Morning Sun, Edward Hopper (1952)
What to do before calling depression treatment-resistant
STUDY: Amiri D et al, J Pers Med 2026
STUDY TYPE: Narrative review
FUNDING: Independent
Background
Treatment-resistant depression usually means no remission after two adequate antidepressant trials in the same episode. This review of 96 sources argues that the category mixes several problems, each calling for a different next step.
The Workup
The authors propose a sequence to follow before escalating treatment:
- Confirm the diagnosis. Look for bipolarity, substance or medication effects, and medical causes such as thyroid, vitamin and nutritional deficiencies, inflammatory and vascular disease, sleep apnea, circadian disruptions (night owls, insomnia, shift work). Consider medication (new data on finasteride), and substance induced.
- They recommend, at a minimum: CBC, TSH, glucose or HbA1c, electrolytes, renal and hepatic function. Also consider hs-CRP if signs of inflammation; testosterone (in older men); vitamins B12, folate, and D.
- Reconstruct each trial in the current episode: the dose, weeks at that dose (at least 6), adherence, and measured change.
- Classify the outcome: nonresponse (under 20% improvement), partial response (20% to 49%), response with residual symptoms, or loss of response.
- Look for comorbid conditions that slow recovery: ADHD, autism, PTSD, personality disorders, insomnia, substance use, and medical illness.
Next Steps
- No early improvement: switch to an antidepressant with a different mechanism.
- Partial response: keep the antidepressant and augment or add targeted therapy.
- Residual symptoms: treat the specific leftover problem, such as insomnia, anhedonia, or behavioral avoidance.
- Lost response (tachyphylaxis): check adherence, new drugs, substance use, stressors, new medical problems, lifestyle changes (eg, processed foods, physical activity) and emerging mixed symptoms before changing treatment.
- Psychotic, catatonic, or life-threatening depression: go to ECT (for psychotic or catatonic) or ketamine for acute suicidality.
- Bipolar depression: use a bipolar algorithm and avoid escalating antidepressants.
What the Evidence Shows
- Adding psychotherapy, mostly CBT, nearly doubled remission rates (risk ratio 1.92).
- Antipsychotic augmentation doubled the odds of remission but nearly quadrupled the odds of dropping out from side effects. TMS outperformed aripiprazole augmentation in a RCT.
- Lithium lowered suicide risk in long-term trials across mood disorders.
- Pramipexole had a large effect size in a year-long randomized trial of TRD.
Practice Implications
- Learn more strategies in Difficult to Treat Depression, including thyroid, celecoxib, d-cycloserine, pindolol, probiotics, omega-3, methylfolate, lightbox, and psychotherapy.
- Learn more about the newly approved ProLivRx, and at-home device effective after one failed antidepressant, in the Carlat Podcast.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
