Which medications cause extrapyramidal side effects?

60.2.6 Motor parkinsonism

Extrapyramidal signs (EPS) are reported in 25–50% of DLB cases at diagnosis and 75–80% develop some EPS during the natural course. This means that up to 25% of patients with pathologically confirmed LB disease will have no clinical history of parkinsonism and clinicians must be prepared to consider and diagnose DLB in its absence. Originally said to ‘be mild and to appear late in the clinical course’, the profile of EPS in DLB is now generally thought to be similar to that in age‐matched non‐demented PD patients with regard to overall severity (Aarsland et al., 2001b). There is however greater symmetry and axial tendency, postural instability and facial impassivity but less tremor (Burn et al., 2003). The rate of motor deterioration on the Unified Parkinson's Disease Rating Scale (UPDRS) (Fahn and Elton, 1987) is about 10% per annum, similar to PD (Ballard et al., 2000a). Levodopa‐responsiveness is reduced in DLB compared with PD (Bonelli et al., 2004; Molloy et al., 2005), possibly due to additional intrinsic striatal pathology and dysfunction (Duda et al., 2002) and the fact that some of the parkinsonian features are non‐dopaminergic in origin (Burn and McKeith, 2004).

2.2.2.1 Extrapyramidal symptoms

Extrapyramidal symptoms (EPS) are primarily associated with excessive blockade of DRD2 and primarily a problem for the typical antipsychotics. Nevertheless, in addition to rs1124491 of DRD2, additional SNPs affecting different neurotransmitters have been identified to be associated with EPS. These include rs9567733 of HTR2A, rs363341 of the solute carrier family 18 member A2 (SLC18A2) gene that encodes vesicular monoamine transporter 2 (VMAT2), and rs1334802 of the glutamate ionotropic receptor kainate type subunit 3 (GRIK3) gene that encodes a kainic-acid type glutamate receptor (Mas et al., 2016).

Among the different EPS, tardive dyskinesia (TD) is a severe and often irreversible movement disorder that develops with long-term use of antipsychotics. Both positive (Guzey et al., 2007) and negative (Mihara et al., 2000b) association of the DRD2 gene rs1800497 Taq1A polymorphism have been reported with EPS in carriers of the A1 allele, whereas increased risk of TD was reported in two meta-analyzes for carriers of the A2 allele (Bakker et al., 2008; Zai et al., 2007). The conflicting results reported for association between DRD2 polymorphism and overall EPS versus TD risk (Bakker et al., 2008; Guzey et al., 2007; Mihara et al., 2000b; Zai et al., 2007) could be a result of sample size differences, lower A1 allele frequencies in Caucasians compared to Asians, as well as genetic variants in DRD1, since an imbalance between D1 and D2 receptors had been suggested to result in TD (Gerlach and Casey, 1988). The SNP rs4532 in DRD1 was shown to be significantly associated with TD risk in a study of 220 Chinese patients with TD and 162 Chinese patients without TD. The study result reported by Gerlach and Casey (1988) had also been confirmed in another study (Lai et al., 2011).

The DRD3 is also involved with the pharmacologic effect of antipsychotics (Sokoloff et al., 2006). Other than DRD1 and DRD2, a meta-analysis of data from 317 patients with TD and 463 patients without TD identified rs6280 of DRD3 to have a modest effect on TD association (Lerer et al., 2002). Similar association was also reported in another meta-analysis, although ethnicity seems to be a confounding variable, with a stronger association in non-Asians versus Asians (Bakker et al., 2006). Thus, ethnicity of subjects could play a role in the negative association reported by the CATIE trial and another meta-analysis (Tsai et al., 2010a,b). The COMT within the dopaminergic pathway also has been reported to play a role in TD, with the Val allele of the rs4680 polymorphism associated with modest risk (Bakker et al., 2008).

Positive TD associations with rs6313 polymorphism of the HTR2A gene have been reported in a pooled analysis of 256 patients with TD and 379 patients without TD, especially in the elderly. This suggests that 5-HT receptors could play a role in etiology of TD (Lerer et al., 2005). However, this association had not been demonstrated by an earlier study (Basile et al., 2001). It is also of note that all the positive association results with the dopaminergic and serotonergic system genes contrast the negative association with 128 candidate genes in 710 patients reported by Tsai et al. and based on analysis of samples from the CATIE study, even though as noted before, the CATIE was not designed as a pharmacogenomic study (Tsai et al., 2010a). Finally, the association of TD with rs2015586, rs363390, rs363224, and rs14240 of the SLC18A2 gene is particularly interesting (Zai et al., 2013), since valbenazine, a selective inhibitor of VMAT2, has been shown to decrease TD symptoms in patients with psychosis (Factor et al., 2017; Hauser et al., 2017). These association results show that a large number of genes affecting different neurotransmitters could have potential role in mediating risk of EPS, in particular TD. Given the clinical evidence for valbenazine, the role of SLC18A2 is of significance and warrants further studies.

Tetracyclic antidepressants

Extrapyramidal symptoms

Extrapyramidal symptoms were reported in an 87 YOF in China following initiation of donepezil 5 mg daily for the treatment of AD (Li et al., 2020) [A]. Her concurrent medications included amlodipine 5 mg daily for hypertension, glimepiride 4 mg daily for type 2 diabetes mellitus, methylcobalamin 1.5 mg daily for diabetic neuropathy, simvastatin 20 mg daily and aspirin 100 mg daily for arterial plaques, and calcium carbonate D3 600 mg daily for osteoporosis. After taking donepezil for 4 days at the prescribed dose, she experienced fatigue, sweating, and an episode of emesis. The following day, left-sided torticollis, indifferent expression, involuntary tremors of the upper limbs, and difficulty speaking were reported. No CT scan abnormalities were found, and no abnormalities in blood work including electrolyte levels, renal function, and hepatic function were present. Thus, the treatment team suspected donepezil as the causative factor and discontinued the medication. Following donepezil discontinuation, symptoms resolved and did not return, although the time-course of resolution was not provided by the authors. Based on the temporal relationship of donepezil with the development and resolution of symptoms, the authors concluded that donepezil was a possible cause for the extrapyramidal symptoms. The authors hypothesized that this patient may have been exposed to excessive plasma concentrations of donepezil despite a normal dosing regimen. Because donepezil is metabolized by the CYP450 system, the concurrent use of other drugs utilizing the CYP450 system including amlodipine, simvastatin, and glimepiride, may have led to competitive inhibition of donepezil metabolism. Additionally, authors noted that renal function declines with advancing age, so a decline in renal function may have also contributed to an increase in donepezil exposure. Of note, authors did not disclose the patient's renal test results but did note in the case presentation that there were no renal abnormalities present per kidney function tests. This case is unique in that the subject was not taking other psychotropic medications. In contrast, in the majority of prior case reports for AChEI associated movement disorders, the concurrent use of a psychotropic medication, such as an antipsychotic, was present (Liu et al., 2002 [A]; Diaz & Rosales, 2015 [A]; Mukku et al., 2018 [A]). The authors concluded that clinicians should be alert to rare adverse reactions of donepezil including extrapyramidal symptoms, even in patients not receiving concurrent psychotropic medications.

Organs and Systems

Selective serotonin reuptake inhibitors (SSRIs)

Movement disorders

Extrapyramidal symptoms (including akathisia, dystonia, dyskinesia, tardive dyskinesia, parkinsonism, and bruxism) have been reported in association with SSRIs, especially in the presence of predisposing factors [13]. Current data suggest that SSRIs should be used with caution in patients with parkinsonism (see the monograph on fluoxetine). Concomitant treatment with neuroleptic drugs and high concentrations of SSRIs seems to predispose to extrapyramidal symptoms. Elderly patients and women are also at increased risk.

It is believed that SSRIs produce movement disorders by facilitating inhibitory serotonin interactions with dopamine pathways. While all SSRIs are potent inhibitors of serotonin re-uptake, they have other pharmacological actions that might contribute to their clinical profile. Sertraline has an appreciable affinity for the dopamine re-uptake site, and for this reason might be presumed less likely to cause movement disorders than other SSRIs. However, there is little clinical evidence to support this suggestion and a case of sertraline-induced parkinsonism has been reported [14].

SSRI-induced movement disorders have been comprehensively reviewed [15]. The use of SSRIs was associated with a range of movement disorders, the most frequent of which was akathisia. However, clinician-based reports of adverse events solicited from SSRI manufacturers suggested that parkinsonism might occur with an equal frequency but with a later onset during treatment. As suggested before [16], concomitant treatment with antipsychotic drugs and lithium, as well as pre-existing brain damage, predisposes to the development of movement disorders with SSRIs. Case reports have suggested that akathisia can be associated with suicidal impulses.

Spontaneous reports received by the Netherlands Pharmacovigilance Foundation between 1985 and 1999 have been analysed in a case–control study [17]. Relative to other antidepressants, SSRIs were about twice as likely to be implicated in spontaneous reports of extrapyramidal reactions (OR = 2.2; 95% CI = 1.2, 3.9). The risk was greater in patients who were also taking neuroleptic drugs. This result suggests that SSRIs have a modestly increased risk of producing extrapyramidal reactions compared with other antidepressants. However, increased reporting can be influenced by increased awareness. In addition, no account was apparently taken in this study of relative prescription rates of different antidepressants.

Withdrawal of SSRIs usually results in remission of symptoms of extrapyramidal movement disorders. However, occasionally, SSRIs can unmask a vulnerability to Parkinson’s disease, and can also worsen established Parkinson’s disease [16] (see monographs on citalopram and sertraline) [18].

Drug-Induced Movement Disorders

•

Extrapyramidal Symptom Rating Scale (ESRS): 12-item instrument assessing four types of drug-induced MD: parkinsonism, akathisia, dystonia, and tardive dystonia. Using a 7-point response option for each item, it rates both frequency and movement amplitude. The ESRS has a 6-factor structure, which has shown satisfactory inter-rater reliability, convergent validity and sensitivity to change.

Simpson–Angus Scale (SAS): 10-item scale, with item scores ranging from 1 to 5, designed to assess the presence and severity of rigidity and bradykinesia. It is the most widely used scale for extrapyramidal symptoms in clinical assays. Thanks to its fast and easy mode of administration, it is also suitable for clinical practice. There are 1- and 4-item short versions.

Abnormal Involuntary Movement Scale (AIMS): This assesses MD (dyskinesia, akathisia, and chorea) associated with psychotropic medication. The AIMS is made up of 12 items scored from 1 to 5. Widely used in clinical assays as an outcome measure, this instrument registers good inter-rater and test–retest reliability, and convergent validity.

Which types of medications cause extrapyramidal side effects?

Which medication causes extrapyramidal reactions during treatment?

What are the 4 extrapyramidal symptoms?

What is an example of an extrapyramidal side effects?