The underlying pathology of TD involves dopamine receptor blockade by medications that are used in the treatment of schizophrenia and other psychiatric illnesses. Some medications that are used for gastrointestinal conditions, especially antiemetics such as metoclopramide, are also D2 receptor blockers and can cause TD. Other categories of drugs, including some antidepressants and even lithium, have also been implicated.

However, the theory that dopamine receptor blockade causes TD may not be the whole story. It is possible that some of the other treatments that can cause TD may be indirectly disrupting the balance in the dopamine system, especially the direct or indirect pathways in the basal ganglia, which coordinate movement.

Nonetheless, the leading theory remains that postsynaptic receptor blockade leads to an upregulation and supersensitization of dopamine receptors, which then disrupts the balance of the direct and indirect pathways. This may be associated with a cascade of other events that result in neurotoxicity, the development of oxidative stress, and disruptions of neuronal integrity, synaptogenesis, and neuroplasticity.

Not every patient who receives a DRBA develops TD. Additionally, when a DRBA is withdrawn, dopamine receptors revert to the way they were before treatment, but this does not always result in a resolution of the TD. It is possible that individuals have different genetic susceptibilities with differing underlying pathologies. The coordination and regulation of the dopamine system in the parts of the brain that regulate movement are very complicated, and the interplay between the direct and indirect pathways is also quite complicated. Besides dopamine-containing neurons, there are various interneurons and microglia that nourish neurons and help recycle neurotransmitters. The interneurons can either facilitate or inhibit some of the firing in the involved neurons.

There are likely many different ways in which things can become out of balance. Researchers are looking at various other types of treatments to find out whether specific patients might have positive results with, for instance, medications that can help balance glutamate, GABA, or acetylcholine. Researchers are also examining ways to enhance the brain’s ability to decrease oxidative stress and clear free radicals and various toxic compounds, in addition to treatments that may enhance synaptic plasticity, neuronal health, and neural connections.

We know that the vesicular monoamine transporter 2 (VMAT2) inhibitors are very effective and safe. A leading explanation of the effect of VMAT2 inhibition is that we are decreasing presynaptic dopamine release to help rebalance or reregulate the dysregulated, supersensitive dopamine system of TD, thereby restoring the balance between the direct and indirect dopamine pathways. However, it is also possible that decreasing the amount of dopamine in the synapse may lead to less neurotoxicity or less oxidative stress, meaning that VMAT2 inhibitors may be effective for different reasons and in many patients.