Antipsychotics stop being counted by dose: 49 drugs folded into 32 receptor occupancies, and cognition tracks the receptor profile
Synopsis
Cognitive differences in psychotic disorders have mostly been grouped by diagnosis or drug dose, leaving the medication's own contribution hard to isolate. A cross-sectional study converted prescriptions for 1,067 patients into individualised occupancy profiles across 49 drugs and 32 receptor targets, then used gradient boosting to predict cognition. Shuffling the receptor profiles within diagnosis roughly halved the pharmacological contribution, with negative signal concentrated in a cluster of alpha2-adrenergic, DRD4, DRD5 and several serotonergic receptors, while dopamine transporter SLC6A3 occupancy tracked better cognition.
Interpretation
Prescriptions are no longer recorded only as drug class or dose equivalent, but converted into each patient's occupancy profile across 32 receptor targets, so cognitive differences can be read as receptor combinations. Earlier work often pooled diagnoses or compressed medication into coarse categories and dose equivalents, making drug-level comparisons too coarse to resolve receptor-level effects. Among 1,067 people with psychotic disorders, block-permuting the receptor profiles within diagnostic group and refitting the model cut total pharmacological attribution from 0.224 to a permutation null mean of 0.112, roughly halving it, p=0.002.
The occupancy profile is built step by step from recorded dose, first estimating plasma concentration, then brain concentration, then occupancy from binding affinity. Occupancy uses the classical receptor-occupancy relationship, switching to a competitive binding model when several drugs act at the same receptor and weighting by intrinsic activity to give a functional modulation index. Drug-target affinities came mainly from the Psychoactive Drug Screening Program database, the final matrix covered 49 drugs and 32 receptor targets, and receptors were grouped into seven clusters by the similarity of their occupancy profiles.
Negative signal concentrates in a cluster of alpha2-adrenergic, DRD4, DRD5 and several serotonergic receptors, while dopamine transporter occupancy points the other way. The cluster containing DRD2 showed no association with cognition after correction for multiple testing, so the signal is not carried by the usual D2-blockade explanation. That cluster showed an observed mean absolute SHAP of 0.059 against a permutation null mean of 0.017, FDR-adjusted p=0.014; the SLC6A3 cluster showed 0.034 against 0.012, FDR-adjusted p=0.047.
Perspective
The results come from 1,067 people with psychotic disorders recruited at six US sites between 2008 and 2020, with cognition assessed by the six BACS domains and drug exposure derived from recorded dose and literature affinities. The intended readers are researchers and clinical investigators working on psychopharmacology and cognition. The source proposes next steps: longitudinal studies, ideally in first-episode cohorts, should examine cognition from before antipsychotic initiation and prospectively during single-agent treatment, incorporating objective measures of exposure, adherence and substance use.
Occupancy is estimated rather than directly measured, resting on recorded dose, literature-derived affinity and intrinsic activity values, and pharmacokinetic assumptions, so it cannot fully capture individual differences in metabolism, blood-brain barrier penetration, receptor availability or endogenous ligand competition. Medication records were not objectively verified for adherence, previous psychotropic exposure was incompletely captured, and confounding by indication and reverse causation remain possible. SLC6A3 modulation was sparse, and the authors caution that this signal should be interpreted with care, with residual confounding possible; the receptor clusters represent correlated modulation profiles and should not be read as isolated receptor-specific effects.