Anticholinergics and VMAT-2 Inhibitors: Different MOAs, Different Results

This detailed video will explain the importance of understanding the mechanism of action that is associated with better treating tardive dyskinesia.

Read the transcript:

To understand the treatment of tardive dyskinesia, or TD, it’s important to appreciate how the forces of dopamine and acetylcholine act in the dorsal striatum. These 2 circuits converge at the medium spiny neuron, or MSN, which interacts with the direct pathway. Dopamine neurons of the nigrostriatal pathway inhibit the MSN by stimulating D2 receptors. This inhibition is counterbalanced by the effects of acetylcholine released by cholinergic interneurons onto muscarinic M1 receptors.

Antipsychotics can disrupt this balance in 2 ways: First, the dopaminergic signal is interrupted by blocking D2 receptors on the MSN. Second, D2 blockade on the cholinergic interneuron causes more acetylcholine to be released, further unbalancing the system. At certain thresholds of D2 blockade at the MSN, typically well above 80%, the rigidity, bradykinesia or tremor of parkinsonism may emerge. Anticholinergic medications can restore balance to the system by blocking M1 receptors on the MSN. Although anticholinergics do not stimulate dopamine release from nigrostriatal neurons, the net effect is similar to providing a greater dopamine signal.

Tardive dyskinesia also represents an imbalanced state at the MSN, but in the form of excessive dopamine signaling. Chronic blockade of MSN D2 receptors causes upregulation of supersensitive D2 receptors. Any dopamine released from the presynaptic nigrostriatal neuron causes an exaggerated effect on the MSN.

Administering an anticholinergic will decrease the cholinergic M1 signal, further throwing the system out of balance, and potentially worsening the symptoms of TD. Since they may potentially worsen TD, a very slow taper of anticholinergics may be warranted in patients with TD who have no evidence of Parkinsonism in order to examine any effects on abnormal movements.

Dopamine is packaged into presynaptic vesicles by Vesicular Monoamine Transporter Type 2, or VMAT2. VMAT2 inhibitors decrease the amount of dopamine in each presynaptic vesicle, which reduces the amount of dopamine released. The diminished dopamine signal to the MSN decreases the imbalance in the system and improves the symptoms of tardive dyskinesia.

In summary, the nature of the imbalance at the medium spiny neuron between dopamine signaling at D2 receptors and cholinergic signaling at M1 receptors dictates the choice of intervention differently for drug-induced Parkinsonism and TD. While anticholinergics are able to treat parkinsonism, they can potentially make TD worse by reducing the cholinergic counterbalance to excessive dopamine signaling at the upregulated, supersensitive D2 receptors. VMAT2 inhibitors restore balance by decreasing dopamine release from the presynaptic nigrostriatal neuron, and represent the most effective and evidence-based method for treating TD.