Extra-pyramidal side-effects are caused by anti-psychotic medications.  While these are more common with the more potent traditional anti-psychotics like haloperidol or fluphenazine (Prolixin), they can and do occur with the atypical anti-psychotics, especially risperidone, even occasionally with low potency traditional anti-psychotics (e.g. chlorpromazine, loxapine, and thiothixene).  The side-effects can include Parkinsonian tremors, muscular rigidity, and akinesia or a lack of movement.  The patient's facial movements may be so restricted as to appear as if the patient was wearing a rigid mask. There might be sudden muscle spasms of the head, neck, limbs, or trunk.  

Akathisia may also be present in the form of fidgety movements of the legs, rocking from foot to foot, pacing, or inability to sit or stand still.  There might be a powerful and uncomfortable feeling of inner restlessness. It has its own page since medication strategies may vary.

Benztropine (Cogentin) (2-6 mg once a day) is the most popular treatment and preventive medication used for EPS.  Its cost is currently 10 cents a tablet.  Unfortunately, as noted below, it causes more side-effects than some other alternatives.  Amantadine works just as well for EPS with fewer side-effects.  Its current price is 31 cents a tablet.  Propranolol, a beta-blocker high blood pressure medication, works as well or better for akathisia and costs as little as 1 cent a tablet.

Benztropine and trihexyphenidyle (Artane) are sometimes abused by patients and others for a type of drug high.

EPS, Akathesia, and Tardive Dyskinesia Common with Atypicals: Of 51 individual patient trials of atypical neuroleptic agents (17 risperidone, 13 olanzapine, 11 quetiapine, 8 ziprasidone, and 2 aripiprazole) in 37 bipolar patients (type I or type II) with an average duration of treatment was 25.5 weeks, 63% of trials resulted in moderate to severe EPS. EPS and discontinuation frequencies were similar between specific neuroleptic agents or between high potency (risperidone/ziprasidone/aripiprazole; 53%, 27/51 trials) and low potency (quetiapine/olanzapine; 47%, 24/51 trials) agents. Akathisia was less common with low potency agents. Younger age was associated with more akathisia. 31% discontinued due to side effects. 8% (4/51) of trials led to mild de novo tardive dyskinesia. Extrapyramidal side effects with atypical neuroleptics in bipolar disorder. Ghaemi SN, et al. Emory University. Prog Neuropsychopharm Biol Psychiatry 2006 Jan 10.

Amantadine As Good As Biperidin (Akineton): In a DB study of 42 patients treated with high dose haloperidol, amantadine 100 mg t.i.d. vs. biperidin 2 t.i.d. for four weeks, no difference was found in EPS although there were 2 dropouts with amantadine and 5 with biperidin. Anticholinergic treatment of neuroleptic extrapyramidal movement disorders (EPS) has been associated with induction of tardive dyskinesia. Also an increasing abuse of anticholinergics by schizophrenic patients is noted. Austria, Amantadine versus biperiden: a double-blind study of treatment efficacy in neuroleptic extrapyramidal movement disorders. Konig P, Chwatal K, Havelec L, Riedl F, Schubert H, Schultes H. Neuropsychobiol ‘96;33:80

Amantidine No Benefit for Essential Tremor: Increased Postural Tremor:  In a 15-day each DB PC crossover study of 16 patients with ET, amantadine 100 mg b.i.d. was of no benefit. An increase in postural tremor was reported by 37.5% on amantidine. Results from the present trial indicate amantadine at 100 mg b.i.d. is not effective as a treatment for ET. 2005 Oct 14

Amantadine Preferable to Trihexyphenidyl: DB cross-over 30 healthy volunteers. Trihexyphenidyl 4-8 mg/d vs. Amantadine 100-200 mg/d. Memories were more impaired with trihexyphenidyl which caused more discomfort, less vigor, more dry mouth, dizziness, confusion, and nausea. J McEvoy, Am J Psychiatry 87;144:573-7

Amantidine Helped Visuomotor Coordination: In a 3-week each DB PC crossover study of 29 adults with chronic schizophrenia or schizoaffective disorder, amantadine 200 mg/day improved visuomotor coordination, but no significant changes in cognitive functions were noted. Clinical symptoms, extrapyramidal side-effects and blood prolactin levels were not altered. The mechanism is more likely to involve glutaminergic NMDA than dopaminergic mechanisms. A double-blind, cross-over comparison of the effec Silver H, et al. Hadera, Israel. Int Clin Psychopharmacol. 2005 Nov;20(6):319-326.

Biperidin Impairs Memory More Than Amantadine: DB study 26 pts. Amantadine 200 mg/d vs Biperidin 4 mg/d. Biperiden treatment was associated with significantly lower scores on Benton Visual Retention Test (P < 0.003) and the visual subscale of Wechsler Memory Scale (WMS) (P < or = 0.02), with a trend to poorer scores on WMS total (P = 0.086) and the digit span (P = 0.07) and logical memory (P = 0.06) subscales. Israel, Effects of biperiden and amantadine on memory in medicated chronic schizophrenic patients. A Double-blind cross-over study. Silver H, Geraisy N. Br J Psych ’95;166:241

Benztropine Worse Side-Effects Than Amantadine: 60 healthy adults DB crossover amantadine 200/d vs benztropine 4 mg/d. Side effects in general were worse with benztropine, particularly such anticholinergic effects as dry mouth and blurred vision, and benztropine decreased measured salivary flow to a significantly greater degree than amantadine. MGH. Anticholinergic effects on memory: benztropine versus amantadine. Gelenberg AJ, Van Putten T, et al. J Clin Psychopharmacol 1989 Jun;9(3):180-5

Trihexyphenidyl Worse on Memory Than Amantadine: DB 9 patients with chronic schizophrenia. Differential memory function with dopaminergic versus anticholinergic treatment of drug-induced extrapyramidal symptoms. U Chic: Fayen M, Goldman MB, Moulthrop MA, Luchins DJ. Am J Psychiatry 1988 Apr;145(4):483-6

Amantadine Better Tolerated by Normals: In a DB PC study of 90 normals, anticholinergic antiparkinson drugs administered orally at standard clinically prescribed doses impaired new memory acquisition and mood based on tests of free recall, recognition memory, and time production, self-rating of memory function, and an evaluation of mood states. Elderly subjects were more severely impaired than were young adults. Amantadine did not impair new memory acquisition, and on self-report measures, it was significantly better tolerated. A double-blind crossover comparison of antiparkinson drug therapy: amantadine versus anticholinergics in 90 normal volunteers, with an emphasis on differential effects on memory function. McEvoy JP. J Clin Psychiatry 1987 Sep;48 Suppl:20-3

Switch-Over to Amantadine, When Successful, Better Memory: 22 schizophrenic patients on anti-cholinergics in a DB study were switched to either benztroptine or amantadine. Five of 10 were not adequately controlled on amantadine alone. Four of other five had improved memory testing at 4 weeks vs. 36% on benztropine. Replacement of chronically administered anticholinergic drugs by amantadine in outpatient management of chronic schizophrenia. McEvoy JP, McCue M, Freter S. Clin Ther 1987;9(4):429-33

First Study Showing Amantadine Better: A double-blind study of amantadine hydrochloride versus benztropine mesylate in drug-induced parkinsonism. Kelly JT, Zimmermann RL, Abuzzahab FS, Schiele BC. Pharmacology 1974;12(2):65-73

Amantadine: Amantadine does not exacerbate positive symptoms in medicated, chronic schizophrenic patients: evidence from a double-blind crossover study. Silver H, Geraisy N. J Clin Psychopharmacol 1996 Dec;16(6):463-4

Amantadine: Randomized controlled trial. No difference in the effect of biperiden and amantadine on negative symptoms in medicated chronic schizophrenic patients. Silver H, Geraisy N. Biol Psychiatry 1995 Sep 15;38(6):413-5

Amantadine: 32 stable schizophrenics on trihexyphenidyl in a DB PC study found no difference in the effect between biperiden and amantadine on parkinsonian- and tardive dyskinesia-type involuntary movements: a double-blind crossover, placebo-controlled study in medicated chronic schizophrenic patients. Silver H, Geraisy N, Schwartz M. J Clin Psychiatry 1995 Apr;56(4):167-70

Amantadine Helps Parkinson's But Wears Off Within Eight Months: In a DB PC trial of patients on levo-dopa for an average of 7 years but still experiencing difficulty, Amantadine resulted in a 45% decrease in symptoms within two weeks.  However, amantidine was discontinued in 3-8 months due to a waning of its benefit. Duration of amantadine benefit on dyskinesia of severe Parkinson's disease. Thomas A, Iacono D, Luciano AL, Armellino K, Di Iorio A, Onofrj M. J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):141-3

Amantadine: Several DB studies shows modest benefit of amantadine in treating multiple sclerosis. Rosenberg GA, Appenzeller O. Arch Neurol 1988 Oct;45(10):1104-6

Cyproheptidine Helped EPS, Not Psychosis: DB study 40 pt 6 wk. Lee, Korea, Int Clin Psychopharm ’95;10:67

Nefazodone Helped EPS, But Not Akathisia: Nefazodone, a relative of trazodone, blocks postsynaptic 5HT2A receptors and weakly inhibits serotonin reuptake. In a DB PC study of 49 patients on haloperidol 10 mg/d who developed EPS, nefazodone significantly reduced EPS as measured by both the Simpson Angus scale and CGI (p=0.007 and 0.0247) but akathisia and tardive dyskinesia did not differ between the two groups (p=0.601 and p=0.507). Efficacy of nefazodone in the treatment of neuroleptic induced extrapyramidal side effects: a double-blind randomised parallel group placebo-controlled trial. Wynchank D, Berk M. Witwatersrand University. Hum Psychopharmacol. 2003 Jun;18(4):271-5

74% Able Do Without Benztropine: Study of patients on maintenance benztropine for EPS. Gradual withdrawal found 26% needed reinstatement. Those on depot or over 1000 chlorpromazine equivalents least able. A study of the need for anticholinergic medication in patients treated with long-term antipsychotics. Caradoc-Davies G, Menkes DB, Clarkson HO, Mullen PE. Aust N Z J Psychiatry 1986 Jun;20(2):225-32

Benztropine Can Worsen Schizophrenia: Studied effect of benztropine on psychosis as part of an 18 patient haldol to chlorpromazine crossover study. Significant therapeutic reversal was observed with benztropine in terms of the social, affective, and cognitive dysfunctions characteristically seen in schizophrenic psychosis. The hallucinatory behavior and disturbed attention were not so affected. The effect was one of exacerbation of the disorder and not a toxic confusional state sometimes associated with anticholinergic drugs. Therapeutic reversal with benztropine in schizophrenics. Practical and theoretical significance. Singh MM, Kay SR. J Nerv Ment Dis 1975 Apr;160(4):258-66

CYP2D6 Variants Detect Poor Metabolizers: CYP2D6 genotype was assessed in 241 psychiatric patients for the five most common allelic variants ( CYP2D6*3, *4, *6, *7, *8) and the presence of gene duplication using allele-specific polymerase chain reaction. Data was analyzed on differences observed in pharmacy records concerning the different metabolic classes: ultra rapid metabolisers (UMs), extensive metabolisers (EMs) and poor metabolisers (PMs). For CYP2D6, 2.5% was UM (n=6) and 8.3% was PM (n=20). Drugs metabolized by CYP2D6 were less frequently prescribed in PMs than EMs (21.1% vs 33.6%, P=0.023). The average duration of prescriptions was significantly lower in PMs than EMs (54 days vs. 106 days, P=0.010). Between UMs and EMs, no significant differences were found, although a similar tendency was observed. With regard to dose, no consistent differences were observed between the CYP2D6 genotype classes. Drugs against Parkinsonian-like side effects were given twice as frequently in PMs as EMs (6.9% vs 3.4%, P=0.045). Dose titrations were not often used to compensate for genetic polymorphisms. Netherlands. Polymorphic drug metabolism (CYP2D6) and utilization of psychotropic drugs in hospitalized psychiatric patients: a retrospective study. Tamminga WJ, Wemer J, et al. Eur J Clin Pharmacol. 2003 May;59(1):57-64. (Ed: While it is currently too expensive to do this type of gene study, I expect that the costs of testing each patient's entire genome will be reasonable within the decade and be of great clinical benefit.)

Fluoxetine Akathisia: The typical fluoxetine-induced symptoms of restlessness, constant pacing, purposeless movements of the feet and legs, and marked anxiety were indistinguishable from those of neuroleptic-induced akathisia. Three patients who had experienced neuroleptic-induced akathisia in the past reported that the symptoms of fluoxetine-induced akathisia were identical, although somewhat milder. Akathisia appeared to be a common side effect of fluoxetine and generally responded well to treatment with the beta-adrenergic antagonist propranolol, dose reduction, or both. Tricyclic antidepressant-induced "jitteriness" may be identical. Fluoxetine-induced akathisia: clinical and theoretical implications. McLean:Lipinski JF Jr, Mallya G, Zimmerman P, Pope HG Jr. J Clin Psychiatry 1989 Sep;50(9):339-42

Thomas E. Radecki, M.D., J.D.

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