What it means for treatment
The new VMAT2 inhibitors for TD—valbenazine and deutetrabenazine—were developed to address part of the known pathophysiology of TD: dopaminergic hypersensitivity. They are effective for TD, with a number needed to treat (NNT) between 4 and 7.5 But will they work for SDs? After all, these dyskinesias have a different etiology and may arise from different biological pathways. SDs improve, rather than worsen, with antipsychotics. How they will respond to VMAT2 inhibitors is an open question, but a neglected theory of schizophrenia may point the way toward an answer.
That theory is dopamine hypersensitivity. There is evidence from biological and family studies that hypersensitivity of the dopamine system is a risk factor for schizophrenia, and that it plays a causative role in SD just as it does in TD.1 If that is true, the SDs would improve with VMAT2 inhibitors, and psychosis may improve with these agents as well.6 Indeed, one of the first medications for psychosis, and one that actually preceded the antipsychotics, was reserpine; a VMAT2 inhibitor.7
The bottom line
TD is ripe with paradox. SDs actually improve with antipsychotics, while TDs may appear to improve, because antipsychotics can mask tardive movements through their Parkinsonian effects.8 As part of the disease process, SDs may worsen when antipsychotics are discontinued. TD can worsen during antipsychotic withdrawal as well, in the form of withdrawal dyskinesias.7 With all of this uncertainty, measurement is essential.
Before starting a VMAT2 inhibitor, rate the symptoms with an AIMS. Patient report is not enough, as awareness of the problem tends to be low. If there’s no improvement after two months, taper off the VMAT2 inhibitor and measure once more a few months later to see if the movements are worse without treatment.
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2. Peralta V, Campos MS, De Jalón EG, et al. Motor behavior abnormalities in drug-naïve patients with schizophrenia spectrum disorders. Mov Disord. 2010;25:1068-1076.
3. Mittal VA, Neumann C, Saczawa M, et al. Longitudinal progression of movement abnormalities in relation to psychotic symptoms in adolescents at high risk of schizophrenia. Arch Gen Psychiatry. 2008;65:165-171.
4. Merrill RM, Lyon JL, Matiaco PM. Tardive and spontaneous dyskinesia incidence in the general population. BMC Psychiatry. 2013;13:152.
5. Solmi M, Pigato G, Kane JM, et al. Treatment of TD with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:1215-1238.
6. Skaff R. Valbenazine and Deutetrabenazine as possible treatments for neuroleptic-induced supersensitivity psychosis and antipsychotic dependence. CNS Spectr. 2018:1-2.
7. Goldberg JF and Ernst CL. Managing the Side Effects of Psychotropic Medications, 2nd edition,. Washington, DC: American Psychiatric Press; 2018.
8. D'Abreu A, Akbar U, Friedman JH. TD: Epidemiology. J Neurol Sci. 2018;389:17-20.