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Neuroleptic-induced parkinsonism (NIP) is defined as parkinso-nian signs or symptoms (tremor, muscle rigidity, or akinesia) that develop in association with the use of an antipsychotic medica-tion. NIP is presumed to result from blockade of postsynaptic dopamine (D2) receptors in the corpus striatum causing a patho-logical state functionally resembling the loss of dopaminergic cells in the striatum in idiopathic Parkinson’s disease (PD). However, it is not clear whether nigrostriatal dopamine loss is adequate to explain the clinical symptoms seen in NIP or PD. It is possible that other neurochemical abnormalities may coexist with dopaminergic depletion to produce the syndrome. Abnor-malities in norepinephrine and serotonin have also been reported to be involved in the mechanism.
Positron emission tomography (PET) and other technolo-gies have been utilized to examine the relationship between D2 receptor blockade in the basal ganglia with antipsychotic efficacy and NIP. Clinically effective doses of conventional antipsychot-ics have been shown to block 70 to 90% of D2 receptors in the basal ganglia. Of note are findings that with conventional agents at least 60% occupancy is needed for satisfactory antipsychotic response but that NIP tends to occur with 80% or greater oc-cupancy of the D2 receptors. With regard to atypical agents, the lower D2 receptor blockade at recommended dosages with some agents and the serotonergic blockade seen with these medications are believed to lead to the reduced risk of NIP. Similar to conven-tional antipsychotics, higher doses of some atypical agents also appear to be related to an increase in NIP, as greater D2 receptor blockade has been reported.
The reported frequency of NIP varies from 5 to 90%, depend-ing on the study reviewed. This wide variation is due to differ-ent definitions of parkinsonism in different studies as well as the inclusion of mild bradykinesia as a sign of NIP in some in-vestigations. The usual incidence of “clinically significant” NIP with conventional antipsychotics is 10 to 15. When, however, high-potency conventional agents are used without anticholin-ergic drugs and signs of rigidity are carefully assessed, one is likely to find that the majority of patients have some NIP. Rates of parkinsonism induced by atypical antipsychotics are con-siderably lower (American Psychiatric Association, 2000). The incidence of NIP in older psychiatric patients is considerably greater. A study of newly medicated older patients on low doses of conventional antipsychotics found 32% of patients met criteria for NIP (Caligiuri et al., 1999). In an investigation of extrapy-ramidal side effects in patients with Alzheimer disease treated with very low dose conventional antipsychotics, 67% of patients met criteria for NIP at some time during the 9-month follow-up period (Caligiuri et al., 1998).
A number of patient-related and medication-related risk factors have been proposed. A history of prior episodes of NIP, older age, and concomitant dementia or delirium are thought to predispose to NIP (American Psychiatric Association, 2000). Neuroleptic potency and preexisting extrapyramidal symptoms may also increase the risk of NIP.
Rapid increases in antipsychotic dosage, administration of higher absolute doses of antipsychotics and absence of con-current anticholinergic medication represent other risk factors for NIP initiation (American Psychiatric Association, 2000). Highly anticholinergic antipsychotics (i.e., chlorpromazine and thioridazine) are less likely to cause NIP than less anticholinergic agents (i.e., haloperidol and fluphenazine).
NIP symptoms may develop quickly after the initiation of an antipsychotic or insidiously during the course of treatment. It most typically develops 2 to 4 weeks after antipsychotic initia-tion. The three cardinal symptoms of NIP are tremor, muscle ri-gidity and akinesia.
Parkinsonian tremor is a steady, rhythmical, oscillatory motion generally at an alternating rhythm of 3 to 6 Hz. The most affected body area tends to be the upper extremities, but the tremor may spread to the head, neck, jaw, face, tongue, legs and trunk. The tremor is typically suppressed during action and increases during times of anxiety, stress, or fatigue (American Psychiatric Association, 2000).
Parkinsonian muscle rigidity appears clinically as a firm-ness and spasm of muscles at rest that may affect all skeletal mus-cles or be confined to just a few specific muscle groups. It can ap-pear as a continuous lead pipe-type rigidity that resists movement or a cogwheel-type rigidity that presents a “ratchet-like” resist-ance when a muscle is moved around a joint. Cogwheeling may represent an extremely high frequency (8–12 Hz) “action” tremor that is physiologically imposed on the rigidity. The psychiatrist may diagnose cogwheel rigidity by placing his or her hand over the joint that is being passively moved. Generalized muscle pain, body aches and discoordination are features associated with NIP rigidity (American Psychiatric Association, 2000).
Parkinsonian akinesia is seen clinically as decreased spon-taneous motor activity and a global slowness in the initiation and execution of movements. It can be associated with drooling, bent over neck, stooped shoulders and masked facial expression (the so-called masked facies) (American Psychiatric Association, 2000). Parkinsonism occurs in numerous medical and neurologi-cal conditions and can be caused by many medications or sub-stances. Idiopathic PD can be difficult to distinguish from NIP.
The tremor of NIP must be distinguished from tremor caused by other conditions. In general, nonparkinsonian trem-ors are finer, faster and worse on intention. Tremor associated with substance withdrawal typically presents with associated hyperreflexia and increased autonomic signs. Cerebellar disease-induced tremor may present with associated nystagmus, ataxia, or scanning speech. Strokes and other central nervous system le-sions usually have associated focal neurological symptoms. NMS can often present with akinesia and lead pipe-type rigidity butalso has other associated findings, such as fever, elevated creat-ine kinase and fluctuating consciousness (American Psychiatric Association, 2000). It appears that TD and NIP frequently coex-ist in the same patient.
A number of primary psychiatric illnesses may mimic symptoms of NIP and may be difficult to separate. These include major depressive disorder, catatonic-type schizophrenia, mood disorder with catatonic features, schizophrenia with a predomi-nance of negative features, delirium, dementia, anxiety disorders and certain conversion disorders (American Psychiatric Asso-ciation, 2000). It may be particularly easy to confuse negative symptoms of schizophrenia and depression with the akinesia and rigidity of NIP. Catatonia and NIP may also be difficult to differentiate, and there is evidence that the two conditions are related to each other. Often, the diagnosis of NIP should be made provisionally and clarified by a dosage reduction of antipsychotic or trial of anticholinergic medication (American Psychiatric Association, 2000).
NIP symptoms usually continue unchanged or diminish slowly in 2 to 3 months after onset. The signs and symptoms typically improve with a dose reduction, discontinuation of antipsychotic medication, or switch to an atypical antipsychotic in patients pre-viously receiving a conventional antipsychotic. Improvement is also seen with the addition of antiparkinsonian agents.
Many milder cases of NIP do not require treatment because they are not bothersome to the patient. A switch to an atypical agent should be strongly considered if troublesome NIP develops while on a conventional antipsychotic. Large randomized controlled tri-als have demonstrated reductions in parkinsonian symptoms in patients treated with atypical antipsychotics. If symptoms become troublesome, the initial step should be to decrease the dose of antip-sychotic to the lowest effective dose for the patient. The next step is to add a low dosage of an anticholinergic medication. The equiva-lent of 2 mg/day of benztropine generally represents a reasonable starting point. Periodic attempts should be made to wean the pa-tient from the anticholinergic agent. As many as 90% of patients do not require anticholinergic medication at the end of 3 months. An-ticholinergic medication should always be tapered slowly to avoid the rapid redevelopment of parkinsonian symptoms as well as the possibility of uncomfortable cholinergic rebound symptoms.
Refractory cases of NIP do occur and may require more aggressive management. Increasing the dose of the anticholin-ergic medication is a good starting point because some patients may require up to the equivalent of 20 mg/day of benztropine to achieve relief from NIP. If such high doses are to be employed, they should be used for the shortest possible time, and rigorous attention should be paid to the possibility of untoward anticholin-ergic effects (i.e., delirium, urinary retention, fecal impaction). Consideration may be given to starting a dopamine-releasing agent, such as amantadine or perhaps even levodopa. A major concern with this treatment approach is the possibility of exacer-bating the psychosis for which the antipsychotic medication was prescribed in the first place. Trials of dopaminergic agents are therefore best attempted in an inpatient setting or with careful outpatient observation and assessment. A number of experimen-tal treatment strategies have been proposed for the treatment of the refractory cases including vitamin E, calcium supplementa-tion, electroconvulsive therapy and L-deprenyl.
Another treatment approach for the refractory case is to lower the dose of the antipsychotic medication or even discon-tinue it until the NIP resolves, then resume the antipsychotic (preferably a different one) at a lower dose. This treatment strat-egy may also need to be carried out in an inpatient setting to monitor early emergence of psychotic symptoms.
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