Reanalysis of paroxetine and imipramine Use in Adolescence for the Treatment of Major Depression

Sara Griffin, Mercer University College of Pharmacy

Major depression is defined as a unipolar depression characterized by a combination of symptoms that interfere with daily activities (i.e. work, study, and sleep). While only one episode of major depression may occur during one’s life, it more commonly reoccurs throughout one’s life. In order to receive appropriate treatment, one must first visit a physician to rule out potential causes of depressive symptoms (i.e. medications or medical conditions). Psychotherapy and medication are common treatments for depressive disorders in adolescents. Selective serotonin reuptake inhibitors (SSRIs) are noted to be the most popular antidepressant medications used in treatment. 1

Per the National Institute of Mental Health (NIMH), major depression is one of the most common mental disorders in the United States (U.S.) and in 2013 estimated that 10.7% of the U.S. population, ages 12 to 17 years had at least one major depressive within the last year. 2

An initiative called “restoring invisible and abandoned trials” (RIAT) began in 2013 due to the selective reporting of outcomes in randomized controlled trials. Researchers identify trials requiring restoration and contacted the funders to ask for them to publish corrected versions of misreported trials or to signal their intention to publish an unpublished (abandoned) trial. 3 The study below represents a RIAT publication of Study 329. 4

Title: Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence 5
Design Randomised, double-blind, placebo-controlled trial; N = 275
Objective To see whether access to and reanalysis of a full dataset from a randomized controlled trial would have clinically relevant implications for evidence-based medicine
Study Groups Paroxetine (20-40 mg; n = 93), imipramine (200-300 mg; n = 95), or placebo (n = 87)
Methods Reanalysis of the data from Study 329 according to the restoring invisible and abandoned trials (RIAT) recommendations
Duration 8 weeks: acute phase; 6 month: continuation phase
Primary Outcome Measure The change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤ 8 or ≥ 50% reduction in baseline HAM-D) at acute endpoint.
Baseline Characteristics Adolescents with major depression of at least 8 weeks duration; Age (range, years): 12 to 18
Baseline characteristics of groups in Study 329
Paroxetine Imipramine Placebo
Mean (SD) age (years) 14.8 (1.6) 14.9 (1.6) 15.1 (1.6)
Sex (male/female) 35/58 39/56 30/57
No. (%) by race

-White

-African American

-Asian American

-Other

77 (83)

5 (5)

1 (1)

10 (11)

83 (87)

3 (3)

2 (2)

7 (7)

70 (81)

6 (7)

2 (2)

9 (10)

HAM-D (SEM) 18.9 (0.44) 18.1 (0.43) 19.0 (0.44)
Results Data Paroxetine Imipramine Placebo p-value
HAM-D response
                Least squares mean

(95% CI), SEM

Least squares mean (95% CI), SEM Least squares mean (95% CI), SEM ANCOVA*
OC -12.1 (-13.1 to -10.5), 0.88 (n = 67) -10.6 (-12.5 to -8.7), 0.97 (n = 56) -10.5 (-12.3 to -8.8), 0.88 (n = 66) 0.26
LOCF -10.7 (-12.3 to -9.1), 0.81 (n = 90) -9.0 (-10.5 to -7.4), 0.81 (n = 94) -9.1 (-10.7 to -7.5), 0.83 (n = 87) 0.20
MI -12.5 (-14.2 to -10.9), 0.83 (n = 90) -11.1 (-12.9 to -9.4), 0.89 (n = 94) -10.7 (-12.4 to -9.1), 0.83 (n = 87) 0.24
HAM-D response (> 50% or < 8%)
Criteria met; Yes/no Criteria met; Yes/no Criteria met; Yes/no 2
OC 80.6%; 54/13 73.2%; 41/15 65.2%; 43/23 0.13
LOCF 66.7%; 60/30 58.5%; 55/39 55.2%; 48/39 0.27
MI 73.3%; 66/24 70.2%; 66/28 70.1%; 61/26 0.24
Adverse Events Common Adverse Events:
Adverse event (SOC) Paroxetine

(n = 93)

Imipramine

(n = 95)

Placebo

(n = 87)

Cardiovascular 43 127 32
Gastrointestinal 87 127 75
Psychiatric 71 59 18
Neurological 94 100 70
Serious Adverse Events:
Adverse event (SOC) Paroxetine

(n = 93)

Imipramine

(n = 95)

Placebo

(n = 87)

Cardiovascular 1 3 0
Gastrointestinal 25 20 4
Psychiatric 32 4 6
Respiratory 2 1 4
Neurological 7 14 7
Other 3 8 5
Total number 70 50 26
Percentage that Discontinued due to Adverse Events:
Phase Paroxetine Imipramine Placebo
Acute 14 32.6 6.9
Post-acute 7.5 (n = 67) 7.1 (n = 56) 0 (n = 66)
Study Author Conclusions Contrary to the original report by Keller and colleagues, our reanalysis of Study 329 showed no advantage of paroxetine or imipramine over placebo in adolescents with symptoms of depression on any of the pre-specified variables. The extent of the clinically significant increases in adverse events in the paroxetine and imipramine arms, including serious, severe, and suicide related adverse events, became apparent only when the data were made available for reanalysis.

HAM-D: Hamilton depression scale (scores can vary from to 52; SD: standard deviation; SEM: standard error of mean; No.: number; OC: observed cases; LOCF: last observation carried forward; MI: multiple imputation; SOC: system organ class

*All p-values uncorrected for multiple variable sampling

The reanalysis of the Study 329 concluded that the use of paroxetine or high dose imipramine showed efficacy for major depression in adolescents. Furthermore, the use of these medications in this patient population poses an increase in harm to the patients. The adverse events (AEs) found in case report forms (CFRs) compared to those listed in the clinical study report (CSR) of Study 329 found an underestimate in the reliability for each treatment arm. This assessment of the previous study re-iterates the importance of making primary trial data and protocols available to provide more accurate evidence-based practices for treatment.

References

  1. Depressive disorders (children and adolescents). Psychology Today. https://www.psychologytoday.com/conditions/depressive-disorders-children-and-adolescents. Last reviewed November 24, 2014. Accessed September 22, 2015.
  2. Major depression among adolescents. National Institute of Mental Health. http://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adolescents.shtml. Accessed September 22, 2015.
  3. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013;346:f2865.
  4. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry. 2001;40(7):762-72.
  5. Le noury J, Nardo JM, Healy D, et al. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ. 2015;351:h4320.
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