Pathophysiological Mechanisms of Antipsychotic-Induced Parkinsonism

Abstract

Among neurological adverse reactions in patients with schizophrenia treated with antipsychotics (APs), drug-induced parkinsonism (DIP) is the most common motility disorder caused by drugs affecting dopamine receptors. One of the causes of DIP is the disruption of neurotransmitter interactions that regulate the signaling pathways of the dopaminergic, cholinergic, GABAergic, adenosinergic, endocannabinoid, and other neurotransmitter systems. Presently, the development mechanisms remain poorly understood despite the presence of the considered theories of DIP pathogenesis.

Keywords: antipsychotic-induced parkinsonism; antipsychotics; drug-induced parkinsonism; pathogenesis; pathophysiology; theories of pathogenesis.

Figure 1

Theories for the development of antipsychotic-induced parkinsonism.

Figure 2

Pathways of dopaminergic neurotransmission. Note: VTA—ventral tegmental area; PFC—prefrontal cortex; NA—nucleus accumbens: SN—substance nigra; BG—basal ganglia (striatum); NAH—nucleus arcuatus (hypothalamus); MNH—middle nucleus (hypothalamus).

Figure 3

Schematic diagram of the excitatory and inhibitory ganglia involved in the development of AIP (Adapted from [25], Copyright year 2020, BMJ Neurol. Open). Note: Substantia nigra dopaminergic projections exert an exciting effect on stria-pallidal fibers of the direct pathway through dopamine D1 receptors, which leads to disinhibition of the thalamic nuclei and increased thalamocortical excitation, facilitating movements initiated by the cortex. The obstruction of voluntary movement occurs due to thalamic inhibition, due to the inhibition of stria-pallidal fibers in an indirect pathway through dopamine D2 receptors. The direct pathway is due to the activation of glutamate neurons in the sensorimotor cortex, and the indirect pathway is due to the activation of GABA-ergic neurons. The dotted line shows the inhibitory action due to the action of GABA. The straight line shows the excitatory effect due to the action of glutamate.

Figure 4

Distribution of A1 and A2A adenosine receptors in the human brain. Note: GPe—globus pallidus external; GPi—globus pallidus internal; STN—subthalamic nucleus; SN—substantia nigra; GABA—gamma aminobutyric acid.

Figure 5

Mechanisms of action of a 5-HT1A agonist in modulating extrapyramidal motility disorders (Adapted from [65], Copyright year 2012, Adv. Biol. Psychiatry). Note: GLU—glutamate; GABA—gamma aminobutyric acid; Ach—acetylcholine; DA—dopamine.

Figure 6

Candidate genes for the risk of developing antipsychotic-induced parkinsonism.

Figure 7

Pathogenesis of antipsychotic-induced tardive dyskinesia (Adapted from [119], Copyright year 2016, J. Exp. Pharmacol): Note: DA—dopamine; GABA—gamma aminobutyric acid; GSH—glutathione; SOD—superoxide dismutase.