A standardized stepwise drug treatment algorithm for depression reduces direct treatment costs in depressed inpatients - Results from the German Algorithm Project (GAP3).

BACKGROUND: In a previous single center study we found that a standardized drug treatment algorithm (ALGO) was more cost effective than treatment as usual (TAU) for inpatients with major depression. This report aimed to determine whether this promising initial finding could be replicated in a multicenter study. METHODS: Treatment costs were calculated for two time periods: the study period (from enrolment to exit from study) and time in hospital (from enrolment to hospital discharge) based on daily hospital charges. Cost per remitted patient during the study period was considered as primary outcome. RESULTS: 266 patients received ALGO and 84 received TAU. For the study period, ALGO costs were significantly lower than TAU (ALGO: 7 848 ± 6 065 €; TAU: 10 033 ± 7 696 €; p = 0.04). For time in hospital, costs were not different (ALGO: 14 734 ± 8 329 €; TAU: 14 244 ± 8 419 €; p = 0.617). Remission rates did not differ for the study period (ALGO: 57.9%, TAU: 50.0%; p=0.201). Remission rates were greater in ALGO (83.3%) than TAU (66.2%) for time in hospital (p = 0.002). Cost per remission was lower in ALGO (13 554 ± 10 476 €) than TAU (20 066 ± 15 391 €) for the study period (p < 0.001) and for time in hospital (ALGO: 17 582 ± 9 939 €; TAU: 21 516 ± 12 718 €; p = 0.036). LIMITATIONS: Indirect costs were not assessed. Different dropout rates in TAU and ALGO complicated interpretation. CONCLUSIONS: Treatment algorithms enhance the cost effectiveness of the care of depressed inpatients, which replicates our prior results in an independent sample.

How Effective Is Algorithm-Guided Treatment for Depressed Inpatients? Results from the Randomized Controlled Multicenter German Algorithm Project 3 Trial.

Background: Treatment algorithms are considered as key to improve outcomes by enhancing the quality of care. This is the first randomized controlled study to evaluate the clinical effect of algorithm-guided treatment in inpatients with major depressive disorder. Methods: Inpatients, aged 18 to 70 years with major depressive disorder from 10 German psychiatric departments were randomized to 5 different treatment arms (from 2000 to 2005), 3 of which were standardized stepwise drug treatment algorithms (ALGO). The fourth arm proposed medications and provided less specific recommendations based on a computerized documentation and expert system (CDES), the fifth arm received treatment as usual (TAU). ALGO included 3 different second-step strategies: lithium augmentation (ALGO LA), antidepressant dose-escalation (ALGO DE), and switch to a different antidepressant (ALGO SW). Time to remission (21-item Hamilton Depression Rating Scale ≤9) was the primary outcome. Results: Time to remission was significantly shorter for ALGO DE (n=91) compared with both TAU (n=84) (HR=1.67; P=.014) and CDES (n=79) (HR=1.59; P=.031) and ALGO SW (n=89) compared with both TAU (HR=1.64; P=.018) and CDES (HR=1.56; P=.038). For both ALGO LA (n=86) and ALGO DE, fewer antidepressant medications were needed to achieve remission than for CDES or TAU (P<.001). Remission rates at discharge differed across groups; ALGO DE had the highest (89.2%) and TAU the lowest rates (66.2%). Conclusions: A highly structured algorithm-guided treatment is associated with shorter times and fewer medication changes to achieve remission with depressed inpatients than treatment as usual or computerized medication choice guidance.

The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression.

OBJECTIVE: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. METHODS: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10). RESULTS: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46; p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52; p=0.01). CONCLUSIONS: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment.

Characteristics and differences in treatment outcome of inpatients with chronic vs. episodic major depressive disorders.

BACKGROUND: Approximately 20-30% of patients with Major depressive disorder (MDD) develop a chronic course of their disease. Chronic depression is associated with increased health care utilisation, hospitalisation and a higher disease burden. We identified clinical correlates and differences in treatment response of chronic MDD (cMDD) patients compared with non-chronic episodic depression in a huge sample of depressive inpatients. METHODS: Data were collected from 412 inpatients who had been diagnosed with a major depressive episode (MDE; according to ICD-10) and scored 15 or higher on the 21-item Hamilton Depression Rating Scale (HRSD-21). All subjects were participants in the German Algorithm Project, phase 3 (GAP3). Patients who were diagnosed with a MDE within the last two years or longer (herein referred to as CD) were compared with non-chronic depressive patients (herein referred to as non-CD). CD and non-CD patients were assessed for the following: psychosocial characteristics, symptom reduction from hospital admission to discharge, symptom severity at discharge, remission and response rates, and pharmacological treatment during inpatient treatment. The primary outcome measure was the HRSD-21. RESULTS: 13.6% (n=56) of patients met the criteria for chronic depression. Compared with non-CD patients, patients with CD showed increased axis I comorbidities (74% vs. 52%, χ(2) (1)=7.31, p=.02), a higher level of depressive symptoms at baseline and discharge, increased duration of inpatient treatment (64.8 vs. 53.3 days; t=2.86, p=.03) and lower response (HRSD: 60.0% vs. 72.0%; χ(2) (1)=3.61, p<.04; BDI: 40.5% vs. 54.2%; χ(2) (1)=3.56, p=.04) and remission rates (BDI 17.9.% vs. 29.7%; χ(2) (1)=3.42, p=.05. However, both groups achieved a comparable symptom reduction during inpatient treatment. The prescribed pharmacological strategy had no significant influence on treatment outcome in patients with CD. CONCLUSION: Inpatients with CD show higher symptom severity, lower response and remission rates and a longer duration of inpatient treatment, although they achieve comparable symptom reduction during treatment. These findings support the need to recognise CD and its defining characteristics as a distinct subclass of depression.

Pretreatment anterior cingulate activity predicts antidepressant treatment response in major depressive episodes.

Major depressive disorder leads to substantial individual and socioeconomic costs. Despite the ongoing efforts to improve the treatment for this condition, a trial-and-error approach until an individually effective treatment is established still dominates clinical practice. Searching for clinically useful treatment response predictors is one of the most promising strategies to change this quandary therapeutic situation. This study evaluated the predictive value of a biological and a clinical predictor, as well as a combination of both. Pretreatment EEGs of 31 patients with a major depressive episode were analyzed with neuroelectric brain imaging technique to assess cerebral oscillations related to treatment response. Early improvement of symptoms served as a clinical predictor. Treatment response was assessed after 4 weeks of antidepressant treatment. Responders showed more slow-frequency power in the right anterior cingulate cortex compared to non-responders. Slow-frequency power in this region was found to predict response with good sensitivity (82 %) and specificity (100 %), while early improvement showed lower accuracy (73 % sensitivity and 65 % specificity). Combining both parameters did not further improve predictive accuracy. Pretreatment activity within the anterior cingulate cortex is related to antidepressive treatment response. Our results support the search for biological treatment response predictors using electric brain activity. This technique is advantageous due to its low individual and socioeconomic burden. The benefits of combining both, a clinically and a biologically based predictor, should be further evaluated using larger sample sizes.

Algorithm-guided treatment of depression reduces treatment costs--results from the randomized controlled German Algorithm Project (GAPII).

BACKGROUND: The German Algorithm Project, Phase 2 (GAP2) revealed that a standardized stepwise treatment regimen (SSTR) results in better treatment outcomes than treatment as usual (TAU) in depressed inpatients. The objective of this study was a health economic evaluation of SSTR based on a cost effectiveness analysis (CEA). METHODS: GAP2 was a randomized controlled study with 148 patients. In an intention to treat (ITT) analysis direct treatment costs for study duration (SD) and total time in hospital (TTH; enrolment to discharge) were calculated based on daily hospital charges followed by a CEA to calculate cost expenditure per remitted patient. RESULTS: Treatment costs in SSTR compared to TAU were significantly lower for SD (SSTR: 10 830 € ± 8 632 €, TAU: 15 202 € ± 12 483 €; p = 0.026) and did not differ significantly for TTH (SSTR: 21 561 € ± 16 162 €; TAU: 18 248 € ± 13 454; p = 0.208). CEA revealed that the costs per remission in SSTR were significantly lower for SD (SSTR: 20 035 € ± 15 970 €; SSTR: 38 793 € ± 31 853 €; p<0.0001) and TTH (SSTR: 31 285 € ± 23 451 €; TAU: 38 581 € ± 28 449 €, p = 0.041). LIMITATIONS: Indirect costs were not assessed. Different dropout rates in TAU and SSTR complicated interpretation of data. CONCLUSION: An SSTR-based algorithm results in a superior cost effectiveness at no significant extra costs. Implementation of treatment algorithms in inpatient-care may help reduce treatment costs.

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.

Olanzapine in the treatment of depression with psychotic features: A prospective open-label study.

Objective. Depression with psychotic features is a severe subtype of major depression associated with the presence of delusions, hallucinations and specific neurobiological features. Despite clinical consensus and guideline recommendations, data comparing the efficacy of combining antipsychotics with antidepressants compared to antidepressants alone remain inconclusive. The aim of the study was to investigate effectiveness and tolerability of the atypical antipsychotic olanzapine in acute depression with psychotic features. Methods. Seventeen inpatients with major depressive disorder with psychosis (MDDp) were treated with a combination of an antidepressant and olanzapine for 6 weeks in a prospective open-label study. Depressive and psychotic symptoms, extrapyramidal and general side effects were assessed every 2 weeks. Sixteen patients were eligible for final analysis. Results. The Brief Psychiatric Rating Scale (BPRS) showed a 30% symptom reduction after week 2, a 45% symptom reduction after week 4 and no considerable improvement thereafter. Depressive symptoms (Bech-Rafaelsen Melancholia Scale, BRMS) receded by 37% after week 2 and 50% after week 4. No extrapyramidal side effects occurred. Conclusion. Olanzapine is effective and tolerable in combination with an antidepressant in an MDDp inpatient sample. The results concur with data supporting good efficacy in negative and depressive symptoms of patients with schizophrenic and schizoaffective diseases.

Response to lithium augmentation in depression is associated with the glycogen synthase kinase 3-beta -50T/C single nucleotide polymorphism.

BACKGROUND: Glycogen synthase kinase 3-beta (GSK3B) is a serine/threonine kinase which is directly inhibited by lithium. A -50T/C single nucleotide polymorphism (SNP) localized within the promoter region of the GSK3B gene has previously been shown to be associated with response to lithium prophylaxis in bipolar disorder. This study investigates the association of the GSK3B -50T/C SNP and response to lithium augmentation in acutely depressed antidepressant nonresponders. METHODS: Eighty-one patients who had not responded to at least one adequate trial of antidepressant monotherapy underwent a standardized trial of lithium augmentation for up to 8 weeks. We genotyped for the GSK3B -50T/C SNP using polymerase chain reaction and restriction fragment length polymorphism methods and investigated the association with remission. RESULTS: The allele frequencies in our sample were CC 14.8%, CT 48.2% and TT 37% (no deviation from the Hardy-Weinberg equilibrium). Carriers of the C-allele of the -50T/C SNP showed a significantly better response to lithium augmentation (hazard ratio: 2.70, p = .007), with a mean remission rate of 56.25% after 4 weeks compared to 31% in patients with the TT-genotype (chi(2) = 4.1; p = .04). CONCLUSIONS: Our results support the finding of recent studies demonstrating a superior response of C-allele carriers with bipolar disorder to lithium prophylaxis.