[Providing Cognitive Remediation Therapy to People with Schizophrenia: Results of a Survey in Psychiatric Clinics in Germany]. / Die Versorgung von an Schizophrenie erkrankten Menschen mit Kognitiver Remediationstherapie ­ Ergebnisse einer Befragung in psychiatrischen Kliniken in Deutschland.

Schizophrenia is accompanied by significant cognitive impairments, which often persist to a relevant extent after remission of clinical symptoms and has a negative impact on psychosocial functioning. These impairments are often experienced as very stressful by those affected. Under the umbrella term of Cognitive Remediation Therapy (CRT), evidence-based therapy options are available that improve both the respective cognitive target functions and the psychosocial functioning. According to expert recommendations, at least 20 sessions should be carried out, accompanied by qualified therapeutic staff. The current edition of the S3 treatment guideline schizophrenia of the German Society for Psychiatry and Psychotherapy, Psychosomatics and Neurology recommends CRT with the highest level of recommendation. It is unclear to what extent CRT has become part of routine inpatient care. Between July 2021 and May 2022, 395 psychiatric university hospitals and non-university psychiatric specialist hospitals in Germany were invited to fill in a 14-item questionnaire. A total of 103 institutions took part in the survey; 56.3% of these hospitals used at least one evidence-based CRT programme. Among the CRT programmes used, Cogpack, Rehacom and the Integriertes Psychologisches Therapieprogramm (IPT) were named most frequently. In 87.5% of the participating facilities, fewer than half of the people with schizophrenia received CRT. With regard to the clinics which used evidence-based CRT, 64.3% carried out fewer than 11 therapy sessions, 28.6% between 11 and 20 sessions and 7.2% more than 20 sessions. It is thus clear that CRT is not yet offered in all of the participating psychiatric hospitals in Germany, not yet for all people with schizophrenia, and not yet with sufficient intensity, with clinics indicating the need for more technical and personnel resources and more extensive development of competencies for CRT application.The low response rate of 26.1% and possible selection effects for participation in the study are addressed and are to be seen as limitations.

Comparison of 8-vs-12 weeks, adapted dialectical behavioral therapy (DBT) for borderline personality disorder in routine psychiatric inpatient treatment-A naturalistic study.

Dialectical behavior therapy (DBT) is widely acknowledged as an effective treatment for individuals with borderline personality disorder (BPD). However, the optimal treatment duration within DBT remains a topic of investigation. This retrospective, naturalistic non-randomized study aimed to compare the efficacy of 8 week and 12 week DBT interventions with equivalent content, focusing on the change of BPD-specific symptomatology as the primary outcome and depressive symptoms as the secondary outcome. Overall, 175 patients who participated in DBT and received either 8 week or 12 week intervention were included in the analysis. Routine inpatient treatment was adapted from standard DBT with the modules: skill training, interpersonal skills, dealing with feelings, and mindfulness. Measurements were taken at baseline, mid-point, and endpoint. The borderline symptom list-23 (BSL-23) was used for the assessment of borderline-specific symptoms, while the Beck depression inventory-II (BDI-II) was used for the assessment of depressive symptoms. Statistical analysis was conducted using linear mixed models. Effect sizes were calculated for both measures. The results of the analysis indicated an improvement in both groups over time. Effect sizes were d = 1.29 for BSL-23 and d = 1.79 for BDI-II in the 8 week group, and d = 1.16 for BSL-23 and d = 1.58 for BDI-II in the 12 week group. However, there were no differences in the change of BPD-specific symptoms or the severity of depressive symptoms between the 8 week and 12 week treatment duration groups. Based on these findings, shorter treatment durations, like 8 weeks, could be a viable alternative, offering comparable therapeutic benefits, potential cost reduction, and improved accessibility. However, further research is needed to explore factors influencing treatment outcomes and evaluate the long-term effects of different treatment durations in DBT for BPD.Trial registration: drks.de (DRKS00030939) registered 19/12/2022.

Theta burst stimulation add on to dialectical behavioral therapy in borderline-personality-disorder: methods and design of a randomized, single-blind, placebo-controlled pilot trial.

Specialized psychotherapeutic treatments like dialectical behavioral therapy (DBT) are recommended as first treatment for borderline personality disorder (BPD). In recent years, studies have emerged that focus on repetitive transcranial magnetic stimulation (rTMS) in BPD. Both have independently demonstrated efficacy in the treatment of BPD. Intermitted theta burst stimulation (iTBS), a modified design of rTMS, is thought to increase the excitability of neurons and could be a supplement to psychotherapy in addition to being a standalone treatment. However, no studies to date have investigated the combination of DBT and rTMS/iTBS. This study protocol describes the methods and design of a randomized, single-blinded, sham-controlled clinical pilot study in which BPD patients will be randomly assigned to either iTBS or sham during four consecutive weeks (20 sessions in total) in addition to standardized DBT treatment. The stimulation will focus on the unilateral stimulation of the left dorsolateral prefrontal cortex (DLPFC), which plays an important role in the control of impulsivity and risk-taking. Primary outcome is the difference in borderline symptomatology, while secondary target criteria are depressive symptoms, general functional level, impulsivity and self-compassion. Statistical analysis of therapy response will be conducted by Mixed Model Repeated Measurement using a 2 × 2-factorial between-subjects design with the between-subject factor stimulation (TMS vs. Sham) and the within-subject factor time (T0 vs. T1). Furthermore, structural magnetic resonance imaging (MRI) will be conducted and analyzed. The study will provide evidence and insight on whether iTBS has an enhancing effect as add-on to DBT in BPD.Trial registration: drks.de (DRKS00020413) registered 13/01/2020.

Feasibility of six-month outpatient cognitive remediation in schizophrenia: Experience from the randomized controlled integrated social cognition and social skills therapy study.

Patients with schizophrenia often have cognitive impairments that contribute to diminished psychosocial functioning. Cognitive remediation therapy (CRT) has proven efficacy and is recommended by evidence-based treatment guidelines. Important moderators of efficacy include integration of CRT into a psychiatric rehabilitation concept and patient attendance at a sufficient number of therapy sessions. These conditions can probably best be met in an outpatient setting; however, outpatient treatment is prone to higher rates of treatment discontinuation and outpatient settings are not as well protected as inpatient ones and less closely supervised.The present study investigated the feasibility of outpatient CRT in schizophrenia over a six-month period. Adherence to scheduled sessions and safety parameters were assessed in 177 patients with schizophrenia randomly assigned to one of two matched CRT programs.Results showed that 58.8 % of participants completed the CRT (>80 % of scheduled sessions) and 72.9 % completed at least half the sessions. Predictor analysis revealed a high verbal intelligence quotient as favorable for good adherence, but this factor had only low general predictive power. During the six-month treatment phase, serious adverse events occurred in 15.8 % (28/177) of the patients, which is a comparable rate to that reported in the literature.Our findings support the feasibility of six-month outpatient CRT in schizophrenia in terms of adherence to scheduled sessions and safety. Trial registration number: NCT02678858, DRKS00010033.

Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial.

BACKGROUND: Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. METHODS: A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. FINDINGS: Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). INTERPRETATION: The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. FUNDING: German Federal Ministry of Education and Research.

[Antipsychotic Polypharmacy in the Treatment of Patients with Schizophrenia in Nine Psychiatric Hospitals of the Landschaftsverband Rheinland, Germany]. / Antipsychotische Polypharmazie in der Behandlung von Patientinnen und Patienten mit Schizophrenie am Beispiel von neun psychiatrischen Fachkliniken des Landschaftsverbandes Rheinland.

BACKGROUND: Antipsychotics are the cornerstone in the treatment of schizophrenia and are primarily recommended as monotherapy by evidence-based guidelines. Nevertheless, antipsychotic polypharmacy (APP) is prevalent in routine practice and APP is also used as a quality indicator since 2016 in quality management programs. OBJECTIVE: Based on routine data of nine psychiatric hospitals of the Landschaftsverband Rheinland (LVR)/Germany the prevalence of APP was determined and correlated with factors of routine healthcare in order to monitor the adoption of APP and to discuss its feasibility as a quality indicator. MATERIALS AND METHODS: All cases with schizophrenia (ICD-10 F20.x; ≥ 18 years) discharged between June 1st, 2016, and June 1st, 2017, (in-patient and day clinic) were extracted from an established research database shared by all nine hospitals and analyzed regarding APP prevalence at the time of discharge. RESULTS: Based on 6,788 cases, the prevalence of APP was 55.5 % with an average of 2.4 antipsychotics (SD = 0.6) administered simultaneously. In multivariate analyses, significant predictors for APP were: gender (male > female), the number of days in hospital (long > short), involuntary treatment (no > yes) and the location of the hospital. CONCLUSIONS: We found a high proportion of polypharmacy in inpatient schizophrenia patients and significant differences between hospitals. The use of the results as a quality indicator (criteria ≥ 2 antipsychotics) remains dependent on the background of the individual treatment courses, which cannot be adequately represented by the existing routine data. The LVR has been using the quality indicator of ≥ 3 antipsychotics since 2018, which is discussed as a more appropriate approach for future evaluations.

Accuracy of diagnostic classification and clinical utility assessment of ICD-11 compared to ICD-10 in 10 mental disorders: findings from a web-based field study.

In this web-based field study, we compared the diagnostic accuracy and clinical utility of 10 selected mental disorders between the ICD-11 Clinical Descriptions and Diagnostic Guidelines (CDDG) and the ICD-10 CDDG using vignettes in a sample of 928 health professionals from all WHO regions. On average, the ICD-11 CDDG displayed significantly higher diagnostic accuracy (71.9% for ICD-11, 53.2% for ICD-10), higher ease of use, better goodness of fit, higher clarity, and lower time required for diagnosis compared to the ICD-10 CDDG. The advantages of the ICD-11 CDDG were largely limited to new diagnoses in ICD-11. After limiting analyses to diagnoses existing in ICD-11 and ICD-10, the ICD-11 CDDG were only superior in ease of use. The ICD-11 CDDG were not inferior in diagnostic accuracy or clinical utility compared to the ICD-10 CDDG for any of the vignettes. Diagnostic accuracy was consistent across WHO regions and independent of participants' clinical experience. There were no differences between medical doctors and psychologists in diagnostic accuracy, but members of other health professions had greater difficulties in determining correct diagnoses based on the ICD-11 CDDG. In sum, there were no differences in diagnostic accuracy for diagnoses existing in ICD-10 and ICD-11, but the introduction of new diagnoses in ICD-11 has improved the diagnostic classification of some clinical presentations. The favourable clinical utility ratings of the ICD-11 CDDG give reason to expect a positive evaluation by health professionals in the implementation phase of ICD-11. Yet, training in ICD-11 is needed to further enhance the diagnostic accuracy.

Promoting stigma coping and empowerment in patients with schizophrenia and depression: results of a cluster-RCT.

There is a need for interventions supporting patients with mental health conditions in coping with stigma and discrimination. A psycho-educational group therapy module to promote stigma coping and empowerment (STEM) was developed and tested for efficacy in patients with schizophrenia or depression. 30 clinical centers participated in a cluster-randomized clinical trial, representing a broad spectrum of mental health care settings: in-patient (acute treatment, rehabilitation), out-patient, and day-hospitals. As randomized, patients in the intervention group clusters/centers received an illness-specific eight sessions standard psychoeducational group therapy plus three specific sessions on stigma coping and empowerment ('STEM'). In the control group clusters the same standard psychoeducational group therapy was extended to 11 sessions followed by one booster session in both conditions. In total, N = 462 patients were included in the analysis (N = 117 with schizophrenia spectrum disorders, ICD-10 F2x; N = 345 with depression, ICD-10 F31.3-F31.5, F32-F34, and F43.2). Clinical and stigma-related measures were assessed before and directly after treatment, as well as after 6 weeks, 6 months, and 12 months (M12). Primary outcome was improvement in quality of life (QoL) assessed with the WHO-QOL-BREF between pre-assessment and M12 analyzed by mixed models and adjusted for pre-treatment differences. Overall, QoL and secondary outcome measures (symptoms, functioning, compliance, internalized stigma, self-esteem, empowerment) improved significantly, but there was no significant difference between intervention and control group. The short STEM module has proven its practicability as an add-on in different settings in routine mental health care. The overall increase in empowerment in both, schizophrenia and depression, indicates patients' treatment benefit. However, factors contributing to improvement need to be explored.The study has been registered in the following trial registers. ClinicalTrials.gov: https://register.clinicaltrials.gov/ Registration number: NCT01655368. DRKS: https://www.drks.de/drks_web/ Registration number: DRKS00004217.

A randomized double-blind controlled trial to assess the benefits of amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill schizophrenia patients (COMBINE): methods and design.

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400-800 mg/day), and olanzapine (10-20 mg/day) and amisulpride-olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment.

The long-term antipsychotic treatment of schizophrenia: A selective review of clinical guidelines and clinical case examples.

There is a long-lasting debate regarding the long-term antipsychotic treatment of schizophrenia. The most frequently advocated strategy is continued antipsychotic maintenance treatment (i.e., continuous treatment with a constant dose of antipsychotic medication after symptom remission). Yet, because of the potential side effects of continued antipsychotic medication, other treatment strategies such as targeted intermittent treatment (i.e., stepwise drug discontinuation and early drug intervention in case of prodromal symptoms or early warning signs) have been discussed. In this manuscript, we review recommendations regarding the long-term antipsychotic treatment of schizophrenia from six evidence-based clinical guidelines. In line with the current state of research, all six clinical guidelines recommend continued antipsychotic maintenance treatment. Recommendations regarding other aspects of long-term antipsychotic treatment (e.g., the dosage of antipsychotic medication for long-term treatment, the minimum duration of antipsychotic long-term treatment, and discontinuation strategies) are more vague and heterogeneous. Additionally, we provide clinical case examples to illustrate different course types of patients exposed to targeted intermittent treatment. Finally, we discuss gaps in current clinical guidelines and future research avenues in antipsychotic maintenance treatment.

[Return-to-Work after depression - evaluation of a retrospective case-control study of an operational integrated care model]. / Rückkehr an den Arbeitsplatz nach depressiver Erkrankung - Evaluation einer retrospektiven Fall-Kontroll-Studie eines betriebsnahen integrierten Versorgungsmodells.

The objective of the study was to evaluate an operational integrated care model (IC) aiming at optimized treatment of depression. It consisted of cooperation between a company and an external clinic with respect to early recognition of the disorder, early access to treatment and support for return to work. METHOD: A retrospective group comparison of patients with depression receiving IC in a psychiatric outpatient clinic (N=64) and a control group with standard care in the same clinic (N=64) was performed. Primary outcome was return to work. RESULTS: Patients of the IC group returned to work significantly more often (Odds Ratio 11.9; p<0.001) and 91.2 days earlier (p=0.010) than those of the group that received standard care. CONCLUSION: Specific measures of an IC program might accelerate the process of return to work.

[Web-based field studies on diagnostic classification and code assignment of mental disorders: comparison of ICD-11 and ICD-10]. / Internetbasierte Untersuchungen zur diagnostischen Klassifikation und Kodierung psychischer Störungen im Vergleich von ICD-11 und ICD-10.

The German Society for Psychiatry, Psychosomatics and Psychotherapy (DGPPN,) conducted a comprehensive field study (principal investigator WG) funded by the German Federal Ministry of Health in cooperation with 4 other German medical societies in the field of mental health (DGPM, DGPPR, DeGFS, DGfS) * to support WHO's development of the ICD-11 (Chapters 6 and 17). The objective of the web-based field study was to compare ICD-10 and ICD-11 (beta draft) for selected mental disorders, regarding consistency, accuracy and assessment of utility. The first study (TP1) focused on the diagnostic classification and the second (TP2) on assignment of diagnostic codes.In TP1, clinicians used either the ICD-10 Clinical Descriptions and Diagnostic Guidelines (CDDG) version or a draft version of the ICD-11 CDDG to evaluate 10 case vignettes in a randomized study implemented through the WHO GCPN **. As hypothesized, consistency was in favor of the ICD-11 (p = .02; n = 319 expert participants) though there was some variability across the different diagnostic categories. In addition, time for diagnosis was shorter (p = .01) and clinicians' judgment of utility (ease of use; goodness of fit) was better for ICD-11 (p = .047 and p < .001 respectively).TP2 focused on consistency of diagnostic code assignment for 25 short case descriptions (including explicit diagnosis and additional clinical information) using both ICD-10 and ICD-11 in a randomized web-based field study which was run on the WHO ICD-FiT *** platform. Based on 531 code assignments by120 expert clinicians, consistency for ICD-11 was significantly lower compared to ICD-10 (71 % vs. 82 %, p < .001) contrary to study hypothesis, and time required was significantly higher for ICD-11 (p < .001). Nevertheless, utility assessments were in favor of ICD-11 (p < .005).In summary, in TP1, given vignettes with more complex clinical descriptions more similar to clinical cases, ICD-11 showed advantages in the consistency of correct diagnoses among clinicians, time required to reach a diagnosis, and clinicians' ratings of clinical utility. These results provide evidence for quality improvement of the diagnostic process due to the revision of the more complete diagnostic guidelines for ICD-11. In the coding task of TP2, coding by clinicians using the ICD-10 was more consistent and faster than coding using the ICD-11. This may be a result of the greater complexity for coding use of the ICD-11 (e. g., due to 'post-coordination'), as well as greater familiarity with the ICD-10 system (which German clinicians currently use) and lack of practice with the new ICD-11 codes and tools. In spite of this, users assessed the ICD-11 system as more useful than the ICD-10, in part also because of ICD-11's more systematic and comprehensive coding tools. In addition, time needed for coding improved with practice, indicating need for intense education and training initiatives when ICD-11 is adopted and implemented into clinical practice.

Predictors for symptom re-exacerbation after targeted stepwise drug discontinuation in first-episode schizophrenia: Results of the first-episode study within the German research network on schizophrenia.

BACKGROUND: After a first episode in schizophrenia guidelines recommend antipsychotic maintenance treatment (MT) for at least 1year. Recent RCTs on subsequent targeted intermittent treatment (IT) after stepwise drug discontinuation yielded noticeably higher relapse rates than during MT also in first-episode patients. Nevertheless, about 50% of patients remain stable under IT. Given the potential adverse effects of antipsychotics and the preference of many patients to discontinue drugs, valid predictors for the feasibility of IT are urgently needed to support decision making. METHODS: Based on a one-year RCT phase comparing MT with IT in first-episode patients after 1year of MT, conducted within the German Research Network on Schizophrenia (GRNS), predictors for deterioration under IT in 19 feasible patients were identified by logistic regression analysis. RESULTS: Deterioration occurred in 10 patients (52.6%). Univariate analyses indicated a lower PANSS positive score after acute treatment as well as after one year of MT as significant predictors; in multivariate logistic regression, in addition to the lower PANSS positive score after acute treatment, reaching enduring remission and having had a deterioration both during MT evolved as significant predictors and indicate a higher risk for deterioration. CONCLUSIONS: Although limited by the small sample size, our findings suggest that patients who show a favorable response and full and enduring symptom remission during antipsychotic treatment, as well as those with marked deterioration despite MT should rather be recommended to remain on treatment because they are at higher risk for symptom re-exacerbation after (stepwise) drug discontinuation.

Are there clinically useful predictors and early warning signs for pending relapse?

OBJECTIVE: Despite the availability of effective long-term treatment strategies in schizophrenia, relapse is still common. Relapse prevention is one of the major treatment objectives, because relapse represents burden and costs for patients, their environment, and society and seems to increase illness progression at the biological level. Valid predictors for relapse are urgently needed to enable more individualized recommendations and treatment decisions to be made. METHODS: Mainly recent evidence regarding predictors and early warning signs of relapse in schizophrenia was reviewed. In addition, data from the first-episode (long-term) study (FES; Gaebel et al., 2007, 2011) performed within the German Research Network on Schizophrenia were analyzed. RESULTS: On the basis of FES data, premorbid adjustment, residual symptoms and some side effects are significant predictors. Although a broad spectrum of potential parameters has been investigated in several other studies, only a few and rather general valid predictors were identified consistently. Data of the FES also indicated that predictive power could be enhanced by considering interacting conjunctions, as suggested by the Vulnerability-Stress-Coping model. Prospective studies, however, are rare. In addition, prodromal symptoms as course-related characteristics likewise investigated in the FES add substantially to early recognition of relapse and may serve as early warning signs, but prognosis nevertheless remains a challenge. CONCLUSIONS: Comprehensive and well-designed studies are needed to identify and confirm valid predictors for relapse in schizophrenia. In this respect, broadly accepted and specifically defined criteria for relapse would greatly facilitate comparison of results across studies.

Rates and predictors of remission in first-episode schizophrenia within 1 year of antipsychotic maintenance treatment. Results of a randomized controlled trial within the German Research Network on Schizophrenia.

OBJECTIVE: Full and sustained symptom remission is a major treatment objective after a first-episode in schizophrenia. Findings regarding differences in remission between first- and second-generation antipsychotics are inconclusive. This study aimed to provide rates and predictors of remission in first-episode schizophrenia and to identify symptoms that prevent remission. METHODS: Prevalence rates of "symptomatic remission" (symptom criteria only) and "enduring remission" (symptom and 6-month time criteria), defined according to Andreasen et al. (2005), were determined in first-episode patients participating in a RCT by the German Research Network on Schizophrenia (GRNS) that compared post-acute, 1-year maintenance treatment with risperidone or haloperidol. Respective predictors at baseline were identified by logistic and Cox regression analysis. RESULTS: Prevalence rates were 91.5% for symptomatic remission (n=152/166 eligible patients) and 58.6% for enduring remission (n=65 of 111 patients who continued for at least 6 months; 39.2% of all 166 patients included), with no significant differences between risperidone and haloperidol in either type of remission. Enduring remission often was not reached because of negative symptoms: After 6 months, 40.5% of the patients had at least 1 negative symptom, whereas only 10.8% of the patients had "persisting" positive symptoms. Of the different predictors identified in univariate analyses, (lower) negative symptoms and participating in standardized psychological treatment remained significant in multivariate (stepwise forward) analyses for enduring remission. CONCLUSIONS: By far most of the first-episode patients reached a temporary state of full symptomatic remission within 1 year of antipsychotic treatment. However, only about 50% achieved sustained, enduring remission. Negative symptoms are still a major treatment obstacle to enduring remission in schizophrenia.

Schizophrenia guidelines across the world: a selective review and comparison.

Treatment guidelines provide evidence-based recommendations to assist practitioners in specific clinical situations. They are a major tool to assure and enhance treatment quality and to overcome existing disparities. However, guideline quality itself varies and needs to be considered. Based on a former review, schizophrenia guidelines with high methodological quality were identified and examined regarding updated versions. Five guidelines were selected, of which three updates have been newly evaluated with the AGREE instrument. In addition, clinical content regarding seven core topics in schizophrenia treatment decisions was compared. Guideline quality on average is good, with highest AGREE scores for the NICE guideline. Updating of the German guideline resulted in noticeable quality improvements. Regarding content, recommendations largely correspond in five areas across guidelines, whereas discrepancies or vagueness exist in two areas due to newly emerging (drug choice) or still restricted evidence (duration of antipsychotic treatment). There are increasing efforts to develop guidelines with improved quality. Also, there is a need to equalize and improve healthcare quality across countries. Since many formal and content-related issues are 'universal', development of trans-national guidelines seems indicated. Nevertheless, core guideline recommendations should be adapted to regional conditions using available tools for adaptation.

Relapse prevention in first-episode schizophrenia--maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia.

OBJECTIVE: After acute treatment of the first illness episode in schizophrenia, antipsychotic maintenance treatment is recommended for at least 1 year. Evidence for the optimal subsequent treatment is still scarce. Targeted intermittent treatment was found to be less effective than continuous treatment at preventing relapse in multiple episode patients; however, a post hoc analysis of our own data from a previous study suggested comparable efficacy of the 2 treatment approaches in first-episode patients. The current study was therefore designed to compare prospectively the relapse preventive efficacy of further maintenance treatment and targeted intermittent treatment in patients with ICD-10-diagnosed first-episode schizophrenia. METHOD: A randomized controlled trial was conducted within the German Research Network on Schizophrenia. Entry screening took place between November 2000 and May 2004. After 1 year of antipsychotic maintenance treatment, stable first-episode patients were randomly assigned to 12 months of further maintenance treatment or stepwise drug discontinuation and targeted intermittent treatment. In case of prodromal symptoms of an impending relapse, patients in both groups received early drug intervention, guided by a decision algorithm. The primary outcome measure was relapse (increase in the Positive and Negative Syndrome Scale positive score > 10, Clinical Global Impressions-Change score ≥ 6, and decrease in Global Assessment of Functioning score > 20 between 2 visits). RESULTS: Of 96 first-episode patients, only 44 were eligible for the assigned treatment (maintenance treatment, n = 23; intermittent treatment, n = 21). The rates of relapse (19% vs 0%; P = .04) and deterioration (up to 57% vs 4%; P < .001) were significantly higher in the intermittent treatment group than in the maintenance treatment group, but quality-of-life scores were comparable. Intermittent treatment patients received a significantly lower amount of antipsychotics (in haloperidol equivalents; P < .001) and tended to show fewer side effects, particularly extrapyramidal side effects. CONCLUSIONS: Maintenance treatment is more effective than targeted intermittent treatment in preventing relapse, even in stable first-episode patients after 1 year of maintenance treatment, and should be the preferred treatment option. However, about 50% of patients remain stable at a significantly lower drug dose and show fewer side effects, and a substantial proportion refuse maintenance treatment. Alternative long-term treatment strategies, including targeted intermittent treatment, should therefore be provided in individual cases. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00159120.

Drug attitude as predictor for effectiveness in first-episode schizophrenia: Results of an open randomized trial (EUFEST).

Effectiveness has become more and more important as a comprehensive outcome measure for (long-term) treatment in schizophrenia. Early predictors to identify patients at a high risk for not succeeding the initiated treatment would be very useful. Discontinuation of the initiated treatment was used as criterion for effectiveness and patients' drug attitude was shown to be predictive for non-adherence or discontinuation of long-term treatment in schizophrenia. Accordingly, the predictive validity of the Drug Attitude Inventory (DAI) for effectiveness should be evaluated. Based on a sub-sample of patients from the EUFEST study for whom DAI assessments were available significant predictors for effectiveness as measured by discontinuation of initiated treatment were identified based on a logistic and a Cox-regression analysis. A Receiver-Operating Characteristic- (ROC-) analysis was conducted for the DAI, prognostic / diagnostic parameters (sensitivity, specificity) were calculated and a cut-off value suggested. In a sample of 228 first-episode patients, the DAI score was the most powerful predictor for effectiveness (p<0.001) besides two other significant predictors (PANSS-positive score and sexual side effects). The ROC-analysis revealed an area under the curve of 0.64 (p<0.001). The suggested cut-off point of about 20 yielded a sensitivity of 70-75% and a specificity of 40-45%. Study results indicate that the Drug Attitude Inventory, filled in by patients early in treatment seems to be a valid predictor for effectiveness as measured by discontinuation of the initiated treatment. DAI scores could also serve as an (differential) indicator for the need of enhanced treatment monitoring. These findings have to be validated in other (first-episode) samples.

Internal capsule size associated with outcome in first-episode schizophrenia.

Subtle structural brain abnormalities are an established finding in first-episode psychosis. Nevertheless their relationship to the clinical course of schizophrenia is controversially discussed. In a multicentre study 45 first-episode schizophrenia patients (FE-SZ) underwent standardized MRI scanning and were followed up to 1 year. In 32 FE-SZ volumetric measurement of three regions of interests (ROIs) potentially associated with disease course, hippocampus, lateral ventricle and the anterior limb of the internal capsule (ALIC) could be performed. The subgroups of FE-SZ with good (12 patients) and poor outcome (11 patients), defined by a clinically relevant change of the PANSS score, were compared with regard to these volumetric measures. Multivariate analysis of covariance revealed a significant reduced maximal cross sectional area of the left ALIC in FE-SZ with clinically relevant deterioration compared to those with stable psychopathology. There were no differences in the other selected ROIs between the two subgroups. In conclusion, reduced maximal area of ALIC, which can be interpreted as a disturbance of fronto-thalamic connectivity, is associated with poor outcome during the 1 year course of first-episode schizophrenia.