by CAROLYN O’DONNELL, PharmD; TAMMIE LEE DEMLER, BS, PharmD, MBA, BCGP, BCPP; EILEEN TRIGOBOFF, RN, PMHCNS-BC, DNS, DABFN;
and CLAUDIA LEE, MD

Dr. O’Donnell is with Edward Hines Jr. Veterans Administration Hospital in Hines, Illinois, and was with the New York State Office of Mental Health at Buffalo Psychiatric Center in Buffalo, New York, at the time of the study. Dr. Demler is with Department of Pharmacy Practice, State University of New York at Buffalo, School of Pharmacy and Pharmaceutical Sciences in Buffalo, New York; Department of Pharmacy, New York State Office of Mental Health at Buffalo Psychiatric Center in Buffalo, New York; and Department of Psychiatry, State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences in Buffalo, New York. Dr. Trigoboff is with SCH Pharmacy, SCH Medicine Department of Psychiatry at The State University of New York at Buffalo in Buffalo, New York. Dr. Lee is with Buffalo Psychiatric Center in Buffalo, New York.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article.

Innov Clin Neurosci. 2024;21(4–6):27–30.

Abstract

Introduction: Well-known adverse events of antipsychotics are movement disorders, or extrapyramidal symptoms, such as drug-induced parkinsonism and tardive dyskinesia. Objective: With new evidence suggesting a link between low high-density lipoprotein cholesterol (HDL-C) and risk of Parkinson’s disease, this study sought to investigate if that link also translated to patients taking antipsychotics with low HDL-C and an increased risk for developing a movement disorder. Design: Adult patients (n=89) at an inpatient state psychiatric facility taking at least one antipsychotic with at least one HDL-C level were assessed for signs of a movement disorder through their history and physical, progress notes, and Abnormal Involuntary Movement Scale (AIMS) score. Results: There was no statistical significance when comparing a patient’s movement disorder, AIMS scores, and HDL-C levels to suggest that the HDL-C level influenced a patient’s movement disorder. Conclusion: This study did not show a correlation between HDL-C levels and a patient’s risk of developing a movement disorder while taking an antipsychotic.

Keywords: Cholesterol, antipsychotics, movement disorders, HDL

There has been evidence suggesting a correlation between lower high-density lipoprotein cholesterol (HDL-C) levels and an increased risk of developing Parkinson’s disease (PD).^1,2 Low HDL-C levels are defined as less than 40mg/dL for men and less than 50mg/dL for women,³ and HDL-C levels higher than that contribute to better metabolic health. The mechanism of why or whether lower HDL-C levels may lead to PD is not entirely understood. Some of the symptoms of PD include bradykinesia, muscle rigidity, instability, and a resting tremor.⁴ Drug-induced parkinsonism can be caused by different medications, including antipsychotics, most notably first-generation antipsychotics.⁵ It is often difficult to differentiate between PD and drug-induced parkinsonism, since the two may present similarly.⁵ Since lower HDL-C levels have the potential to influence the risk of developing PD, this study sought to investigate if lower HDL-C levels might lead to an increased risk of movement disorders in patients taking antipsychotics. 

The brain contains the highest amount of cholesterol, with approximately 20 to 25 percent of the body’s cholesterol being found in the brain in glial cells, myelin, and neurons.^6–9 Myelin contains 70 to 80 percent of the brain’s cholesterol and is responsible for nerve fiber insulation, which speeds up nerve impulse conduction.¹⁰ HDLs are the most abundant form of lipoprotein found in the brain.⁶ However, no cholesterol in the brain comes from the body’s peripheral circulation.^7,9 Cholesterol produced in the brain can enter the body’s circulation and become metabolized by the liver.^7,9

There is a potential link between cholesterol and other neurological disorders, such as amyotrophic lateral sclerosis (ALS), Huntington’s disease, Alzheimer’s disease, mild cognitive impairment, and dementia.^6,8,9,11,12 Low HDL-C levels have the potential to impair memory, leading to some of these neurodegenerative diseases.⁶ There are also different hereditary diseases defined by mutations in cholesterol-related genes that impact neurological function.⁹ Low HDL-C and high total cholesterol have been shown to cause amyloid beta fibril formation, thereby causing amyloid plaques.⁶ A study by Svensson et al¹¹ showed that higher HDL-C levels were inversely associated with both mild cognitive impairment and dementia, compared to low HDL-C levels (odds ratio [OR]: 0.37; 95% confidence interval [CI]: 0.28–0.79). Lower HDL-C levels have also been associated with damage to the blood brain barrier.⁶ There is also evidence that HDL-C levels can influence neuronal degeneration due to anti-inflammatory and antioxidant effects of HDL-C.⁶

Lipids have been found to be involved in many of the different processes that are associated with PD, including oxidative stress, inflammation, endosomal-lysosomal function, immune reactions, and cellular stress.¹³ A study by Park et al¹⁴ found that patients who had the lowest baseline and mean HDL-C levels, as well as a greater amount of HDL-C changes over time, had a higher risk of developing PD. Patients with an HDL-C level less than 40mg/dL had a hazard ratio of 1.63 for developing PD, compared to patients with an HDL-C level greater than or equal to 60mg/dL. Park et al hypothesized that since HDL-C can lead to antioxidation and anti-inflammation, decreased HDL-C levels might lead to oxidative stress and inflammation, thereby creating a higher risk for PD.¹⁴ A study by Choe et al¹⁵ identified that there were lower HDL-C levels in patients with PD, but this did not correlate with decreased cognitive or motor functioning.

Two studies by Swanson et al­­­^1,2 suggest that lower levels of apolipoprotein A1 (ApoA1), a major protein that is found in HDL, might lead to an earlier onset of PD and more severe symptoms relating to motor control. Qiang et al¹⁶ also found that patients with higher HDL levels and ApoA1 were less likely to have PD at earlier ages for patients. Qiang et al also identified a correlation between lower ApoA1 levels and a decrease in dopamine transporters.¹⁶ Since antipsychotics often block dopamine, which can lead to movement disorders,¹⁷ this might explain a potential association between lower HDL-C levels and an increase in movement disorders.

However, to contrast these studies, Li et al¹⁸ found that patients with PD had higher HDL-C levels, which might be an independent risk factor for the disease. Another study by Cassani et al¹⁹ found that HDL levels were positively associated with the duration of PD, suggesting that PD might lead to some cardiometabolic protection. Bakeberg et al²⁰ identified that higher HDL levels were associated with worsening cognitive function for female patients, but not for male patients. A study by Huang et al²¹ did not find a link between HDL-C levels and PD.

Current literature shows a potential link between PD and HDL-C levels; however, the majority of the literature focuses on lower HDL-C levels leading to cognitive impairment, rather than impaired motor functioning. Although there is evidence suggesting a link between HDL-C levels and risk for PD, from our review of the literature, there are no other studies investigating the risk of antipsychotic-induced movement disorders in patients with low HDL-C levels. 

Common side effects of antipsychotics are movement disorders, or extrapyramidal side effects (EPS), which include parkinsonian symptoms; these movement disorders can lead to increased feelings of stigma among the patients.²² Symptoms of drug-induced parkinsonism include bradykinesia, muscle rigidity, instability, tremor, and salivation.²³ Drug-induced parkinsonism can occur in as many as 20 to 35 percent of patients taking antipsychotics and can be difficult to differentiate from PD.²² Drug-induced parkinsonism can differ from other movement disorders, such as tardive dyskinesia, in that parkinsonian symptoms typically appear after treatment initiation or dosage change.²² Tardive dyskinesia can appear after longer periods of antipsychotic drug therapy, and it is associated with symptoms that include lip smacking, facial grimacing, chewing, quickly blinking eyes, and tongue thrusting or protrusion.²² Parkinsonian symptoms are reversible, whereas tardive dyskinesia can be irreversible.²² Antipsychotics can also lead to other movement disorders, such as acute dystonic reactions, which include involuntary muscle contractions, and akathisia, which can lead to restlessness when trying to sit or stand still.²³ A study by Janno et al²⁴ investigated the prevalence of movement disorders in patients with schizophrenia taking antipsychotics. Their study identified that as many as 31.3 percent of patients had akathisia, 32.3 percent had tardive dyskinesia, and 23.2 percent had parkinsonism that could be attributed to antipsychotic use.²⁴

The best practice for evaluating changes in involuntary movement from baseline is using the Abnormal Involuntary Movement Scale (AIMS).²⁵ AIMS is specifically designed to test for tardive dyskinesia,²⁵ though many hospitals use it as their sole assessment for movement disorders. An AIMS assessment takes about 10 minutes, and it includes a five-point rating scale,²⁶ with higher numbers signifying more significant involuntary movements.²⁵ The assessment looks at different areas of the body, including the facial area, jaw, tongue, lips, upper extremities, lower extremities, and trunk area.^25,26

Patients with schizophrenia treated with antipsychotics are at higher risk for metabolic conditions, including dyslipidemia.²⁷ Antipsychotics also impact cholesterol by decreasing HDL-C and increasing low-density lipoprotein cholesterol (LDL-C) levels.²⁸ Patients with schizophrenia have evidence of decreased myelination and changes in white matter, suggesting that cholesterol might play a role in schizophrenia.^29–31 A study by Gjerde et al³¹ demonstrated that an increase in HDL levels might lead to an improvement in negative symptoms for patients experiencing first-episode psychosis. The objective of this study was to assess the impact on low HDL-C levels among adult patients at an inpatient state psychiatric facility taking antipsychotics and to determine their risk of developing a movement disorder.

Methods 

This study was approved by the New York State Office of Mental Health’s Institutional Review Board. Adult patients at an inpatient state psychiatric facility in August 2021 were assessed for their HDL-C levels and movement disorders, shown in the initial physical upon admission and through routine AIMS assessments and progress notes. There were 149 inpatients at the institution during the study, but 34 patients were excluded from the study due to their Criminal Procedure Law status, leaving 115 patients. Patients’ charts were retrospectively reviewed, and their HDL-C levels were averaged over each year due to some patients receiving HDL-C levels as often as monthly and others with HDL-C levels recorded only once yearly with their annual physical. Patients who did not have HDL-C levels or AIMS scores were excluded from the study, leaving a total of 89 patients enrolled in the study. HDL-C levels and AIMS scores were analyzed using a two-tailed t-test with unequal variance.

Results 

Empirically, there was concern that HDL-C level influenced a patient’s movement symptoms when taking an antipsychotic, but no one in the subject pool reflected that concern. There were 89 adult patients (aged 19–77 years), with the most common diagnoses being schizophrenia (n=47), schizoaffective disorder (n=37), and cannabis use disorder (n=18; Table 1). The most prescribed antipsychotics were olanzapine (n=38), clozapine (n=33), and haloperidol (n=18; Table 1).

Of the 89 patients in the study, 34 patients had low HDL-C levels, and only eight patients had an AIMS score greater than zero. The HDL-C levels ranged from 17mg/dL to 83mg/dL. There was no statistical significance when comparing a patient’s movement disorder, AIMS scores, and HDL-C levels to suggest that the HDL-C level influenced a patient’s movement disorder. 

Our study also sought to rule out additional confounding variables, such as trigeminal neuralgia, which is more prevalent in patients over 50 years of age, especially female patients.³² However, we did not see more movement disorders in this patient population. Patients’ iron levels were also analyzed because iron deficiency has been associated with movement disorders³³ and restless leg syndrome.³⁴ Unfortunately, most patients in this study did not have iron levels in their medical records; therefore, we were unable to determine whether iron levels influenced movement disorders in these patients.

Discussion 

Given the complexity of the psychiatric and medical conditions experienced by the patients in this study and the challenges associated with the medication regimens prescribed to address these conditions, we hypothesized that these patients are more likely to experience physiological issues, including movement disorders. However, there was no evidence of HDL-C levels influencing the patient’s movement disorders, as evidenced by their physicals, AIMS scores, and progress notes, at this inpatient state psychiatric facility. Establishing metabolic monitoring for overall health benefits and addressing abnormal findings with nonpharmacologic and pharmacologic interventions can reduce any potential association with adverse outcomes. Regardless, further research should be conducted to determine if HDL-C levels influence movement disorders for adult patients taking antipsychotics. 

Limitations. Within the inpatient state psychiatric facility, patients with lower HDL-C levels experienced movement disorders, which led to the initiation of this investigation. However, the patients of interest did not fall within the inclusion criteria of this study due to having Criminal Procedure Law status, so those patients were eliminated from the study. There was also a small study sample, with only eight patients having AIMS scores greater than zero. Another limitation is that some patients were already taking medications to mitigate movement disorders, which might have influenced their presentation. Also, with drug-induced parkinsonian symptoms, typically, symptoms show within the first three months of treatment, so patients who have been taking these medications for a longer period might not have shown signs of drug-induced parkinsonian symptoms, which might have manifested when they first began taking the medication. Patients at this facility are also only assessed for movement disorders using the AIMS assessment, so the results might have differed had they been assessed using other movement disorder scales designed for movement disorders but not including tardive dyskinesia. 

Conclusion 

This study did not show a correlation between HDL-C levels and a patient’s risk of developing movement disorders while taking an antipsychotic. It is our hope that our research  will support prioritized prescribing decisions focused more directly on removing offending medications, versus exploring hypothesized physiologic factors such as HDL-C, because earlier recognition of drug-induced movement disorders permits rapid intervention and decreased risk of permanently disfiguring and debilitating extrapyramidal symptoms. 

References 

1. Swanson CR, Berlyand Y, Xie SX, et al. Plasma apolipoprotein A1 associates with age at onset and motor severity in early Parkinson’s disease patients. Mov Disord. 2015;30(12):1648–1656. 
2. Swanson CR, Li K, Unger TL, et al. Lower plasma apolipoprotein A1 levels are found in Parkinson’s disease and associate with apolipoprotein A1 genotype. Mov Disord. 2015;30(6):805–812.  
3. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines [published correction appears in Circulation. 2019;139(25):e1182–e1186] [published correction appears in Circulation. 2023;148(7):e5]. Circulation. 2019;139(25):e1082–e1143.
4. Jankovic J, Tan EK. Parkinson’s disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020;91(8):795–808. 
5. Shin HW, Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8(1):15–21. 
6. Bahrami A, Barreto GE, Lombardi G, et al. Emerging roles for high-density lipoproteins in neurodegenerative disorders. Biofactors. 2019;45(5):725–739. 
7. Mahley RW. Central nervous system Lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler Thromb Vasc Biol. 2016;36(7):1305–1315. 
8. Jin U, Park SJ, Park SM. Cholesterol metabolism in the brain and its association with Parkinson’s disease. Exp Neurobiol. 2019;28(5):554–567. 
9. Martín MG, Pfrieger F, Dotti CG. Cholesterol in brain disease: sometimes determinant and frequently implicated. EMBO Rep. 2014;15(10):1036–1052. 
10. Hayashi H. Lipid metabolism and glial lipoproteins in the central nervous system. Biol Pharm Bull. 2011;34(4):453–461. 
11. Svensson T, Sawada N, Mimura M, et al. The association between midlife serum high-density lipoprotein and kild cognitive impairment and dementia after 19 years of follow-up. Transl Psychiatry. 2019;9(1):26. 
12. Hottman DA, Chernick D, Cheng S, et al. HDL and cognition in neurodegenerative disorders. Neurobiol Dis. 2014;72 Pt A:22–36. 
13. Xicoy H, Wieringa B, Martens GJM. The role of lipids in Parkinson’s disease. Cells. 2019;8(1):27.  
14. Park JH, Lee CW, Nam MJ, et al. Association of high-density lipoprotein cholesterol variability and the risk of developing Parkinson’s disease. Neurology. 2021;96(10):e1391–e1401. 
15. Choe CU, Petersen E, Lezius S, et al. Association of lipid levels with motor and cognitive function and decline in advanced Parkinson’s disease in the Mark-PD Study. Parkinsonism Relat Disord. 2021;85:5–10. 
16. Qiang JK, Wong YC, Siderowf A, et al. Plasma apolipoprotein A1 as a biomarker for Parkinson’s disease. Ann Neurol. 2013;74(1):119–127. 
17. Sethi KD. Movement disorders induced by dopamine blocking agents. Semin Neurol. 2001;21(1):59–68. 
18. Li J, Gu C, Zhu M, et al. Correlations between blood lipid, serum cystatin C, and homocysteine levels in patients with Parkinson’s disease. Psychogeriatrics. 2020;20(2):180–188. 
19. Cassani E, Cereda E, Barichella M, et al. Cardiometabolic factors and disease duration in patients with Parkinson’s disease. Nutrition. 2013;29(11–12):1331–1335. 
20. Bakeberg MC, Gorecki AM, Kenna JE, et al. Elevated HDL levels linked to poorer cognitive ability in females with Parkinson’s disease. Front Aging Neurosci. 2021;13:656623.
21. Huang X, Chen H, Miller WC, et al. Lower low-density lipoprotein cholesterol levels are associated with Parkinson’s disease. Mov Disord. 2007;22(3):377–381. 
22. Ward KM, Citrome L. Antipsychotic-related movement disorders: drug-induced parkinsonism vs. tardive dyskinesia–key differences in pathophysiology and clinical management. Neurol Ther. 2018;7(2):233–248. 
23. Mathews M, Gratz S, Adetunji B, et al. Antipsychotic-induced movement disorders: evaluation and treatment. Psychiatry (Edgmont). 2005;2(3):36–41.
24. Janno S, Holi M, Tuisku K, et al. Prevalence of neuroleptic-induced movement disorders in chronic schizophrenia inpatients. Am J Psychiatry. 2004;161(1):160–163. 
25. Guy W. Abnormal Involuntary Movement Scale (117-AIMS). FCDEU Assessment Manual for Psychopharmacology: Revised, 1976. Rockville (MD): US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administrations. National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976: 534–537.
26. Psychiatric Times. AIMS Abnormal Involuntary Movement Scale. 1 Apr 2019. https://www.psychiatrictimes.com/view/aims-abnormal-involuntary-movement-scale. Accessed 29 Jun 2022.
27. Gautam S, Meena PS. Drug-emergent metabolic syndrome in patients with schizophrenia receiving atypical (second-generation) antipsychotics. Indian J Psychiatry. 2011;53(2):128–133. 
28. Ono S, Sugai T, Suzuki Y, et al. High-density lipoprotein-cholesterol and antipsychotic medication in overweight inpatients with schizophrenia: post-hoc analysis of a Japanese nationwide survey. BMC Psychiatry. 2018;18(1):180. 
29. Bernstein HG, Steiner J, Guest PC, et al. Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy. Schizophr Res. 2015;161(1):4–18. 
30. Davis KL, Stewart DG, Friedman JI, et al. White matter changes in schizophrenia: evidence for myelin–related dysfunction. Arch Gen Psychiatry. 2003;60(5):443–456. 
31. Gjerde PB, Dieset I, Simonsen C, et al. Increase in serum HDL level is associated with less negative symptoms after one year of antipsychotic treatment in first-episode psychosis. Schizophr Res. 2018;197:253–260. 
32. Majeed MH, Arooj S, Khokhar MA, et al. Trigeminal neuralgia: a clinical review for the general physician. Cureus. 2018;10(12):e3750. 
33. Treloar AJ, Crook MA, Tutt P, et al. Iron status, movement disorders, and acute phase response in elderly psychiatric patients. J Neurol Neurosurg Psychiatry. 1994;57(2):208–210. 
34. Sun ER, Chen CA, Ho G, et al. Iron and the restless legs syndrome. Sleep. 1998;21(4):371–377.