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Greetings, this is David Rosenberg, representing the Psychopharmacology Institute. In this CAP—or Child and Adolescent Psychiatry—Smart Take, we will examine the impact of age on treatment response among patients diagnosed with major depressive disorder. The primary takeaway is the significant and profound influence of age on antidepressant response. This research by Strawn et al. provides a comprehensive investigation of a large mega-analysis, rather than merely a meta-analysis, of individuals diagnosed with major depressive disorder.
Obtaining a robust understanding of how age impacts patients undergoing antidepressant treatment has been complex due to the small-scale nature of existing studies. The research studies are heterogeneous, encompassing numerous comorbidities and factors. Nevertheless, understanding the influence of age on treatment response, or the absence thereof, is critical to prevent homogeneous treatment of patients.
We have learned that merely mirroring adult treatments and extrapolating them for use in children can lead to substantial repercussions. It is well-known that developmental maturation, particularly in the prefrontal cortex—the brain’s chief executive—often persists into the late 20s and even early 30s. Therefore, we are considering differentially developing neurotransmitter and brain systems, which can inevitably influence treatment. From past experiences, it is understood that tricyclic antidepressants—although effective in adults with major depressive disorder—have not proven to be superior to placebo in children and adolescents. This finding served as an imperative reminder that children are not merely smaller adults; we cannot assume that therapies effective in adults will be equally successful in children.
This particular analysis evaluated comprehensive, rigorously executed controlled trials of pharmacotherapy for patients with depression from the National Institutes of Health (NIH). These trials include the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study; the Treatment of Adolescents with Depression Study (TADS), in which our team was involved; and the Combining Medications to Enhance Depression Outcome (CO-MED) study, which included patients diagnosed with major depressive disorder. They evaluated over 900 patients across the age spectrum to discern potential variations in age response to specific classes of antidepressants and factors predicting treatment response or absence thereof.
The findings were intriguing, with some expected and others surprising. As the article clearly illustrates, the response to antidepressant treatment varies across the lifespan. This variation can inform differential treatment paradigms needed for youth and adults. Notably, the response varies by age, with less improvement seen in both younger and older individuals. The optimal response to monotherapy or combinations of antidepressant treatment appears to be between the ages of 21–35. This analysis underscores the significant variation in response to antidepressants among youth and adults—even within adult cohorts. Suppose you fall within the 21–35 age range. In that case, your likelihood of responding to monotherapy or a combination of antidepressant treatment is considerably higher than for younger age groups and older adults.
The study also revealed that women are more likely to respond to antidepressant treatment than men. This observation aligns with historical reports that certain tricyclic antidepressants, such as nortriptyline, have a higher response rate in women than men. The reasons for age-related differences in response can be attributed to many factors across the lifespan. In younger patients, family and school-related factors significantly influence outcomes. It is well-established that child and adolescent depression presents a much higher rate of family history and familial loading. Although familial loading and family history of mood disorders are high in adults, they are even more prevalent in children and adolescents. Moreover, an expressed emotion within the family can exacerbate the situation. Families with higher rates of depression—particularly if the parents or siblings are depressed—can influence the mental health of the affected youth and vice versa, thereby creating a vicious cycle.
As previously mentioned, developmental factors play a role in the differential responses observed. The dopamine system continues to develop throughout adolescence and into adulthood. Similarly, the glutamate system, shown to have a critical role in depression, continues to develop into young adulthood. Notably, glutamate is the target of the novel antidepressant therapy, ketamine, which is used in treatment-resistant depression and suicidal depression, potentially providing a more rapid effect.
In conclusion, age is a key variable across the lifespan—in youth, adulthood, and older adulthood. It is of critical importance to individualize treatment based on these age variations.
Abstract
The Impact of Age on Antidepressant Response: A Mega-Analysis of Individuals With Major Depressive Disorder
Jeffrey R Strawn, Jeffrey A Mills, Vikram Suresh, Taryn Mayes, Melanie T Gentry, Madhukar Trivedi, Paul E Croarkin
Introduction: Understanding how age affects antidepressant response in patients with major depressive disorder has been complicated by small and heterogeneous studies. Yet, understanding how age-across the lifespan-contributes to variation in response could inform treatment selection across the lifespan. This study sought to identify how age impacts antidepressant response using participant-level data from large, NIH-sponsored trials in individuals with MDD aged 12-74 years.
Materials and methods: Participant-level data were abstracted from three NIH-sponsored trials of pharmacotherapy (Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Study, Treatment of Adolescent Depression Study (TADS), and the Combining Medications to Enhance Depression Outcomes Study (COMED)) in patients with MDD. Bayesian Hierarchical Models (BHMs) of individual treatment trajectories were developed using Hamiltonian Monte Carlo No U-Turn Sampling. The individual trajectory of improvement in depressive symptoms (Clinical Global Impression-Severity [CGI-S] and CGI-S equivalent from COMED) was modeled across studies and across individuals with logarithmic trend “random effects” coefficients BHMs. Age and sex (and their interaction) were examined categorically across patients.
Results: Study participants (N = 907) were 29.7 ± 17 years of age, 66.3% women, and had a mean baseline CGI-S score of 4.6 ± 0.9. Patients ≤21 years and those >55 years had slower and less response to pharmacotherapy compared to those aged 21-35. Additionally, women improved more than men, and this effect did not differ across ages.
Discussion: The patient’s age should be considered in predicting antidepressant response, particularly in older and younger individuals who may benefit from other interventions to enhance treatment response.
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Reference
Strawn, J. R., Mills, J. A., Suresh, V., Mayes, T., Gentry, M. T., Trivedi, M., & Croarkin, P. E. (2023).
Journal of Psychiatric Research, 159
, 266-273.
