Outcomes of 1014 naturalistically treated inpatients with major depressive episode

European Neuropsychopharmacology (2010) 20, 346–355

www.elsevier.com/locate/euroneuro

Outcomes of 1014 naturalistically treated inpatients with major depressive episode Florian Seemüller a,⁎, Michael Riedel a , Michael Obermeier a , Michael Bauer b , Mazda Adli c , Klaus Kronmüller d , Florian Holsboer e , Peter Brieger f , Gerd Laux g , Wolfram Bender h , Isabella Heuser i , Joachim Zeiler j , Wolfgang Gaebel k , Eva Dichgans a , Roland Bottländer a , Richard Musil a , Hans-Jürgen Möller a a

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336 Munich, Germany Department of Psychiatry and Psychotherapy, Carl Gustav Carus University Dresden, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany c Department of Psychiatry and Psychotherapy, Campus, Charité Mitte (CCM), Charitéplatz 1, 10117 Berlin, Germany d Department of Psychiatry and Psychotherapy, University of Heidelberg, Voßstr. 2, 69115 Heidelberg, Germany e Department of Psychiatry and Psychotherapy, Max Planck Institute of Psychiatry, Kraepelinstr. 2-7, 80804 Munich, Germany f Department of Psychiatry and Psychotherapy, Martin-Luther University Halle-Wittenberg, Julius-Kühn-Str.7, 06097 Halle, Germany g Department of Psychiatry and Psychotherapy, Inn-Salzach-Klinikum, Garbersee 7, 83512 Wasserburg, Germany h Department of Psychiatry and Psychotherapy, Isar-Amper-Klinikum Munich East, Vockestr. 72, 85540 Haar, Germany i Department of Psychiatry and Psychotherapy, Campus Charité Benjamin Franklin (CFB), Eschenallee 3, 14050 Berlin, Germany j Department of Psychiatry and Psychotherapy, Auguste-Viktoria-Krankenhaus, Rubensstr. 125, 12157 Berlin, Germany k Department of Psychiatry and Psychotherapy, University of Düsseldorf, Bergische Landstr. 2, 40629 Düsseldorf, Germany b

Received 5 March 2009; received in revised form 6 November 2009; accepted 26 November 2009

KEYWORDS Depression; Inpatient; Outcome

Abstract 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 4 years. 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 ± 47.5 days. 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

⁎ Corresponding author. Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstr. 7, 80336 Munich, Germany. Tel.: +49 89 5160 5846; fax: +49 89 5160 5774. E-mail address: [email protected] (F. Seemüller). 0924-977X/$ - see front matter © 2009 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2009.11.011

Outcomes of depressed inpatients

347 classified as responders (≥50% reduction of the initial HAMD-17 score), whereas 51.9% achieved remission (HAMD-17 total score ≤ 7). Of those who ultimately achieved response more than 40% did so within the first 2 weeks. An individualized naturalistic inpatient treatment approach appears to be beneficial in terms of effectiveness. © 2009 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction With respect to efficacy the FDA requires two adequately powered positive randomized controlled studies (RCTs) against placebo for a new antidepressant before it can authorize the drug to be put onto the market. Although results from such RCTs reflect the highest scientific evidence level, they are still far away from being satisfactory. Remission rates in RCTs with SSRIs and an average duration of 6–8 weeks for example reach 33% (Beasley et al., 1993). Thus, about two thirds of all patients do not achieve remission at endpoint. Beside the limited duration of such trials one reason might be that some patients do not get the most appropriate treatment considering their individual needs right from the beginning. Apart from that, it has to be considered that remission rates observed in RCTs account for a highly selected study population which even might be not representative for “real world patients” which we see in our day to day routine. Some authors even speak of “symptomatic volunteers” enrolled in US American RCTs as opposed to patients seeking help due to their psychological strain. Zimmerman and Posternak recently pointed out, that only 14% of all antidepressant users seen in their outpatient population would comply with the strict inclusion criteria of RCTs (Zimmerman et al., 2002). Thus, clinicians face a complex challenge, transferring research results when consulting “non-study real world patients” with medical and psychiatric comorbidities. As yet, we still don't have enough valid biological or sociodemographic predictors to initially “treat the right patient with the right drug”. Thus, the most common approach remains to follow the rules of “good clinical practice”(Moller et al., 2008) including e.g. compiling a careful medication history, considering the side effect profile and finally choosing the most suitable antidepressant on the basis of clinical experience and in consideration of available evidence-based research data and guidelines. Scientific approaches to overcome these limitations RCT, are stepwise algorithm based effectiveness trials with broad inclusion and few exclusion criteria like the recent STAR*D study which rightly attracted much interest in the research community. However, the main result so far is that there were no significant differences between different strategies within the respective treatment steps. Thus, STAR*D offers no significant help in the decision process which treatment should initiated first and which should subsequently follow when one treatment has failed (Rush et al., 2006b). In particular, it could not prove that a sophisticated algorithm treatment approach is superior to “treatment as usual” (TAU), because a TAU group has not been included. Evidence for the superiority of a complex algorithm approach was suggested by the Texas Algorithm Project (Trivedi et al., 2004). However, the results should be questioned, because the study did not follow the rules of an RCT. In fact it compared hospitals, from which some

did offer the algorithm treatment, while others did offer TAU finally resulting in significant different baseline characteristics between the two groups. Thus, it is still an open question whether a clinical treatment following the best standards of guidelines and “good clinical practice” with a highly individualized approach, reveals comparable or even better outcomes as sequenced treatment algorithms. So in addition to the scientific gap due to the limited generalizability of RCTs there is also a gap of evidence regarding the outcome of such individualized treatment as usual (TAU) in “real world” patients in major depression. To further bridge the gap between randomized double-blind placebo-controlled trials, not or only partial randomized effectiveness studies like STAR*D (Trivedi et al., 2006) or the Texas Algorithm Project (Trivedi et al., 2004) and clinical psychiatric care, the assessment of outcomes of individualized treatment approaches carried out according to guidelines used in everyday clinical practice on a “real world sample”, might contribute to a more generalizable picture of treatment effectiveness. In particular, this study focuses the following factors: 1. The development of remission and response rates over the acute inpatient treatment course and the corresponding mean scores of depression rating scales. 2. The results of secondary outcome measures such as quality of life, side effect burden in a representative sample under routine clinical inpatient care of psychotic or non-psychotic major depressive disorder.

2. Methods 2.1. Study overview and organization This prospective naturalistic multicenter trial was primarily designed to address the issues of treatment resistance, relapse, chronicity and suicidality in depressive disorders within the framework of psychiatric university and district hospitals. It was part of the German research network on depression and was funded by the German Federal Ministry of Education and Research (BMBF). The study was planned to be conducted in representative inpatient groups and settings using clinical management tools that easily can be applied in daily practice. The core of this multicenter trial was the biweekly observation of inpatients with a major depressive episode under naturalistic treatment conditions until discharge and a subsequent annual follow-up for a period of 4-years. Here, only the results of the acute inpatient treatment period are presented. 12 study centres across Germany participated in this trial, including seven university hospitals (Berlin: Campus Charité Mitte and Campus Benjamin Franklin, Düsseldorf, Halle, Heidelberg, Munich: MPI and LMU) and five district hospitals (Gabersee/Bavaria, Haar/Bavaria, Berlin: Auguste-Viktoria-Hospital, St Joseph hospital and St Hedwig hospital). Clinical research coordinators at each site assisted in protocol implementation and computerized data collection. The primary enrollment goal was to include 800–850 patients

348 with any depressive episode. All in all, a total of 1079 patients were enrolled, resulting in a final data set of 1014 patients with a minimum of two complete observations.

3. Experimental procedures 3.1. Sample and data collection To allow inclusion of clinical representative populations the following inclusion and exclusion criteria was required. Inclusion criteria were: 1) Age between 18 and 65 2) Signed written informed consent 3) Hospitalization and fulfilling of ICD-10 diagnostic criteria for any major depressive episode (ICD-10: F31.3x–5x, F32, F33, F34, F38) or for a depressive disorder not otherwise specified (ICD-10: F39) as primary diagnosis. Exclusion criteria were: 1) Organic cause of depression 2) Insufficient knowledge of German language 3) Distance from place of residence to the study centre of more than 100 km. Moreover, the diagnosis of a depressive spectrum disorder according to DSM-IV was confirmed at baseline, at discharge and at each annual follow-up visit using the Structured Clinical Interview for DSM-IV (SCID-I) (Wittchen et al., 1997). SCID II was applied to carefully assess comorbid axis II personality disorders. The biweekly ratings included clinician rated psychopathologic assessments with the Hamilton Depression Rating Scale, 21 items (HAMD-21) (Hamilton, 1967) and the Montgomery Asberg Rating Scale (MADRS) (Montgomery and Asberg, 1979). Apart from depression ratings for assessment of overall symptom severity, the Clinical Global Impression was used (Guy, 1976). Side effects were assessed using the Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) (Lingjaerde et al., 1987). Assessments at baseline, at discharge and at the annual follow-up additionally consisted of the comprehensive collection of socio-demographic and clinical variables using the systematic basic assessment scale of clinical and socio-demographic variables in psychiatry (BADO) (Cording et al., 1995). Furthermore, functional outcome comprised the Global Assessment of Functioning Scale (GAF) (APA—American Psychiatric Association, 2000) and scale for quality of life assessments using the Lancashire Quality of Life Profile (LQLP) (Oliver et al., 1997; Priebe et al., 1995). Quality of life (QoL) was only measured at discharge with the LQLP. The LQLP is a selfrating scale, which comprises 11 sections (work, free time, religion, finance, living situation, safety, family, friends, health, self-esteem and overall quality of life (QoL)). Each section can be scored individually on a range from 1 to 7, with a higher score indicating a higher QoL.

3.2. Treatment Patients were treated at the discretion of the psychiatrist in charge under consideration of the international clinical guidelines for the treatment of depression (APA-, WSFBP-guidelines) (American Psychiatric Association, 2000; Bauer et al., 2007; Deutsche Gesellschaft für Psychiatrie, 2000). In addition, the medication class, their active compounds, the dosage and the treatment duration have been recorded. Furthermore, the duration and type of other biological treatments like ECT, sleep deprivation, transcranial magnetic stimulation (TMS) or psychotherapy was recorded.

F. Seemüller et al. 3.3. Statistics Patients were included into analysis if in addition to the baseline assessment at least one post baseline assessment was available. Discharged patients (patients with at least one second HAMD-21 assessment) and drop outs were included into analysis on an intention to treat basis, using the last observation carried forward method (LOCF) for the mean course graphs. Missing follow up HAMD21 data between baseline and final visit were imputed with the last&next method (Engels and Diehr, 2003). Side effects as rated with the UKU were only described for adverse events when classified by the clinician as possibly or probably related to medication. The main outcome criteria response and remission referred to HAMD-17 which was extracted from the original HAMD-21. Response was defined as ≥50% HAMD-17 score reduction of the baseline score at endpoint. Remission was defined as HAMD-17 ≤ 7. As LQLP measures were only assessed at discharge, we compared quality of life in remitters vs. non-remitters on an individual item basis, in order to demonstrate the effectiveness of inpatient treatment. Apart from the usual descriptive statistics, Fisher's exact test, t-tests and Wilcoxon tests were applied as appropriate. All statistical analyses were performed using the statistical software package R 2.5.1.

4. Results 4.1. Sample characteristics 4.1.1. Socio-demographic variables 1073 patients were enrolled into the study. 59 patients had to be excluded due to missing baseline data. 78 patients refused to continue inpatient treatment after start of the antidepressant treatment after a mean treatment time of 20.9 days (±21.97 days) and were classified as drop outs. About two thirds of all patients were female (62.6%). About 37% of the patients were older than 51 years. 41% were married and 63% were employed (including housewives, part-time, vocational training). The majority was treated at university hospitals (72%) (Table 1).

4.1.2. Clinical variables Subjects were moderate to severely depressed according to baseline scores. Mean initial scores were 24.8 ± 6.9 (HAMD-21), 22.25 (HAMD-17) and 29.8 ± 7.9 (MADRS), respectively (Table 2). The majority of patients (71.4%) had an initial HAMD-17 score above 18, which meets the inclusion cut-off criteria for most RCTs (Guelfi and Corruble, 1997). The distribution of the initial HAMD-17 score is plotted in Fig. 1. The mean duration of inpatient treatment was 53.6 days with a standard deviation of ±47.5 days. Patients had a mean age of 45.1 ± 11.9 years and mean illness duration of 7.1 ± 9.1 years. The length of the current episode before hospitalization varied highly. Thus, about one third of all patients (32%) suffered from episodes lasting longer than 6 months, suggesting a substantial number of partially refractory patients (Table 3). The mean age at onset was 37.9 ± 12.8 years and approximately half of all patients (48.4%) had been hospitalized prior to the current episode. According to ICD-10 criteria (World Health Organization, 1992) 12.1% had bipolar depression (F31), 41% were classified as single depressive episode (F32), 50.8% suffered from recurrent depressive disorder (F33) and 5.5% had a persistent affective disorder with 2% having cyclothymia and 1% dysthymia.

Outcomes of depressed inpatients Table 1

349

Socio-demographic baseline variables.

Gender Male Female Age group 18–30 31–50 N51 Age Education Marital status Married Never married Widowed Divorced Not married. Living together Married. Living separately Other Unknown Employment status Employed (1–8) Unemployed (9) Retired (10–12) Unknown Setting University hospital District hospital

N

%

379 635

37.38 62.62

127 508 379

12.52 50.10 37.38

398 275 30 113 69 78 6 45

41.07 28.38 3.10 11.66 7.12 8.05 0.62 4.44

604 137 153 48

62.53 14.18 15.84 4.73

730 284

72.00 28.00

Mean

SD

45.09

11.89

Figure 1

HAMD-17 baseline score distribution of all patients.

Other highly prevalent comorbid psychiatric conditions according to ICD-10 criteria were abuse of psychoactive substances (10.8%) (F10–F19), with 8.3% having mental and behavioural disorders due to use of alcohol (F10) and neurotic and stress-related somatoform disorders (F4) (11.4%) (Table 5). About 9% had more than two psychiatric comorbid disorders. Medical illnesses were also highly prevalent as reflected by the 44% of patients requiring medication for medical conditions (Table 6).

Only 5.3% have been classified according to ICD-10 as psychotic depression (Table 4).

4.2. Treatment 4.1.3. Comorbidities About 37.3% had a comorbid personality disorder according to SCID II, with avoidant personality disorder being the most prevalent (15.65%), followed by obsessive compulsive (14.34%) and borderline personality disorder (6.91%). Table 2

Baseline severity and outcome variables. N

Symptom severity baseline HAMD-17 MADRS Unknown Symptom severity final visit HAMD-17 MADRS UKU baseline N 0 UKU final visit N 0 Length of stay in hospital Remission Response GAF baseline Unknown GAF final visit Unknown

%

Mean

4.2.1. Medication Medication data was available for 859 patients of the sample. At baseline a total of 184 patients were without medication whereas at discharge 748 patients received psychoactive compounds. Overall, a total of 821 patients received antidepressant medication, 491 patients received tranquillizers and 363 got hypnotic medication. Antipsychotic medication was taken by 365 patients.

SD Table 3

22.25 29.77 107

10.55 8.84 12.15

6.80 9.80

53.62

47.52

46.99

16.19

49.80 56.80 526 699

51.870 68.930

27

2.66 69.71

257

25.35

History of illness.

6.22 7.87 Length of current episode Less than 1 month Less than 3 months Less than 6 months Less than 1 year Less than 2 years Less than 5 years Less than 10 years More than 10 years Unknown Length of illness (years) Unknown Number of hospitalisations

N

%

134 283 228 153 80 32 15 24 65

14.12 29.82 24.03 16.12 8.43 3.37 1.58 2.53 6.41

127 491 (≥2)

12.52 48.42

Mean

SD

7.10

9.12

2.41

2.48

350 Table 4

F. Seemüller et al. Table 6

Clinical baseline variables. N

Age at first treatment b 18 Age at onset Unknown Family history Affective disorder Schizophrenia Alcohol/drug abuse/ dependence Suicide Other Unknown Depression (ICD-10) (mild/moderate/severe) Mild (F32.0. F33.0) Moderate (F32.1. F33.1) Severe (F32.2. F32.3 F33.2. F33.3) Recurrent depression (F33.0–33.9) Psychotic depression (F33.3.F32.3.F31.5) Bipolar depression (F31) Unknown

34

%

SD

37.9

12.81

3.35

90

8.88

316 42 96

32.28 4.29 9.81

98 13 35

10.01 1.33 3.45

25 314 243

2.47 30.97 23.96

510

50.30

54

5.33

63/521 117

Mean

Personality disorder general SCID II Avoidant p.d. Dependent p.d. Obsessive p.d. Negativistic p.d. Schizotypal p.d. Paranoid p.d. Schizoid p.d. Histronic p.d. Narcissistic p.d. Borderline p.d. Anti social p.d. Unknown No. of comorbid axis 1 disorders 0 1 2 3 ≥4 Unknown

%

286 120 49 110 24 76 39 5 13 16 53 18 247

37.29 15.65 6.39 14.34 3.13 9.90 5.08 0.65 1.69 2.09 6.91 2.35 24.36

716 194 60 24 8 12

71.46 19.36 5.99 2.40 0.80 1.18

Regarding tranquillizers the overwhelming majority of patients got lorazepame (N = 451) followed by diazepame (N = 39) alprazolame (N = 21), oxazepame (N = 5) and bromazepame (N = 2). Each patient took on average one antidepressant per day. 32% of all patients were discharged with an antidepressant monotherapy. 45% received co-medications at discharge. In total, a mean of 1.7 medications from all classes was taken per patient day. Discharge augmentation strategies like lithium augmentation, augmentation with an antipsychotic or augmentation with a

Table 7

Medication classes and treatment duration.

Psychiatric comorbid ICD-10 disorders. N

Comorbid axis I disorders ICD-10 Organic, including symptomatic, mental disorders Mental and behavioural disorders due to psychoactive substance use Schizophrenia, schizotypal and delusional disorders Neurotic, stress-related and somatoform disorders Behavioural syndromes associated with physiological disturbances and physical factors Disorders of adult personality and behaviour Behavioural and emotional disorders with onset usually occurring in childhood and adolescence Unknown

N

12.10 11.54

Only 10 patients received no psychoactive compounds at all (Table 7). In Table 8 all antidepressant compounds and the treatment duration are listed. The ten antidepressants most often prescribed in declining order were: venlafaxine (N = 311), mirtazapine (N = 198), sertraline (N = 145), citalopram (N = 129), trimipramine (N = 102), amitriptyline (N = 100), reboxetine (N = 67), doxepine (N = 56), paroxetine (N = 44) and tranylcypromine (N = 34) (Table 8). Table 5

Comorbid personality disorders (SCID II) DSM-IV.

N

Mean treatment SD/treatment duration (days) duration (days)

365 821 491 363 172 3

39.79 48.02 28.13 28.87 37.31 17.33

42.17 39.00 31.50 31.64 28.32 13.65

15 25.20 108 41.30 33 35.70

24.40 39.27 33.75

4 19.25 442 41.61

20.90 41.78

255 40.60

37.90

% 2

0.20

108

10.78

2

0.20

114

11.38

10

1.00

121

12.08

3

0.30

12

1.18

Neuroleptics Antidepressants Tranquillizers Hypnotics Lithium Other psychopharmacologic compounds Betablockers Anticonvulsants Medication for Parkinsonism Not further specified Agents for medical conditions Non-pharmacologic treatments No psychopharmacologic compounds

10

9.80

9.13

Outcomes of depressed inpatients Table 8

351

Antidepressants and treatment duration.

Antidepressant (generic name)

N

Mean treatment duration (days)

SD/treatment duration (days)

Venlafaxine Mirtazapine Sertraline Citaloprame Trimipramine Amitriptyline Reboxetine Doxepine Paroxetine Tranylcypromine Amitriptylinoxide Moclobemide Nortriptyline Maprotiline Clomipramine Fluoxetine Opipramole Trazodone Fluvoxamine Imipramine Mianserine Nefazodone Desipramine Escitaloprame Melitracene Dibenzepine Duloxetine

311 198 145 129 102 100 67 56 44 34 28 20 16 13 11 7 7 6 6 5 4 4 3 3 1 1 1

40.43 30.65 37.68 37.12 37.50 36.47 26.84 31.27 26.00 43.79 38.32 34.10 40.44 26.46 42.18 32.57 31.14 8.50 50.83 36.60 31.50 14.75 29.66 18.00 1.00 28.00 69.00

26.58 23.77 26.78 26.56 33.27 31.49 22.33 31.65 23.63 28.11 26.81 49.57 46.11 17.85 33.10 20.60 24.221 7.64 64.12 37.25 38.44 14.29 20.55 5.29 NA NA NA

tricyclic antidepressant were used in 14%, 22% or 7% of all patients. Augmentation with antiepileptics was used in 7% of the cases.

4.2.2. Other treatments With respect to non-pharmacologic biological treatments, 44 patients got sleep deprivation, 22 patients got ECT, 8 patients light-therapy and 7 patients got TMS. A total of 255 patients received also additional treatments for a mean duration of 40 days. In further detail, a total of 201 patients received cognitive behavioural therapy (CBT) by a fully trained psychologist, 186 patients had physiotherapy, 148 patients received occupational therapy, and 95 patients received art and music therapy.

Table 9 Number of UKU global assessments of the interference of existing side effects with the patient's daily performance (patient/clinician) at baseline and at discharge: (0 = No side effects. 1 = Mild side effects that do not interfere with the patient's performance. 2 = Side effects that interfere moderately with the patient's performance. 3 = Side effects that interfere markedly with the patient's performance).

Patient (baseline) Doctor (baseline) Patient (discharge) Doctor (discharge)

0

1

2

3

% any side effects

245 242 274 269

181 200 285 312

48 35 55 39

8 5 8 2

49.17 49.79 55.95 56.75

4.3. Outcome 4.3.1. HAMD and MADRS mean scores HAMD-17 and MADRS baseline scores declined from 22.3 ± 6.2 (HAMD-17) and 29.8 ± 7.9 (MADRS) at admission to 8.8 ± 6.8 (HAMD17) and 12.15 ± 9.8 (MADRS) at discharge (Table 2). A statistical significant reduction in clinician rating scales (HAMD-17, MADRS) was evident as early as week 2 and remained significant until the primary endpoint at discharge. In Fig. 2 the mean value courses are displayed up to week 10 (LOCF) for both depressions rating scales. Statistical significant differences were found between baseline and endpoint and in addition between each visit and the following visit (e.g. V1 and V2, V2 and V3, V3 and V4…). The actual number of subjects giving data to the analysis at baseline and at week 2, 4, 6, 8, 10 and N 12 were 1014, 937, 810, 599, 417 and 296, respectively. The by far most pronounced decline was seen in week 2 with a HAMD-17 and MADRS reduction of 34.3% and 33.3%. At endpoint HAMD and MADRS showed a decline of 59% and 63%. With respect to overall CGI, 33.63% were classified as severely to very severely ill (CGI 6–7), 65.08% as moderate (CGI 4–5) and 1.29% were mildly (CGI 2–3) ill at baseline. At discharge 8.22% were classified as not ill, 50% as mildly, 35% as moderately and only 6.5% as severely ill.

4.2.3. Safety measures During the whole observation period a total of 10 suicide attempts (0.97%) and 2 suicides (0.2%) have been reported (Seemuller et al., 2008). Severe adverse events occurred at baseline in 1.8% and at discharge in 0.3% of all patients. Adverse events to a milder degree occurred in 50% of patients at baseline and in 57% at endpoint, respectively (Table 9). The most prevalent adverse event was dry mouth. At discharge patients suffered in declining order from perspiration (17%), tremor (17%), tiredness (16%), weight gain (14%), obstipation (14%), orthostatic dysregulation (11%), inner tension (10%), accommodation disturbances (9%) and decreased libido (7%).

Figure 2 Mean value courses (LOCF) of HAMD-17 and MADRS (***p b 0.001).

352

F. Seemüller et al.

4.3.2. HAMD-17 remission and response rates About 68.9% could be classified as HAMD-17 responders at endpoint and more than half of all patients (51.9%) achieved HAMD-17 remission (HAMD-17 ≤ 7) at discharge (ITT population). A total of 25.35% were neither responder nor remitter at discharge. The distribution of the time to first remission and response for those who ultimately did achieve remission and response in this study based on HAMD-17 remission and response rates are shown in Fig. 3. Patients newly responded to antidepressant treatment at week 2, 4, 6 ,8 ,10 and b 12 to 41.34% 30.47% 13.88% 6.01% 3.86% and 4.43% and newly remitted to 34.03% 25.86% 15.78% 11.22% 6.27% and 6.84%. Up to week four response rates clearly surpass remission rates but thereafter remission rates equal or even outperform response rates.

Figure 5 Partially refractory patients (index episode N 6 months) (***p b 0.001, **p b 0.01).

Fig. 4 displays Kaplan–Meier curves for time to response and time to remission. Mean time to response was 33 days and mean time to remission 39.10 days. Response preceded remission or appeared simultaneously in most cases (with the exception of only 4 cases), the mean time from first response to remission at discharge was 10 days.

4.3.3. Course of partially refractory patients

Figure 3 Percent of 1014 inpatients with major depressive episode who ultimately achieved response or remission.

In order to further investigate outcome and illness course of partially refractory patients with episodes under antidepressant treatment lasting longer than 6 months at baseline, we additionally plotted course graphs for both subgroups. In Fig. 5 the mean HAMD-17 course graph for partially refractory patients is displayed. Patients with episodes below 6 months showed significantly higher symptom reduction on HAMD-17 scale (p b 0.0001).

4.3.4. Functional outcome The average level of global functioning (GAF score) increased significantly during inpatient treatment from 47 to 69 at discharge. Mean GAF at discharge was significantly higher for remitters 64 than for non-remitters 75. LQLP was only evaluated at discharge. The LQLP total score was significantly higher with a mean score of 4.8 for remitters and 3.9 for non-remitters. In 9 of 11 domains remitters had a significant higher score in the LQLP at discharge than non-remitters. In detail, remitters had better Quality of Life (QoL) in terms of leisure time, religion, finance, safety, family, friends, health, self-worth and general QoL. No differences were found in the fields work and home.

5. Discussion Figure 4 Kaplan–Meier estimates for response and remission at discharge.

This study was designed to close the gap between efficacy trials and effectiveness studies. Therefore outcomes in a representative sample of depressed inpatients, which were

Outcomes of depressed inpatients treated according to guideline recommendations, were determined. All inpatients received a highly individualized inpatient treatment regimen under consideration of the respective psychiatric comorbidities and other personnel aspects. In particular, we sought to answer the question if individualized antidepressant treatment according to current treatment guidelines and the rules of “good clinical practice” (Moller et al., 2008) would be effective in the real world of day to day clinical practice. Effectiveness evaluation included the calculation of remission and response rates, courses of mean values of depression rating scales, functional outcome and assessment of adverse events.

5.1. Comparison to phase III efficacy trials In the present analysis we found relatively high HAMD-17 response (69%) and remission rates (52%) in a sample of moderately to severely depressed patients with high medical and psychiatric comorbidity rates, high rates of severe suicidal ideation (28% HAMD item 3 ≥ 3) and a substantial rate of partially refractory patients (32%). The absolute HAMD-17 remission rates observed here, are higher than those found in 6–8 week placebo-controlled trials with modern SSRIs (25–35%) or SNSRIs (45%) (Beasley et al., 1993; Keller et al., 1998; Thase et al., 2001) The major factor in this respect is the long mean treatment duration of 7.5 weeks (54 days) giving the patient better chances to achieve a positive treatment outcome. Second, individual complex treatment regimens, might in fact yield higher remission rates as in RCTs (Schatzberg et al., 2005). Mean value courses showed significant reduction on HAMD17 and MADRS as early as week 2. After week two a significant decrease from visit to visit still remained. This might point into the direction that the observed improvement could be due to antidepressant treatment effects. Mean MADRS reduction from baseline to endpoint in phase III efficacy trials can e.g. range from 15.9 for Venlafaxine (Bielski et al., 2004) to 13.6 for escitaloprame (Bielski et al., 2004) for example. This is quite comparable with the mean MADRS reduction in the present trial of 17.6. Like STAR*D and other effectiveness trials we have not included a placebo control group. Thus, some patients might have remitted spontaneously. However, the time to spontaneous remission usually ranges between 6 and 12 months (Lavori et al., 1984), which is much longer than the mean length of hospital stay of 7.4 weeks in this sample.

5.2. Comparison to other effectiveness trials Although comparability to effectiveness is better as to RCTs, there still remain considerable sample and study protocol differences, which need to be considered. Concerning sample differences the following factors have been most consistently found to have an effect on outcome: A higher baseline depression severity, a longer index episode and the presence of psychiatric comorbidities like anxiety disorders, personality disorders and alcohol/drug abuse (Bagby et al., 2002). Below we will briefly compare our results with results of two “real world” trials under special consideration of these factors.

353 One trial, quite similar to the present study, investigated prescription patterns on 1202 depressed inpatients in day-today practice (Schneider et al., 2005). Higher remission rates and higher response rates of 76% were observed. With respect to depression severity 20 patients fulfilled remission criteria already at baseline and almost a third of all patients (28%) were mildly depressed at baseline, as compared to 20% of mildly depressed patients in the present study. The authors provided no information about the length of the index episode and reported lower HAMD-21 baseline scores of 22.8 (as compared to 24.8 in our trial) and lower rates of any comorbid anxiety disorder (6% as compared to 11.4% in our trial). Additionally, comorbid personality disorders were found to a lower prevalence rate of 6.3% (as compared to 37.2% diagnosed with SCID II in our trial). Medical comorbidities, which most recently have shown to have negative impact on prognosis, were also less prevalent than in our trial (33.5% vs. 41.6%). One possible underlying reason for the above-named differences might be that about 21.3% of all patients (Schneider et al., 2005) were treated at an universitary site as compared to 72% in our trial. This notion finds also support in our own data where patients from universitary sites presented significantly more often with personality disorders (p = 0.035) and suffered from significant longer index episodes (p = 0.014) than patients in district hospitals. The STAR*D trial is a multisite randomized effectiveness trial on 2876 outpatients with non-psychotic major depressive disorder with up to 5 treatment steps. Looking at the theoretical overall cumulative remission rate (assuming no drop outs) after all 5 treatment steps, STAR*D found a higher Quick Inventory of Depressive Symptoms self-rating version (QUIDS-SR16) remission rate of 67% as compared to 52% in our study (Rush et al., 2006a). On the other side, the time to remission at each single step was 5.4 to 7.4 weeks across all 5 treatment steps and comparable to 5.6 weeks in the present trial. Three major aspects should find consideration in this comparison. First, STAR*D preferentially included a more chronic but maybe less acute (e.g. patients without acute suicidality) patient sample: The degree of depression severity (HAMD-17: 21.8, compared to 22.04) and rates of alcohol abuse 12% (as compared to 11%) were comparable, but more patients with long index episodes 25% N 2 years (as compared to 7.5%) and higher rates of comorbid anxiety disorders (23% generalized anxiety disorder, as compared to 6% in this trial) were included. Personality disorders had not been assessed. Second, the treatment period observed in STAR*D was considerably longer. A cumulative mean treatment duration of 39 weeks across all 5 steps as compared to a mean of length of hospital stay of 7.5 weeks of the present study approximates a fivefold longer mean treatment duration (Rush et al., 2006b). Third, remission rates based on self rated QUIDS tend to be about 15% higher than HAMD17 remission rates (Trivedi et al., 2006). In summary, the STAR*D remission rates might in fact be higher than in the present trial but the absolute rates are hardly comparable due these differences.

5.3. Functional outcome Functional outcome was measured with the GAF. Over the treatment course the mean GAF increased from an average

354 global functioning of almost 47 at baseline to nearly 70 at discharge, which can be described as “having some mild symptoms or some difficulties in social functioning, but generally functioning pretty well”. Remitters (GAF = 62) and non-remitters (GAF = 75) differed significantly with respect to GAF at discharge The results observed here resemble the mean GAF rate of 72 at discharge as observed by Schneider (Schneider et al., 2005). The second measure of functional outcome was Quality of life (QoL) which was assessed with LQLP at baseline. We found in 9 out of 11 LQLP items significant higher Qol scores for remitters vs. non-remitters. The lack of difference in the two items housing situation and work seems likely as inpatient treatment can have only little impact on those two fields.

5.4. Safety Concerning adverse events and safety, the 2 suicides and 10 suicide attempts with non-fatal outcome are comparable to the rate seen in randomized controlled trials. Rate and risk factors for the emergence of suicidal ideation in this sample are described in detail elsewhere (Seemuller et al., 2008). At baseline 49% of all patients and at discharge 57% reported side effects as measured with the UKU. Amongst others this increase might be explained by the 184 drug naive patients at baseline and a more complex/aggressive treatment for those who did not respond during the course of treatment. Taking into account that a substantial number of patients did receive a combination of different medication classes, a rate of 6.2% experiencing side effects to a moderate and 0.3% to a severe degree demonstrates that the drug treatment in general was quite well tolerated. For comparison, in STAR*D based on completion of self ratings about 16.3% reported intolerable side effect at step 1 which went up to 30.1% at step 4 (Rush et al., 2006b).

5.5. Conclusion In summary, the comparability between different effectiveness studies appears to be limited due to substantial differences in baseline characteristics, instruments used and outcome definitions. Therefore, the variance in the different outcomes may be explainable. Nevertheless, absolute numbers of response and remission rates as well as secondary outcome measures like time to response and time to remission are higher than in phase III studies and comparable to other effectiveness studies. The major strength of this study might also be its major limitation. Patients enrolled in this study were seeking treatment in psychiatric university and district hospitals with a high rate of recurrent depressive disorder, axis I and axis II comorbid disorders, psychotic depression and suicidal ideation. Since there were broad inclusion and only few exclusion criteria, patients who would have been excluded in most randomized controlled trials, were included in our study. Therefore, results of this study should be more generalizable to routine clinical practice and exert high external validity. On the other hand internal validity is reduced due to the lack of any control group.

F. Seemüller et al.

Role of the funding source The study was performed within the framework of the German Research Network on Depression, which was funded by the German Federal Ministry for Education and Research BMBF (01GI0219). The BMBF had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors Professor H.-J. Möller designed the study together with Christoph Mundt, Florian Holsboer, Peter Brieger, Gerhard Laux, Wolfram Bender, Mazda Adli, Isabella Heuser, Joachim Zeiler, and Wolfgang Gaebel and wrote the study protocol. Authors Klaus Kronmüller, Florian Holsboer, Peter Brieger, Gerhard Laux, Wolfram Bender, Mazda Adli, Isabella Heuser, Joachim Zeiler, and Wolfgang Gaebel provided the infrastructure for recruitment of all patients. Authors H.-J. Möller, Michael Riedel, Roland Bottländer and Richard Musil carefully supervised and corrected the manuscript drafts. Markus Jäger, Eva Dichgans and Florian Seemüller recruited all patients at the Munich site, maintained and supervised the electronic database. Authors Verena Henkel and Florian Seemüller managed the literature searches and analyses. Michael Obermeier undertook the statistical analysis, and author Florian Seemüller wrote all drafts of the manuscript.

Conflict of interest All authors declare that they have no conflicts of interest. All authors contributed substantially to and have approved the final manuscript.

Acknowledgements The network study was conducted in 12 psychiatric hospitals: Berlin Charite Campus Mitte (Andreas Heinz, Mazda Adli, Katja Wiethoff), Berlin Charité Campus Benjamin Franklin (Isabella Heuser, Gerd Bischof), Berlin Auguste Viktoria Klinik (Joachim Zeiler, Robert Fisher, Cornelia Fähser), Berlin St. Hedwig (Florian Standfest), Berlin St. Joseph (Dorothea Schloth), Düsseldorf (Wolfgang Gaebel, Joachim Cordes, Arian Mobascher), Gabersee (Gerd Laux, Sissi Artmann), Haar (Wolfram Bender, Nicole Theyson), Halle (Andreas Marneros, Dörthe Strube, Yvonne Reinelt), Heidelberg (Christoph Mundt, Klaus Kronmüller, Daniela Victor), München LMU (Hans-Jürgen Möller, Ulrich Hegerl, Roland Mergel, Michael Riedel, Florian Seemüller, Florian Wickelmaier, Markus Jäger, Thomas Baghai, Ingrid Borski, Constanze Schorr, Roland Bottlender), and München MPI (Florian Holsboer, Matthias Majer, Marcus Ising). We thank Miss Thelma Coutts who carefully undertook native speaker language revision of the manuscript.

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