Parkinsonism from neuroleptics

Lim TT, Ahmed A, Itin 1, Gostkowski M, Rudolph J, Cooper S, et al. Is 6months of neuroleptic withdrawal sufficient to distinguish drug-induced parkinsonism from Parkinson s disease Int J Neurosci 2013 123(3) 170-4. 

Trihexyphenidyl (Artane) and benztropine (Cogentin) are prescription drugs used in the treatment both of Parkinson s disease and the extrapyramidal side effects produced by neuroleptic medication. They are occasionally abused for their mind-altering properties, which occur at toxic doses (Perry et al. 1978). Abusers often try to obtain these drugs by false representation of extrapyramidal symptoms, which are claimed to result from the use of phenothi-azines or other neuroleptics (Rubinstein 1978). 

Effects similar to those of the neuroleptics have also been described for other dopamine-blocking agents. Thus, parkinsonism and tardive symptoms may result from use of metoclopramide, a drug which is commonly used to enhance gastric motility, or certain antiemetics, such as perphenazine. 

In CONCLUSION, the use of the "classical" neuroleptics, as exemplified by the phenothiazines, thioxanthines, butyrophenones and diphenylbutyl-piperidines, has been a landmark in the pharmacotherapy of schizophrenia and psychotic disorders. The efficacy of such drugs in the alleviation of the symptoms of schizophrenia is universally accepted. However, it is also evident that they have a spectrum of adverse effects that frequently renders their long-term use problematic. Side effects such as akathisia, Parkinsonism, tardive dyskinesia and the all too frequent changes in peripheral autonomic activity are largely predictable from the structure of the molecules and the basic animal pharmacology data. Such adverse effects, and the difficulties encountered when attempting to reduce their frequency and severity by concurrent medication, has stimulated the development of "atypical" neuroleptics such as clozapine and risperidone which, hopefully, will combine efficacy with a reduction in side effects. 

In addition to acute and chronic schizophrenia, the neuroleptics are sometimes used in the management of mania, delirium, and severe agitation, whatever the cause of these symptom complexes. It must be noted that unlike parkinsonism, where a definite dysfunction in the DA system has been established, for schizophrenia and other psychiatric diseases, no unequivocal evidence has yet been presented to prove that there is a disturbance of the DA system (e.g., dopaminergic overactivity or receptor hypersensitivity). In untreated schizophrenics the production of DA metabolites is normal. Conflicting results have been obtained in studies of the DA receptors in schizophrenics (11,12,13), but in the case of patients who have not received neuroleptics, the receptor density and affinity appear to be normal (13). The "dopamine hypothesis" in these disorders derives from the beneficial effects of drugs that block DA receptors. 

Circunstantial evidence directly implicating dopamine in the pathogenesis of duodenal ulcer in man is the unusual incidence of peptic ulcer disease in dopamine-deficient disorders. From purely descriptive clinical and epidemiologic studies we know that patients with Parkinson s disease, before the introduction of dopamine therapy, had an excess of ulcer disease (72). One report even comments on the curiosity that after initiation of L-DOPA administration the ulcer symptoms have virtually disappeared (72 ). On the other hand, less clearly, schizophrenia which is associated with dopamine excess and/or receptor hyperactivity is accompanied by virtual lack, or decreased prevalence, of peptic ulcer (73-76). Schizophrenia associated with ulcer disease has been viewed as a reportable curiosity in medical literature (75). At present, possibly because of the widespread therapeutic application of neuroleptics, the lack of peptic ulcer disease in schizophrenics is less striking than in the past. On the other hand, we recently observed in our autopsy series perforated duodenal ulcers in two schizophrenic patients who had been on large doses of haloperidol therapy (Szabo, unpublished observation). Thus, even in man, dopamine may indeed be implicated in the pathogenesis of duodenal ulcer disease. 

A report found that even small doses of Risperdal (average dose of 1.7 mg/day) produced or worsened acute extrapyramidal reactions in one-third of an elderly population suffering from dementia (Baker, 1996). Among 41 patients, 6 developed new parkinsonism, 5 had a worsening of previous parkinsonism, one developed cervical dystonia, and one developed neuroleptic malignant syndrome while also taking Tegretol and Mellaril. 

These acute EPS reactions often resemble TD, and indeed, the dystonias and akathisia can become tardive (persistent) disorders. All of them, including parkinsonism, result from neuroleptic effects on the dopaminergic neurotransmitter system in the basal ganglia. 

As more was written on the subject of negative symptoms the literature became blurred as to whether the symptoms discussed were related to state or trait (Sommers, 1985). To refine the concept, negative symptoms resulting from treatment (e.g., Parkinsonism related to neuroleptics), psychosis (e.g., elective mutism related to paranoia), institutionalization/monotonous routine, and/or related to depression were referred to as secondary negative symptoms (Carpenter et al., 1985). In contrast, primary negative symptoms were due to the illness itself. These enduring traits were labeled deficit symptoms (Carpenter et al., 1985). 

Parkinsonism and pseudoparkinsonism Parkinsonism or pseudoparkinsonism induced by neuroleptic drugs is clinically indistinguishable from postencephalitic... 

Lewy body disease Difficult to clinically distinguish from Alzheimer s disease at times and may coexist with Alzheimer s disease frequent fluctuations in cognition and behavior (can look like delirium but persists) tremor and rigidity similar to Parkinson s disease repeated unexplained falls unusual sensitivity to neuroleptic medications (more side effects). Lewy bodies are found in neurons at autopsy. 

The principal manifestations of phenothiazine toxicity involve the CNS and cardiovascular system. Signs of CNS toxicity include sedation, coma, respiratory depression (uncommon), seizures, hypothermia or hyperthermia, and extrapyramidal movement disorders (acute dystonia, parkinsonism, akathisia, tardive dyskinesia, and neuroleptic malignant syndrome) the extrapyramidal symptoms result from an imbalance between inhibitory dopamine and... 

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