Depressive symptoms and their association with acute treatment outcome in first-episode schizophrenia patients: comparing treatment with risperidone and haloperidol.

OBJECTIVE: To evaluate depressive symptoms regarding their association with the acute outcome in first-episode schizophrenia comparing risperidone and haloperidol. METHOD: A total of 274 patients were analysed within a double-blind randomized controlled trial and treated with risperidone or haloperidol. The patients were grouped according to their baseline HAMD-21 total score in a "depressed" (HAMD-21 ≥16) or "non-depressed" (HAMD-21 <16) patient subgroup. PANSS, HAMD-21, GAF, SOFAS and AIMS ratings were performed. Early response was defined as an initial 20% reduction of the PANSS total score from admission to week 2, response as an at least 50% reduction of the PANSS total score from admission to discharge and remission according to the consensus criteria. RESULTS: A total of 124 patients were classified as depressive at baseline with 22 patients still being depressive at discharge. The depressed and non-depressed patients did not significantly differ regarding the treatment with risperidone and haloperidol (P = 0.2270). The depressive patients suffered from significantly more suicidal tendencies (P = 0.0165), had significantly less insight into their illness (P = 0.0152) and featured significantly worse functioning (P = 0.0066). Patients with depressive symptoms achieved remission significantly less often than non-depressed patients. CONCLUSION: The importance of a specific and adequate treatment of depressive symptoms is highlighted.

Influencing factors and predictors of early improvement in the acute treatment of schizophrenia and schizophrenia spectrum disorder.

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.

Is the PANSS used correctly? a systematic review.

BACKGROUND: The PANSS (Positive and Negative Syndrome Scale) is one of the most important rating instruments for patients with schizophrenia. Nevertheless, there is a long and ongoing debate in the psychiatric community regarding its mathematical properties.All 30 items range from 1 to 7 leading to a minimum total score of 30, implying that the PANSS is an interval scale. For such interval scales straightforward calculation of relative changes is not appropriate. To calculate outcome criteria based on a percent change as, e.g., the widely accepted response criterion, the scale has to be transformed into a ratio scale beforehand. Recent publications have already pointed out the pitfall that ignoring the scale level (interval vs. ratio scale) leads to a set of mathematical problems, potentially resulting in erroneous results concerning the efficacy of the treatment. METHODS: A Pubmed search based on the PRISMA statement of the highest-ranked psychiatric journals (search terms "PANSS" and "response") was carried out. All articles containing percent changes were included and methods of percent change calculation were analysed. RESULTS: This systematic literature research shows that the majority of authors (62%) actually appear to use incorrect calculations. In most instances the method of calculation was not described in the manuscript. CONCLUSIONS: These alarming results underline the need for standardized procedures for PANSS calculations.

Clinical predictors of response and remission in inpatients with depressive syndromes.

BACKGROUND: Most predictor analyses search for single predictors or rely on data from randomized controlled trials. We aimed at detecting a set of clinical baseline variables for prediction of response and remission in 1014 naturalistically treated inpatients with major depressive episode treated for 53.62 ± 47.5 days. METHODS: A three-staged procedure was implemented. First, univariate tests were used for finding associations with baseline variables. Second, logistic regression and third-CART analyses were used to determine predictors of response to inpatient treatment. RESULTS: Presence of suicidality, a higher initial HAMD-21 total score, an episode length <24 months, fewer previous hospitalizations, and absence of any ICD-10F4 comorbidity predicted response in 2 different statistical models. Remission was predicted by lower HAMD-21 baseline score, episode length <24 months and fewer previous hospitalizations in both models. LIMITATION: Results were assessed by a post-hoc analysis, based on prospectively collected data. No controlled study design. CONCLUSION: Contrary to current beliefs, baseline suicidality might be associated with higher chances for response. In addition, baseline severity might impact outcome depending on which criterion (remission or response) used.

Predictors of response and remission in the acute treatment of first-episode schizophrenia patients--is it all about early response?

BACKGROUND: To evaluate the predictive validity of early response compared to other well-known predictor variables in acutely ill first-episode patients. METHODS: 112 patients were treated with a mean dosage of 4.14 mg (±1.70) haloperidol and 112 patients with a mean dosage of 4.17 mg (±1.55) risperidone for a mean inpatient treatment duration of 42.92 days (±16.85) within a double-blind, randomized controlled trial. Early response was defined as a ≥ 30% improvement in the PANSS total score by week 2, response as a ≥ 50% reduction in the PANSS total score from admission to discharge and remission according to the consensus criteria. Univariate tests and logistic regression models were applied to identify significant predictors of response and remission. RESULTS: 52% of the patients were responders and 59% remitters at discharge. Non-remitters at discharge were hindered from becoming remitters mainly by the presence of negative symptoms. Univariate tests revealed several significant differences between responders/non-responders and remitters/non-remitters such as age, severity of baseline psychopathology as well as the frequency of early response. Both early response (p<0.0001) and a higher PANSS positive subscore at admission (p=0.0002) were identified as significant predictors of response at discharge, whereas a shorter duration of untreated psychosis (p=0.0167), a lower PANSS general psychopathology subscore (p<0.0001), and early treatment response (p=0.0002) were identified as significant predictors of remission. CONCLUSION: Together with the finding that early response is a significant predictor of response and remission, the relevance and predictive validity of negative and depressive symptoms for outcome is also highlighted.

Does clinical judgment of baseline severity and changes in psychopathology depend on the patient population? Results of a CGI and PANSS linking analysis in a naturalistic study.

BACKGROUND: Linking of the Clinical Global Impression (CGI) Scale and the Positive and Negative Syndrome Scale (PANSS) was performed within a naturalistic sample. Furthermore, these linking results were compared with those derived from randomized controlled trials to examine if the baseline severity might influence the linking results. METHODS: Biweekly PANSS and CGI ratings were performed from admission to discharge in 398 schizophrenia patients treated within a naturalistic study. Equipercentile linking was performed using the statistical program, R 2.8.1. To evaluate how the naturalistic study design would influence linkage results, a so-called study sample was computed with patients of the naturalistic study fulfilling common inclusion criteria of randomized controlled trials (n = 199). Patients not fulfilling these criteria (less ill sample) and those fulfilling the criteria (study sample) were compared using confidence intervals. RESULTS: We found a considerable difference between the linking of the CGI severity score and the PANSS total score comparing the less ill sample and the study sample. Being considered "mildly ill" at admission in the less ill sample corresponded to a PANSS total score of 47 points and to a PANSS total score of 67 points in the study sample. Considering the linking of the CGI improvement score and PANSS changes, similar results were found for CGI improvement ratings ranging from "very much improved" to "minimally improved". CONCLUSIONS: Despite considerable differences, a 50% PANSS reduction was found to correspond to a clinical rating of much improved, which seems to be a suitable definition for response in clinical drug trials.

Do efficacy and effectiveness samples differ in antidepressant treatment outcome? An analysis of eligibility criteria in randomized controlled trials.

BACKGROUND: Because of strict inclusion and exclusion criteria, results drawn from placebo-controlled randomized antidepressant efficacy trials may not be transferable to real-world patients. METHOD: This study was performed from March 2000 to September 2005 as a prospective, multicenter follow-up. Patients were recruited from February 2000 to June 2005. All patients were hospitalized (N = 1,014) and met DSM-IV criteria for major depressive episode. Assessments with the 21-item Hamilton Depression Rating Scale were conducted biweekly until discharge. According to the most commonly applied exclusion criteria in randomized controlled antidepressant efficacy trials, patients were retrospectively divided into 2 groups: (1) patients not fulfilling exclusion criteria and therefore eligible for a randomized placebo-controlled trial, referred to as "efficacy sample," and (2) patients fulfilling at least 1 exclusion criterion, not being eligible for inclusion in an efficacy trial ("nonefficacy sample"). The efficacy sample was compared with the nonefficacy sample in terms of sociodemographic and clinical baseline variables and outcome measures, such as remission and response rates, 17-item Hamilton Depression Rating Scale mean scores, time to remission, and time to response. RESULTS: Significant differences were found, with the efficacy sample being older (P = .03) and being more often treated at a university hospital (P = .02). The efficacy sample demonstrated superior outcome only in significantly higher mean Global Assessment of Functioning scores at discharge (P = .03). There were no differences regarding remission (P = .68) and response (P = .06) rates, length of hospital stay (P = .49), 17-item Hamilton Depression Rating Scale total score at discharge (P = .13), or time to response (P = .39) or remission (P = .16). CONCLUSIONS: Both groups differed significantly in several baseline measures and final Global Assessment of Functioning scores but not in any other outcome measure. Challenging current beliefs, our findings show that results from efficacy antidepressant trials might be more generalizable than previously thought.

An early improvement threshold to predict response and remission in first-episode schizophrenia.

BACKGROUND: Early improvement with treatment is thought to be important in patients with first-episode schizophrenia, yet a valid definition is still outstanding. AIMS: To develop a valid definition of early improvement and test its predictive validity regarding response and remission. METHOD: We examined 188 in-patients with first-episode schizophrenia. Early improvement was defined as improvement in Positive and Negative Syndrome Scale (PANSS) total score at week 2, response as a 40% PANSS total score improvement at end-point, and remission according to consensus criteria. RESULTS: Reasonable predictive validity of early improvement was found for a 46% PANSS total score improvement at week 2 and a 50% improvement for remission (area under the curve: response 0.707, remission 0.692). Estimated confidence intervals ranged from 26 to 62% PANSS reduction for response and remission. CONCLUSIONS: Patients with a first episode of schizophrenia should improve by at least 30% in PANSS total score at week 2 to achieve response and remission.

Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment.

Recent trials support the hypothesis of the role of inflammation in the pathogenesis of schizophrenia. The overall therapeutic benefit of anti-inflammatory medication, in particular cyclo-oxygenase-2 (COX-2) inhibitors in schizophrenia, is still controversial. There are suggestions that therapy with COX-2 inhibitors may influence the early stages of the disease. Taking these findings into account, we conducted a double-blind, placebo-controlled, randomized trial of celecoxib augmentation to amisulpride treatment in patients with a first manifestation of schizophrenia. Forty-nine patients diagnosed with schizophrenia were randomly assigned. They were treated either with amisulpride (200-1000 mg) plus celecoxib (400 mg) or amisulpride (200-1000 mg) plus placebo. Inclusion criterion was the diagnosis of schizophrenia during the past two years according to DSM-IV. The trial lasted six weeks. At weekly intervals an assessment of the psychopathology was performed using the Positive and Negative Symptom Scale (PANSS) and the Global Clinical Impression Scale (CGI). A significantly better outcome was observed in the patient group treated with amisulpride plus celecoxib compared to the group with amisulpride plus placebo (PANSS negative: p=0.03; PANSS global; p=0.05 and PANSS total: p=0.02). In addition, ratings by the CGI scale during therapy with amisulpride and celecoxib showed a significantly better result (p< or =0.001). A significantly superior therapeutic effect could be observed in the celecoxib group compared to placebo in the treatment of early stage schizophrenia. This is the first time an improvement in patients' negative symptoms has been demonstrated with celecoxib. In future, further trials are needed to investigate the effect of COX-2 inhibitors on prodromal and negative symptoms of schizophrenia.

Response and remission criteria in major depression--a validation of current practice.

Remission and response were suggested as the most relevant outcome criteria for the treatment of depression. There is still marked uncertainty as to what cut-offs should be used on current depression rating scales. The goal of the present study was to compare the validity of different HAMD, MADRS and BDI cut-offs for response and remission. The naturalistic prospective study was performed in 12 psychiatric hospitals in Germany. All evaluable patients (n=846) were hospitalized and had to meet DSM-IV criteria for major depressive disorder. Biweekly ratings were assessed using HAMD-21, MADRS and BDI. A CGI-S score of 1 and a CGI-I score of at least 2 was used as the primary comparative measure of remission and response, respectively. A HAMD-21 cut-off ≤7 (AUC: 0.92), HAMD-17 cut-of ≤6 (AUC: 0.90), MADRS cut-off ≤7 (AUC: 0.94) and BDI cut-off ≤12 (AUC: 0.83) were associated with a maximum of specificity and sensitivity for defining remission. A minimum decrease of 47% of the HAMD-21 (AUC: 0.90), ≤57% for HAMD-17 (AUC: 0.89), ≤ 46% for MADRS (0.91) and a decrease of 47% for the BDI baseline score (AUC: 0.78) best corresponded CGI response criteria. Our data largely confirmed currently used remission and response criteria in naturalistically treated patients.

Safety evaluation of zotepine for the treatment of schizophrenia.

IMPORTANCE OF THE FIELD: Atypical antipsychotics have become the first-line treatment for patients suffering from schizophrenia in the industrialized world. Given the frequent necessity of a life-long enduring antipsychotic treatment, the compounds' safety profile is of great importance for patients and caregivers. Zotepine is an antipsychotic with atypical properties and previous data have suggested a very favorable side effect profile. AREAS COVERED IN THIS REVIEW: The aim of this review is to provide a broad knowledge base on the safety profile of zotepine deriving from currently available research results published in English medical databases. The focus of this research reports starts in the 1990s with zotepine's approval in Europe. WHAT THE READER WILL GAIN: This paper incorporates data on placebo-controlled studies of zotepine as well as studies with comparator compounds also beyond the diagnostic boarder of schizophrenia regarding zotepine's safety. TAKE HOME MESSAGE: The take home message of this safety evaluation of zotepine is that compared to typical compounds zotepine induces less extrapyramidal side effects; however, in terms of comparing zotepine's safety with other atypical antipsychotics more studies are needed to draw final conclusions.

Quality of life and subjective well-being in schizophrenia and schizophrenia spectrum disorders: valid predictors of symptomatic response and remission?

OBJECTIVES: To examine quality of life and subjective well-being as predictors of symptomatic treatment outcome. METHODS: Biweekly PANSS ratings were performed in 285 inpatients with schizophrenia spectrum disorders within a multicenter trial by the German Research Network on Schizophrenia. Quality of life and subjective well-being were assessed using the Medical Outcomes Study-Short Form 36-Item Health Survey (SF-36), the Subjective Well-being Under Neuroleptic Treatment Scale (SWN-K) and the Adjective Mood Scale (AMS). Response was defined as an initial 20% PANSS total score reduction and remission according to the consensus criteria. Correlation analysis, logistic regression and CART-analysis were performed. RESULTS: In total, 81% of the sample achieved symptom response and 48% symptom remission. The statistical analyses revealed early improvement within the first two treatment weeks in the SWN-K scale to be a significant predictor for symptomatic response. Concerning symptomatic remission the SF-36 and SWN-K baseline scores as well as SWN-K early improvement showed significant predictive value. CONCLUSIONS: These results highlight the importance of the patient's self-perception and especially of early improvement of quality of life and subjective well-being for symptomatic treatment outcome.

Does early improvement in major depression protect against treatment emergent suicidal ideation?

OBJECTIVE: To investigate the association of early improvement and treatment emergent suicidal ideation in a large sample (N=705) of naturalistically treated inpatients with major depressive disorder. METHOD: In line with previous reports early improvement was defined as a 20% HAMD improvement within the first two weeks of antidepressant treatment. Treatment emergent suicidal ideation was defined by a sudden increase from 0 or 1 to at least 3 on HAMD item 3 and from 0.1 to at least 4 on MADR item 10 for suicidal ideation. Early improvers were compared with non-early improvers with respect to the occurrence of treatment emergent suicidality during treatment. RESULTS: Early improvers were 3 (MADRS) to 3.4 (HAMD) times less likely to experience new emergence of suicidal ideation during the treatment course than non-improvers. In addition, early improvement was associated with significantly less pessimistic thoughts. LIMITATIONS: The analysis is based on secondary analysis of prospectively collected data. No controlled study design. CONCLUSION: Early improvement is associated with significantly less treatment emergent suicidal ideation for it may provide rapid symptom relief and reduce hopelessness.

Should the PANSS be rescaled?

The design of the Positive and Negative Syndrome Scale (PANSS) with item levels ranging from 1 to 7 leads to the trivial result that the 30-item scale's zero level (no symptoms) is 30. This causes serious problems when ratios are calculated which always implicitly depend on a natural zero point (equals 0). Recent publications concerning efficacy of antipsychotics correctly suggest a subtraction of 30 points to every PANSS before calculating percent change (PC). Nevertheless, the traditional approach using uncorrected scores is still in common practice. This analysis aims to clarify which approach is the most appropriate from a statistical perspective.For analysis, data from a naturalistic study on 400 patients with a schizophrenic spectrum disorder and simulated data sets were used. While calculations concerning absolute score values and their differences are not affected, considerable problems arise in calculations of PC and related response criteria. Even significance levels of estimated treatment effects change, depending on the structure of the data (eg, baseline symptom severity). Using a PANSS version with items ranging from 0 to 6 would avoid such often neglected pitfalls.

Attitude towards adherence in patients with schizophrenia at discharge.

BACKGROUND: Purpose of the present study was to assess the attitude towards adherence at discharge and to verify its predictability using anamnestic and sociodemographic variables, factors influencing clinical treatment as well as the medical treatment applied. METHODS: Attitude towards adherence was evaluated in 369 inpatients with schizophrenic spectrum disorders within a naturalistic multicenter trial using the Compliance Rating Scale (CRS) by Kemp. Biweekly ratings of the PANSS, UKU and the Subjective Well-being under Neuroleptic Treatment Scale (SWN-K) were applied. Logistic regression and CART analyses were used to determine significant predictor variables for the attitude towards adherence at discharge. RESULTS: Sixty-seven percent of the patients were rated to have an attitude of active participation and moderate participation (=positive attitude towards adherence) and 33% of the patients to have an attitude of passive acceptance, occasional or permanent reluctance towards treatment as well as refusing treatment (=negative attitude towards adherence). A significant correlation was found between patients with a positive attitude towards adherence and course of all PANSS subscales. Statistical analyses revealed a reduction in PANSS general psychopathology subscore, employment status, greater illness insight and treatment with atypical antipsychotics to be significantly predictive for a positive attitude towards adherence at discharge. CONCLUSIONS: The importance of an adequate antipsychotic treatment as a precondition for a favourable adherence attitude and the need to incorporate adherence-focused psychotherapy and psychoeducation into daily clinical practice are highlighted.

Defining and predicting functional outcome in schizophrenia and schizophrenia spectrum disorders.

BACKGROUND: To assess criteria and to identify predictive factors for functional outcome. The criteria should cover all domains proposed by the Remission in Schizophrenia Working Group. METHOD: PANSS ratings were used to evaluate the symptomatic treatment outcome of 262 inpatients with schizophrenia spectrum disorders within a naturalistic multicenter trial. Functional remission was defined as a GAF score >61 (Global Assessment of Functioning Scale), SOFAS score >61 (Social and Occupational Functioning Scale) and a SF-36 mental health subscore >40 (Medical Outcomes Study-Short Form Health Survey). Multivariate logistic regression and CART analyses were used to determine valid clinical and sociodemographic predictors. RESULTS: In total, 52 patients (20%) fulfilled the criteria for functional remission, 125 patients (48%) achieved symptomatic resolution and when criteria for functional remission and symptomatic resolution were combined 33 patients (13%) achieved complete remission. Younger age, employment, a shorter duration of illness, a shorter length of current episode, less suicidality, and a lower PANSS negative and global subscore at admission were predictive of functional remission. The regression model showed a predictive value of more than 80%. CONCLUSIONS: A significant association was found between functional remission and symptomatic resolution, indicating reasonable validity of the proposed definition for functional outcome. The revealed predictors for functional treatment outcome emphasize the need for psychosocial and vocational rehabilitation in schizophrenic patients.