A 2026 DIVERGE analysis of 3,677 antidepressant-exposed patients with major depressive disorder in Pakistan classified 34% as treatment resistant, while 86% received psychotropic polypharmacy and only 6% received psychotherapy.1 The CYP2C19 signal is real enough to study prospectively, but the main treatment-system finding is medication stacking in a setting where psychological care was rare. Research …
A 2026 multimodal MRI study found that treatment-resistant depression had lower coordination between brain structure and brain activity than non-treatment-resistant depression in frontal, parietal, motor, and temporal regions. Machine-learning models using those structure-function coupling measures classified treatment-resistant vs. non-treatment-resistant depression with AUC values from 0.886 to 0.950 in the primary atlas analysis.1 Research Highlights TRD …
Intranasal esketamine — FDA-approved for treatment-resistant depression in 2019 — failed cost-effectiveness benchmarks against four cheaper third-line options in a 2026 Hong Kong modeling study, with incremental cost-effectiveness ratios (ICERs) of US$134,127 to US$312,750 per quality-adjusted life-year (QALY) at a US$50,000/QALY willingness-to-pay (WTP) threshold.1 Combination antidepressant therapy was the most cost-effective strategy modeled. Research Highlights …
A 2026 systematic review of subcallosal cingulate (SCC) functional connectivity found 28 qualifying resting-state fMRI studies in depression: 21 rTMS/iTBS studies, 4 ECT studies, 3 focused-ultrasound studies, and 0 DBS or tDCS studies.1 That number is the useful correction: SCC DBS may still be biologically plausible, but the current fMRI connectivity literature mostly explains noninvasive …
A 2026 retrospective case series of 22 adults with treatment-resistant depression and comorbid PTSD found that trauma re-experiencing during intranasal esketamine disappeared over later sessions in 72.7% of patients, while 27.3% stopped esketamine because the flashbacks persisted.1 Research Highlights Flashbacks usually faded, but not always: In 16 of 22 patients (72.7%), esketamine-related trauma re-experiencing disappeared …
Parenteral clomipramine has a strong clinical myth around it: bypass the gut, raise parent-drug exposure quickly, and maybe accelerate rescue in severe depression or OCD. A 2026 systematic review found the route advantage was not clearly proven: in depression, 5 RCTs without high risk of bias did not show clear IV or IM superiority over …
An ear-clip that modulates mood by stimulating the vagus nerve has obvious appeal — but the evidence base for non-invasive tVNS in depression has been mixed for a decade. A 2026 cross-over RCT by Forbes et al. sharpens what specifically tVNS does well.1 Research Highlights Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive ear-electrode version …