Key words depression - depression treatment - antidepressants
Introduction
A main result of the Sequenced Treatment Alternatives to Relieve Depression (STAR * D) trial [1 ] was that outpatients who initially received monotherapy with citalopram only showed
remission in 28% of the cases. Nevertheless, remission should be the aim of treatment
[2 ]. Consequently failure to primary antidepressant treatment is quite common. However,
strategies for second treatment steps, especially in comparison to each other, have
rarely been investigated [3 ].
There are 4 frequently used pharmacological strategies for treatment of depression
after initial antidepressant monotherapy showed no response: Lithium augmentation,
switch of antidepressants, combination of antidepressants and augmentation with second
generation antipsychotics (SGA). Evidence for the effectiveness of these strategies
varies and there are hardly any data analyzing superiority of one treatment step over
the other [4 ]. Especially empirically evidence for antidepressant switch or antidepressant combination
is poor [5 ]
[6 ]
[7 ]
[8 ]. In contrast, there are more studies showing a better level of evidence for augmentation
strategies with lithium or SGA: Efficacy of lithium-augmentation was shown in a meta-analysis
of 10 studies [9 ]. Odds ratio (OR) for probability of response to lithium was 3.11 compared to placebo
and a number needed to treat (NNT) of 5. Also SGA was found to be a reasonable augmentation
strategy for non-response to antidepressant (AD) monotherapy. In a meta-analysis including
16 studies with 3 480 patients, Nelson and Papakostas (2009) found that augmentation
with 4 SGA (aripiprazole, olanzapine, risperidone, quetiapine) was superior to augmentation
with placebo [10 ]. The OR for response to SGA vs. placebo was 1.69 and an NNT of 9 patients was calculated.
In conclusion, the evidence for differences regarding the efficacy of different pharmacological
treatment strategies after failure to AD monotherapy varies and there are hardly any
competitive investigations of these strategies [11 ]. Therefore further insight not only from RCTs but also from naturalistic trials
of everyday clinical routine are warranted [12 ]. Particularly results gained from trials in clinical practice are required because
the patient population of randomized controlled trials (RCTs) is often found to be
biased [13 ]
[14 ]. However RCTs are the basis of advancing knowledge. Due to the lack of RCTs on this
issue, the aim of this study was to find differences in treatment response after failure
of primary antidepressant monotherapy in a naturalistic design (lithium-augmentation,
antidepressant-combination, switch of antidepressants, augmentation with SGA).
Methods
The study was naturalistic in design and treatment was implemented according to the
special needs of each patient. Treatment was not influenced due to the design of the
study and analyses have been performed post-hoc. Over a period of 2 years all patients
with a unipolar depression were included in the trial. The entry criteria included:
(i) ICD-10 criteria for a major depressive episode or recurrent depression as the
principal current diagnosis, (ii) aged 18 or older, (iii) informed consent from the
patient, (iv) inpatient treatment duration ≥21 days [15 ]. After admission, the diagnosis of a depressive episode was done by the attending
physicians within 3 days according to ICD-10 using the International Diagnostic Checklist
[16 ]. Participants were excluded (i) if they had current severe alcohol or drug dependence
(participants with mild to moderate alcohol or drug dependence were included), (ii)
if they had a previous history of schizophrenia, schizoaffective disorder, bipolar
I disorder (a history of hypomania was permitted), (iii) if the depressive episode
was attributable to organic illness and (iv) if they had such severe concentration
deficits to complete the questionnaires at admission (e. g.), had language difficulties
or did not complete the questionnaires at discharge ([Fig. 1 ]). The study has been conducted in accordance with the current version of the Declaration
of Helsinki and was approved by the local Ethics Committee. Patients were treated
under consideration of the German S3 guideline for treatment of depression [17 ]. All psychiatric drugs, the medication class, the dosage and the treatment duration
were recorded systematically. In addition, the duration and type of other treatments
like psychotherapy, occupational therapy, physical therapy or art therapy were recorded.
Fig. 1 Study protocol and reasons for exclusion.
Assignment
Only patients with an initial antidepressant monotherapy with a duration of 21–35
days (phase I) were analyzed followed by an evaluation of the response to treatment
by the attending clinicians. In 135 cases, patients showed an indication for change
of treatment according to the clinical judgement (no defined measurement). 98 patients
met criteria for assignment to one of the 4 treatment groups (phase II): 1) Lithium-augmentation
(Li-Augm), 2) switch of antidepressants (AD-Switch), 3) combination of antidepressants
(AD-Comb), 4) augmentation with SGA (SGA-Augm). Criteria for enrolment into analysis
were: patients had to have an adequate antidepressant monotherapeutic treatment in
phase I according to duration (21–35 days) and dosage ([Table 1 ], recommendations for doses of antidepressants, doses used in this study). Only experienced
clinicians assigned the patients to the appropriate treatment group according to the
patients’ medical/psychiatric needs. Change of medication was not caused by side effects
of the phase I treatment. There were no other psychotropic drugs in phases I and II
other than the medication of the treatment groups. Treatment in phase II was adequate
in doses and duration. Patients who received a third treatment step due to failure
in phase II were not included in the analysis. To assess the severity of depressive
symptoms, clinician-rated and self-rating instruments were used at admission and at
discharge (t1 and t2). Treatment groups were as heterogeneous as they normally appear
in clinical practice.
Table 1 Antidepressants and dose recommendation.
Dose recommendation according to guideline in mg
Doses used in this study in mg
venlafaxine
75–225
150–300
duloxetine
60
60–120
mirtazapine
15–45
30–45
paroxetine
20–40
20–40
escitalopram
10–20
10–20
fluoxetine
20–40
40–60
clomipramin
100–250
150–225
amitriptyline
100–300
150–250
doxepin
100–300
100–200
sertraline
50–100
100–150
Diagnostic methods
The severity of depressive symptoms was measured using clinician-rated and self-rated
assessment procedure. The Hamilton rating scale for depression (HRSD17 ) was used to assess the severity of depressive symptoms [15 ] and was the primary outcome criterion. It was performed by trained psychologists
who were blinded regarding the treatment arm. Secondary measures included the Beck
depression inventory [18 ] and the Brief symptom inventory (BSI) to assess the patients’ depressive and general
psychological symptoms as means of self-assessment [19 ]. The attending physicians rated the patient’s global level of functioning using
the Global assessment of functioning scale (GAF) [20 ] as well as the global severity of the psychiatric disorder using the Clinical global
impression scale (CGI) [21 ]. The assessment of personality disorders was performed using the structured clinical
interview for DSM-IV personality disorders (SKID II) and was conducted by trained
and experienced clinical psychologists 3 weeks after admission [22 ]. All raters were given training and supervision to perform clinician-rated assessment
procedures (HRSD, CGI, GAF, SKID II).
Statistics
To analyze if patients in the 4 treatment groups were comparable, analysis of variance
followed by post-hoc tests (parametric data) or Kruskall-Wallis test followed by Mann-Whitney
U-test (non-parametric data) for important psychometric characteristics were performed.
Significant differences were added as covariates in the following analyses. The primary
analysis for examining changes over time was a 2×2 ANCOVA with the 2 factors “treatment”
and “time”, controlling for pre-treatment scores (repeated-measure ANCOVA). Afterwards,
post-hoc analyses for differences between treatment groups were performed. All significance
tests were performed at a 2-tailed alpha level of 0.05, incorporating an LSD procedure
for multiple comparisons.
For all tests, effect sizes (ES) for independent random samples were calculated using
Cohen's d statistic and the effect sizes for repeated measures [23 ]. At the end of treatment, the remission rates under the 4 treatment conditions were
compared using 2-sided Pearson’s χ2 tests (remission: HRSD <8) [24 ]. The statistical analyses were carried out using SPSS 17.
Results
A total of 283 patients were screened. 277 patients met the inclusion criteria and
224 patients were enrolled in the study. 135 patients (47.7%) showed no response after
initial antidepressant monotherapy and were therefore assigned to one of the 4 treatment
groups. Another 37 patients (13.1%) were excluded due to polypharmacy, different treatment
strategies or treatment steps after phase II. Therefore 98 patients (34.6%) were included
in the study protocol. [Fig. 1 ] shows the study chart including reasons for drop out. [Table 2 ] displays baseline demographic and illness characteristics for the entire sample.
A severe depressive episode was the principal diagnosis in 43.7% of patients and a
recurring severe depressive episode was diagnosed in 27.6% of all cases using ICD-10.
There were no significant treatment group differences in baseline demographic or illness
characteristics and comorbidities. The average HRSD score on admission was 28.2 (SD =11.1) characterising a patient group with rather severe depressive symptoms. Antidepressant
medication in phase I was similar in the treatment groups ([Table 2 ]). Change of treatment was performed after an average of 27.3 days (SD: 5.7) without
differences between the treatment groups (F=1.27; p=0.28). Characteristics of treatment
in phase II including medication classes are displayed in [Table 3 ] and were also checked for duration and dosage. Again there was no difference between
the treatment groups in terms of duration in phase II (F=1.02, p=0.47). Additionally,
patients took part in occupational therapy (92%, n =206), additional cognitive-behavioural therapy (55.8%, n =125), cognitive-behavioural group therapy for anxiety disorders (17%, n =38), music therapy (25.4%, n =57), progressive muscle relaxation training (17%, n =38), addiction therapy (8%, n =18), physical and sports therapy (81.7%, n =183 ) and dance- and motion therapy (40.2%, n =90).
Table 2 Baseline demographic and sample characteristics of the patients.
Li-Augm
AD-Switch
AD-Comb
SGA-Augm
F/χ2
p
Li-Augm, lithium augmentation; AD-Switch, antidepressant switch; AD-Comb, antidepressant
combination, SGA-Augm, augmentation with second generation antipsychotics; SSRI, selective
serotonin reuptake inhibitors; TCA, tricyclic antidepressants; SNRI, serotonin-norepinephrine
reuptake inhibitors; AD, antidepressants; SD, standard deviation; n, numbers; χ2 chi square
number of patients
28
27
14
29
age in y (SD)
50.76 (13.73)
57.97 (11.06)
50.47 (12.41)
50.89 (11.95)
F=3.0
0.75
range
26–64
26–65
30–68
33–76
female n (%)
17 (60.71)
16 (59.26)
9 (64.3)
18 (62.07)
χ2 =0.06
0.997
education n (%):
apprenticeship
13 (46.4)
11 (40.7)
9 (64.3)
14 (48.3)
graduate degree
15 (53.5)
16 (59.2)
4 (28.5)
14 (48.2)
χ2 =0.59
0.89
other
1 (3.6)
0
1 (7.1)
1 (3.6)
working Situation n (%)
working
12 (42.8)
8 (29.6)
4 (28.5)
9 (31.3)
χ2 =1.42
0.7
unemployed
6 (21.4)
1 (3.7)
5 (35.7)
9 (31.3)
other
10 (36.4)
18 (66.7)
5 (35.7)
11 (37.9)
family status, n (%)
single
3 (10.7)
2 (7.4)
5 (35.7)
9 (31.0)
married
15 (53.5)
15 (55.6)
1 (7.1)
13 (44.8)
χ2 =10.0
0.02
separated
5 (17.9)
3 (28.6)
4 (28.5)
1 (3.6)
divorced
4 (14.3)
5 (18.5)
3 (21.4)
5 (18.5)
widowed
1 (3.6)
2 (7.4)
1 (7.1)
1 (3.6)
comorbidity axis I, n (%)
10 (36.4)
5 (18.5)
6 (42.8)
12 (41.9)
χ2 =8.15
0.06
comorbidity axis II
11 (39.3)
9 (28.0)
4 (28.6)
11 (37.9)
χ2 =6.57
0.08
duration of Treatment, in d (SD)
56.89 (16.85)
50.74 (17.12)
54.36 (14.88)
57.55 (17.37
F=3.0
0.09
duration of treatment in phase I in d (SD)
26.11 (2.07)
28.89 (3.09)
27.93 (2.52)
26.11 (3.07)
F=1.27
0.28
treatment of phase I
SSRI
4 (14.3)
9 (28.0)
8 (27.6)
8 (27.6)
χ2 =0.56
0.91
SSNRI
5 (17.9)
11 (40.7)
9 (64.3)
11 (37.9)
χ2 =0.04
1.0
TCA
3 (10.7)
5 (18.5)
4 (28.5
6 (33.3)
χ2 =0.45
0.36
Mirtazapine
2 (7.4)
4 (14.8)
6 (40.0)
3 (15.3)
χ2 =0.12
0.99
diagnosis
Moderate depressive episode (F 32.1)
0 (0)
3 (28.6)
1 (7.1)
3 (15.3)
Severe depressive episode (F 32.2)
16 (57.1)
15 (55.6)
7 (49.9)
13 (44.8)
Recurrent depressive disorder, current episode moderate (F 33.1)
0 (0)
0 (0)
0 (0)
0 (0)
Recurrent depressive disorder, current episode severe (F 33.2)
12 (42.9)
9 (28.0)
6 (42.8)
10 (35.0)
Table 3 Treatment in phase II.
Li-Augm
AD-Switch
AD-Comb
Atypical-Augm.
Li-Augm, lithium augmentation; AD-Switch, antidepressant switch; AD-Comb, antidepressant
combination, SGA-Augm, augmentation with second generation antipsychotics; SSRI, selective
serotonin reuptake inhibitors; TCA, tricyclic antidepressants; SNRI, serotonin-norepinephrine
reuptake inhibitors; AD, antidepressants; SD, standard deviation; n, numbers
number of patients
27
27
14
28
specific characteristics of strategy:
average lithium level:
0.82 mmol/L
switch-strategy:
n
combination strategy:
n
SGA:
SSRI→SSNRI:
5 (18.5%)
SSRI-SSNRI
3 (21.4%)
amisulpride
3 (10.3%)
SSRI→mirtazapine
2 (7.4%)
SSRI-mirtazapine
1 (7.1%)
aripiprazole
5 (17.2%)
SSNRI→mirtazapine
4 (14.8%)
SSRI-TCA
1 (7.1%)
clozapine
2 (6.9%)
SSNRI→TCA
4 (14.8%)
SSNRI-mirtazapine
3 (21.4%)
olanzapine
7 (24.1%)
SSNR→SSRI
2 (7.4%)
SSNRI-SSRI
2 (14.2%)
quetiapine
7 (24.1%)
TCA→SSNRI
1 (3.7%)
TCA-SSNRI
2 (14.2%)
risperidone
3 (10.3%)
TCA→SSRI
5 (18.5%)
mirtazapine–SSRI
2 (14.2%)
ziprasidone
2 (6.9%)
mirtazapine→SSNRI
3 (11.1%)
mirtazapine→TCA
1 (3.7%)
Treatment effects
Analysis of variance for repeated measures revealed a significant improvement and
large effect sizes for all patients from baseline to discharge in all inventories
(HRSD: F=648, p=<0.001; BDI: F=194.7, p=<0.001; BSI-GSI, F=167.59, p=<0.0). According
to [23 ] effect sizes d for repeated measurements indicate a substantial reduction (d>0.80)
of depressive symptoms (ESHRSD d=3.2, ESBDI =1.9) and general psychological distress (ESBSI-GSI =1.6) during treatment. The interaction effect “time by treatment condition” indicated
a significant difference in the amount of reduction of the depression severity measured
using the HRSD between the 4 treatment groups (HRSD: F=2.84, p=0.04; BDI: F=3.68,
p=0.01; [Table 4 ]). The subsequent post-hoc analyses ([Table 5 ]) revealed a significantly higher improvement for Li-Augm over AD-Switch (mean difference
[MD]: 2.72, p=0.02) and for Li-Augm over AD-Comb (MD=3.45, p=0.02) in the HRSD. Likewise
SGA-Augm showed a significant higher improvement compared to AD-Switch (MD=2.34, p=0.04)
and AD-Comb. (MD=3.07, p=0.03). The BDI score showed similar results: Patients in
the Li-Augm rated a higher improvement of their depressive symptoms compared to AD-Switch
(MD=3.32, p=0.04) and AD-Comb. (MD=6.32, p<0.01). Patients augmented with SGA also
showed a greater reduction in the BDI than patients with AD-Comb (MD=4.03, p=0.04),
but not compared to AD-Switch (MD=1.03, p=0.56). There were no significant differences
between Li-Augm and SGA-Augm in the HRSD or the BDI. Regarding the amount of reduction
in general psychological symptoms (BSI-GSI) significant differences between the treatment
groups could be found (BSI-GSI, F=2.87; p=0.04). Patients with Li-Augm and SGA-Augm
had higher amount of reduction than patients with AD-Comb (Li-Augm: MD=0.44, p<0.01,
SGA-Augm: MD=0.31, p=0.03).
Table 4 Baseline and post-treatment scores.
Interaction factors “treatment vs. time”
Total
Li-Augm
AD-Switch
AD-Comb
SGA-Augm
F (adj.Greenh.-Geisser)
df
p
Li-Augm, lithium augmentation; AD-Switch, antidepressant switch; AD-Comb, antidepressant
combination, SGA-Augm, augmentation with second generation antipsychotics; HAMD, Hamilton
Depression; BDI, Beck Depression Inventory; BSI-GSI, Brief Symptom Inventory-Global
Severity Index; CGI, Clinical Global Impression Scale, GAF, Global Assessment of Functioning;
F values referring to the interaction of the factors “treatment” and “time” in the
2×2 ANCOVA, adjusted via Greenhouse-Geisser, df, degrees of freedom
HAMD
baseline mean (SD)
28.22 (6.83)
27.68 (8.33)
29.04 (6.62)
29.5 (6.47)
27.38 (5.67)
2.84
1
0.04
post-treatment mean (SD)
7.52 (4.61)
5.36 (3.86)
9.44 (4.48)
10.43 (5.54)
6.41 (3.56)
BDI
baseline mean (SD)
28.58 (11.05)
27.25 (11.08)
26.78 (9.02)
31.29 (9.96)
30.24 (13.11)
3.68
1
0.01
post-treatment mean (SD)
11.77 (6.31)
8.11 (5.18)
15.22 (4.91)
16.71 (6.41)
9.69 (5.4)
BSI-GSI
baseline mean (SD)
1.44 (0.63)
1.33 (0.52)
1.34 (0.45)
1.8 (0.5)
1.48 (0.85)
2.87
1
0.04
post-treatment mean (SD)
0.64 (0.41)
0.49 (0.34)
0.71 (0.4)
0.91 (0.52)
0.6 (0.38)
CGI
baseline mean (SD)
5.51 (0.58)
5.41 (0.57)
5.56 (0.64)
5.64 (0.5)
5.48 (0.57)
4.28
1
<0.01
post-treatment mean (SD)
3.06 (0.89)
2.89 (0.75)
3.32 (0.9)
3.85 (0.8)
2.66 (0.77)
GAF
baseline mean (SD)
47.6 (10.1)
46.2 (13.6)
50 (8.8)
43.3 (6.5)
48.3 (8.5)
5.21
1
<0.01
post-treatment mean (SD)
69.6 (10.2)
73.3 (9.2)
64.8 (9.2)
62.3 (10.1)
73.4 (8.6)
Table 5 Post-hoc-tests for 2×2 ANCOVA.
Post-Hoc-Tests
HAMD; p
BDI, p
BSI-GSI, p
CGI, p
GAF, p
ANCOVA, analysis of covariance; Li-Augm, lithium-augmentation; AD-Switch, antidepressant-switch;
AD-Comb, antidepressant-combination, SGA-Augm, augmentation with second generation
antipsychotics; HAMD, Hamilton depression; BDI, Beck depression inventory; BSI-GSI,
brief symptom inventory-global severity index; CGI, clinical global impression scale,
GAF, global assessment of functioning, *, significance on the 0.05 level
Li-Augm vs. AD-Switch
0.02*
0.04*
0.32
0.25
0.25
Li-Augm vs. AD-Comb
0.02*
0.03*
<0.01*
<0.01*
<0.01*
Li-Augm vs. SGA-Augm
0.74
0.20
0.25
0.57
0.54
AD-Switch vs. AD-Comb
0.61
0.18
0.32
0.02*
0.05*
SGA-Augm vs. AD-Switch
0.04*
0.56
0.89
0.08
0.08
SGA-Augm vs. AD-Comb
0.03*
0.04*
0.03*
<0.01*
<0.01*
Remission rates
Comparing the remission rates between the 4 treatment conditions, patients with Li-Augm
showed higher remission rates (89.3%) in the HRSD with a statistical trend (p<0.1)
compared to AD-Switch (40.7%; χ2 =3.07; p=0.08) but not to AD-Comb (AD-Comb: 42.9%; χ2 =1.75, p=0.19). The SGA-Augm-group also had higher remission rates (86.2%) compared
to AD-Switch (χ2 =2.82, p=0.09) but not to AD-Comb (χ2 =1.59, p=0.21). All remission rates are displayed in [Fig. 2 ].
Fig. 2 Remission rates in HAMD and BDI in % comparing phase II patients only.
Global functioning and clinical global impression
Overall functioning improved considerably from baseline to discharge (GAF: F=250.1,
p<0.001, ESpre–post : d=2.3) for all patients. Also there was a significant reduction in general severity
of disorder from intake to discharge (CGI: F=524.2, p<0.001, ESpre–post : d=3.4). The interaction effect “time by treatment condition” indicated significant
differences between treatment conditions regarding the amount of reduction from baseline
to discharge (GAF: F=5.21, p=0.002; CGI: F=4.28, p=0.007; [Table 3 ]). Post-hoc analyses ([Table 4 ]) again revealed a higher gain of functioning (GAF) for the Li-Augm compared to AD-Comb
(MD=0.78, p<0.01). Patients in the SGA-Augm group also had a higher improvement compared
to AD-Switch and AD-Comb (AD-Comb: MD=0.90, p<0.01 [trend]; AD-Switch: MD=0.37, p=0.08).
Improvement in GAF did not differ between Li-Augm and SGA-Augm. Both groups Li-Augm
and SGA-Augm had significantly higher improvement in the CGI compared to AD-Comb (Li-Augm:
MD=0.58, p<0.01; SGA-Augm: MD=0.66, p<0.01) and to AD-Switch (Li-Augm: MD=0.29, p=0.05;
SGA-Augm: MD=0.37, p=0.01).
Safety measurements and compliance
Adverse events reported by the patients were recorded. Somatic complaints were assessed
and recorded.
There was no relevant difference between the groups in the percentage of patients
in the safety set who reported at least one emergent adverse event on treatment (51%).
There were no deaths during the study and no suicide attempts. The most frequently
affected systemic organ classes were gastrointestinal disorders (18.4%) and nervous
system disorders (20.5%). The most frequent emergent adverse events were headache,
nausea, and somnolence.
Discussion
The present study investigated differences in treatment outcome between 4 different
pharmacological treatment strategies after failure of the primary antidepressant monotherapy.
In this naturalistic design, 60% of the depressive patients failed to show remission
after primary treatment. This number is lower compared to the the STAR*D trial, where
72% of patients failed to reach remission after citalopram monotherapy in treatment
step one (1). Contrary to the STAR*D study, which only included outpatients, the present
study only included inpatients. Nevertheless, overall results are comparable to those
of other “effectiveness” studies investigating the quality of inpatient treatment
of depression. In a multicenter trial of the German Research Network on Depression
investigating suicidality in 1 014 patients, response rates of 68.9% and remission
rates of 51.9% in the HRSD could be achieved [25 ].
The second treatment step showed different response and remission rates depending
on the treatment group. Generally, all patients showed relatively high response rates
after treatment in step 2 (remission rate in HRDS: 30%). Compared to the second treatment
step in the STAR*D study, (remission rate 25%), remission rates of the present study
were to some extent higher. Possible explanations are the multiprofessional treatment
approach including high additional effords such as psychotherapy, occupational therapy
or physical therapy in the current study. However, comparing only the treatment step
2 of STAR*D (AD-Switch or -combination) with the corresponding treatment groups of
the present study, remission rates do approach comparable numbers (remission rate
[HRSD]: AD-comb: 42.9%; AD-Switch: 40.7%).
Focussing on the differences between the 4 treatment groups in step 2, it is notable
that patients who received a non-antidepressant as the second step (lithium or SGAs)
had lower depressive symptoms than subjects who received continued treatment with
antidepressants (switch or combination). The good outcome of the lithium augmented
patients is in line with empirical evidence for this treatment approach [9 ].
Also augmentation with SGA showed lower scores of depressive symptoms compared to
AD-Switch and AD-Comb. Response rates were relatively high compared to previous studies.
Bauer et al. (2009) found response rates of 55% for augmentation after non-response
to antidepressant monotherapy [26 ]. For antidepressant augmentation with aripiprazole [27 ] and olanzapine [28 ], response rates were 33.7% and 25%, respectively. In the meta-analysis of Nelson
and Papakostas (2009) overall efficacy of augmentation with SGA in treatment-resistant
depression has been proven and is in line with the data of our naturalistic study.
There has been a lot of research regarding possible antidepressant effects of SGA
focusing on the multiple effects of those substances on different neurotransmitters
and their second messengers.
The mediocre outcome of switching the antidepressant in this naturalistic study is
in line with recent findings of RCTs showing that there is no evidence supporting
this strategy [5 ]. Instead there are data suggesting inferiority of continuing the hitherto not effective
antidepressant [8 ]. Also AD-Comb was part of the second step of STAR*D: The combination included citalopram
and bupropion with remission rates of 30%. But RCTs only found superiority for reuptake-inhibitors
in combination with alpha-2-antagonists compared to placebo [29 ]
[30 ].
In summary, although AD-Switch and AD-Comb show moderate remission rates in the present
study, they might produce lower improvement and lower remission rates compared to
Li-Augm or augmentation with SGAs. As noticed before, a possible reason for this is
the relatively similar way of functioning of ADs, increasing the levels of serotonin
and/or norepinephrine in the synaptic cleft (with few exceptions). However, antidepressant
agents differ in the mode of action and specificity of increasing neurotransmitters.
A possible conclusion could be that patients who do not respond to substances with
this mode of functioning do have a higher benefit with medications of a different
mode of action. Possible explanations of superiority of Li-Augm compared to AD-Switch
or AD-Comb include the diversity of pharmacological functioning: Lithium influences
the neurotransmitter-system on the level of second messengers and gene-regulation
[31 ]. Previous research has also focused on possible antidepressant effects of SGAs particularly
on the multiple effects of those substances on different neurotransmitters and their
second messengers. For example, aripiprazole has a partial dopamine receptor agonism
and quetiapine an additional norepiphrenin-reuptake-inhibition, which both are relevant
in other antidepressant substances [32 ]
[33 ]. In contrast, AD just have impact on extracellular receptors with a minor influence
on multiple neurotransmitters.
Conclusion
This naturalistic study confirmed that lithium augmentation as well as augmentation
with SGA each showed better outcome than AD-Switch and AD-Comb. Possible reasons are
the diversity of functioning compared to the homologous effects in the group of antidepressants.
However, there is nevertheless the risk of additional side effects of these 2 medication
groups. Lithium treatment should be conducted in line with the established safety
procedures. SGA and their effect on metabolic function as well as tardive dyskinesias
are present and are criticized as underestimated [34 ]. Especially for the group of SGA the costs of medication should be taken into account.
Therefore different treatment options, for example, additional psychotherapy or ECT
[35 ]
[36 ] should be considered. In conclusion, this study indicates differences between treatment
strategies after failure of primary treatment in unipolar depression. RCTs are absolutely
necessary to confirm these findings.
Limitations
Despite the statistical control for influencing variables (medication, psychosocial
factors, additional therapies, duration of treatment), the naturalistic design (no
randomization to treatment groups) of the study can be regarded as a shortcoming and
could influence the results. The lack of a defined measurement of non-response after
phase I is also a major limitation. Therefore it is possible that not all patients
really did show non-response to primary treatment. Furthermore the heterogeneous treatment
in phase I could have had an influence on treatment outcome. Phase II was heterogeneous
in treatment as well (different SGAs, different switch strategies, different AD combinations).
Pharmacological differences of ADs were not fully considered in the question of the
AD-comb or AD-switch. Therefore inferiority of those strategies could have been influenced
by irrational switching or combination strategies. However, there is low evidence
of efficacy of switching [5 ] or combination strategies [7 ] at all, and especially with regard to certain combinations or switching sequences. Another relevant aspect is that measurement at t2 was at discharge and not on a predefined
time point. Although there were no significant differences of treatment duration between
the 4 treatment arms, this could have had an influence on the results. In general
it should be mentioned that there was no placebo group. Both groups with augmentation
strategies received prolonged treatment with one antidepressant. It cannot be excluded
that patients in these groups had lower depressive symptoms mainly because of prolonged
exposure to the antidepressants. In conclusion, there is the possibility that treatment
groups are not comparable. In further research there also should be an arm that continues
the last treatment to observe effects of longer treatment and of spontaneous response.
Therefore, the results in this naturalistic study indicate differences between these
treatment strategies but all significant associations must be viewed with caution.
Nevertheless, the present study is the first study that compared different pharmacological
treatment options after failure of primary antidepressant monotherapy with each other.
Despite the methodological limitations mentioned, this study under naturalistic condition
is an important completion to findings from randomised and controlled studies [37 ]
[38 ]. Either way, controlled studies, e. g., with randomization are required to confirm
the findings from this study.
