Gerd Laux

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.

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.

MAO-inhibitors in Parkinson's Disease

Monoamine oxidase inhibitors (MAO-I) belong to the earliest drugs tried in Parkinsons disease (PD). They have been used with or without levodopa (L-DOPA). Non-selective MAO-I due to their side-effect/adverse reaction profile, like tranylcypromine have limited use in the treatment of depression in PD, while selective, reversible MAO-A inhibitors are recommended due to their easier clinical handling. For the treatment of akinesia and motor fluctuations selective irreversible MAO-B inhibitors selegiline and rasagiline are recommended. They are safe and well tolerated at the recommended daily doses. Their main differences are related to (1) metabolism, (2) interaction with CYP-enzymes and (3) quantitative properties at the molecular biological/genetic level. Rasagiline is more potent in clinical practise and has a hypothesis driven more favourable side effect/adverse reaction profile due to its metabolism to aminoindan. Both selegiline and rasagiline have a neuroprotective and neurorestaurative potential. A head-to head clinical trial would be of utmost interest from both the clinical outcome and a hypothesis-driven point of view. Selegiline is available as tablet and melting tablet for PD and as transdermal selegiline for depression, while rasagiline is marketed as tablet for PD. In general, the clinical use of MAO-I nowadays is underestimated. There should be more efforts to evaluate their clinical potency as antidepressants and antidementive drugs in addition to the final proof of their disease-modifying potential. In line with this are recent innovative developments of MAO-I plus inhibition of acetylcholine esterase for Alzheimers disease as well as combined MAO-I and iron chelation for PD.

Prevalence and Treatment Outcome in Anxious Versus Nonanxious Depression: Results From the German Algorithm Project

OBJECTIVE The objective of this study was to explore the prevalence of anxious depression in an inpatient population, to describe its clinical and sociodemographic correlates, and to compare treatment outcomes between patients with anxious and nonanxious depression. Furthermore, the efficacy of algorithm-guided treatment versus treatment as usual in patients with anxious versus nonanxious depression was evaluated. METHOD Data were collected on 429 inpatients with the diagnosis of a depressive episode (according to ICD-10) and a score of ≥ or = 15 on the 21-item Hamilton Depression Rating Scale (HDRS-21). The German Algorithm Project, phase 3 (GAP3), was conducted between 2000 and 2005 in 10 psychiatric departments throughout Germany. A baseline HDRS-21 anxiety/somatization factor score of ≥ or = 7 was considered indicative of anxious depression. Remission was defined as an HDRS-21 score or ≤ = 9. To evaluate the efficacy of algorithm-guided treatment, patients were randomly assigned into 3 groups: 2 different treatment algorithms or treatment as usual. RESULTS The prevalence of anxious depression was 49%. Patients with anxious depression were more likely than those with nonanxious depression to be older (mean ± SD = 45.3 ± 12.8 vs 42.9 ± 12.0 years, odds ratio [OR] = 1.02 [95% CI, 1.00-1.03], P = .046), retired (70% vs 30%, OR = 3.09 [95% CI, 1.70-5.62], P = .000), without school qualification (74% vs 26%, OR = 3.11 [95% CI, 1.09-8.83], P = .035), more severely depressed (mean ± SD HDRS-21 score = 20.1 ± 5.0 vs 18.5 ± 4.4, OR = 1.08 [95% CI, 1.03-1.12], P = .001), and more likely to have a longer duration of the current episode (mean ± SD = 20.9 ± 26.2 vs 13.7 ± 14.3 weeks, OR = 1.02 [95% CI, 1.01-1.03], P = .011). Patients with anxious depression were more likely to display a variety of melancholic features. In patients with anxious depression compared to those with nonanxious depression, remission was less likely to be achieved (48.6% vs 61.5%, OR = 0.63 [95% CI, 0.42-0.92], P = .018) and took longer to occur (mean ± SD = 44 ± 3.4 vs 30 ± 2.8 days, HR = 0.65 [95% CI, 0.50-0.85], P = .001). There was no significant interaction with the treatment mode with regard to remission (Wald = 0.20, P = .890). CONCLUSIONS Anxious depression is common in patients diagnosed with depression. The poorer treatment outcome in patients with anxious depression demonstrates the need to address the issue of specific treatment strategies for this subgroup. However, anxious depression has no moderating effect on the efficacy of algorithm-guided treatment. TRIAL REGISTRATION http://www.germanctr.de/ Identifier: DRKS00000161.

Costs and Effects of Long-acting Risperidone Compared with Oral Atypical and Conventional Depot Formulations in Germany

Schizophrenia is one of the most expensive psychiatric conditions because of high direct and indirect costs associated with the nature of the illness, its resistance to treatment and the consequences of relapse. Long-acting risperidone is a new formulation of an atypical antipsychotic drug that also offers the improvements in compliance associated with haloperidol depot. The aim of this simulation study was to compare the benefits and costs of three pharmacological treatment strategies comprising first-line treatment with long-acting risperidone injection, a haloperidol depot or an oral atypical antipsychotic agent, over a 5-year period in Germany. A discrete event simulation model was developed to compare three treatment scenarios from the perspective of major third-party payers (sickness funds and social security ’sozialversicherung’). The scenarios comprised first-line treatment with haloperidol depot (scenario 1), long-acting risperidone (scenario 2) and oral olanzapine (scenario 3). Switches to second or third-line options were allowed when side-effects occurred or a patient suffered more than a fixed number of relapses. The model accounted for fixed patient characteristics, and on the basis of these, simulated patient histories according to several time-dependent variables. The time horizon for this model was limited to 5 years, and in accordance with German guidelines, costs and effects were discounted by between 3 and 10%. Direct costs included medication, type of physician visits and treatment location. Indirect costs were not included. Information on treatment alternatives, transition probabilities, model structure and healthcare utilization were derived from the literature and an expert panel. Outcomes were expressed in terms of the number and duration of psychotic episodes, cumulative symptom scores, costs, and quality-adjusted life-years (QALY). Univariate sensitivity analyses were carried out, as were subgroup analyses based on disease severity and for patients at high risk of being non-compliant. The long-acting risperidone strategy was calculated to avoid 0.23 and 0.33 relapses per patient, decrease the cumulative symptom score by 25 and 33 points, and decrease the costs by €2017 and €6096 per patient (€1608 and €5422 discounted), compared with the haloperidol depot and olanzapine strategies, respectively, over a 5-year period (year of costing 2004). Among high-risk non-compliant patients, long-acting risperidone was estimated to avoid 0.23 and 0.47 relapses and save €4822 and €10 646 per patient (€4107 and €9490 discounted), compared with the haloperidol depot and olanzapine strategies, respectively. Sensitivity analyses showed that the results were robust and mainly sensitive to changes in the reported relative effectiveness of atypical and conventional formulations for preventing symptom recurrence, and in the relative compliance with oral and long-acting formulations. In this model, long-acting risperidone is a dominant strategy compared with a haloperidol depot or oral atypical antipsychotic agent, being both more effective and less costly over a 5-year period. Results for longacting risperidone are even more favourable among patients at high risk of being noncompliant or with more severe disease.

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.

The impact of antipsychotics on psychomotor performance with regards to car driving skills

Cognitive and psychomotor impairments are a core feature of most patients with schizophrenia and may have an important influence on driving ability. The present study investigated the effects of neuroleptic monotherapy on psychomotor functions related to car driving skills in schizophrenic patients. Consecutively admitted schizophrenic inpatients (n = 120) were tested under steady state plasma level conditions before discharge to outpatient treatment. Patients met the International Classification of Diseases, Tenth Revision criteria for schizophrenia. The study followed a naturalistic nonrandomized design. Data were collected with the computerized Act & React Testsystem and were analyzed according to medication, severity of illness, and age. Only 32.5% of the schizophrenic inpatients passed the tests without major impairments. Patients treated with atypical neuroleptics or clozapine showed a better test performance on skills related to driving ability when compared with patients on typical neuroleptics. Differences were most pronounced in measures of divided attention, stress tolerance, and attention. Data also suggest that treatment with clozapine had an overall positive impact on measures of reactivity and stress tolerance. These results show that even under steady state pharmacologic conditions psychomotor functions of most schizophrenic patients partly remitted must be considered as impaired. To evaluate these effects, a systematic neuropsychologic examination is recommended.

Predictors of Relapse in the Year After Hospital Discharge Among Patients With Schizophrenia

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

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.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

Authors C. Hiemke1, 2, N. Bergemann3, H. W. Clement4, A. Conca5, J. Deckert6, K. Domschke7, G. Eckermann8, K. Egberts9, M. Gerlach9, C. Greiner10, G. Gründer11, E. Haen12, U. Havemann-Reinecke13, G. Hefner14, R. Helmer15, G. Janssen16, E. Jaquenoud17, G. Laux18, T. Messer19, R. Mössner20, M. J. Müller21, M. Paulzen11, B. Pfuhlmann22, P. Riederer6, A. Saria23, B. Schoppek24, G. Schoretsanitis25, M. Schwarz26, M. Silva Gracia12, B. Stegmann12, W. Steimer27, J. C. Stingl10, M. Uhr28, S. Ulrich29, S. Unterecker6, R. Waschgler30, G. Zernig23, 31, G. Zurek32, P. Baumann33