Methylphenidate-Induced Akathisia in a Patient With Multiple Sclerosis (2006)

Sir: Methylphenidate is a short-acting psychostimulant that is structurally and pharmacologically similar to dextroamphetamine and is primarily used in the treatment of attention-deficit/hyperactivity disorder (ADHD).1,2 Its use has also been explored for the treatment of apathy and for augmentation of effects of antidepressants.3 It acts as a dopaminergic and nor-adrenergic reuptake inhibitor. Its dopaminergic activity has been implicated in causation of tics, choreiform disorder, and dyskinesias. Several reports1,2 have highlighted increased incidence of tics and dyskinesia in particularly vulnerable groups of patients such as children with ADHD. In previous reports,1,2 association of extrapyramidal symptoms (EPS) has been noted with chronic use of stimulants at high doses. This is the first report of EPS induced by methylphenidate in a patient with multiple sclerosis.

Case report. Ms. A, a 46-year-old white woman with a history of DSM-IV-TR major depressive disorder recurrent type and alcohol dependence in full sustained remission, presented to our clinic with apathy. Her psychiatric history included dysthymia and depression since age 18 years and an inpatient hospitalization for severe depression at age 25 years. The patient ever since had been treated in an outpatient setting and was currently being managed on a complex medication regimen including venlafaxine, mirtazapine, buspirone, and quetiapine that she felt worked best for her. Her medical history included nicotine dependence, chronic obstructive pulmonary disease, multiple sclerosis, and multiple pulmonary eosinophilic granulomas. The patient was taking several medications including tizanidine, oxybutynin, interferon-beta, hydrochlorothiazide, baclofen, diazepam, and clonazepam.

Ms. A also complained of memory problems. Initial cognitive testing yielded the following results: Mini-Mental State Examination4 score, 29/30; long-term memory score, 8/12; abstraction score, 3/4; judgment score, 2/2. Detailed neuropsychological testing (word fluency, some attentional tasks, response inhibition, and executive functioning) revealed evidence of impairment in frontal lobe functioning. Her apathy was assessed using the Apathy Evaluation Scale.5 She scored 47 on a scale of 18 to 72, with 72 being the worst apathy.

She was started on methylphenidate treatment at 10 mg twice a day for the treatment of apathy after discussing various treatment options. She reported feeling restless after the third dose of methylphenidate but continued to take the medication. By the fifth day of treatment, she described feeling as if wanting to crawl out of her skin and was restless and pacing. She took clonazepam and valium, which did not provide relief of her symptoms. Her left leg stiffened and tremors started in her left arm by day 6. She was taken to the emergency room and was given an intramuscular injection of benztropine, which resulted in immediate relief of her symptoms. She was instructed to discontinue methylphenidate and was given oral benztropine, which she took for a week. No recurrence of the above symptoms was noted.

Akathisia is a subjective feeling of motor restlessness with anxiety. The objective signs of restlessness include pacing, rocking back and forth, marching-like movements of the feet, and other repetitive, purposeless actions. Its etiology is poorly understood, although it is thought to be due to adrenergic excess. Treatment includes reduction in the dose or discontinuation of the medication causing akathisia. The typical agents used to treat EPS are not very effective in reducing symptoms of akathisia. β-Blockers, benzodiazepines, and less commonly, anticholinergics and antihistaminergics are used to treat akathisia.6

Stimulants are implicated in the production of tics and dyskinesias with an estimated incidence ranging from 1.3% to 60% in children treated with stimulants.7 Methylphenidate is similar to dextroamphetamine in pharmacologic properties, and both drugs have been shown to produce stereotyped behavior. In patients with alteration of postsynaptic dopamine receptor sites, an increase of dopaminergic activity together with altered receptor responsiveness exacerbated existing chorea.2

The patient in this report presented with symptoms suggestive of akathisia following the introduction of methylphenidate. These symptoms did not respond to benzodiazepines, which are usually the treatment of choice for akathisia. Symptom relief was obtained with the addition of benztropine, an anticholinergic agent. Our patient was also taking quetiapine, and although quetiapine has a low potential to cause EPS, her presentation could be due to the unmasking of latent EPS by the addition of methylphenidate.