Opparounds

Divergent Patterns of Genetic Overlap Between Severe Mental Disorders and Metabolic Markers

van der Meer D, Shadrin AA, Stinson SE, Koch E, Rokicki J, Rahman Z, Bergstedt J, Ottas A, Sønderby IE, Rødevand L, Fuhrer J, Quintana DS, Dale AM, O'Connell KS, Djurovic S, Lehto K, Milani L, Alver M, Andreassen OA · American Journal of Psychiatry · July 2026

Using genome-wide data, this study mapped the genetic overlap between three severe mental disorders — schizophrenia, bipolar disorder, and major depression — and 249 circulating metabolic markers, plus type 2 diabetes, coronary artery disease, and BMI. The authors used linkage disequilibrium score regression and bivariate causal mixture modeling to quantify polygenic overlap beyond simple genetic correlation, then mapped over a thousand shared genes to disorder-specific biological processes.

All three disorders showed extensive genetic overlap with the metabolic markers, but the direction diverged: major depression's genetic relationship to the metabolic traits ran in the same direction as type 2 diabetes, coronary disease, and BMI, while schizophrenia and bipolar disorder showed the opposite pattern. Metabolite-to-disorder causal effect estimates were robust and widespread, and the shared genes clustered around different biology depending on the disorder — mitochondrial function and synaptic processes for psychosis and bipolar disorder, more general metabolic activity for depression.

Read the paper →  doi:10.1176/appi.ajp.20250259

Engage & Connect psychotherapy improves social reward responsivity and reduces postpartum depression

Solomonov N, Bein O, Himelfarb A, Schier M, Mir Z, Brown S, McDarby M, Osborne L, Gunning FM, Reading Turchioe M, Benda N, Wilkins V · Psychotherapy Research · October 2025

In an open pilot, 38 women with postpartum depression received nine weeks of Engage & Connect (E&C), a brief manualized psychotherapy built on the observation that PPD blunts both motivation for rewarding activity and pleasure during social contact. E&C targets these two processes directly rather than treating mood as the primary lever.

Depression severity fell by 8.6 points on the EPDS on average, with 83% remission and 73% clinical response, and 86% of participants completed all nine weeks. Critically, improvement in behavioral activation and social reward responsivity statistically mediated the reduction in depressive symptoms — the treatment appears to work through the mechanism it was built to target, not through a nonspecific supportive effect. Anxiety, perceived social support, and mother-infant bonding improved alongside mood.

Read the paper →  doi:10.1080/10503307.2025.2569046

The five-week MAOI washout is really about one metabolite

Every SSRI needs a washout before starting an MAOI, but only fluoxetine needs five weeks — the others clear in one to two. The reason is norfluoxetine, fluoxetine's active metabolite, which is itself a potent serotonin reuptake inhibitor with a half-life of 4 to 16 days on its own, versus fluoxetine's 1 to 3 days. Norfluoxetine is cleared mainly through CYP2D6, and CYP2D6 activity varies enormously across patients — a poor metabolizer can still be carrying clinically active drug well past the five-week mark, making the standard figure a population estimate, not a guarantee. The practical corollary: paroxetine and sertraline, whose active moieties clear within days, only need the ordinary two-week washout, so treating every SSRI-to-MAOI switch as a uniform five-week rule either strands patients unnecessarily or undersells the one drug that actually needs it. Before committing to exactly five weeks on a fluoxetine switch, it's worth asking about prior poor tolerability at low doses or concurrent CYP2D6 inhibitors — both suggest slower clearance than the label assumes.

Pretend mode isn't insight — it's mentalizing about nothing

Psychic equivalence collapses thought and reality — "I feel it, so it's true." Pretend mode is the opposite failure, and it's easier to miss because it can look like therapy working. Mental states are represented fluently, but the representation is disconnected from any real feeling or consequence — the patient produces smooth, psychologically sophisticated-sounding narrative about their inner life that never actually touches anything. Sessions can feel insightful, even moving, while nothing outside the room changes. The technical trap is rewarding elaboration for its own sake: a well-formed account of "why I do this" is not the same as mentalizing. The diagnostic sign isn't the content — it's the flatness: no curiosity pulled from the therapist, no friction, no surprise. The move is to interrupt the pseudo-mentalizing rather than affirm it, which means noticing and resisting your own pulled-along admiration for a narrative that is working a little too well.