The mechanism underlying tardive dyskinesia: an exploratory test of the dopamine overactivity hypothesis using MRI imaging of midbrain neuromelanin

Rationale Tardive dyskinesia (TD) is a neurological syndrome of involuntary repetitive movements which results from treatment with antipsychotic medication. The pathoetiology of TD is not well understood but a possible mechanism involves dopaminergic overactivity in the nigrostriatal pathway. If this theory is correct, then levels of neuromelanin (a long-term marker of dopaminergic activity) should be higher in people with TD than those without TD. Objectives The aim of the study was to test the hypothesis that neuromelanin levels are higher in patients with TD relative to those without TD. Methods Data from 27 participants (TD: n = 13; non-TD n = 14) with a diagnosis of schizophrenia, all taking antipsychotic drugs, was used. Neuromelanin was measured in the midbrain via Magnetic Resonance Imaging (MRI) and compared between the groups. Movement symptoms were measured using the Abnormal Involuntary Movement Scale (AIMS), and antipsychotic dose recorded. Results MRI-measured neuromelanin levels were significantly higher in patients with TD, as compared to those without (mean = 0.223; t(17.27) = 3.817, p = 0.001; g = 1.386, 95% CI=[0.559, 2.213]). This remained significant after controlling for age, sex, substantia nigra/ventral tegmental area volume and antipsychotic dose (ANCOVA: F(1,20) = 12.08, p = 0.0024; adjusted β = 0.0301, 95% CI [0.0120, 0.0481]). The most pronounced difference was seen in the ventral substantia nigra. Conclusions The finding of higher midbrain neuromelanin in patients with TD aligns with the dopamine overactivity hypothesis of TD aetiology. It also supports a neurobiological basis for treatment of TD with drugs that target presynaptic dopamine activity, such as VMAT2 inhibitors. Additionally, it identifies the ventral substantia nigra as a key locus. Future longitudinal studies are needed to delineate if dopamine overactivity develops in response to antipsychotic treatment or is a trait vulnerability marker for risk of TD.