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Components and trends in treatment effects in randomized placebo-controlled trials in major depressive disorder from 1979–2016.

Authors:
Diane Stephenson1, Theresa Mullin2,Eric Bastings2, Billy Dunn2, Susanne Goldstein2,Gerald Podskalny2
1Critical PathInstitute, Tucson, AZ;2U.S. Food and Drug Administration (FDA), SilverSpring,MD
Net Treatment Effect by Drug
Interaction of Age and Severity
.Background and Objectives Time Trend Analysis
Disclaimer: The views and opinions presented here represent those of the authors and should not be considered to represent advice or guidance on behalf of the U.S. Food and Drug Administration.
Antidepressants are currently a standard treatment for major depressive
disorder, supported by comparisons to placebo treatment under blinded
conditions in randomized controlled trials (RCTs). Fifteen years following the
advent of several new antidepressants in the mid‐1980s, it became evident
that the “success” rate of antidepressant clinical trials was low; less than 50%
of trials demonstrated statistical superiority for antidepressants over placebo.
Following several findings of a rising placebo response, it was assumed that
the clinical trial failure rate was related to this phenomena. Furthermore,
limited analysis exists regarding changes in antidepressant effect over time.
Objective:
The aim of this exploratory analysis is to longitudinally describe changes in
placebo and treatment response. Impact on response by baseline
predictors such as baseline depression severity, gender, and age will also
be evaluated.
Components and Trends in Treatment Effects in Randomized
Placebo-controlled Trials in Major Depressive Disorder from 1979-2016
Methods
Marc Stone1, Shamir Kalaria2, Kyle Richardville3, Brian Miller4
1Division of Psychiatry Products, Office of New Drugs, CDER, US Food and Drug Administration
2University of Maryland School of Pharmacy 3University of North Carolina School of Medicine 4Georgetown University School of Medicine
Study Population:
The Division of Psychiatry Products at FDA has constructed a database of
all randomized placebo-controlled trials of antidepressants in the
treatment of Major Depressive Disorder submitted between 1979 and
2016.
228 studies were included in the analysis with a total of 22 different
antidepressants and 73,178 patients
MDD Severity Equivalents and Score Conversion:
Impact of Patient Characteristics on Effect
Conclusion and Potential Considerations
33.7%
Placebo
(N=24,661) 66.3%
Anti-
Depressant
(N=48,517)
Figure 1: Pooled distribution of
patients from selected
randomized controlled trials
24.5
16.2
13.8
22.2
13.9
12.3
15
20
25
10
MDD Severity
1980 1985 1990 1995 2000 2005 2010 2015
year
Placebo Drug Baseline Severity
Scaled to HAMD17
Baseline Severity and Treatment Effects over Time
Figure 2: Change in Baseline
Severity, Placebo Effect and
Treatment Effect over Time
-7
-8
-9
-10
Change in MDD Severity (scaled to HAMD17)
10 20 30 40 50 60 70 80
age
Male Placebo Male Drug
Female Placebo Female Drug
Treatment Effect by Age and Sex
-5
-10
0
-15
Change in MDD Severity
10 20 30 40
Baseline MDD Severity
Placebo Drug
Scaled to HAMD17
Treatment Effect and Baseline Severity
-1.79 (-2.02, -1.55)
-2.89 (-3.61, -2.17)
-1.58 (-2.69, -0.48)
-2.08 (-2.51, -1.65)
-1.62 (-2.00, -1.25)
-1.79 (-2.25, -1.33)
-1.69 (-1.98, -1.40)
-1.95 (-2.62, -1.28)
-1.49 (-1.86, -1.11)
-0.79 (-1.55, -0.03)
-0.92 (-2.55, 0.71)
-1.94 (-2.28, -1.60)
-1.52 (-1.97, -1.06)
-1.51 (-1.89, -1.14)
-1.76 (-2.23, -1.29)
-2.01 (-2.61, -1.42)
-1.23 (-1.72, -0.75)
ES (95% CI)
-0.77 (-2.56, 1.02)
-1.87 (-2.22, -1.51)
-0.80 (-1.35, -0.25)
-2.13 (-2.46, -1.80)
-3.00 (-3.32, -2.68)
-3.30 (-4.77, -1.83)
-1.79 (-2.02, -1.55)
-2.89 (-3.61, -2.17)
-1.58 (-2.69, -0.48)
-2.08 (-2.51, -1.65)
-1.62 (-2.00, -1.25)
-1.79 (-2.25, -1.33)
-1.69 (-1.98, -1.40)
-1.95 (-2.62, -1.28)
-1.49 (-1.86, -1.11)
-0.79 (-1.55, -0.03)
-0.92 (-2.55, 0.71)
-1.94 (-2.28, -1.60)
-1.52 (-1.97, -1.06)
-1.51 (-1.89, -1.14)
-1.76 (-2.23, -1.29)
-2.01 (-2.61, -1.42)
-1.23 (-1.72, -0.75)
ES (95% CI)
-0.77 (-2.56, 1.02)
-1.87 (-2.22, -1.51)
-0.80 (-1.35, -0.25)
-2.13 (-2.46, -1.80)
-3.00 (-3.32, -2.68)
-3.30 (-4.77, -1.83)
-5 -4 -3 -2 -1 0
Net Change in MDD Severity over Placebo (Scaled to HAMD17)
Adjusted for Age, Sex and Baseline Severity
Net Treatment Effect by Drug
Figure 3: Changes in Placebo and
Treatment Effect by Age and Sex
Figure 4: Influence of Baseline
Severity on Response
15
20
25
30
Baseline MDD Severity
10 20 30 40 50 60 70 80
age
-14
-12
-10
-8
-6
-4
Change in Severity
Scaled to HAMD17
Response to Placebo by Age and Baseline Severity
15
20
25
30
Baseline MDD Severity
10 20 30 40 50 60 70 80
age
-15
-10
-5
0
Change in Severity
Scaled to HAMD17
Response to Drug by Age and Baseline Severity
15
20
25
30
Baseline MDD Severity
10 20 30 40 50 60 70 80
age
-3
-2
-1
0
Difference between Drug and Placebo
Scaled to HAMD17
Net Drug Effect over Placebo by Age and Baseline Severity
-5 50-10-15-20-25 Treatment Effect
placebo drug
Scaled to HAMD17
Distribution of Treatment Outcomes in MDD
0
.2
.4
.6
.8
1
.5
Proportion of Subjetcs
0-3-6-9-12-15-18-21-24 3 6
Threshold for Change in MDD Severity (Scaled to HAMD17)
Placebo Drug
Cumulative Distribution
Treatment Effect on MDD Severity
Baseline severity averaged the
equivalent of 23.0 points on
the HAMD17 scale but has
declined by 2.3 points from
1979-2016. Placebo response
showed little change over time
averaging 8.3 points. Net drug
effect over placebo controlled
for age and baseline severity
has averaged 1.8 points but has
declined from 2.4 points to 1.6
points
Women appeared to have a
greater net effect from active
treatment, perhaps due to a
larger average dosage relative
to weight. Placebo response
diminished with increasing age
and observed response with
active treatment was less in
older subjects. The greatest
improvement relative to
placebo was in subjects aged
35 to 60
Treatment response was
influenced by baseline severity,
with an average equivalent
improvement of 2.4 points in
subjects with a baseline
severity of 30 points and 1.1
points in subjects with baseline
severity of 17 points.
Both drug and placebo responses showed evidence
of bimodal distribution with a majority of patients
suggesting an improvement in scaled HAMD17
scores. Significant overlap between distributions
indication reduced net drug effect.
Approximately, 50% of drug subjects and
40% of placebo subjects showing
improvements of nine points or more. 50%
of subjects on placebo showed an
improvement of 6 points or more. This
indicates median drug treatment effect of
3 points.
Figure 7: Influence of Age and Baseline Severity
on Placebo Response
Figure 8: Influence of Age and Baseline Severity
on Drug Response
Figure 8: Influence of Age and Baseline Severity
on Net Drug Effect
Figure 5: Distribution of placebo and drug
response in Scaled HAMD17 scores
Figure 6: Distribution of placebo and drug
response in Scaled HAMD17 scores
Scale
Random Effects Mean Severity
-Study Standard Deviation
HAMD17
23.0 3.7
BPI
4.7 1.6
CDRS
59.3 9.9
COGNI
22.9 7.0
HAMD21
26.1 4.1
HAMD24
30.2 5.1
HAMD28
31.1 5.1
HAMDP
52.6 20.7
IDS
46.0 9.2
MADRS
30.7 4.4
Statistical Analysis
Multivariate mixed effects regression model was used to predict drug
response, placebo response, and net drug effect
Baseline score, treatment group, gender, gender-treatment interaction,
age, and age-treatment interaction were used as covariates to predict
response
On average, a net drug effect of 2 points in MDD severity over placebo was observed across 22 different antidepressants
after adjusting for age, sex, and baseline severity. Differences among drugs were modest but statistically significant,
possibly due to differences in trial characteristics
Patients with a higher baseline severity were found to have a larger
placebo and drug response
Net drug effect was highest in patients 35-60 years old
Female patients experienced greater drug response than males
Potential predictors of placebo and drug response can assist in informing
future clinical trials for MDD
... The findings suggest that patients whose onset of depression is very new may not be suitable to antidepressant treatment because they respond similarly to antidepressants and placebo. Sex was recently shown to be an effect modifier in a large individual participant data meta-analysis of antidepressants (228 studies examining 22 different antidepressants, 73,178 patients): women tended to show greater superiority of antidepressants over placebo than men [35]. Our results are in line with this finding: among those whose onset of illness was within a year of treatment commencement, men responded worse to antidepressants than to placebo, while women responded equally to antidepressants and placebo. ...
... Second, because the aim of personalised medicine is to identify the right treatment from among the available alternatives, differential therapeutics among the active medications would have been more clinically useful. However, in this study we were interested in knowing which patients would be more suitable for antidepressant pharmacotherapy and also to identify currently unmet needs by delineating subgroups of patients unresponsive to drugs, as have been done in the large analyses referenced above which all pooled various trials using various drugs [1,35]. Moreover, QUINT can presently only examine interactions for two alternative treatments. ...
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Background Personalized medicine in depression has been much discussed but has seen little success so far. We applied Qualitative interaction trees (QUINT), a recently developed method that focuses on qualitative, rather than quantitative, treatment-subgroup interactions, to identify subgroups of patients for whom efficacy of antidepressants may vary. Methods We had direct access to four placebo-controlled randomized trials of antidepressants and remote access to three trials. We applied QUINT to the first half of the first four trials (the derivation set, n = 704). We used 15 baseline demographic or clinical variables as candidate effect modifiers. We then tested the temporal validity of the obtained subgroups with the second half of the first four trials (the temporal validation set, n = 778), and their external validity with the remaining three trials (the external validation set, n = 1321). Results “Years since onset” and “Sex” were retained in the final model. The antidepressants were significantly inferior to placebo among men with recent onset of depression, not significantly so among women with recent onset, but was significantly superior among men and women whose onset of depression was one or more years before treatment commencement. The ordering of the subgroups in terms of antidepressant efficacy was replicated in the temporal validation set but was poorly replicated in the external validation set. Conclusion Time since illness onset and sex may be important effect modifiers. However, the models need external validation. To advance personalized medicine in psychiatry, concerted efforts are called for to obtain larger datasets with common key measurements.
... It is also assumed that antidepressant drugs work better for more severe depression. 56 The inclusion of these studies might therefore have resulted in an overestimation of the effects of pharmacotherapy in the present NMA. ...
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Purpose: Most patients with depression are treated by general practitioners, and most of those patients prefer psychotherapy over pharmacotherapy. No network meta-analyses have examined the effects of psychotherapy compared with pharmacotherapy, combined treatment, care as usual, and other control conditions among patients in primary care. Methods: We conducted systematic searches of bibliographic databases to identify randomized trials comparing psychotherapy with pharmacotherapy, combined treatment, care as usual, waitlist, and pill placebo. The main outcome was treatment response (50% improvement of depressive symptoms from baseline to end point). Results: A total of 58 studies with 9,301 patients were included. Both psychotherapy and pharmacotherapy were significantly more effective than care as usual (relative risk [RR] for response = 1.60; 95% CI, 1.40-1.83 and RR = 1.65; 95% CI, 1.35-2.03, respectively) and waitlist (RR = 2.35; 95% CI, 1.57-3.51 and RR = 2.43; 95% CI, 1.57-3.74, respectively) control groups. We found no significant differences between psychotherapy and pharmacotherapy (RR = 1.03; 95% CI, 0.88-1.22). The effects were significantly greater for combined treatment compared with psychotherapy alone (RR = 1.35; 95% CI, 1.00-1.81). The difference between combined treatment and pharmacotherapy became significant when limited to studies with low risk of bias and studies limited to cognitive behavior therapy. Conclusions: Psychotherapy is likely effective for the treatment of depression when compared with care as usual or waitlist, with effects comparable to those of pharmacotherapy. Combined treatment might be better than either psychotherapy or pharmacotherapy alone.
... Thus, we examined whether responses in groups of participants whose symptoms were initially more severe would be more variable because the effects of antidepressants may be more pronounced in individuals with severe depression. 22,23 We also expected that variability might differ based on the way that different antidepressant classes interact with different neurotransmitter systems. Specifically, antidepressants affecting multiple neurotransmitter systems might produce more variable outcomes than would antidepressants with more selective effects. ...
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Importance: Antidepressants are commonly used to treat major depressive disorder (MDD). Antidepressant outcomes can vary based on individual differences; however, it is unclear whether specific factors determine this variability or whether it is at random. Objective: To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether variability is associated with MDD severity, antidepressant class, or study publication year. Data sources: Data used were updated from a network meta-analysis of treatment with licensed antidepressants in adults with MDD. The Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycInfo were searched from inception to March 21, 2019. Additional sources were international trial registries and sponsors, drug companies and regulatory agencies' websites, and reference lists of published articles. Data were analyzed between June 8, 2020, and June 13, 2020. Study selection: Analysis was restricted to double-blind, randomized placebo-controlled trials with depression scores available at the study's end point. Data extraction and synthesis: Baseline means, number of participants, end point means and SDs of total depression scores, antidepressant type, and publication year were extracted. Main outcomes and measures: Log SDs (bln σ̂) were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference in bln σ̂ between treatment groups while controlling for end point mean. Secondary models determined whether differences in variability between groups were associated with baseline MDD severity; antidepressant class (selective serotonin reuptake inhibitors and other related drugs; serotonin and norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; noradrenergic agents; or other antidepressants); and publication year. Results: In the 91 eligible trials (18 965 participants), variability in response did not differ significantly between antidepressants and placebo (bln σ̂, 1.02; 95% CI, 0.99-1.05; P = .19). This finding is consistent with a range of treatment effect SDs (up to 16.10), depending on the association between the antidepressant and placebo effects. Variability was not associated with baseline MDD severity or publication year. Responses to noradrenergic agents were 11% more variable than responses to selective serotonin reuptake inhibitors (bln σ̂, 1.11; 95% CI, 1.01-1.21; P = .02). Conclusions and relevance: Although this study cannot rule out the possibility of treatment effect heterogeneity, it does not provide empirical support for personalizing antidepressant treatment based solely on total depression scores. Future studies should explore whether individual symptom scores or biomarkers are associated with variability in response to antidepressants.
... An antidepressant was originally recommended as the initial treatment for patients with moderate to severe depression by several guidelines (8,11,12,24), whereas APA guideline recommends antidepressant as the first-line treatment also for mild patients (10,25). Two individual participant data metaanalysis (26,27) indicated that patients with lower baseline severity would achieve smaller improvement compared to placebo. However, a more recent study (28) found that the differential response of patients with different severity was due to larger improvement on non-core symptoms, and that baseline severity did not affect the efficacy for core depression symptoms. ...
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