Validity of remission and recovery criteria for schizophrenia and major depression: comparison of the results of two one-year follow-up naturalistic studies.

The objective of the present study was the application and comparison of common remission and recovery criteria between patients with the diagnosis of schizophrenia and major depressive disorder (MDD) under inclusion of other outcome parameters. Patients with schizophrenia and MDD who were treated as inpatients at the beginning of the study were examined within two naturalistic follow-up trials from admission to discharge of an inpatient treatment period and the one-year follow-up assessment. PANSS criteria of the Remission in Schizophrenia Working Group (RSWG) for schizophrenia and HAMD criteria of the ACNP Task Force in MDD for depressive patients as well as the Clinical Global Impression-Severity Scale (CGI-S) were applied as symptomatic outcome measures additionally to functional outcome parameters. Data of 153 schizophrenia patients and 231 patients with a MDD episode have been included in the analysis. More depressive than schizophrenia patients reached a threshold score of ≤3 on the CGI-S, indicating symptomatic remission at discharge and at the one-year follow-up. In contrast similar proportions of patients reaching symptomatic remission at discharge from inpatient treatment and at the one-year follow-up in the schizophrenia and in the MDD group were found when disease-related consensus criteria (RSWG vs. ACNP Task Force) were used. Functional remission and recovery rates were significantly lower in schizophrenia than in depressive patients at the one-year follow-up visit. Common outcome criteria for remission and recovery in schizophrenia and major depression were not directly comparable. However, our results indicated a significantly poorer outcome in schizophrenia than in depressive patients according to terms of remission and recovery.

Three-Year long-term outcome of 458 naturalistically treated inpatients with major depressive episode: severe relapse rates and risk factors.

In randomized controlled trials, maintenance treatment for relapse prevention has been proven to be efficacious in patients responding in acute treatment, its efficacy in long-term outcome in "real-world patients" has yet to be proven. Three-year long-term data from a large naturalistic multisite follow-up were presented. Severe relapse was defined as suicide, severe suicide attempt, or rehospitalization. Next to relapse rates, possible risk factors including antidepressant medication were identified using univariate generalized log-rank tests and multivariate Cox proportional hazards model for time to severe relapse. Overall data of 458 patients were available for analysis. Of all patients, 155 (33.6%) experienced at least one severe relapse during the 3-year follow-up. The following variables were associated with a shorter time to a severe relapse in univariate and multivariate analyses: multiple hospitalizations, presence of avoidant personality disorder, continuing antipsychotic medication, and no further antidepressant treatment. In comparison with other studies, the observed rate of severe relapse during 3-year period is rather low. This is one of the first reports demonstrating a beneficial effect of long-term antidepressant medication on severe relapse rates in naturalistic patients. Concomitant antipsychotic medication may be a proxy marker for treatment resistant and psychotic depression.

No influence of brain-derived neurotrophic factor (BDNF) polymorphisms on treatment response in a naturalistic sample of patients with major depression.

The role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD) remains to be elucidated. Recent post hoc analyses indicated a potential association of three polymorphisms in the BDNF gene with worse treatment outcome in patients with the subtype of melancholic depression. We aimed at replicating these findings in a German naturalistic multicenter follow-up. Three polymorphisms in the BDNF gene (rs7103411, rs6265 (Val66Met) and rs7124442) were genotyped in 324 patients with MDD and 470 healthy controls. We applied univariate tests and logistic regression models stratifying for depression subtype and gender. The three polymorphisms were not associated with MDD as diagnosis. Further, no associations were found in univariate tests. With logistic regression, we only found a tendency towards an association of the rs6265 (Val66Met) polymorphism with overall response to treatment (response rates: GG (val/val) < GA (val/met) < AA (met/met); p = 0.0129) and some gender differences for the rs6265 (Val66Met) and rs7103411 polymorphisms. Treatment outcome stratified for subtypes of depression did not differ significantly between the investigated polymorphisms or using haplotype analyses. However, results showed a tendency towards significance. At this stage, we cannot support an influence of these three polymorphisms. Further studies in larger patient samples to increase sample sizes of subgroups are warranted.

The controversial link between antidepressants and suicidality risks in adults: data from a naturalistic study on a large sample of in-patients with a major depressive episode.

Some meta-analyses of randomized placebo-controlled trials on antidepressants conclude that there might be an increased risk for suicidal behaviour, especially in children and adolescents but also in adults. Placebo-controlled trials exclude patients with serious suicidality and might therefore underestimate the risk of respective adverse events. The change of suicidal ideation and the prevalence of suicides and non-fatal suicide attempts were therefore analysed in a large naturalistic prospective multicentre study of depressed in-patients. Additionally, specific risk factors for new emergence of suicidal ideation were investigated. The naturalistic prospective study was performed in 12 psychiatric hospitals of the German research network on depression and suicidality (seven psychiatric university hospitals and five district hospitals) in Germany. All patients (n=1014) were hospitalized and had to meet DSM-IV criteria for major depressive disorder. Six events were defined for the purposes of statistical analysis: 'emergence', 'extended emergence', 'improvement' and 'worsening of suicidal ideation', 'suicide attempts' and 'suicides'. Logistic regression analysis and classification and regression trees (CART) analyses were conducted to determine specific risk factors for new emergence of suicidal ideation. The mean HAMD total score decreased from 24.8 at baseline to 10 after 10 wk. An effect on suicidality was evident by week 2 in the sense of a decrease of the mean HAMD item-3 score. Emergence, worsening and improvement of suicidal ideation occurred in 3.2%, 14.74% and 90.79% of patients, respectively. A total of 10 suicide attempts and two suicides were reported. The rate of suicides (13.44/1000 patient-years) was rather low and comparable to the rate observed in randomized controlled antidepressant trials. Five risk factors for emergence of suicidal ideation were determined with two independent statistical methods: age (with higher risk at age <45 yr), treatment resistance, number of hospitalizations, presence of akathisia and comorbid personality disorder. Age <45 yr as one of five risk factors for the emergence of suicidal ideation is in line with the meta-analysis performed for the recent US Food & Drug Administration (FDA) memorandum; although the naturalistic study design does not permit definite conclusions to be made about certain compounds. The rate of suicides was comparable to that seen in randomized controlled trials, as were the rates of emergence and worsening of suicidal ideation, but more improvement was found. Thus, in-patient treatment in a psychiatric care setting, including daily assessments of suicidality by trained psychiatrists adhering to the rules of good clinical practice (e.g. use of specific co-medications, supportive psychotherapy and continuous medical attendance by nursing staff) might be beneficial.

Remission in schizophrenia - What are we measuring? Comparing the consensus remission criteria to a CGI-based definition of remission and to remission in major depression.

BACKGROUND: Despite being recommended for use in clinical trials, the consensus remission criteria were found to leave patients with persisting symptoms, relevant areas of functional impairment and a decreased sense of wellbeing. Therefore, to evaluate the appropriateness of the schizophrenia consensus criteria, a definition of remission based on the Clinical Global Impression Scale (CGI) was developed and remitter subgroups were compared. METHODS: 239 patients with a schizophrenia spectrum disorder were evaluated regarding their remission status after inpatient treatment. Remission in schizophrenia was defined according to the symptom-severity component of the consensus criteria by Andreasen et al. and a CGI based definition was calculated using sensitivity and specificity using receiver operating curves (asymptomatic remitter). Both remitter groups (schizophrenia consensus versus asymptomatic remitters) were compared regarding different clinical variables at discharge as well as the likelihood to relapse within a 1-year follow-up period. Both schizophrenia remitter subgroups were compared to remitters in major depression as a reference value. RESULTS: Following the consensus criteria, 63% of the schizophrenia patients were in remission compared to only 18% following the asymptomatic criterion. The schizophrenia consensus remitters were less likely to be concurrent treatment responders (p < 0.0001), had a significantly greater illness severity (p < 0.0001) and less functioning (p = 0.0358) as well as a significantly greater risk to relapse (p = 0.0174) compared to the schizophrenia asymptomatic remitters as well as the depressed remitters. CONCLUSION: It should be critically re-evaluated if the currently proposed consensus criteria are adequate to measure what is traditionally understood to be remission.

Atypical symptoms in hospitalised patients with major depressive episode: frequency, clinical characteristics, and internal validity.

OBJECTIVE: The objective was (1) to assess the frequency of atypical depression (AD) in depressed inpatients; (2) to compare clinical features of patients with atypical and nonatypical depression (Non-AD) (3) to evaluate the meaning of single psychopathological symptoms with special respect to mood reactivity. METHOD: Diagnoses of 1073 inpatients were assessed according to DSM-IV using SCID (Structured Clinical Interview for the DSM-IV) and AMDP (Association for Methodology and Documentation). Diagnosis of atypical depression was defined according to criteria of the DSM-IV specifier for AD. All patients were rated using HAMD-21 (Hamilton Depression Scale). RESULTS: A high percentage of patients met criteria for AD (15.3%, 95% CI 13.0-17.9%). Women were more likely to suffer from AD (OR=1.54, p=0.037). There were no significant differences between AD and Non-AD patients regarding age, HAMD total baseline score, and diagnosis of any bipolar illness. In terms of psychopathology patients with AD were significantly more likely to suffer from somatic anxiety, somatic symptoms, guilt, genital symptoms, depersonalisation and suspiciousness as defined by HAMD-21 items. Interestingly, mood reactivity was not found to be significantly associated with the presence of two or more additional symptoms of AD. LIMITATIONS: Results were assessed by a post-hoc analysis, based on prospectively collected data. Compared to other inpatient samples with MDE, prevalence of bipolar disorder was rather low. CONCLUSION: (1) Frequency of AD may be underestimated, especially in inpatient samples. Further studies of inpatient samples are recommended. (2) Quality of distinct anxiety symptoms may be different in both groups, with AD patients being more likely to suffer from somatic symptoms and somatic anxiety. The presence of suspiciousness and even paranoid phenomena may not exclude a diagnosis of AD, but may be related to rejection sensitivity. (3) The mandatory presence of mood reactivity for the diagnosis of AD needs further consideration, regarding its validity for the concept.

Subtypes of depression and their overlap in a naturalistic inpatient sample of major depressive disorder.

Subtyping depression is important in order to further delineate biological causes of depressive syndromes. The aim of this study was to evaluate clinical and outcome characteristics of distinct subtypes of depression and to assess proportion and features of patients fulfilling criteria for more than one subtype. Melancholic, atypical and anxious subtypes of depression were assessed in a naturalistic sample of 833 inpatients using DSM-IV specifiers based on operationalized criteria. Baseline characteristics and outcome criteria at discharge were compared between distinct subtypes and their overlap. A substantial proportion of patients (16%) were classified with more than one subtype of depression, 28% were of the distinct anxious, 7% of the distinct atypical and 5% of the distinct melancholic subtype. Distinct melancholic patients had shortest duration of episode, highest baseline depression severity, but were more often early improvers; distinct anxious patients had higher NEO-Five Factor Inventory (NEO-FFI) neuroticism scores compared with patients with unspecific subtype. Melancholic patients with overlap of anxious features had worse treatment outcome compared to distinct melancholic and distinct anxious subtype. Distinct subtypes differed in only few variables and patients with overlap of depression subtypes may have independent clinical and outcome characteristics. Studies investigating biological causes of subtypes of depression should take influence of features of other subtypes into account.

Psychoeducation and compliance in the treatment of schizophrenia: results of the Munich Psychosis Information Project Study.

OBJECTIVE: The present study examined whether psychoeducational groups for patients with schizophrenic disorders and for their families can reduce rehospitalization rates and improve compliance. METHOD: 236 inpatients who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and who had regular contact with at least 1 relative or other key person were randomly assigned to 1 of 2 treatment conditions. In the intervention condition, patients and their relatives were encouraged to attend psychoeducational groups over a period of 4 to 5 months. The patients' and relatives' psychoeducational programs were separate, and each consisted of 8 sessions. Patients in the other treatment condition received routine care. Outcomes were compared over 12-month and 24-month follow-up periods. The study was conducted from 1990 to 1994. RESULTS: It was possible to significantly reduce the rehospitalization rate after 12 and 24 months in patients who attended psychoeducational groups compared with those receiving routine care (p < .05). Patients who attended psychoeducational groups showed better compliance than patients under routine care without psycho-education. CONCLUSIONS: The results suggest that a relatively brief intervention of 8 psychoeducational sessions with systematic family involvement in simultaneous groups can considerably improve the treatment of schizophrenia. Psychoeducation should be routinely offered to all patients with schizophrenia and their families.

Genetics of emergent suicidality during antidepressive treatment--data from a naturalistic study on a large sample of inpatients with a major depressive episode.

Factors contributing to treatment-emergent suicidal ideation (TESI) using antidepressants have been in the focus of recent research strategies. We investigated previously established clinical predictors of TESI and combined these with several polymorphisms of candidate genes in patients with major depressive disorder. Common polymorphisms involved in the tryptophan hydroxylase 1 (TPH1) and 2 (TPH2), serotonin transporter, monoamine oxidase A (MAOA) and brain-derived neurotrophic factor (BDNF) were investigated in a naturalistic inpatient study of the German research network on depression. We compared patients showing TESI with non-TESI suicidal patients and with non-suicidal patients using univariate tests to detect relevant factors, which were further tested in logistic regression and CART (Classification and Regression Trees) analyses. Of the 269 patients, TESI occurred in 22 patients (17 female), 117 patients were defined as non-TESI suicidal patients, and 130 patients were classified as non-suicidal. When comparing cases with both control groups we found the TPH2 rs1386494 (C/T) polymorphism to be moderately associated with TESI (Univariate tests: TESI vs. non-suicidality: p=0.005; adjusted: p=0.09; TESI vs. non-TESI suicidal patients: p=0.0024; adjusted: p=0.086). This polymorphism remained the only significant genetic factor in addition to clinical predictors in logistic regression and CART analyses. CART analyses suggested interactions with several clinical predictors. Haplotype analyses further supported a contribution of this polymorphism in TESI. The TPH2 rs1386494 (C/T) polymorphism might contribute to the genetic background of TESI. This polymorphism has been previously associated with committed suicide and major depressive disorder. The small number of cases warrants replication in larger patient samples. Lack of a placebo control group hampers definite conclusions on an association with antidepressive treatment.

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.

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.

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.

Outcomes of 1014 naturalistically treated inpatients with major depressive episode.

Due to strict exclusion criteria the generalizability of randomized controlled trials appears to be limited. Therefore, outcomes of naturalistically treated depressive inpatients with respect to depression mean scores, response and remission rates were evaluated. This was a multicenter trial, conducted in 12 psychiatric hospitals in Germany with a follow-up period of 4years. Patients were assessed biweekly from admission to discharge with diverse psychopathological rating scales. All patients (n=1014) met DSM-IV criteria for major depressive episode. Results are presented only for the acute inpatient treatment period. Mean inpatient treatment duration was 53.6+/-47.5days. Reduction on depression scales was evident as soon as week 2 and remained significant. Mean HAMD-17 total score decreased from 22.3 to 8.8. A total of 68.9% were classified as responders (> or =50% reduction of the initial HAMD-17 score), whereas 51.9% achieved remission (HAMD-17 total score < or =7). Of those who ultimately achieved response more than 40% did so within the first 2weeks. An individualized naturalistic inpatient treatment approach appears to be beneficial in terms of effectiveness.

Does early improvement triggered by antidepressants predict response/remission? Analysis of data from a naturalistic study on a large sample of inpatients with major depression.

BACKGROUND: Delayed onset of efficacy of antidepressants and a high proportion of depressed patients being poor or non-responders to antidepressants are well known clinical challenges. Therefore, it seems to be necessary to identify predictors for response and - even more important - for remission. It has been suggested that reduction of depressive symptoms at an early stage of antidepressant treatment may predict treatment outcome. Our objective was to test, if this hypothesis derived from randomized controlled studies (RCTs) in outpatients, would be confirmed in a large naturalistic study in a cohort of inpatients with major depression. Patients were treated with various antidepressants and co-medication according to the protocol based on evidence-based clinical guidelines. METHODS: This was a large naturalistic prospective study. All patients (N=795) were hospitalized and met DSM-IV criteria for major depression according to a structured clinical interview (SCID). Assessments were conducted biweekly. Several definitions of early improvement (20%, 25% and 30% reduction in HAMD-21 baseline total scores) at two different visits were tested. Sensitivity, specificity and predictive values were calculated for the different definitions of early improvement. ROC-analyses as well as logistic regression models have been performed. Response was defined as 50% improvement of the total baseline HAMD-21 score and remission as a score of