BARCELONA – New evidence from the landmark 12-year-old STAR*D clinical trial provides fresh support for a novel Italian hypothesis that the efficacy of selective serotonin reuptake inhibitors in major depressive disorder results from their capacity to amplify the influence of living conditions upon mood.
Bruce Jancin/MDedge News
Aurelia Viglione
“This hypothesis claims that SSRIs do not affect mood by themselves, but by increasing brain plasticity to render an individual more susceptible to the influence of living conditions. So in a positive environment, treatment leads to a beneficial outcome, and in a stressful environment it may lead to a worse prognosis,” Aurelia Viglione explained at the annual congress of the European College of Neuropsychopharmacology.
This originally was demonstrated by her senior coinvestigators in mouse studies, which showed increased brain plasticity and responsiveness of mood to living conditions in the presence of the serotonin boost provided by SSRIs. Now this animal research has been confirmed in a more clinically relevant fashion via a secondary analysis of the venerable National Institute of Mental Health–funded STAR*D (Sequenced Treatment Alternatives to Relieve Depression) data set, which Ms. Viglione presented at the ECNP congress.
This hypothesis, which she and her colleagues have dubbed the “undirected susceptibility to change” hypothesis of the mechanism of action of SSRIs, attempts to account for the drugs’ highly variable efficacy. As prescribing physicians and their often-frustrated patients with major depression are all too aware, the SSRIs – the most widely prescribed treatment for the disorder – induce remission in only 30%-40% of patients, while an additional 30%-40% fail to experience even a significant response. And despite much research effort, to date there is no reliable way to match the best antidepressant to a given individual in accord with the current priority to develop a personalized medicine approach.
The undirected susceptibility to change hypothesis provides a plausible explanation for these mixed clinical outcomes. The hypothesis posits that high serotonin levels lead to increased brain plasticity and consequent openness to change in mood, which can be for the better or worse – depending upon the quality of the surrounding environment.
Ms. Viglione, a PhD student in neuroscience at the University of Pisa (Italy), presented a study of a 591-patient subset of patients with major depression in STAR*D who received citalopram at 20 mg/day for 4 weeks, at which point the 40% of participants who weren’t showing a sufficiently favorable response trend had their citalopram increased to 40 mg/day. Patients’ living conditions were categorized as favorable or adverse based upon an amalgam of sociodemographic characteristics, including employment status, education, marital status, income, insurance status, ethnicity, drug abuse, and history of traumatic events. Treatment response was measured using the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) score.
. Patients were more likely to achieve remission as defined by a QIDS-SR16 score of 5 or less at week 6 if they had a college education, a job, higher income, and/or private health insurance than if those proxies for favorable living conditions were not present.
The impact of sociodemographic factors on change in mood was much larger in patients on citalopram at 40 mg/day than 20 mg/day. For example, having a college education rather than a high school education was independently associated with up to a 37-fold greater remission rate among patients on the higher dose of the SSRI, depending upon their sociodemographic status, compared with a 2-fold greater likelihood of remission in patients on citalopram at 20 mg/day.
“The correlation is very high. It’s a very huge effect,” Ms. Viglione commented.
On the other hand, the 40-mg dose also was associated with an increased likelihood of worsening in patients living in an unfavorable environment. For example, 35% of patients in the 40-mg group with only a high school degree showed worsening depression, compared with 21% on citalopram at 20 mg/day. And 40% of low-income patients on citalopram at 40 mg/day showed worsening depression, compared with 35% of low-income patients on 20 mg. These figures probably underestimate the true downside of higher-dose treatment in patients living in an adverse environment, because STAR*D guidelines called for treatment discontinuation in the setting of worsening depression, she noted.
The correlation between higher-dose SSRI therapy, sociodemographic environment, and change in depressive symptoms was not uniform across all symptom categories. Ms. Viglione and her colleagues grouped the elements of the QIDS-SR16 rating scale into three domains: core emotional symptoms, sleep/insomnia symptoms, and weight/appetite. They found that the impact of higher-dose therapy in combination with favorable living conditions was greatest on sleep/insomnia symptoms.
The next step for the Italian investigators will be to determine in a prospective study whether the undirected susceptibility to change hypothesis can predict which patients will benefit from SSRI therapy.
Ms. Viglione reported having no financial conflicts regarding her study, which was funded by the Italian Ministry of Health.