Cognitive Biotype, New Depression Subtype, Resistant to Common Antidepressants

Approximately 27% of patients with previously unmedicated depression have the “cognitive biotype” that is characterized by prominent impairments in 2 domains of cognitive control.

Cognitive impairment, as it relates to major depressive disorder (MDD), is a major contributor to poorer functional and treatment outcomes. Researchers proposed a new subtype of depression in patients with cognitive impairment — cognitive biotype — that encapsulates the difficulty patients have in performing cognitive tasks, according to a study published in the JAMA Network Open.

The researchers conducted a secondary analysis on 1,008 patients who participated in the International Study to Predict Optimized Treatment in Depression (iSPOT-D; Identifier: NCT00693849) to validate the existence of the cognitive biotype. Individuals who were outpatients and who were medication-free and diagnosed with nonpsychotic MDD were included in the study.

Individuals were randomly assigned in a 1:1:1 ratio to receive treatment of 3 widely prescribed antidepressants (escitalopram, sertraline, venlafaxine) and assessed on cognitive testing, functional capacity, and functional imaging at baseline, and then 8 weeks after treatment.

For cognitive testing, the researchers used the computerized test IntegNeuro that assessed 9 cognitive domains:

  • sustained attention,
  • cognitive flexibility,
  • decision speed,
  • executive function,
  • information processing speed,
  • psychomotor response speed,
  • response inhibition,
  • verbal memory, and
  • working memory.
Biomarker trials targeting the cognitive biotype with more selective treatment strategies are urgently needed.

Depressive symptoms were reported using standardized criterion scales, including the 17-item Hamilton Rating Scale for Depression (HRSD-17) with masked clinician ratings and 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16).

A subsample of 96 individuals underwent magnetic resonance imaging (MRI) during an established cognitive task, with activation of the cognitive control circuit (dorsolateral prefrontal [dLPFC] and dorsal anterior cingulate regions [dACC]) quantified and compared against a healthy reference group.

A total of 27% of individuals were found to have marked impairment in all cognitive measures, with reduced activity in specific frontal brain regions; they were considered the “cognitive positive biotype.”

Compared with the cognitive biotype negative group, the cognitive positive biotype group was found to have slower information processing, more waking during the night, awaking early, and sleeping too little, based on standardized scales.

Lower rates of response and remission to antidepressants was noted in the cognitive biotype positive group, when compared with the cognitive biotype negative group (HRSD-17 response, 103 of 188 [54.8%] vs 340 of 524 [64.9%]; P =.02; HRSD-17 remission, 73 of 188 [38.8%] vs 250 of 524 [47.7%]; P =.04).

Of note, the cognitive biotype positive group showed reduced activation of the dLPFC and dACC, suggesting a specific neuropathy which underlies the biotype.

Study limitations included the possibility of unidentified behavioral or neurobiologic factors that may contribute to the cognitive biotype, as well as further investigation being needed on medications other than the 3 prescribed during the study.

The researchers wrote, “If the prevalence of cognitive deficits in our sample is generalized to the US population, then approximately 5.7 million individuals with depression have cognitive impairments (27% of 21 million).” “Biomarker trials targeting the cognitive biotype with more selective treatment strategies are urgently needed,” they concluded.


Hack LM, Tozzi L, Zenteno S, Olmsted AM, Hilton R, Korgaonkar MS, et al. A cognitive biotype of depression and symptoms, behavior measures, neural circuits, and differential treatment outcomes. JAMA Netw Open. Published June 1, 2023. doi:10.1001 jamanetworkopen.2023.18411