By David N. Osser, M.D.
Chapter 10 in: Movement Disorders in Neurology and Neuropsychiatry, Second edition. Joseph AB, Young RR, eds. Boston: Blackwell; 1999. Reprinted by permission of Blackwell Science, Inc.
Introduction
Since the first version of this Chapter, the diagnosis and treatment of neuroleptic-induced pseudoparkinsonism (NP) have become of somewhat less concern. With the current availability of risperidone, olanzapine, and quetiapine, new antipsychotics associated with minimal NP, and the anticipation of additional similar agents in the near future, clinical and basic research on NP has declined. However, during the same period we have seen an increase in the influence of managed care on the availability and usage of medications by clinicians. Due to cost considerations, the older neuroleptics are still being advocated and sometimes required for first-line use. In addition, some practice guidelines endorsed by prominent experts still indicate encouragement of routine use of the standard, typical, NP-producing antipsychotics. [1] Hence, a thorough familiarity with their side effects and their clinical implications still seems essential for the prescribing clinician for at least the near future.
A few historical observations may be of interest. When chlorpromazine was first used in manic and schizophrenic patients in 1952, it was noted to be particularly effective in reducing excitement, but often the patients developed symptoms resembling Parkinson's disease, such as motor retardation, a wooden facial expression, and an unsteady gait. [2] In a review of the history of neuroleptic-induced extrapyramidal symptoms (EPS), Rifkin recalls that some early investigators assumed that this neurologic slowing was the cause of the patients' reduced excitement. [3] This notion was not supported by subsequent observations, such as the fact that antiparkinsonian drugs reduced EPS while generally not reducing the improvement in psychosis, and that some drugs developed later, such as clozapine, were effective antipsychotics but caused practically no EPS. [4] Hence, the parkinsonian syndrome came to be understood as a common but undesirable neurologic side effect of "typical" neuroleptics such as chlorpromazine and haloperidol.
Ayd's two surveys of EPS (1961, 1981) involving 8,775 patients helped establish the phenomenology of NP. [5,6] He and others [7,8] considered its essential features of tremor and rigidity to be quite similar to those of Parkinson's disease.
In this Chapter, the plan is to focus on the diagnosis and treatment of NP, and on the use of mild NP as a potential marker for the minimally effective antipsychotic dose of a typical neuroleptic. The latter may have applicability in the treatment of acutely psychotic patients. [9,10] At the conclusion, reference will also be made to the use of this marker in the assessment and treatment of patients with neuroleptic-resistant psychoses.
Diagnosis
Symptoms of NP were in the past regarded as being the last to appear of the three main types of EPS (dystonia, akathisia, and pseudoparkinsonism) that occur after treatment is commenced with a typical neuroleptic. [5,6] In the Ayd surveys, 90% of cases of pseudoparkinsonism occurred within the first 72 days. However, Ayd only recorded cases of moderate to severe NP, as indicated by the finding of a total incidence of only15%. [5] Efforts to define the more common, milder spectrum of NP have been frustrated by the difficulty in distinguishing mild akinesia from negative and catatonic schizophrenic symptoms or the motor retardation of depression in schizophrenia. [11] Despite these problems, it seems quite clear now that the large majority of patients treated with therapeutic doses of typical neuroleptics will show some signs of mild parkinsonism within the first few days of treatment if a careful examination is performed. [9] However, some patients are at greater risk for more severe NP at low doses. These risk factors include female sex (2:1 over males in all age groups except under 10 and over 80), increased age, children and adolescents [12], hyperthyroidism [13], family history of Parkinson's disease, and family history of affective disorder. [5,14]
Parkinsonian Tremor
Parkinsonian tremor is perhaps the most easily recognized sign of NP, but it tends to occur in patients with moderate to severe symptoms [15] and therefore is not particularly useful for identifying early and subtle cases. In contrast, patients with Parkinson's disease most often present initially with tremor. [16] The tremor is a regular, rhythmic, 4-8 per second (Hz) oscillation noted most often in the extremities, fingers, jaw, mouth, tongue, and lips. Tremor of the lips has been termed the Rabbit Syndrome, and although it may be confused with tardive dyskinesia because of the location, it is in all respects a typical parkinsonian tremor. [8,17] The tremors of NP and Parkinson's disease have both been described as occurring asymmetrically, with greater effect noted on the right side. [18] They occur characteristically when the affected body part is at rest and disappear temporarily with voluntary movement.
To examine for this tremor, the patient is observed with hands hanging unsupported between or in front of the legs. Also, the tongue is examined at rest in the floor of the mouth. The tremor is reduced or stops on initiation of movement. Tardive dyskinesia is also a resting tremor and it may be observed during this examination of resting body parts [19], but the choreiform and athetoid movements of this disorder should be sufficiently different in appearance from NP so that there will not be confusion between the two. Action tremors may also be noted as the patient initiates an activity during the examination. Such tremors are extremely common in psychiatric patients, and are often caused by high doses of the neuroleptic itself [15], or may be physiologic or essential tremors amplified by other drugs, caffeine, alcohol withdrawal, or other medical conditions. [15,20] Most are moderately rapid (8-12 Hz) and of small amplitude and so should be easily distinguished from the parkinsonian variety, although with increased age they may get slower and eventually assume the same frequency as the tremor of NP. They should still be recognizable as different from NP by the action occurrence, lack of accompanying bradykinesia or rigidity (to be described), and frequent presentation in the head as a whole or in the voice. [21]
Even if a parkinsonian tremor is not visually observed, there may be objective, easily-elicited palpable evidence of this tremor in the form of cogwheel rigidity. Cogwheeling is a ratchety pattern of resistance and relaxation noted by an examiner when a limb or joint with an underlying parkinsonian tremor is passively manipulated. It may be felt if the patient does not attempt voluntary movement at the joint, but it may disappear if the patient does move the joint, thereby recruiting the more dominant pyramidal tract influence on the muscles. Studies [9,10] have shown that the incidence of this sign in patients on clinical doses of a typical, high-potency neuroleptic is over 90% if the patient is carefully examined. It is often present even if the patient is on an antiparkinsonian agent such as benztropine. [22]
The diagnosis of cogwheeling is made more complicated, however, by the fact that metabolic or essential tremors are also associated with cogwheel rigidity. The cogwheeling from this kind of underlying tremor feels distinctly different from parkinsonian cogwheeling, however. Robert Stowe, M.D. of the Department of Neurology at Boston's Beth Israel Hospital (personal communication) suggested to us that the cogwheeling of metabolic or essential tremors is rapid, fine, ripple-like, and fluttery, whereas parkinsonian cogwheeling is slower, more coarse, and more ratchety, in correspondence to the slower frequency of the underlying tremor. With experience it has seemed possible to feel the difference between these two common kinds of cogwheeling, but objective proof that they can be validly differentiated is lacking.
A good examination for cogwheeling should include passive extension, flexion, and rotation at the wrist while the patient is performing some task with the other arm that requires concentration, such as writing his name in the air with the index finger or performing dysdiadokokinetic alternating hand movements on the knee. Both wrists should be checked in this manner. Parkinsonian tremors and associated cogwheeling are said to be more evident in distal as opposed to proximal joints (eg - wrist vs. elbow).
A brief description of how to place highly psychotic or paranoid patients at ease so as to examine for NP and other neurologic symptoms might be useful at this point. First, the examiner initiates a brief inquiry into the patient's subjective experience of medication side effects. Then, the patient is asked to extend his arms while the examiner observes at a distance for action tremors. Similarly, the arms are observed hanging unsupported. Next, as final preparation for the physical contact that the examiner will soon begin, the patient is asked if he is right or left handed. Then, the examiner asks the patient if he may now check his right arm and wrist for signs of stiffness. If the arm is held rigidly by the patient at first, the examiner verbally encourages him to relax and shakes the arm gently for a few seconds. It is rare that a patient will be uncooperative with this procedure.
Akinesia
Akinesia or bradykinesia (slowness of movement), the second major clinical feature of NP, is defined as a toxic behavioral state of diminished spontaneity, masked facial expression, absent arm swing, rigid and flexed posture, tiredness, emotional blunting, and poor social adjustment. [23,24] By this definition, it too seems to occur to some degree in most patients treated with a neuroleptic, especially when the high potency agents are used. [25] It also can occur to severe degrees, causing gait and posture disturbances and drooling. When akinesia is suspected, the presence of cogwheel rigidity may again provide confirmatory evidence of NP. McEvoy et al. [9,10] consider cogwheeling to be the "primary criterion" of hypokinesia, and Goetz and Klawans [8] also state that cogwheeling is useful in the differential diagnosis of akinesia, although they cite their experience that any parkinsonian feature can rarely occur without the others.
Patients with akinesia may also display a pattern of waxy or lead-pipe resistance to passive movement of the limbs. This "catatonic rigidity" is also a common side effect of neuroleptics, but not as diagnostically specific for NP as cogwheeling since catatonia is frequently seen in unmedicated psychotic patients. [26] Other probable synonyms in the literature for this rigidity include "gegenhalten" [16] and "generalized rigidity." Catatonia may be part of the negative symptom dimension in schizophrenia, and it is also frequently seen in patients with mania. [27]
Other reportedly useful correlates of subtle akinesia include a subjective sense of drowsiness (in 88% vs. 18% of controls) persisting 12 hours after ingestion of a bedtime dose of neuroleptic [28], and a very low frequency of spontaneous leg crossing when seated, seen in 80% versus 10% of controls. [29]
Differential Diagnosis
The differential diagnosis of NP includes primary parkinsonism (or a predisposition to it) co-existing with a psychotic disorder in the same patient. [30] This should not be common, given the 0.1 to 0.15% prevalence of parkinsonism in the general population [16] and 1.0% prevalence in patients over 60 years of age. [31] A 20 year follow-up of 200 NP patients from Ayd's first survey revealed that 3% developed apparent primary parkinsonism within five years after neuroleptics were stopped. [6] This certainly seems to exceed the expected chance occurrence rate, but Ayd only recorded moderate to severe cases of NP in his survey and this may have resulted in a selection for unusually susceptible individuals. Some of these represent cases of neuroleptic-induced persistent parkinsonism, which may be a form of tardive dyskinesia. [32,33] In one report, a series of such cases did not respond well to levodopa therapy. [34]
Recent studies have demonstrated that mild bradykinesia is frequently present in patients with schizophrenia who are first-episode and neuroleptic-naive. In three studies involving 134 patients, 18-24% had some parkinsonian rigidity or bradykinesia. [35-37] These patients seem to be at higher risk for developing NP when treated with a neuroleptic and their psychoses were less responsive to this treatment. [37] Baseline evaluation for this parkinsonism would appear useful for determining how much subsequently-detected parkinsonism is due to the neuroleptic.
These data regarding first-onset patients also suggest that parkinsonian signs may be linked in some fundamental manner to the "primary negative symptoms" of schizophrenia (i.e. - slowed movements, restricted range of affect, and decreased spontaneity and motivation) that have been associated with persistent disability. [38] "Secondary" negative symptoms are presumed to be due to NP and may respond to antiparkinsonian drug treatment or may improve with use of antipsychotics lacking NP side effects. However, distinguishing with certainty which negative symptoms are primary or secondary in any given patient may not be possible.
Some commonly prescribed drugs can cause parkinsonism-like symptoms. Lithium, which is well known for producing a non-parkinsonian action-type tremor, is associated with cogwheel rigidity, although studies vary widely in the frequency with which this is observed, from 5 to 75%. [39] The wide differences in reported incidence of cogwheeling may partly be due to residual effects from previous neuroleptic use in some of the patients studied. [40] Alternatively, it may reflect differences in examination technique: if distraction (as described earlier) is routinely employed, a much higher rate of detection of cogwheeling would be expected. We suspect that this cogwheeling is not parkinsonian but is the fine, "fluttery" type described earlier as being associated with metabolic tremors. Thus for patients on combined therapy with lithium and neuroleptics, cogwheeling can not be assumed to be derived from neuroleptic activity. Notably, these lithium patients described in the literature who had cogwheeling did not seem to have any detectable akinesia. [22]
Selective serotonin reuptake inhibitor antidepressants have been associated with rare reports of parkinsonism [41], which may be due to serotonin-mediated mechanisms in susceptible individuals. [42] However, fluoxetine did not aggravate symptoms of Parkinson's disease in a series of 14 patients. [43]
Metoclopramide [44], amoxapine, reserpine, and prochlorperazine are four drugs whose known neuroleptic effects are sometimes overlooked, and therefore they may seem to be associated with unexpected NP. Tricyclic antidepressants have also been reported to occasionally produce parkinsonian tremor. Goetz and Klawans [8] question these reports and state that all cases they have observed were action tremors and none were the tremors at rest of parkinsonism. Probably any such tremor on a tricyclic alone would be extremely rare.
Management
Treatment strategies for NP include dosage reduction, use of adjunctive symptomatic treatments, and substitution of "atypical" (ie - low parkinsonism-inducing) neuroleptics. [45] Management of NP in patients on long-acting injectable neuroleptics with dosage reduction is especially important. These individuals usually have a history of non-compliance with oral medication. If they are non-compliant with their oral antiparkinsonian medication, they develop even worse NP and akathisia, and they may then be even more reluctant to accept neuroleptic therapy. The ideal approach would be to initiate with the lowest possible dose of injectable medication because subsequent lowering of an initially high dose will result in a significant number of relapses [46,47] It would be a testable hypothesis that the better candidates for dosage reduction without danger of relapse would be patients who manifest moderate or greater NP. They may have some room to go down on side effects without substantial loss of therapeutic effects.
The patient with moderate or greater NP and marginally-controlled aggressive behavior presents a clinical dilemma, however. Clearly, there is a risk of further decompensation if the dose is lowered. The clinician would probably be inclined to actually increase the dose if it were not for the considerable toxicity already present. If immediate exacerbation of psychosis occurs when the dose is lowered slightly, this may exemplify rebound "supersensitivity" psychosis. [48] Other patients who decompensate when the dose is lowered might be neuroleptic non-responders whose apparent improvement so far is due to non-specific sedation, milieu factors, or to physical restraint of the patient by neuroleptic-induced akinesia. Despite the risk of decompensation, it may be reasonable to try to avoid the high risk of tardive dyskinesia associated with more persistent NP [49], which especially applies if the patient is affectively ill. [50] Addition of anticonvulsants (eg- carbamazepine, valproic acid, or clonazepam) may make it easier to lower the neuroleptic and may help the psychosis as well. [51,52]
As noted earlier, NP symptoms sometimes increase when neuroleptics are withdrawn. [33]. Also, it is commonly observed that NP symptoms may disappear at high doses of high potency neuroleptics. Taken together, these observations suggest that clinicians should be prepared to find a "window" dose-response relationship for NP as high potency neuroleptic dosage is changed. This may be the net effect of dose-related interactions with presynaptic and postsynaptic dopamine and serotonin receptors. It also may involve the induction of homeostatic changes. [53]
Adjunctive drug treatments for NP are employed routinely. However, they have significant adverse effects which limit their usefulness, especially in patient with severe NP. Thus, initial reduction of neuroleptic dosage may be critical to getting the optimal cost-to-benefit ratio from neuroleptics. Knowledge of the pharmacokinetics of antiparkinsonians can also help optimize their usefulness. Benztropine's half life is not known but it appears to be quite long, judging by its common successful usage on a once or twice a day basis. In one withdrawal study, its effects seemed to persist on average about twice as long as its competitors. [54] By contrast, trihexyphenidyl's known four hour half life [55] suggests that twice-a day dosage may be insufficient for many patients to maintain control over symptoms. With both drugs, frequent practice of giving the entire daily dose at bedtime results in many patients being quite uncomfortable by late afternoon the next day. Thus, the schedule of administation of these agents may be critical to maximizing their benefits.
Amantadine has received some support as a potentially superior antiparkinsonian agent because of its much lower incidence of memory loss and other central as well as peripheral anticholinergic side effects, compared to the antimuscarinic agents. [56,57] However, these studies used a relatively large dose of the latter compared to the amantadine (eg - two mg of benztropine being considered equal to 100 mg of amantadine, whereas one mg would have been the correct equivalence). In another comparative study, stabilized psychotic patients were blindly switched to amantadine or benztropine from their maintenance antiparkinsonian agent. They frequently developed more severe NP on amantadine. [58] Another concern with amantadine is that it may occasionally exacerbate schizophrenic symptoms, perhaps because of its dopamine agonist properties. [59] There was also a report of a fatality in a 34 year old man who overdosed on twenty 100 mg tablets. [60] However, a recent study comparing amantadine to biperiden, another widely used treatment for NP, found equal efficacy. [61] Overall, amantadine may well have fewer side effects and it perhaps deserves to be tried more often especially in milder cases of NP or following dosage reduction, rather than considering it as a second line agent for severe or refractory symptoms. This particularly applies to the elderly patient.
Early clinical [62] and animal model studies [53,63] suggested that tolerance to NP developed, and that after several months the antiparkinsonian agents could usually be stopped. However, it has become clear that for most patients maintained on typical doses of neuroleptics, the antiparkinsonian agents cannot be withdrawn without eventual (in up to four weeks) recurrence of uncomfortable NP and/or rebound dysphoria. [54,64] Despite this, periodic attempts to remove these agents still seem justified, especially if the antiparkinsonian was originally begun prophylactically and the patient never developed obvious NP.
Besides dosage reduction and adjunctive medication, the predominant strategy today for dealing with NP is switching to an antipsychotic with a low incidence of these side effects. In the past, the older neuroleptics thioridazine or mesoridazine (the latter an active metabolite of thioridazine) were considered to have the least NP and were often employed for this purpose. They are sometimes better tolerated, overall. Mesoridazine might occasionally have slightly superior efficacy, as well. [65-67] Slight superior efficaty is also claimed for the newest antipsychotics: risperidone, olanzapine, and sertindole, at least for secondary negative symptoms which may be related to NP and other EPS. [68-70] The new antipsychotics have become the routine choices today for patients who are sensitive to NP. All show placebo-level frequency of NP in their optimal dose ranges, with some increase of NP above placebo level in the upper range of approved dosage. It should be noted that "placebo level" frequencies of NP in these studies are 10-20%. This is due to the incomplete washout of previous typical neuroleptics prior to the double-blind phase. The real incidence of NP with low to moderate doses of the three new agents in drug-naive patients is unclear, it is probably significantly greater than zero. It is not possible at this time to distinguish if any of the three has significantly less NP than the others.
Clozapine, by contrast, causes practically no NP or tardive dyskinesia. It also clearly provides superior efficacy in patients resistant to typical neuroleptics. In the now classic Kane et al multicenter controlled study of 268 chronically psychotic patients who had failed on several neuroleptics (including an especially good trial of haloperidol during the lead-in phase of the study), clozapine produced significant improvement in 30% versus only 4% in a control group given chlorpromazine. [71] Clozapine is indicated for patients whose response has been unsatisfactory to two adequate trials of standard neuroleptics. Clozapine may also be used in patients who get severe NP and other EPS from all neuroleptics, or who have severe tardive dyskinesia.
Clinical Applications of Basic Science
It is thought that NP results from dopamine-type 2 (D2) receptor blockade in the corpus striatum (a part of the extrapyramidal motor system), and it has been proposed that antipsychotic effects derive from blockade of similar D2 receptors in the limbic nuclei and areas of the prefrontal cortex which have been associated with emotional behavior. [72] Typical neuroleptics block D2 receptors simultaneously and with equal affinity in both systems [73,74], although there are differences among them in the effects on other neurotransmitter systems, such as those involving serotonin, norepinephrine, acetylcholine, gamma-amino butyric acid, and various peptides. These neurotransmitters may interact with dopaminergic transmission and affect the expression of clinical NP. [75] This probably accounts for the low incidence of parkinsonism with clozapine and some of the newer antipsychotics.
In rat brain, typical neuroleptics produce an immediate postsynaptic D2 receptor blockade, and then gradually over the course of several weeks, the presynaptic striatal and ventral tegmental (limbic) neurons stop firing. [76] This "depolarization block" could be the neurophysiological correlate of both the NP and the antipsychotic effects of typical neuroleptics, with the two occurring simultaneously. [77] If this is so, clinical overlap of NP and antipsychotic effects might be expected to occur with these neuroleptics. McEvoy [10] suggested that even minimal NP could reflect the early induction of depolarization block in striatal and limbic neurons and could predict ultimate occurrence of antipsychotic effect over the next several weeks in patients who are capable of an antipsychotic response to neuroleptics. This corresponds to the common clinical experience that once an adequate antipsychotic dose is achieved, patients usually proceed gradually to improvement without need for further increase in dose.
Positron emission tomography (PET) studies have refined these concepts. Blockade of striatal D2 receptors with occupancy of above 80% using typical neuroleptics such as haloperidol produces potent NP and antipsychotic effects simultaneously. [78] However, at occupancies of 50-80% the NP effect is minimal but strong antipsychotic effects still occur. [79] The dosage of oral haloperidol that produces 50-80% occupancy of D2 receptors is 2-4 mg per day, particularly for first-episode patients. This appears to be the dose (or equivalent dose with other neuroleptics) that clinicians should use to initiate treatment with psychotic patients when using the typical neuroleptics in order to maximize benefits while minimizing NP. Other neurobiological lines of evidence support the dosage of 2-4 mg per day. [80,81]
A variety of clinical reviews have also emphasized that more modest doses of standard neuroleptics, by comparison with the higher doses typically used, are both more effective and produce decreased EPS including NP. [82,83] However, routine use of a low dose is not a sufficient strategy: the reviews make it clear that in prospective studies with fixed low doses, more treatment failures or relapses occur along with the benefit of less NP. Perhaps the best way of determining the ideal dose for any individual patient is to utilize the "neuroleptic threshold" approach; this involves finding the dose which produces minimal but clinically detectable NP. It is a dose which can be expected to produce substantial and close to maximal antipsychotic effects while by definition keeping NP to a minimum. [84,85]
McEvoy et al. [9,10,85-87] have provided support for utilizing this technique. Somewhat similar investigations have also been reported by others with perphenazine. [88] Using haloperidol, McEvoy's group has used a simple rating instrument [9] for the presence of NP, which emphasizes a clinical examination for cogwheel rigidity similar to what was described earlier in this chapter. With acute treatment, they checked for NP daily as haloperidol, started at 2 mg per day, is increased by 2 mg every other day. [9] A neuroleptic threshold was identified in 44 of 47 patients (94%) at a median dose of 4 mg per day (most were between 0.5 and 10 mg per day). The rate of moderate or better response for patients at neuroleptic threshold, who had a history of five or fewer previous hospitalizations, was 82% (27 of 33 patients). The results with patients who had more than five previous admissions were that only 33% improved (3 of 9 patients). Fairly small amounts of lorazepam was used as an adjunctive sedative medication when needed. (McEvoy JP, personal communication)
A more rigorous test of this approach occurred in a double-blind study published in 1991. [86] A total of 91 patients treated at neuroleptic threshold dosage of haloperidol for two weeks were then randomly assigned to either an increase in dose to 10-20 mg per day as tolerated, or continued at the original neuroleptic threshold dose for two more weeks. The patients given more neuroleptic had only slightly more antipsychotic benefit (the only difference was on the Suspiciousness Factor of the Brief Psychiatric Rating Scale) but they more frequently developed severe NP compared to the control group. Another finding was that there was no loss of the initial response in the responders in the threshold group during this second phase of the study, as they were continued on this low dose.
The most recent study from McEvoy and colleagues tested whether moving below the neuroleptic threshold dose will result in loss of efficacy. [87] Sixty acutely psychotic patients were titrated to a neuroleptic threshold dose of haloperidol over a two week period (mean 4.3 mg per day). Then, they were randomly assigned to four more weeks of treatment with either the same dose, one third that dose (1.6 mg), or triple that dose (14.3 mg). All patients received benztropine after randomization to prevent dystonia in those who might be susceptible to it. The results were that patients who were randomized to move to the lower dose did not improve over the next four weeks, and if there had been any improvement during the two week neuroleptic threshold identification phase, this was rapidly lost. Patients who continued on the neuroleptic threshold dose improved significantly and so did the patients on triple dosage. As in the earlier controlled study, the high dose group improved a bit more than the threshold dose group (e.g. - about 0.2 on the Clinical Global Impression) but at the cost of more NP and other side effects.
In conclusion, the neuroleptic threshold dose appears to be the best dose for the initial treatment of first-onset or recently relapsed schizophrenic patients. The caveat should be added that if improvement occurs without the clinician noting any NP, the dose need not be increased further: the patient could be at D2 receptor occupancy in the 50-60% range, which is enough to produce substantial antipsychotic effect but with low, clinically undetectable levels of NP. [79] However, it would be important to keep in mind that the improvement could be from nonspecific factors, such as hospitalization. [89] Also, NP might not become detectable until several weeks of treatment have occurred, during the time in which depolarization block may be presumed to be gradually developing in more and more nigrostriatal neurons. Therefore it might be of interest to re-check for neuroleptic threshold parkinsonism a few weeks later so see if it has appeared.
Finally, it may be noted that the neuroleptic threshold examination for NP may be useful (in combination with other information) in identifying subgroups of neuroleptic resistant patients, suggesting reasons for their poor response, and indicating possible treatments. [90-92] This subject is beyond the scope of this Chapter, but the reader is encouraged to consult the indicated references.
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