A statistically significant correlation was observed between subtypes of EPSs or OMDs and the patient characteristics of age, BMI category, and total ACB score (Table 4). Negative correlation coefficients were observed between age and akathisia (r = −0.365, P < 0.05) and dystonia (r = −0.269, P < 0.05), meaning that the likelihood of these subtypes of EPSs increased as age decreased. There was a noted positive correlation between TD and age (r = 0.274, P < 0.05). Body mass index category (underweight, normal, overweight, or obese) was negatively correlated with dystonia (r = −0.203, P < 0.05), indicating that the likelihood of dystonia was greater in underweight and normal weight patients as compared with overweight or obese patients in this population. Daily anticholinergic burden was also negatively correlated with dystonia (r = −0.170, P < 0.05), such that as anticholinergic burden increased, the incidence of dystonia decreased.
Fisher exact test was used to compare subtypes of EPSs or OMDs and dichotomous variables (female sex, DRBA overdose, etc) (Table 5). Odds ratios (ORs) greater than 1 indicate an increased likelihood of a certain subtype of EPSs or OMDs occurring in the presence of a given characteristic or exposure, whereas an OR of less than 1 indicates a decreased likelihood. Female sex, DRBA polytherapy, daily CPZE, and DRBA overdose were not found to be significantly associated with any subtype of EPSs or OMDs.
Statistically significant associations were, however, seen with individual DRBAs and the development of different subtypes of EPSs or OMDs. Clozapine (n = 9) exposure was highly predictive of NMS in this population (OR, 8.824; P = 0.004), whereas iloperidone (n = 10) and lurasidone (n = 9) were associated with an over 4-fold increase in the likelihood of NMS (OR, 4.370; P = 0.044) and parkinsonism (OR, 4.102; P = 0.046), respectively. First-generation DRBAs as a class were associated with a nearly 3-fold greater likelihood of akathisia (OR, 2.897; P = 0.021), likely driven by haloperidol exposure (OR, 2.790; P = 0.028). Akathisia was also more commonly observed in patients who were taking long-acting injectable (LAI) formulations of a DRBA (OR, 3.580; P = 0.034).
This study represents a pilot investigation describing the characteristics of patients seen within a community hospital system that experienced DRBA-related EPSs or OMDs. Descriptive analysis of the population as a whole revealed that these patients tended to be middle-aged, overweight females. Most were taking a single oral second-generation DRBA at a typical maintenance dose at the time of diagnosis, and overdose on these agents was not commonly associated with the patient's presentation. These findings are interesting to consider in the context of published literature describing a dose-dependent relationship for DRBA-related EPSs16,20–22,28,33 and linking risk of EPSs to factors such as dopamine D2 receptor binding affinity22 and association rate.34 Nevertheless, we know this interdependence to be complex and variable based on characteristics of the patient population and treatment. For example, aripiprazole demonstrates a dose-dependent risk of EPSs and other treatment-emergent adverse effects in children, but no noted dose-dependency for these effects in adults.35 Regarding treatment differences, the rates of EPSs for certain second-generation DRBAs such as risperidone and olanzapine positively correlate with dose,15 whereas others such as clozapine and quetiapine do not exhibit dose-dependency effects.22
The concept of dopamine blocking potency is important to consider when accounting for the differences in risk of EPSs or OMDs observed with each DRBA. First-generation agents such as haloperidol are believed to have a propensity to cause EPSs owing to their stronger dopamine blocking effects and lack of serotonin signaling.13,15,20,36 Analysis of the study population did indeed demonstrate that first-generation agents were associated with significantly greater odds of developing akathisia, which is supported by previously published findings.37 First-generation DRBAs are also associated with an increased risk of NMS because of their high dopamine binding affinity.38 However, under the current treatment paradigm, these medications are not used as commonly as second-generation DRBAs for chronic therapy, as reflected in the study population. Although the second-generation class purportedly possesses lower risk of EPSs overall, significant variability exists between agents.15,16,21,36 Clozapine and quetiapine have low dopamine receptor occupancy, whereas that of olanzapine is intermediate, and the binding of risperidone and ziprasidone is considered high.15,22 This corresponds to the risk of developing EPSs with exposure to each agent,20,39,40 with the exception of akathisia, which is thought to be equal across all second-generation agents.22 Besides this idiosyncrasy with akathisia, it has not been established if different presentations of EPSs or OMDs vary in their frequency with exposure to the individual DRBAs.
Analysis of the study population did in fact reveal significant associations between certain DRBAs and the subtype of EPSs or OMDs experienced by a patient. Haloperidol was discovered to confer excess risk for the development of akathisia and lurasidone for parkinsonism, both results which are supported by clinical trial data.41,42 The odds of a patient in the study population experiencing NMS were higher if they were exposed to iloperidone, a finding which supports the notion that greater dopamine blocking affinity is a precipitating factor for the development of NMS, as iloperidone is considered to have high dopamine D2 receptor binding affinity.43,44 Conversely, the association of clozapine with NMS does not follow this pattern, as clozapine is a low potency DRBA.45 This observation may instead reflect the fact that a large percentage of patients (40%) who experienced NMS while taking clozapine were prescribed multiple DRBA agents, which is a known risk factor for the development of NMS.25
It is important to consider these findings in the context of the single patient population in which they occurred. The reported ORs representing the risk of experiencing different subtypes of EPSs or OMDs with exposure to various DRBAs, for instance, are intended to be descriptive and not predictive. A larger or more statistically meaningful relationship for one DRBA than another does not imply that one agent confers a comparatively higher risk for a given outcome, only that in specific population studied, exposure to that agent resulted in a greater risk compared with no exposure. Haloperidol, for example, was found to have a significant positive association with akathisia, whereas lurasidone did not. Nevertheless, in our clinical experience, akathisia tends to be a relatively more problematic adverse movement reaction with lurasidone treatment than with haloperidol.
When examining associations between study population characteristics and subtype of EPSs or OMDs, age emerged as another important patient-related risk factor. Associations of age with dystonia and TD match those found in the literature.46,47 It appears that this work is the first to describe a statistically significant relationship between age and the development of akathisia with the use of DRBAs. To date, prospective cohort studies of community-dwelling patients with schizophrenia48 and literature reviews exploring the epidemiology of drug-induced akathisia49,50 have not been able to draw firm conclusions regarding age as a risk factor for akathisia. It is possible that including a wider age group of patients in the present study population (range, 14–96 years old) allowed for differences in akathisia risk to emerge. This result is intriguing and may provide additional insight into the mechanism and management of a poorly understood subtype of EPSs. Further investigation could assess the interplay of variables such as receptor sensitivity and body composition on the observed relationship of age and akathisia risk.
Another patient-specific factor found to be significantly associated with the risk of developing a specific subtype of EPSs was BMI category. Lower BMI category increased the odds of DRBA-related dystonia in the study population. Age and BMI category were not significantly correlated, so this effect was independent of the increased risk of dystonia seen in younger patients.51 One potential explanation is duration of therapy. Dystonia can occur immediately after administration of a DRBA, compared with weeks or months of exposure required to develop other subtypes of EPSs.46 Accordingly, it is less likely that these patients would have suffered significant weight gain from chronic DRBA use at the time of developing dystonia. It is also possible that there exists an interaction between DRBA-induced metabolic syndrome and the risk of EPSs that has not previously been identified. Assuming that dystonia, like other subtypes of EPSs, is related to total incident exposure, perhaps it could be related to BMI by way of alterations in some pharmacokinetic and/or pharmacodynamic factors related to nutrition, such as protein binding capacity, end organ function, CYP450 enzyme activity, epigenetic modifications, blood-brain barrier permeability, or vitamin/mineral status.52–57
It was surprising that the patient characteristic of sex was not observed to be significantly associated with a subtype of EPSs or OMDs in the study population, as previous research demonstrated that dystonia and NMS are more common in males, whereas parkinsonism and TD are more common in females.13,41 This unexpected outcome may have resulted from the relatively low number of males (n = 50, 33.8%) represented in the study group. There was also noted to be a significant correlation between age and sex in this population, such that males tended to be younger and females tended to be older. This intrinsic relationship may have influenced observed associations between age, sex, and subtype of EPSs or OMDs, and can offer an explanation as to why certain known risk factors were not detected in the study population.
The lack of an observed interaction with DRBA dose was also interesting to note. Daily CPZE was not found to be significantly associated with any subtype of EPSs or OMDs in the study population. The pathogenesis of EPSs is complex and likely results from activity at multiple different receptor subtypes besides simply dopamine D2. Chlorpromazine equivalent may therefore serve as more of a surrogate marker for EPS or OMD-inducing potential of DRBAs,31 which may explain why a clear association was not detected in the present study. It is important to note that many patients in this study were prescribed concurrent anticholinergic medications (33.1%) or benzodiazepines (38.5%), which can have mitigating effects on musculoskeletal dysfunction and are often used to treat EPSs or OMDs.15 As would be predicted, increasing anticholinergic burden was found to have a significant negative correlation with the development of dystonia in the study population. Overall, the lack of a dose-dependent effect as measured by number of agents, overdose, and daily CPZE suggests that the DRBA itself and specific characteristics of the patient taking it are more important in determining the subtype of EPSs or OMDs experienced than the dose.
This retrospective, outcome-driven study has several limitations. First, EPSs are known to occur spontaneously in patients with psychiatric disorders, independently of drug treatment58 and may be similar in terms of severity.59 There was no way to uniformly differentiate disease-related EPSs from drug-related EPSs in this study. It also failed to account for differences in diagnoses, which is significant because patients with mood disorders are observed to have higher rates of DRBA-related EPSs than patients with schizophrenia.17,60,61 Furthermore, DRBA route of administration was not controlled for in this study, which is known to influence the risk of EPSs. For example, EPSs incidence is believed to be lower for depot DRBAs than oral.28 In the study population, akathisia was more commonly observed in patients prescribed LAI formulations of a DRBA (OR, 3.580; P = 0.034), although this finding was likely a function of the specific agents available as LAIs. Of the 11 patients taking LAI DRBAs, 7 were prescribed paliperidone and 2 were prescribed aripiprazole. These particular LAI agents, paliperidone (Invega Sustenna [package insert]; Janssen Pharmaceuticals, Inc, Titusville, NJ) and aripiprazole (Aristada [package insert]; Alkermes, Inc, Waltham, MA), are associated with elevated rates of akathisia in patients taking typical maintenance doses. Finally, the number of DRBA-related EPS or OMD events observed in the study population compared with the number of inpatient encounters during the same time period where DRBAs were administered (148/31,461 = 0.5%) was significantly lower than published prevalence rates of EPSs or OMDs,16,62 which may limit generalizability of this research.
Understanding the nature of patient-treatment interactions can be helpful to predict which individuals might be at risk for developing certain subtypes of EPSs or OMDs related to DRBA therapy. Future directions for this research could include exploring additional patient characteristics such as markers of nutritional status (eg, albumin and vitamin D), as well as searching for risk factors associated with the development of other DRBA-related adverse effects (eg, hyperprolactinemia, hyperglycemia, hyperlipidemia, sedation, hypotension, anticholinergic, and QT interval prolongation). Ultimately, this information can assist clinicians with identifying at-risk patients, setting expectations to anticipate probable adverse effects, and using early intervention strategies aimed to improve adherence and overall outcomes with DRBA therapy.
The authors would like to acknowledge the collaborative contributions by Sun Lee, PharmD; Jessalynn Henney, PharmD; pharmacy students Megan Harshman, Amber Ooley, and Hayley Robertson; and medical students Gabe Martinez and Rohn Nahmias.
AUTHOR DISCLOSURE INFORMATION
The authors declare no conflicts of interest.
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dopamine receptor blocking agent; antipsychotic; extrapyramidal symptom; age; body mass index
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