Neurobiological mechanisms associated with antipsychotic drug-induced dystonia

Abstract

Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.

Psychomotor Symptoms in Chronic Cocaine Users: An Interpretative Model

“…While the reason for this effect is not completely clear, it is thought to be related to dopaminergic dysregulation and considered to be within the EPS group [64]. Dystonia, akathisia, and parkinsonism are known psychomotor symptoms related to central dopaminergic dysregulation [65], and in the case described, they appeared quickly, within a few days, causing a major impact on the quality of life. These EPSs were refractory to symptomatic treatments and regressed only after the suspension of the antipsychotics in use.…”

A Rare Case of Domperidone-Induced Acute Dystonia in a Young Adult Due to Consumption of Combination Drug (Proton Pump Inhibitors With Domperidone) and Its Possible Pathomechanism

“…Only a handful of cases of domperidone-related dystonia and tardive dyskinesia have been published as yet [ 2 , 3 , 8 ], largely in the pediatric population ascribed to under-developed BBB or the elderly age group where the BBB permeability adjusts due to altered protein expression amidst neuronal modulation [ 3 ]. Table 1 enlists few drugs studied to cause EPS [ 3 , 4 , 9 , 10 ] and Table 2 illustrates the differentials that can be contemplated while evaluating a case of drug-induced movement disorders (DIMD) [ 3 , 5 , 11 ].…”

“…Although the precise mechanism of drug-induced dystonia is still in dilemma [ 9 , 13 ], this could be explicated similar to the off-state of Parkinson’s disease (PD) (a hypokinetic state of PD), particularly off drug dystonic state or drug naïve dystonia cases of PD (implying non-dopamine state). The direct striatopallidal pathway goes inhibited and indirect one is activated relaying further to precipitate an outburst of neuronal excitability (high frequency discharge) of subthalamic nucleus (STN).…”

“…respectively, perhaps via upregulating or downregulating the NMDA and AMPA receptors [ 12 ]. Synaptic-plasticity is considered as an important neurophysiological phenomenon for memory forming from repetitive procedures in an attempt to endorse a skill and any unwanted neuroplastic alteration disrupting this synaptic input-output array could induce dystonia [ 9 , 12 , 13 ].…”

“…This was approved by FDA for Huntington chorea [ 17 , 18 ] but off label, it has been used extensively in many hyperkinetic movement disorder treatments namely dystonia, dyskinesia, and tics [ 18 ]. The current modalities of treatment of dystonia are summarized and enlisted in Table 3 [ 3 , 9 , 11 , 19 ].…”