When antidepressants fail, a staging model hopes to predict what will work
STUDY: Carminati M et al, Int Clin Psychopharmacol 2026 (epub ahead of print)
STUDY TYPE: Prospective cohort study
FUNDING: Independent
Background
There are many reasons why antidepressants fail. This Italian inpatient study tested whether a simple two-stage model could predict what will work
The Study
538 hospitalized patients with depression were classified at admission as nonresistant, Stage 1 TRD (TRD1: failed two antidepressants at minimum therapeutic dose), or Stage 2 TRD (TRD2: failed two antidepressants from different classes at maximum tolerated dose). Depression severity was tracked using the Hamilton Depression Rating Scale (HDRS-21) at baseline and at weeks 2, 4, and 8.
Results
The two TRD groups looked strikingly different. TRD1 patients had earlier illness onset and the highest rates of personality disorders (45%), alcohol use disorder, substance use disorder, and tobacco smoking. TRD2 patients had longer, more severe episodes and needed more intensive treatment — including ECT and IV ketamine.
Symptom trajectories told the real story: TRD1 patients had a better course, improving at the same rate as nonresistant patients over 8 weeks. TRD2 patients improved significantly less. The sample was inpatient-only, limiting generalizability to outpatient practice.
Limitations: Not randomized, included bipolar patients in the group (where antidepressants are not indicated).
Practice Implications
This study carves out two types of treatment-resistant depression with pragmatic implications
TRD1: Early onset, loaded with comorbidities, responds well once hospitalized. Here the obstacle is the complex comorbidity. What they need is treatment of the underlying drivers: psychotherapy for personality disorders, substance use treatment, and better psychosocial support.
TRD2 is the patient who’s biologically refractory — fewer comorbidities, longer and more severe episodes, slow to respond even with intensive inpatient care. That’s the patient for whom neuromodulation (TMS, ECT) or ketamine makes sense.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
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