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

Authors:
Marc Stone at U.S. Food and Drug Administration
Marc Stone
Shamir N. Kalaria at U.S. Food and Drug Administration
Shamir N. Kalaria
Kyle Richardville
Kyle Richardville
Kyle Richardville
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Brian J. Miller
Brian J. Miller
Brian J. Miller
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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
Within
-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. ...
Qualitative treatment-subgroup interactions in the antidepressant treatment of major depression: Application of QUINT to individual participant data from seven placebo-controlled randomized controlled trials
Article
  • Jan 2020
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.
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... Regarding baseline depression, our findings are in line with work reporting treatment effects to increase with symptom severity for antidepressants (Stone, Kalaria, Richardville, & Miller, 2018), psychotherapy (Driessen, Cuijpers, Hollon, & Dekker, 2010), and the addition of the cognitive behavioral analysis system of psychotherapy to antidepressants (Furukawa et al., 2018). Thus, Note. ...
Which patients benefit from adding short-term psychodynamic psychotherapy to antidepressants in the treatment of depression? A systematic review and meta-analysis of individual participant data
Article
Full-text available
  • Nov 2022
Background Adding short-term psychodynamic psychotherapy (STPP) to antidepressants increases treatment efficacy, but it is unclear which patients benefit specifically. This study examined efficacy moderators of combined treatment (STPP + antidepressants) v. antidepressants for adults with depression. Methods For this systematic review and meta-analysis (PROSPERO registration number: CRD42017056029), we searched PubMed, PsycINFO, Embase.com, and the Cochrane Library from inception to 1 January 2022. We included randomized clinical trials comparing combined treatment (antidepressants + individual outpatient STPP) v. antidepressants in the acute-phase treatment of depression in adults. Individual participant data were requested and analyzed combinedly using mixed-effects models (adding Cochrane risk of bias items as covariates) and an exploratory machine learning technique. The primary outcome was post-treatment depression symptom level. Results Data were obtained for all seven trials identified (100%, n = 482, combined: n = 238, antidepressants: n = 244). Adding STPP to antidepressants was more efficacious for patients with high rather than low baseline depression levels [ B = −0.49, 95% confidence interval (CI) −0.61 to −0.37, p < 0.0001] and for patients with a depressive episode duration of >2 years rather than <1 year ( B = −0.68, 95% CI −1.31 to −0.05, p = 0.03) and than 1–2 years ( B = −0.86, 95% CI −1.66 to −0.06, p = 0.04). Heterogeneity was low. Effects were replicated in analyses controlling for risk of bias. Conclusions To our knowledge, this is the first study that examines moderators across trials assessing the addition of STPP to antidepressants. These findings need validation but suggest that depression severity and episode duration are factors to consider when adding STPP to antidepressants and might contribute to personalizing treatment selection for depression.
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... 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. ...
Psychologic Treatment of Depression Compared With Pharmacotherapy and Combined Treatment in Primary Care: A Network Meta-Analysis
Article
  • May 2021
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.
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... 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. ...
Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials
Article
  • Feb 2021
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.
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... 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. ...
Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials
Article
  • Feb 2020
Importance Antidepressants are commonly used worldwide to treat major depressive disorder. Symptomatic response to antidepressants can vary depending on differences between individuals; however, this variability may reflect nonspecific or random factors. Objectives To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether this variability is associated with severity of major depressive disorder, antidepressant class, or year of study publication. Data Sources Data used were from a recent network meta-analysis of acute treatment with licensed antidepressants in adults with major depressive disorder. The following databases were searched from inception to January 8, 2016: the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycINFO. Additional sources were international trial registries, drug approval agency websites, and key scientific journals. Study Selection Analysis was restricted to double-blind, randomized placebo-controlled trials with available data at the study’s end point. Data Extraction and Synthesis Baseline and end point means, SDs, number of participants in each group, antidepressant class, and publication year were extracted. The data were analyzed between August 14 and November 18, 2019. Main Outcomes and Measures With the use of validated methods, coefficients of variation were derived for antidepressants and placebo, and their ratios were calculated to compare outcome variability between antidepressant and placebo. Ratios were entered into a random-effects model, with the expectation that response to antidepressants would be more variable than response to placebo. Analysis was repeated after stratifying by baseline severity of depression, antidepressant class (selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone; serotonin and norepinephrine reuptake inhibitors: desvenlafaxine and venlafaxine; norepinephrine-dopamine reuptake inhibitor: bupropion; noradrenergic agents: amitriptyline and reboxetine; and other antidepressants: agomelatine, mirtazapine, and trazodone), and publication year. Results In the 87 eligible randomized placebo-controlled trials (17 540 unique participants), there was significantly more variability in response to antidepressants than to placebo (coefficients of variation ratio, 1.14; 95% CI, 1.11-1.17; P < .001). Baseline severity of depression did not moderate variability in response to antidepressants. Variability in response to selective serotonin reuptake inhibitors was lower than variability in response to noradrenergic agents (coefficients of variation ratio, 0.88; 95% CI, 0.80-0.97; P = .01), as was the variability in response to other antidepressants compared with noradrenergic agents (coefficients of variation ratio, 0.87; 95% CI, 0.79-0.97; P = .001). Variability also tended to be lower in studies that were published more recently, with coefficients of variation changing by a value of 0.005 (95% CI, 0.002-0.008; P = .003) for every year a study is more recent. Conclusions and Relevance Individual differences may be systematically associated with responses to antidepressants in major depressive disorder beyond placebo effects or statistical factors. This study provides empirical support for identifying moderators and personalizing antidepressant treatment.
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... 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. ...
National Prescription Patterns of Antidepressants in the Treatment of Adults With Major Depression in the US Between 1996 and 2015: A Population Representative Survey Based Analysis
Article
Full-text available
  • Feb 2020
Few studies have delineated the real-world, long-term trends of prescription patterns of antidepressants for patients with major depressive disorder (MDD). This study aims to describe their vicissitudes in the nationally representative sample of the US from 1996 to 2015 and explore their characteristics. We used the Medical Expenditure Panel Survey, a nationally representative database of the US population, between 1996 and 2015. We estimated the prevalence of MDD among adults, calculated the proportions of those on antidepressant treatment as well as those on specific drugs through the two decades, and determined their dosages in 2015. We conducted multivariable regression to find possible factors related to their suboptimal prescriptions. The prevalence of adults diagnosed with MDD increased from 6.1% (95% CI, 5.7–6.6%) in 1996 to 10.4% (9.7–11.1%) in 2015. The proportion of patients without any antidepressant therapy decreased but still accounted for 30.6% (28.3–33.1%) in 2015. Sertraline and fluoxetine were among the most frequently prescribed antidepressants throughout the 20 years, while the trend for some new drugs changed dramatically. 16.1% (12.5–20.2%) of patients of MDD on antidepressant monotherapy were prescribed with suboptimal doses in 2015; the risk was lower for those who had higher Body Mass Index (OR 0.94 [0.90–0.99]), longer-term prescriptions (OR 0.92 [0.87–0.97]), and the risk was higher for those who were prescribed with tricyclic antidepressants (OR 11.21 [2.12–59.34], compared with serotonin reuptake inhibitors (SSRIs)), and antidepressants other than SSRIs and serotonin and norepinephrine reuptake inhibitors (OR 4.12 [1.95, 8.73], compared with SSRIs). This study confirmed the growing numbers of patients with MDD and the increase in the antidepressant prescriptions among them. However, the existence of patients without any antidepressant prescriptions or with suboptimal prescriptions and the variable prescription patterns through the decades might suggest some unresolved gaps between evidence and practice.
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Irving Kirsch opens a window on antidepressant medications
Article
  • Jan 2023
  • Am J Clin Hypn
When it comes to antidepressant medications - popular, backbone drugs of modern psychiatry - even learned scholars and savvy clinicians find it difficult to separate honest, rigorous research from that which thrives on hidden agendas and ulterior motives. Fortunately, a mounting corpus of data-based studies, mostly meta-analyses, casts new and critical light on the clinical efficacy, side effects, and therapeutic outcomes of antidepressants. Spearheading these efforts over the past few decades, Irving Kirsch and colleagues have challenged the hegemonic view of antidepressants as an effective therapeutic intervention. Notably, Kirsch illuminates the small difference between antidepressants and placebos in mitigating depression-a difference that may be statistically significant yet fails to reach clinical significance. This piece sketches the important contributions Kirsch has made to the scientific understanding of antidepressant medications.
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Placebo Effect in the Treatment of Depression and Anxiety
Article
Full-text available
  • Jun 2019
The aim of this review is to evaluate the placebo effect in the treatment of anxiety and depression. Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin or norepinephrine in the brain. However, analyses of the published and the unpublished clinical trial data are consistent in showing that most (if not all) of the benefits of antidepressants in the treatment of depression and anxiety are due to the placebo response, and the difference in improvement between drug and placebo is not clinically meaningful and may be due to breaking blind by both patients and clinicians. Although this conclusion has been the subject of intense controversy, the current article indicates that the data from all of the published meta-analyses report the same results. This is also true of recent meta-analysis of all of the antidepressant data submitted to the Food and Drug Administration (FDA) in the process of seeking drug approval. Also, contrary to previously published results, the new FDA analysis reveals that the placebo response has not increased over time. Other treatments (e.g., psychotherapy and physical exercise) produce the same benefits as antidepressants and do so without the side effects and health risks of the active drugs. Psychotherapy and placebo treatments also show a lower relapse rate than that reported for antidepressant medication.
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