Ms. P, a 63-year-old woman with a history of schizophrenia whose symptoms have been stable on haloperidol 10 mg/d and ziprasidone 40 mg twice daily, presents to the outpatient clinic for a medication review. She mentions that she has noticed problems with her “memory.” She says she has had difficulty remembering names of people and places as well as difficulty concentrating while reading and writing, which she did months ago with ease. A Montreal Cognitive Assessment (MoCA) is conducted, and Ms. P scores 13/30, indicating moderate cognitive impairment. Visuospatial tasks and clock drawing are intact, but she exhibits impairments in working memory, attention, and concentration. One year ago, Ms. P’s MoCA score was 27/30. She agrees to a neurologic assessment and is referred to neurology for work-up.
Ms. P’s physical examination and routine laboratory tests are all within normal limits. The neurologic exam reveals deficits in working memory, concentration, and attention, but is otherwise unremarkable. MRI reveals mild chronic microvascular changes. The neurology service does not rule out cognitive impairment but recommends adjusting the dosage of Ms. P’s psychiatric medications to elucidate if her impairment of memory and attention is due to medications. However, Ms. P had been managed on her current regimen for several years and had not been hospitalized in many years. Previous attempts to taper her antipsychotics had resulted in worsening symptoms. Ms. P is reluctant to attempt a taper of her antipsychotics because she fears decompensation of her chronic illness. The treating team reviews Ms. P’s medication regimen, and notes that she is receiving benztropine 1 mg twice daily for prophylaxis of extrapyramidal symptoms (EPS). Ms. P denies past or present symptoms of drug-induced parkinsonism, dystonia, or akathisia as well as constipation, sialorrhea, blurry vision, palpitations, or urinary retention.
Benztropine is a tropane alkaloid that was synthetized by combining the tropine portion of atropine with the benzhydryl portion of diphenhydramine hydrochloride. It has anticholinergic and antihistaminic properties1 and seems to inhibit the dopamine transporter. Benztropine is indicated for all forms of parkinsonism, including antipsychotic-induced parkinsonism, but is also prescribed for many off-label uses, including sialorrhea and akathisia (although many authors do not recommend anticholinergics for this purpose2,3), and for prophylaxis of EPS. Benztropine can be administered intravenously, intramuscularly, or orally. Given orally, the typical dosing is twice daily with a maximum dose of 6 mg/d. Benztropine is preferred over diphenhydramine and trihexyphenidyl due to adverse effects of sedation or potential for misuse of the medication.1
Second-generation antipsychotics (SGAs) have been associated with lower rates of neurologic adverse effects compared with first-generation antipsychotics (FGAs). Because SGAs are increasingly prescribed, the use of benztropine (along with other agents such as trihexyphenidyl) for EPS prophylaxis is not an evidence-based practice. However, despite a movement away from prophylactic management of movement disorders, benztropine continues to be prescribed for EPS and/or cholinergic symptoms, despite the peripheral and cognitive adverse effects of this agent and, in many instances, the lack of clear indication for its use.
According to the most recent edition of the American Psychiatric Association’s (APA) Practice Guideline for the Treatment of Patients with Schizophrenia,4 anticholinergics should only be used for preventing acute dystonia in conjunction with a long-acting injectable antipsychotic. Furthermore, the APA Guideline states anticholinergics may be used for drug-induced parkinsonism when the dose of an antipsychotic cannot be reduced and an alternative agent is required. However, the first-line agent for drug-induced parkinsonism is amantadine, and benztropine should only be considered if amantadine is contraindicated.4 The rationale for this guideline and for judicious use of anticholinergics is that like any pharmacologic treatment, anticholinergics (including benztropine) carry the potential for adverse effects. For benztropine, these range from mild effects such as tachycardia and constipation to paralytic ileus, increased falls, worsening of tardive dyskinesia (TD), and potential cognitive impairment. Literature suggests that the first step in managing cognitive concerns in a patient with schizophrenia should be a close review of medications, and avoidance of agents with anticholinergic properties.5
Prescribing benztropine for EPS
EPS, which include dystonia, akathisia, drug-induced parkinsonism, and TD, are very frequent adverse effects noted with antipsychotics. Benztropine has demonstrated benefit in managing acute dystonia and the APA Guideline recommends IM administration of either benztropine 1 mg or diphenhydramine 25 mg for this purpose.4 However, in our experience, the most frequent indication for long-term prescribing of benztropine is prophylaxis of antipsychoticinduced dystonia. This use was suggested by some older studies. In a 1987 study by Boyer et al,6 patients who were administered benztropine with haloperidol did not develop acute dystonia, while patients who received haloperidol alone developed dystonia. However, this was a small retrospective study with methodological issues. Boyer et al6 suggested discontinuing prophylaxis with benztropine within 1 week, as acute dystonia occurred within 2.5 days. Other researchers7,8 have argued that short-term prophylaxis with benztropine for 1 week may work, especially during treatment with high-potency antipsychotics. However, in a review of the use of anticholinergics in conjunction with antipsychotics, Desmarais et al5 concluded that there is no need for prophylaxis and recommended alternative treatments. As we have noticed in Ms. P and other patients treated in our facilities, benztropine is frequently continued indefinitely without a clinical indication for its continuous use. Assessment and indication for continued use of benztropine should be considered regularly, and it should be discontinued when there is no clear indication for its use or when adverse effects emerge.
Prescribing benztropine for TD
TD is a subtype of tardive syndromes associated with the use of antipsychotics. It is characterized by repetitive involuntary movements such as lip smacking, puckering, chewing, or tongue protrusion. Proposed pathophysiological mechanisms include dopamine receptor hypersensitivity, N-methyl-D-aspartate (NMDA) receptor excitotoxicity, and gamma-aminobutyric acid (GABA)-containing neuron activity.
According to the APA Guideline, evidence of benztropine’s efficacy for the prevention of TD is lacking.4 A 2018 Cochrane systematic review9 was unable to provide a definitive conclusion regarding the effectiveness of benztropine and other anticholinergics for the treatment of antipsychotic-induced TD. While many clinicians believe that benztropine can be used to treat all types of EPS, there are no clear instances in reviewed literature where the efficacy of benztropine for treating TD could be reliably demonstrated. Furthermore, some literature suggests that anticholinergics such as benztropine increase the risk of developing TD.5,10 The mechanism underlying benztropine’s ability to precipitate or exacerbate abnormal movements is unclear, though it is theorized that anticholinergic medications may inhibit dopamine reuptake into neurons, thus leading to an excess of dopamine in the synaptic cleft that manifests as dyskinesias.10 Some authors also recommend that the first step in the management of TD should be to gradually discontinue anticholinergics, as this has been associated with improvement in TD.11
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