Are extrapyramidal symptoms less recognized? Case report of modern practitioners' unfamiliarity with first generation antipsychotics

The case report was published in Pharmacotherapy February 2011 and presented as a clinical pearl at the CPNP Annual Meeting. In that presentation however. emphasis was placed on the pharmacokinetics of fluphenazine decanoate.

A case is presented where initial suspicion of lithium toxicity was truly drug-induced Parkinsonism and tardive dyskinesia. The mistaken diagnosis underscores the need to improve training for movement disorder assessment.

INTRODUCTION

First generation antipsychotics (FGAs) were discovered in the 1950's to manage patients with psychosis. Thirty years later, second generation antipsychotics (SGAs) were developed with the "atypical" features of reduced incidence of extrapyramidal side effects (EPS) and less hyperprolactinemia. A 2004 review estimated a 4.6% decrease in the annual incidence of tardive dyskinesia with the use of SGAs compared to FGAs; however, results may have been over-stated based on the moderate to high doses of haloperidol used in the trials.¹ The concern for both late onset (tardive dyskinesia) and early-onset (dystonia, akathisia, drug-induced Parkinsonism) EPS have been reduced with the prevalent use of SGAs. As a result, a generation of clinicians lacks clinical experience in both screening and diagnosing EPS leading to under-recognition and delayed intervention. The following case illustrates the continued risk for EPS and importance of training practitioners to develop a comfort level with screening, recognizing, rating, and managing drug-induced movement disorders.

CASE

A 55 year-old Caucasian male diagnosed with paranoid schizophrenia was transferred from a nursing home to a state psychiatric hospital due to suspicion of lithium toxicity and the nursing home's inability to care for his ongoing medical problems. Axis III diagnoses included type 2 diabetes mellitus, hyperlipidemia, hypertension, hypothyroidism, and obesity. The admission comprehensive metabolic panel, complete blood count, and thyroid panel were all within normal limits. Psychotropic medications on admission included aripiprazole 5mg daily, sertraline 50mg daily, and lithium 1200mg daily. The patient presented to the facility with a resting bilateral tremor, pill-rolling, stiffness, postural instability, extreme rigidity of major joints including cogwheel rigidity. The patient was immediately transferred to a medical hospital for evaluation of suspected lithium toxicity. The lithium plasma concentration, taken 12 hours post-dose, was 0.17 mEq/L, indicative of a non-toxic level. After excluding the possibility of lithium toxicity, the patient was transported back to the state psychiatric hospital 2 days later for further psychiatric evaluation with no intervention, assessment, or resolution of his profound movement disorder.

Antipsychotic-induced EPS was initially not suspected due to his current low dose of aripiprazole. After further investigation, medication history revealed that the patient had been previously treated with fluphenazine decanoate (FPD) 62.5mg every two weeks for several years. His last dose of FPD was 16 weeks prior to admission. The patient's continued presentation of severe EPS prompted the treatment team to then obtain a fluphenazine serum level. Drawn 17 weeks after his last injection, this patient had a detectable fluphenazine level of 0.6 ng/mL, using gas-chromatography, mass spectrometry methodology, providing a likely explanation for his severe EPS. Scheduled benztropine titrated to 4mg daily was added to his medication regimen with resolution of pseudoparkinsonism symptoms occurring within 72 hours. After successfully treating his drug-induced Parkinsonism, emergence of underlying tardive dyskinesia was identified. The patient scored a 26 on the Dyskinesia Identification System: Condensed User Scale (DISCUS), which is an assessment tool for tardive dyskinesia consisting of 15 items rated on a continuum of 0–4. The patient's tardive dyskinesia was overlooked at presentation due to suspected lithium toxicity. The individual was discharged after 9 weeks of hospitalization on aripiprazole 20mg daily, sertraline 50mg daily, and benztropine 2mg twice daily.

DISCUSSION

The aforementioned case describes a patient who was treated with FPD for several years, resulting in severe EPS that continued four months after the offending medication was discontinued. The pharmacokinetics of fluphenazine decanoate, including a review of the literature, and proposed theories of the drug's prolonged half-life, are beyond the scope of this paper and described elsewhere.² The severe bilateral tremor was mistaken for lithium toxicity, which resulted in delayed treatment of EPS, posing a major distress to the patient. Under-recognition of EPS may result in poor quality of life due to functional impairment, medication nonadherence, increased suicidality, potential behavioral disturbances, and misdiagnosis.³⁴

This case highlights the importance of being able to distinguish the differences between various types of tremor and potential adverse events while realizing the complexity of diagnosing movement disorders. In 1986, lithium tremor was described as "involuntary movement characterized by rhythmic oscillations of a part of the body", known as postural tremor and further categorized as an exaggerated physiologic tremor which is not associated with the occurrence of EPS.⁵ However it has been reported that in patients receiving chronic lithium treatment, the incidence of experiencing co-occurring EPS increases. Fine hand tremor occurring as a common side effect should be distinguished from the coarser hand tremor that may indicate lithium intoxication. Our patient developed a resting bilateral tremor, was on a relatively low dose of lithium, with no significant interacting concomitant medications, and showed no symptoms of neurotoxicity including ataxia, dysarthria, visual disturbances, or confusion. All of the above mentioned clues should have ruled out lithium intoxication early in the diagnostic process. In addition, lithium induced tremor can be distinguished from pseudoparkinsonian tremor by its association with voluntary movement and its lack of response to antiparkinson medications. In this case, the lack of knowledge by the multidisciplinary team surrounding drug-induced movement disorders, prolonged intervention and treatment of EPS.

The use of SGAs in current practice for the treatment of psychiatric and behavioral disturbances has resulted in greatly reduced clinical assessment, diagnosis, and teaching of EPS since the incidence and severity of EPS are lower with SGAs.¹⁶ Kuruvilla and colleagues reported on the deficit by surveying 143 psychiatrists in an attempt to explore the level of training in both recognition and assessment of drug-induced movement disorders.⁶ Results of the survey identified limited training (both formal and informal), low satisfaction in the extent and quality of training, little confidence in the assessment and management of EPS, and minimal training in the use of validated movement disorder rating scales. In addition, twenty years ago, even prior to the introduction of SGAs, studies highlighted the deficiency in documentation, assessment, and overall diagnostic skill in managing drug-induced movement disorders.^7–9 More recent data demonstrated that approximately 75% of psychiatrists reported only a half day or less of formal training received for drug-induced movement disorders and only 25% of psychiatrists received any training on the use of rating scales. Effective management of drug-induced movement disorders depends on the ability of the diagnosing clinician to detect EPS.

The need to increase the utility of rating scales in both the academic and clinical setting is apparent. The DISCUS, Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BAR/BARS), Extrapyramidal Symptom Scale, and Simpson-Angus Scale (SAS) are all tools that are necessary parts of the psychopharmacology residency curriculum. Not only do residents in training need to be educated on the importance of early detection of drug-induced movement disorders, but all disciplines in psychiatry need to develop these skills as well. This training could be accomplished with further didactic lectures on movement disorders in addition to screening requirements for all patients taking antipsychotics, first or second generation. Demonstrating proficiency in such skills should be incorporated into assessment of trainees. Increasing the amount of formal training, both didactic and in the practice setting, and gaining the ability to recognize and manage EPS, is essential to the practice of psychiatry.

As early as twenty years ago, practitioners were opening clinics specifically to prevent and manage drug-induced movement disorders. Opening pharmacist managed EPS or depot clinics in modern day is an avenue, which should be revisited. Mental health pharmacists are trained in this area and have the expertise to intervene and recommend treatment plans. The time needed to properly assess and manage drug-induced movement disorders could be achieved through pharmacist-run depot clinics. Continuing to take an active role as a valuable member of the multidisciplinary team is essential for the progression of our profession. In addition, the increase of SGA polytherapy and associated increased risk for EPS compared to SGA monotherapy heightens the need for continued vigilance in detecting drug-induced movement disorders.^10–12

CONCLUSION

The risk of neuroleptic-induced movement disorders continues to exist despite the prevalent use of SGAs over the past several decades and if undiagnosed can have a negative impact on patient care. Clinical psychiatric pharmacists should seize the opportunity to play an active role in detecting and managing these side effects. Efforts need to be made to reinstitute programs to train clinicians in developing a comfort level with screening, recognizing, rating, and managing EPS.