Parkinsonism antipsychotic-induced

Binder, R. L., Kazamatsuri, H., Hishimura, T. etal. (1987). Tardive dyskinesia and antipsychotic-induced parkinsonism in Japan. Am. J. Psychiatry, 144( 11), 1494-6. 

Both approaches are effective in therapy and may usefully be combined. It therefore comes as no surprise that drugs which prolong the action of acetylcholine (anticholinesterases) or drugs which deplete dopamine stores (reserpine) or block dopamine receptors (antipsychotics, e.g. chlorpromazine) will exacerbate the symptoms of parkinsonism or induce a parkinson-like state. 

Whether Asians are at greater risk of antipsychotic-induced parkinsonism is also uncertain. In one study, Asian patients developed symptoms of parkinsonism while taking lower weight-adjusted doses and exhibiting lower serum haloperidol concentrations in comparison with Caucasian patients (Lin et al. 1989). In contrast, another study found little difference between Asians and whites, with 40% of Asian patients developing parkinsonism within 2 weeks of initiation of haloperidol therapy, compared with 35% of Caucasians (Binder and Levy 1981). In a study conducted in Japan (Binder et al. 1987), the prevalence of antipsychotic-induced parkinsonism was found to be 18%-40%, comparable to rates reported in the United States. Thus the data concerning Asians are contradictory. 

Figure 1.12 Schematic model of a central cholinergic nerve ending indicating possible sites of drug action. Attempts have been made to increase acetycholine synthesis (CAT= choline acetyltransferase) by increasing availability of choline but this has not been successful (1). ACh is stored in vesicles but there are no clinically effective drugs that act at this site (2). There is some evidence that aminopyridines and phosphatidylserines release ACh and may have limited use in Alzheimer s disease patients (3). Muscarinic antagonists are usedfor Parkinson s disease and antipsychotic-induced extrapyramidal side-effects. Presynaptic muscarinic autoreceptors...

Greenbaum L, Smith RC, Lorberboym M, Alkelai A, Zozulinsky P, lifschytz T, et al. Association of the ZFPM2 gene with antipsychotic-induced parkinsonism in schizophrenia patients. Psychopharmacology 2012 220(3) 519-28. 

A number of other conditions must also be excluded, such as medication-induced parkinsonism (e.g., induced by antipsychotics, phenothiazine antiemetics, or metoclopramide). Other diagnostic criteria include lack of other neurologic impairment. 

On the other hand, the effects of two medications can counteract one another. The result is usually that both medications are rendered less effective. A common example is the patient with Parkinson s disease. On occasion, the L-DOPA that is the mainstay of treatment causes hallucinations. The treatment for hallucinations is an antipsychotic, which blocks the activity of dopamine. The problem is that using a typical antipsychotic to treat L-DOPA-induced hallucinations will interfere with the therapeutic effect of the L-DOPA, thereby worsening the symptoms of the Parkinson s disease. Fortunately, the advent of the newer atypical antipsychotics has provided a remedy to this particular Catch-22 drug interaction dilemma. 

Parkinsonism. As will be discussed later, dopamine-blocking antipsychotics and rarely other psychotropic medications can produce symptoms that resemble Parkinson s disease. This includes an expressionless face, slowed movement, and a stooped posture. In many respects, medication-induced parkinsonism resembles both depression and the negative symptoms of schizophrenia. Again, one must decide if it is the illness or the medication. Do you decrease the medication to remedy the side effect Or do you increase the medication to treat the illness, anticipating that a higher dose may prove more beneficial (though this is not always what is found) ... 

Tricyclic antidepressants are notorious for their risk to be involved in drug-drug interactions. Additive anticholinergic effects can be expected in combination with antihistamines, antipsychotics and anticholinergic-type anti-Parkinson agents. Hepatic enzyme-inducing agents increase their hepatic metabolism while enzyme inhibitors may potentiate the effects of tricyclics. Concomitant use with monoamine oxidase inhibitors will produce hypertension, hyperpyrexia and convulsions. 

Another form of parkinsonism is drug-induced, that is, iatrogenic parkinsonism, which often is a comphca-tion of antipsychotic therapy, especially following the use of the butyrophenone and phenothiazine drug classes (see Chapter 34). Unlike idiopathic parkinsonism, striatal content of dopamine is not reduced by administration of these drugs. In contrast, they produce a functional decrease in dopamine activity by blocking the action of dopamine on postsynaptic dopamine receptors. 

Of the drugs used for treating parkinsonism, the anticholinergics are the only class that can provide benefit in the treatment of the drug-induced parkinsonism seen with antipsychotic therapy. This is because the blockade of dopamine receptors by the antipsychotics leads to increased activity of the striatal neurons. Blockade of the muscarinic receptors reduces this excitatory activity. 

Occasionally, long-term use of lithium is associated with cogwheel rigidity and a parkinsonian tremor (189). More often than not, concurrent or past treatment with an antipsychotic drug is involved. In a review of SSRI-induced extrapyramidal adverse effects, lithium was listed, but not discussed, as a possible risk factor (190). A review of drug-induced parkinsonism provided references to case reports of lithium s occasionally inducing or exacerbating parkinsonism (191). 

All related disorders are attributed to a malfunction of the basal ganglia (which contain a rich array of neurotransmitters and receptors controlling muscular movements) and of the substantia nigra (where dopamine is produced). Dopamine is one of the brain chemicals involved in the control of physical movement, and Parkinsonism is characterized by dopamine depletion. Secondary Parkinsonism, in which symptoms are of a passing nature, is due to temporary dopamine depletion, induced most commonly by antipsychotic drugs. 

The classical antipsychotic (see p. 380) drugs block dopamine receptors and their antipsychotic activity relates closely to this action, which notably involves the Dj-receptor, the principal target in Parkinson s disease. It comes as no surprise, therefore, that these drugs can induce a state whose clinical features are very similar to those of idiopathic Parkinson s disease. The piperazine phenothiazines, e.g. trifluoperazine, and the butyrophenones, e.g. haloperidol, are most commonly involved. In one series of 95 new cases of parkinsonism referred to a department of geriatric medicine, 51% were associated with prescribed drugs and half of these required hospital admission. After withdrawal of the offending drug most cases resolved completely in 7 weeks. But... 

When drug-induced parkinsonism is troublesome, an antimuscarinic drug, e.g. benzhexol, is beneficial. Atypical antipsychotics provoke fewer extrap5nimidal effects (see p. 387). 

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