjects were randomly assigned to receive ziprasidone 40 mg or placebo for 2 sessions each composed of 2 consecutive nights (night 1, standard sleep conditions; night 2, acoustic stress) 5 days apart. Treatment was administered orally 2 hours before bedtime. The study was conducted from April 2004 to July 2004., Results: Ziprasidone significantly increased total sleep time, sleep efficiency, percentage of sleep stage 2, and slow wave sleep; decreased the number of awakenings; and significantly affected tonic and phasic REM sleep parameters, i.e., it decreased percentage of REM and REM density and profoundly increased REM latency., Conclusion: Ziprasidone's effects on the sleep profile are somehow opposite to what is known about sleep of depressed patients (e.g., disturbances of sleep continuity, a reduciton of slow wave sleep, and a disinhibition of REM sleep). Its REM sleep-suppressing properties resemble those of most, although not all, antidepressants and may be clinically relevant. The drug also demonstrates sleep-consolidating properties under both standard routine and acoustic stress conditions. These effects are most likely related to ziprasidone's 5-HT(2C) antagonism, 5-HT(1A) agonism, and serotonin and norepinephrine reuptake inhibition.

Neurotoxicity of first-generation antipsychotics (FGAs) may be involved in lipid peroxidation, which is the pathogenesis of extrapyramidal symptoms, including tardive dyskinesia (TD). Blood samples at day 0, 7, and 21 drawn from patients taking antipsychotics were analyzed for malondialdehyde (MDA) in plasma, a marker of lipid peroxidation, by high-performance liquid chromatography. Of 115 patients enrolled, 92 patients completed the study. Most MDA levels were within normal ranges (<1.0 micromol/liter). Malondialdehyde levels in patients receiving clozapine (p = 0.002), quetiapine (p = 0.003), amisulpride (p = 0.008), and risperidone (p = 0.008) were significantly lower than within the first generation antipsychotic group. The authors conclude that lipid peroxidation is significantly higher in treatment with FGAs.

Serious adverse events and even sudden death have been reported during administration of the combination of clozapine and benzodiazepines. However, this combination does not necessarily result in increased frequency of serious adverse events. Thus it is not regarded as an absolute contraindication and might be useful in distinct clinical situations, e.g., during the occurrence of a malignant neuroleptic syndrome, "catatonic dilemma," or severe agitation during clozapine treatment. In the following report, certain suggestions on how to deal with this combination therapy are provided which may provide a basis for discussion that ultimately may lead to the formulation of guidelines for this combination therapy. Such guidelines may help psychiatrists in dealing with this combination in clinical situations. Moreover, the formulation of such guidelines would help with forensic issues in case of serious adverse events occurring during this combination therapy.

Rationale: Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is a frequent finding in psychiatric disorders, including psychotic depression and schizophrenia. Conflicting results exist concerning the influence of antipsychotics on the HPA-axis., Objective: Therefore, this double-blind, placebo-controlled, randomized cross-over study investigated the effect of quetiapine on nocturnal urinary cortisol and melatonin excretion in 13 healthy male subjects under conditions of undisturbed and experimentally disturbed sleep., Methods: Volunteers were studied 3 times for 3 consecutive nights (N0, adaptation; N1, standard sleep conditions; N2, acoustic stress) 4 days apart. Placebo, quetiapine 25 mg or quetiapine 100 mg was administered orally 1 h before bedtime on nights 1 and 2. Urine produced during the 8-h bedtime period was collected for later determination of cortisol and melatonin concentrations by standard radioimmunoassays., Results: MANOVA showed a significant effect for N1 vs. N2 with elevated total amount of cortisol ( p<0.005) and melatonin ( p<0.05) excretion after acoustic stress. Both quetiapine 25 mg and 100 mg significantly ( p<0.0005) reduced the total amount of cortisol excretion in comparison to placebo. No interaction effect of stress condition was observed. There was no effect of quetiapine on melatonin levels., Conclusion: The significant reduction of nocturnal cortisol excretion following quetiapine reflects a decreased activity of the HPA-axis in healthy subjects. This finding may be an important aspect in quetiapine's mode of action in different patient populations.

The aim of this study was to investigate the effects of quetiapine, an atypical antipsychotic, on polysomnographic sleep structure and subjective sleep quality. This double-blind, placebo-controlled, randomized cross-over study investigated the polysomnographic sleep structure and subjective sleep quality of 14 healthy male subjects given placebo, quetiapine 25 mg or quetiapine 100 mg. Volunteers were studied 3 times for 3 consecutive nights (N0, adaptation; N1, standard sleep conditions; N2, acoustic stress) 4 days apart. Treatment was administered orally 1 h before bedtime on nights 1 and 2. Quetiapine 25 mg and 100 mg significantly improved sleep induction and continuity under standard and acoustic stress conditions. Increases in total sleep time, sleep efficiency, percentage sleep stage 2 and subjective sleep quality were seen. A significant increase in periodic leg movements during sleep was observed with quetiapine 100 mg. The sleep-improving properties of quetiapine may be important in counteracting different aspects of psychopathology in schizophrenia and other disorders. These sleep-inducing and sleep-modifying properties are probably related to quetiapine's receptor-binding profile, including its antihistaminergic, antidopaminergic and antiadrenergic properties. Other mechanisms might be relevant as well and further investigation is required.

Numerous studies compare side effects or adverse drug reactions (ADRs) of the various typical and newer atypical neuroleptics in patients with schizophrenia. However, these studies, as controlled randomized trials, represent an artificial setting of drug administration and do not easily relate to the "real-life" setting of psychiatric treatment. In contrast, the AMSP drug safety program allows the monitoring of ADRs of all types of psychopharmacological agents in the naturalistic setting of routine clinical practice. In the present study, the data on neuroleptics acquired in the AMSP program from 1993 to 2000 are analyzed. In this period, 86,439 patients treated with at least one neuroleptic agent were monitored. In 1.1 % of the patients severe ADRs occurred. In contrast to the results from controlled trials, atypical neuroleptics caused more severe ADRs than did typical neuroleptics. This result was mainly caused by the high number of severe ADRs in patients treated with clozapine and concerned delirium and non-EPS neurological, gastrointestinal, hepatic, dermatological, hematological, and endocrinological ADRs. Atypical neuroleptics were found to be superior in EPS and urological ADRs. Excluding the data on clozapine, we found typical and atypical neuroleptics to be similar in the occurrence of severe ADRs, although the profiles differ between these two groups as well as between the single substances. Our findings provide valuable information on the type and frequency of ADRs in psychiatric practice, thus enabling differential indication of neuroleptics based not only on the efficacy and tolerability data of controlled trials but also on their differential ADR profile occurring in the "real-life" setting of routine clinical treatment.

The introduction of new antipsychotics has resulted in the availability of drugs with improved safety and tolerability as well as proven efficacy compared to the older antipsychotics. New compounds might show new or different adverse effects that arise in the post-marketing phase when a greater number of patients are treated. One goal of the drug safety program in psychiatry AMSP ( Arzneimittelsicherheit in der Psychiatrie) is the detection and description of severe, new, or rare adverse drug reactions (ADRs). Between 1993 and 2000, 122,562 patients were monitored in 35 psychiatric institutions, 86,349 patients of which received antipsychotics. Hyperglycemia related to antipsychotics was observed in association with only two compounds so far: clozapine and olanzapine (clozapine 2 cases, olanzapine 7 cases). In 6 of 9 patients, weight gain preceded hyperglycemia. The relative frequency of these adverse drug related events was 0.013 % for clozapine and 0.075 % for olanzapine. The symptomatology included reversible hyperglycemia, worsening of existing diabetes, and new-onset diabetes. Control for glycemic dysregulation should be maintained in clinical practice with these drugs.

Objective: The effectiveness of atypical antipsychotic agents in the treatment of acute schizophrenic episodes is still a subject of controversial debate. The objective, therefore, was to investigate the efficacy and tolerability of an initial therapy with the atypical antipsychotic agent risperidone in acutely exacerbated patients under the conditions of clinical practice. A sub-analysis was performed to show if highly agitated and aggressive patients may profit from an initial risperidone therapy as well., Material and Methods: In a still ongoing prospective multicentre observational trial, schizophrenic patients with acute exacerbations treated with risperidone within 24 hours of in-patient admission were observed for six weeks. Patients showing a total score of > or = 15 in the items "excitement", "hostility" and "uncooperativeness" of the Positive and Negative Syndrome Scale (PANSS) were defined as highly agitated patients. Evaluation of efficacy was carried out according to a modified PANSS, the Clinical Global Impression (CGI) and the Brief Psychiatric Rating Scale (BPRS)., Results: 1,117 patients were evaluated. An improvement of all parameters was shown in the whole study group (51 % males, age 39.8 + 14.3 years, paranoid schizophrenia in 70.1 % of cases) and in particular in the subgroup of highly agitated patients. In these patients (n = 163), a greater improvement of symptoms was observed. Only in 4,1 % of cases was risperidone discontinued because of side effects. At the end of the observation, the mean dosage was 5.1 mg/day in both groups. More than 50 % of the patients were finally treated with a risperidone monotherapy., Conclusion: The initial acute treatment with risperidone proves to be effective and safe even for highly agitated schizophrenic patients under the conditions of clinical practice.

Objective: The goal of this study was to identify adverse effects of the atypical neuroleptic clozapine on liver function and lipid metabolism., Methods: Data which included serum levels of clozapine and its hepatic metabolite N-desmethyl clozapine were collected from medical records of patients treated with clozapine and controls., Results: We identified a clozapine-associated marked elevation of plasma cholinesterase (ChE) with unchanged levels of AST, ALT or g-GT. ChE was correlated to the serum level of clozapine and even closer to N-desmethyl clozapine. For the total patient group we observed significant correlations of ChE with the body-mass index and body weight. However, clozapine-treated patients and controls did not differ with regard to body-mass index, triglycerides, and cholesterol., Conclusion: We report for the first time a clozapine-associated and dose-dependent elevation of plasma ChE, which may be related to clozapine-associated effects on hepatic lipid metabolism or ChE enzyme induction.

Well-known adverse effects of amisulpride include nausea, insomnia or tiredness, gastrointestinal, extrapyramidal and endocrine symptoms. Cardiac disorders, however, appear to be an extremely rare complication of the drug. Only a few case reports on this complication have been published so far, which deal with QT prolongation, hypotension, hypertension and palpitations. Bradycardia has not yet been mentioned. Here, we will report on a case of asymptomatic bradycardia that developed subsequent to therapeutic doses of amisulpride in a 25-year-old male patient with chronic paranoid-hallucinatory schizophrenia. The patient had been rehospitalized for an acute exacerbation of the psychosis. When the patient failed to respond at the beginning of hospitalization, the treatment was changed from clozapine to amisulpride. After a complete switchover to amisulpride, the patient's ECG showed sinus bradycardia and QT prolongation. When the daily dose of amisulpride was reduced from 800 mg/d to 600 mg/d, the patient's ECG quickly normalized (including blood pressure and pulse rate) within a few days. The patient did not report any cardiovascular-related complaints. Since the cardiovascular-specific diagnostics did not yield any indicative results, bradycardia may be a rare complication of amisulpride treatment.

There is evidence for the occurrence of psychopathological symptoms in the adult form of myotonic dystrophy such as disturbance of concentration and memory, chronic depression, disturbed social behaviour, mental retardation, and hypersomnia. In this report we present a patient suffering from multisystemic myotonic myopathy without a cytosine-thymine-guanine [corrected] repeat expansion on chromosome 19q13.3 and schizophrenia. In this patient, a severe increase of creatine kinase (CK) occurred during treatment with olanzapine and amisulpride. The following risperidone medication was well tolerated without side effects. Susceptibility for malignant hyperthermia was detected by a positive in vitro contracture test. The occurrence of elevated muscle enzymes during treatment with atypical neuroleptics is suspicious as a possible side effect of neuroleptic medication and muscle disease.

Background: Pisa syndrome is usually regarded as a rare adverse event of neuroleptic medication. However, its frequency and predisposing factors have yet to be defined. Here, we investigated risk factors of Pisa syndrome occurring in a large population of psychiatric patients surveyed during a multicenter drug safety project., Method: Twenty episodes of Pisa syndrome were documented in 17 patients within a population of 45,000 psychiatric patients monitored by a multicenter drug safety surveillance project (Projekt zur Uberwachung der Arzneimittelsicherheit in der Psychiatrie) between 1990 and 1997. All results were related to the epidemiologic data provided for this population and systematically analyzed regarding history of medication, current medication, comedication, and clinical course., Results: A constellation of putative risk factors was found in the majority of patients: previous treatment with classical neuroleptics, combined pharmacologic treatment, female gender, old age, and the presence of an organic brain disorder. Given these risk factors, Pisa syndrome was also documented with atypical neuroleptic drugs such as clozapine, olanzapine, and sertindole., Conclusion: We conclude that Pisa syndrome is a very rare adverse event occurring with neuroleptic treatment. In patients exhibiting the reported constellation of risk factors, neuroleptic drugs should be administered with particular caution.

Olanzapine is a tricyclic neuroleptic agent that due to structural similarities was expected to be a safe alternative to clozapine, which has a 0.5-2% risk of agranulocytosis. So far, only rare cases of leukocytopenia and thrombocytopenia have become known. In the association, "Drug Safety in Psychiatry", which is made up of 25 German psychiatric hospitals, two cases of olanzapine-induced neutropenia occurred in patients with chronic schizophrenia. The adverse drug reaction was noticed 17 days after the first intake of olanzapine in case 1 and more than 5 months after the first intake in case 2. In the second case, a reexposure to olanzapine caused the neutrophil cells to decrease again. There were no clinical signs of an infection, and the blood cell counts increased immediately to normal ranges after discontinuation of olanzapine. No special treatment was necessary.

Treatment of tardive dystonia with oral baclofen produces ambivalent and overall disappointing results. However, because only a small proportion of the baclofen penetrates into the central nervous system when administered orally, we tested whether it is possible to increase the efficacy of treatment by continuous intrathecal infusion of baclofen (CITB) in a patient with severe tardive axial dystonia unresponsive to conventional therapy. A dose of 100 micrograms/day improved muscle tone, head control, posture, and walking distance; electromyography showed a marked decrease of dystonic muscle activity with fully preserved voluntary muscle activity, and the patient reported substantial reduction of pain. Apart from some minor discomfort at the site of operation, no side effects were noted. Further studies should be encouraged to evaluate the usefulness of CITB for other patients with severe and otherwise untreatable tardive dystonia.

In a retrospective study 100 patients with DSM-III-R/ICD-10 panic disorder and agoraphobia (PDA) were interviewed about the psychopharmacological, psychological and 'alternative' treatments they had received in the course of their illness. Patients gave global statements about how satisfied they were with the various treatments they had experienced. Many patients received treatments that have never been investigated under controlled conditions. The most common drug treatments, in descending order, were: 48% benzodiazepines, 42% tricyclic antidepressants, 32% herbal preparations, 29% neuroleptics, 7% selective serotonin reuptake inhibitors and 6% beta blockers. Of the drug prescriptions, 63% were according to international standards. Of the neuroleptics, two-thirds (63.3%) were prescribed by nonpsychiatric physicians, and only one-third by psychiatrists (33.3%). Tricyclic antidepressants were prescribed more often by psychiatrists (64.7%) than by non-psychiatrists (31.4%). Among psychological treatments, autogenic training (43% of the patients) and psychodynamic therapy (33%) were used far more frequently than behavioural/cognitive therapy (20%). These results confirm the underutilisation of available effective treatments for panic disorder (e.g. tricyclic antidepressants or behavioural therapy) and the overutilisation of treatments without proven efficacy (e.g. herbal preparations or autogenic training). Patients were most satisfied with treatments that have been proven effective in controlled studies. Among drug treatments, benzodiazepines, selective serotonin inhibitors and tricyclic antidepressants were favoured (mean on a 0-4 scale indicating effectiveness: 2.6, 2.6 and 2.4). Neuroleptics (1.4), beta-blockers (1.0) and herbal preparations (0.9) were not rated highly effective by the patients. Among psychological treatments, patients were more satisfied with behavioural/cognitive therapy (2.6) than with psychodynamic therapies (1.5).(ABSTRACT TRUNCATED AT 250 WORDS)

In 45 psychotic in-patients with the paranoid-hallucinatory syndrome, the psychopathology, the extrapyramidal motor disturbances and 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG) in CSF were investigated. A 15-day treatment with haloperidol induced significant increase of MHPG in CSF; after 10 days clozapine treatment MHPG was significantly reduced. 10 days later the normal values were reached again. The investigation of MHPG in CSF under treatment with neuroleptics showed no correlation between antipsychotic activity and the turnover of central norepinephrine.

In an open multicenter trial (7 hospitals) 85 schizophrenic patients were treated with 3-fluoro-6-(4-methyl-piperazinyl)- 11H -dibenz[b,e]azepine ( fluperlapine , NB 106-689) during 20 days. Symptomatology was documented with the AMDP system on days 0, 1, 5, 10, 15 and 20. A mean daily dosage of about 400 mg caused a significant antipsychotic effect and pronounced improvement of depressive symptoms. Fluperlapine was well tolerated. Extra-pyramidal side-effects were very rare.

1. Human neuroleptogenic EPMS-disturbances are reversed by clozapine in animal experiments and in clinical use. This is consistent with the central anticholinergic efficacy of clozapine. 2. Clozapine seems to be a favourable concomitant medication when high dosage therapy of neuroleptics is applied--or at the incidence of dyskinesia.

The prognosis of a clinical neuroleptic treatment was prospectively examined in 26 schizophrenic patients using a predetermined set of predictors and outcome criteria. Prognosis before treatment did not discriminate significantly between patients with good and poor outcome. Significant differences of outcome were observed between the prognostic groups, if prognosis was established after 5 days of treatment. Retrospective analysis of individual predictors indicated the following rank order: initial improvement, age, duration of symptoms before treatment, sex, subjective tolerance of the treatment. The relative weight of the individual predictor in forming the prognosis is still an open question.