Patterns and determinants of drug-related neurological problems in older outpatients: An exploratory analysis of a six-year long observational study in North India

Dear Editor,

Adverse drug reactions (ADRs) and poor compliance to therapy frequently cause hospitalization in older patients (Shah and Hajjar, 2012). So far, bleeding manifestations and metabolic disturbances have been projected as the major drug-related reasons for hospitalization in the elderly (Franceschi et al., 2008; Giardina et al., 2018; Pedrós et al., 2016). Older patients are also prone to drug-related neurological disturbances including sleep disorders, movement disorders, and delirium. However, studies investigating drug-related neurological problems have been scarce in the old. To fill the gap, we conducted a subgroup analysis of a six-year-long prospective study in the geriatric outpatient department of a large referral center in north India (Kaur et al., 2023). The study was conducted from January 2015–September 2021 and patients ≥ 50 years of age developing any drug-related problem (DRP) were enrolled (Pharmaceutical Care Network Europe, 2020). Specifically, for the present analysis, DRPs affecting the nervous system were assessed. Outcomes such as hospitalization and recovery were recorded. Among those with ADRs, patients at risk of drug-induced movement disorders (DIMDs) were identified.

In 10,400 patient registrations, 1031 DRPs (933 ADRs) were observed in 666 patients (Kaur et al., 2023). A total of 187 drug-related neurological issues were reported in 173 patients (1.8%), next only to metabolic disturbances (n = 206) (Table 1). Out of 187, 169 were ADRs and 15 problems were related to drug discontinuation. Sedation (47, 27.8%), tremor (24, 14.2%), and vertigo (20, 11.8%) were the three most common neurological ADRs. Altogether, 47 DIMDs were observed in 46 cases (27.8% of neurological ADRs). Calcium channel blockers (CCBs) including valproate, cinnarizine, amlodipine, cilnidipine, trimetazidine, and pregabalin were the commonest class associated with DIMDs (n = 19, 40.4% DIMDs) followed by antipsychotics (n = 10, 21.3%). Among 187 cases, 36 DRPs in 34 patients (19.3%) needed hospitalization and drug-induced extrapyramidal symptoms (EPS, n = 12, 33.3%) were the commonest reason. Non-antipsychotic drugs were involved in eight (66.7%) cases of EPS. Drug discontinuation and supportive therapy were required in 158 neurological ADRs and caused full improvement in 126 (79.7%). Mortality was recorded in one patient suspected of baclofen-associated seizures.

Table 1. Types of neurological drug-related issues, individual neurological ADRs, ADRs requiring hospitalization, and drugs involved

^$ Only common ADRs mentioned (total does not add up to 169)

^$$ Inclusive of all movement disorders (tremor, parkinsonism etc); this number includes individual ADRs also.

* Alone or in combination with other drugs.

^! In a case of baclofen-associated seizures.

^@ CCBs included valproate, cinnarizine, amlodipine, cilnidipine, trimetazidine, and pregabalin.

ADRs: adverse drug reactions, ARB: Angiotensin receptor blocker (^#telmisartan, olmesartan and losartan, each was involved in one case of vertigo, hence clubbed as ARB), CCB: calcium channel blocker, FGA: first generation antipsychotic, SGA: second generation antipsychotic

In unadjusted analysis, a significant association of DIMDs was observed with age, presence of dementia, parkinsonism, psychiatric diagnoses, and lung disease (p < 0.05). These factors were then included in the regression analysis. After adjusting for co-variates, older adults ≥ 65 years of age, patients with dementia, and patients with lung disease had 3.45, 5.76-, and 3.1 times higher odds of DIMDs, respectively (Supplementary Table 1). No significant interaction was observed between age, presence of dementia, and lung disease.

Drug-induced neurological disturbances were the second most common DRPs in older outpatients. Nearly 20% of drug-related neurological problems required hospitalization with DIMDs being the commonest cause. In few previous studies, neurological problems have been highlighted among the common causes of drug-related hospitalization in the old but with little information on their details and patterns (Giardina et al., 2018; Olivier et al., 2009). In a US-based study of 1999–2000, <5% of adverse drug events were accounted for by neuropsychiatric disturbances with only 0.3% contribution by EPS (Gurwitz et al., 2003). On the other hand, close to 20% of ADRs in the present study were neurological disturbances with 5% of ADRs being DIMDs. Among older adults with ADRs, a 3.5 times higher odds of DIMDs was observed in patients of ≥ 65 years of age. Those with dementia, and underlying lung disease had nearly 6 times and 3 times higher odds of DIMDs, respectively. Patients with dementia are often prescribed valproate and/or antipsychotics for the management of behavioral symptoms. Considering the risk of DIMDs and the subsequent risk of hospitalization, an individualized risk-benefit approach should be considered in such patients. Traditionally, antipsychotics are associated with maximum risk of EPS. On the contrary, CCBs were the commonest class associated with DIMDs including EPS in our study. These disparities might be related to specialty-specific lower prescribing trends of antipsychotics in our center. Interestingly, as per a recent study, CCBs shared a strong association with future idiopathic Parkinson’s disease in patients of drug-induced parkinsonism (DIP) (Jeong et al., 2021). Although causality could not be inferred due to our study design, it would be prudent to have additional vigilance for levosulpiride and cardiac calcium channel blockers such as amlodipine, cilnidipine, and trimetazidine. Levosulpiride is an easily available over-the-counter antiemetic and has been implicated in EPS ranging from DIP to the lethal neuroleptic malignant syndrome (Kaur et al., 2022).

The study is one of the first and the longest study on neurological ADRs in older outpatients. However, neurological ADRs occurring during hospitalization and the percentage of hospital admissions occurring due to neurological ADRs were not estimated. ADR rates were not calculated for patients with specific diseases. With multiple bivariate tests performed, the chances of type 1 error may be above 60%. However, this being an exploratory analysis, the same were conducted to find possible associations between independent variables and DIMDs. The regression results need cautious interpretation as the implicated risk factors might be related to prescribing trends. DIMDs were the most common neurological ADRs with CCBs as common culprits. Head-to-head comparisons with dopamine blockers may illustrate the relative risk of EPS. Mechanistic insights into movement disorders by CCBs and their interaction with dopamine blockers should be explored. An individualized approach is warranted when prescribing behavioral modifiers in older patients with dementia. The ethnicity-related differences in the predilection of older patients to neurological ADRs need investigation.