Results of a clinical trial indicate that patients with major depression who become less irritable within 4 weeks of initiating treatment with an antidepressant medicine are much more likely to have a full remission of depression symptoms by the end of their 8th week of treatment. 

Those whose irritability was reduced in the first month of treatment were found to be about twice as likely as patients taking the same medicines who didn’t report significant reductions in irritability in the same interval.  

The finding is relevant for an estimated 40% to 50% of all patients with major depression—those who say at the beginning of treatment that they have been irritable for at least half the time during their current depressive episode. The antidepressants prescribed in the study included medicines like Prozac and Effexor, which affect levels of the neurotransmitters serotonin and norepinephrine.

Curiously, as researchers who conducted the trial noted, irritability is not one of the nine “core” symptoms currently listed in the Diagnostic and Statistical Manual (the “DSM 5”) used by doctors to diagnose major depression—although it is included among the core symptoms in major depression affecting children and adolescents.  

Noting the omission of irritability as a “core” adult major depression symptom in the DSM, the research team, led by Madhukar Trivedi, M.D., a 2002 BBRF Independent Investigator and 1992 Young Investigator at UT Southwestern Medical Center, set out to discover whether it had any predictive power to help doctors better direct their patient’s care. The team also included John Rush, M.D., a 2000 Falcone Prizewinner and 1991 BBRF Distinguished Investigator. 

The team assessed their idea in two patient samples drawn from six primary care hospitals and nine psychiatric care sites. Results in the first sample, which included 664 patients with major depression, were then tested on the second and independent cohort, numbering 163 patients. A majority of the patients in the trial, aged 18 to 75, were white, female and non-Hispanic.

Although different subsets of participants received different medications, all received at least one antidepressant; some received two; some received a placebo pill in addition to active medication. All participants were assessed after their first 4 weeks of treatment, with irritability and levels of various depression symptoms measured independently.  Then they were assessed again after 8 weeks.  

Those whose irritability declined by 25% or more in the first 4 weeks with antidepressant treatment were about twice as likely to have a remission of their major depression by the end of the 8th week. This fact was independent of whether their depression symptoms also diminished during those first weeks of treatment.  Importantly, when both factors—irritability and severity of depression symptoms—were combined, the researchers found they could determine “with high accuracy” individual patient outcomes after 8 weeks in the independent, “second” patient sample.  

“Improvement in irritability in our study is consistent with that in previous reports of reduced anger or hostility with antidepressant treatment,” the team said.  The result suggests, further, “that improvement with antidepressant treatment extends beyond changes in ‘core’ depressive symptoms.”  In the team’s view, these results “highlight the limitations of the current criteria for major depressive disorder and argue for expansion of assessments beyond the [current] nine core diagnostic assessments.”

To increase the chances of their findings being “clinically actionable,” the team developed a calculator based in part on a five-item irritability self-report for patients to use in coordination with their doctor. Changes in irritability, combined with evidence of response in “core” depression symptoms, enable doctors to predict which patients should continue on their current medications and which—those unlikely to have a remission based on the early evidence—should have their medications adjusted.  It is not yet known if the irritability “predictor” applies to other kinds of antidepressant treatments.

The team advises that further studies are needed, among other things, to test the validity of their calculator with other measures of depression severity.