Groningen Research Institute of Pharmacy, Pharmacotherapy, -Epidemiology and -Economics, University of Groningen, Groningen, The Netherlands.
Geestelijke GezondheidsZorg Westelijk Noord-Brabant (GGZ WNB), Mental Health Hospital, Halsteren, The Netherlands.
J Psychopharmacol. 2021 Jan;35(1):3-14. doi: 10.1177/0269881120944156. Epub 2020 Sep 9.
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.
迟发性运动障碍是最具侵袭性和使人致残的抗精神病药的锥体外系副作用。抗精神病药引起的迟发性运动障碍分为急性和迟发性两种形式。药物引起的迟发性运动障碍的发生率与抑制性多巴胺 D2 受体的亲和力有关。特别是急性迟发性运动障碍可以用抗胆碱能药物治疗，但迟发性运动障碍也可能对这种抗毒蕈碱治疗有反应，这与它们在迟发性运动障碍中的作用形成对比。将原发性局灶性肌张力障碍的病理生理学知识与锥体外系系统的解剖和药理学组织结合起来，可能有助于阐明抗精神病药引起的肌张力障碍的机制。一个合适的假设是基于这样的理解，即局灶性肌张力障碍可能是由于躯体感觉输入处理错误，从而导致经过良好训练的运动计划执行不当。通过特定复杂运动的训练，对锥体外系中型棘突投射神经元的刺激敏感性的神经可塑性改变，导致这些运动计划的复杂执行。多巴胺 D2 受体阻断导致间接通路中型棘突投射神经元的突然和非选择性去抑制，可能会扭曲这个过程。通过阻断毒蕈碱受体，阻断持续活跃的大型胆碱能中间神经元对所有中型棘突投射神经元的广泛影响，可能导致锥体外系皮质-纹状体-丘脑-皮质调节的影响减少。此外，纹状体胆碱能中间神经元在整合小脑输入与大脑皮层输出方面起着重要作用，也是影响多巴胺 D2 受体的黑质纹状体多巴胺纤维的靶标。
