The period of maximum risk is within hours to 5 days of initiation of neuroleptic therapy. There may also be increased risk following increments in dose. High-potency, low-dose antipsychotic drugs are more likely to precipitate an acute dystonic reaction than are low-potency, high-dose antipsychotic drugs, and young males, both children and adolescents, may be at increased risk (APA, 1980b). Untreated acute dystonic reactions may last from a few minutes to several hours, and they may recur. Symptoms, which may be painful and frightening, particularly if the patient does not understand what is happening, include muscular hypertonicity; tonic contractions (spasms) of the neck (torticollis), mouth, and tongue, which may make speaking difficult; oculogyric crisis (eyes rolling upward and remaining in that position); and opisthotonos (spasm in which the spine and extremities are bent with an anterior convexity). Acute dystonic reactions respond rapidly to anticholinergic
and antiparkinsonian drugs, such as 25 to 50 mg diphenhydramine (Benadryl) orally or intramuscularly, or 1 to 2 mg benztropine (Cogentin) intramuscularly. (The manufacturer of benztropine cautions that, because of its atropine-like untoward effects, its use is contraindicated in children younger than 3 years and that it should be used with caution in older children [Physicians’ Desk Reference (PDR), 1995].) If the dystonia is very severe, administering either 25 mg of diphenhydramine or 1 to 2 mg of benztropine intramuscularly will reverse the dystonia within a few minutes. The prophylactic use of anticholinergic and antiparkinsonian agents to prevent acute dystonic reactions is discussed following the section on “Akathisia.”

Symptoms of parkinsonism include tremor, cogwheel rigidity, drooling, and decrease in facial expressive movements (mask-like or expressionless facies), and akinesia (slowness in initiating movements). These symptoms respond to antiparkinsonian medications; for example, benztropine (Cogentin), 1 to 2 mg given two or three times daily, usually provides relief within a day or two. Antiparkinsonian medication may be withdrawn gradually after 1 or 2 weeks to see if it is still necessary for symptomatic relief.

The period of maximum risk for developing parkinsonism is 5 to 30 days after initiation of neuroleptic therapy. The risk for development of parkinsonism appears to be greater for females and to increase with age. It is rarely seen in preschool children treated with therapeutic doses of neuroleptics; it occurs commonly in school-aged children and adolescents (Campbell et al., 1985). Richardson et al. (1991) reported that 21 (34%) of 61 hospitalized children and adolescents, of whom only 7 were diagnosed with psychotic or affective disorders, who were taking neuroleptics at the time of evaluation exhibited symptoms of parkinsonism when rated on several movement disorder scales. Three (14.3%) of the 21 children were rated as having parkinsonism despite the fact that they were concurrently receiving antiparkinsonian drugs. Development of parkinsonism was significantly (P = .05) associated with a longer duration on medication at the time of evaluation (mean of 117 days for patients with parkinsonism and mean of 34 days for patients without parkinsonism).

Akinesia, perhaps the most severe form of parkinsonism, is defined by Rifkin et al. (1975) as a “behavioral state of diminished spontaneity characterized by few gestures, unspontaneous speech and, particularly, apathy and difficulty with initiating usual activities” (p. 672). It may be particularly difficult to differentiate from the negative symptoms of schizophrenia, such as apathy and blunting. Van Putten and Marder (1987) suggested that akinesia might be the most toxic behavioral side effect of antipsychotic drugs. The authors noted that a subjective sense of sedation or drowsiness, excessive sleeping, and a lack of any leg-crossing during an interview of approximately 20 minutes correlated with the presence of akinesia. Akinesia also interferes with social adjustment, and the patient may appear to have a “postpsychotic depression.” Patients with akinesia are often less concerned with any psychotic symptoms and report that everything is fine; they may experience an absence of emotion and appear emotionally dead (Van Putten and Marder, 1987). Although antiparkinsonian drugs may be helpful, in some cases they do not adequately control symptoms of akinesia. There is some evidence that antiparkinsonian drugs become less effective at higher daily dosages of antipsychotics (Van Putten and Marder, 1987).

The prophylactic use of anticholinergic and antiparkinsonian agents to prevent pseudoparkinsonism is discussed following the section on “Akathisia.”

The period of maximum risk for developing this condition is 5 to 60 days after initiation of neuroleptic therapy, but it has been reported to occur in as few as 6 hours after an oral dose of a neuroleptic (Van Putten et al., 1984). Symptoms include
constant uncomfortable restlessness, a feeling of tension in the lower extremities often accompanied by a strong or irresistible urge to move them, inability to sit still, and foot-tapping or pacing. Clinically, blunted affect, emotional withdrawal, and motor retardation may also be observed (Van Putten and Marder, 1987).

Akathisia may or may not respond to antiparkinsonian drugs such as trihexyphenidyl (Artane). Van Putten and Marder (1987) noted the dual nature of akathisia: a subjective experience of restlessness and observable motor restlessness. In their clinical experience, all patients with moderate or severe akathisia exhibited either rocking from foot to foot or walking on the spot. Akathisia was also strongly associated with depression, dysphoria, and, at times in severe and treatment-resistant cases, exacerbation of psychotic symptoms and homicidal and suicidal ideation and behavior (Van Putten and Marder, 1987). Of particular clinical importance, patients who have unpleasant untoward effects, especially akathisia, with antipsychotics, are more likely to be noncompliant and to unilaterally discontinue medication early in treatment (Van Putten and Marder, 1987).

Fleischhacker et al. (1989) have published a rating scale for akathisia that includes two subjective items: “a sensation of inner restlessness” and “the urge to move,” and three items that characterize the frequency and magnitude of observed akathisia phenomena.

Propranolol may be helpful in ameliorating akathisia (Adler et al., 1986); benzodiazepines and clonidine have also been reported to be effective in some cases.

Clonazepam was administered to 10 first-onset psychotic adolescents (8 of whom were diagnosed with schizophrenia, paranoid subtype) between 16 and 19 years of age who experienced distressing akathisia following treatment with antipsychotics (Kutcher et al., 1987). Nine of the patients had also been receiving benztropine concomitantly with their antipsychotic medication. All patients reported subjective improvement, and scores on an akathisia subscale decreased significantly after 1 week’s treatment with 0.5 mg/day of clonazepam.

In some cases, reduction in dose of the antipsychotic may be necessary. Neppe and Ward (1989) recommend that if only akathisia develops (i.e., without accompanying parkinsonism), a beta-blocker be used rather than an anticholinergic agent.

The use of antiparkinsonian (anticholinergic) agents prophylactically to minimize the likelihood of the patient’s developing an acute dystonic reaction, parkinsonism, or akathisia from antipsychotic drug use is controversial. Some of the reasons relate to the effects caused by the anticholinergic agents themselves. Anticholinergic agents may adversely affect cognition and may aggravate psychotic symptomatology. In addition, there is some suggestion that at least part of the effectiveness of these agents is that they may lower the serum concentration of the antipsychotic drug (Rivera-Calimlim et al., 1976). Because of their reluctance to give an additional medication that itself may have untoward effects, many clinicians choose to minimize the risk of these extrapyramidal effects by beginning with a low dose and titrating the medication slowly. If an acute dystonic reaction should occur, it may be treated with diphenhydramine and the dosage of antipsychotic lowered temporarily if necessary. Conversely, some clinicians routinely prescribe an agent such as benztropine for approximately 1 month to 6 weeks, covering the period of maximal risk for the development of both acute dystonic reactions and parkinsonian untoward effects. Another option for outpatients is to prescribe a small amount of an anticholinergic (e.g., diphenhydramine) with an explanation of how it is to be administered should a dystonic reaction occur (e.g., to take one capsule should such a reaction begin, to take another dose in 20 to 30 minutes if there is no improvement, and to go to an emergency room if the reaction is severe and alert the physician to the medication being taken).

In their review of the management of acute extrapyramidal syndromes induced by neuroleptics, Neppe and Ward (1989) note that anticholinergics can significantly reduce the rate of acute dystonias especially in the highestrisk group, males younger than 30 years of age treated with high-potency antipsychotic agents. However, as acute dystonic reactions tend to be transient, prophylactic treatment for more than 2 weeks is not usually indicated. These authors recommend no prophylaxis for parkinsonism and akathisia because they rarely present as dramatically emergent a picture as acute dystonia. The parents and/or patient, as appropriate, may be carefully informed about the possibility of these conditions arising, to aid in their early detection. The clinician can then decide how best to treat the particular symptom in the particular patient (Neppe and Ward, 1989).

Van Putten and Marder (1987) point out that prophylactic use of antiparkinsonian drugs may not fully prevent symptoms of akinesia from developing and that some schizophrenic patients who have been stabilized using antiparkinsonian medication may experience increased anxiety, depression, general dysphoria, and suffering when the anticholinergics are withdrawn.

The clinician should decide on a case-by-case basis which of the preceding possibilities is best for a given patient. This decision will be based on such factors as whether a high- or low-potency neuroleptic is given, how rapidly the dose is increased, previous experience of the patient, whether it is administered to an outpatient or an inpatient (who has ready access to clinical staff), how such a reaction might affect the relationship with the patient and/or the parents and subsequent compliance, and the patient’s environment. For example, it can be particularly difficult for a patient and family if the patient develops an acute dystonic reaction while attending school.

Neuroleptic malignant syndrome is life-threatening and can occur after a single dose, but occurs most frequently within 2 weeks of initiation of neuroleptic therapy or an increase in dosage; males and younger individuals appear to be most often affected (for review see Kaufmann and Wyatt, 1987). Symptoms include severe muscular rigidity, altered consciousness, stupor, catatonia, hyperpyrexia, labile pulse and blood pressure, and occasionally myoglobinemia. Most patients have elevated creatine phosphokinase (CPK) levels. Neuroleptic malignant syndrome can persist for up to 2 weeks or longer after medication is discontinued and can be fatal. Treatment consists of immediate cessation of medication and hospitalization, under intensive care, with supportive treatment. Dopaminergic agonists (e.g., bromocriptine and amantadine) and/or dantrolene have also been reported to reduce the mortality rate significantly (Sakkas et al., 1991). Antiparkinsonian drugs are not useful.

Latz and McCracken (1992) conducted an extensive literature search and reported a total of 49 cases of neuroleptic malignant syndrome (NMS) in patients 18 years or younger. The youngest reported case was that of an 11-month-old. Five (83%) of the six preschoolers developed NMS after a single dose of neuroleptic that either was an accidental overdose or was prescribed for a nonpsychiatric illness. Overall lethality for all cases reviewed was 16.3% (8 of 49). However, the death rate for patients 12 years of age or younger was 27% (3 of 11), more than twice the death rate of 13% (5 of 38) for adolescents 13 to 18 years old.

Steingard et al. (1992) also published a review with detailed summaries of 35 cases of neuroleptic malignant syndrome in patients younger than 19 years of age. Fever, rigidity, altered mental status, and tachycardia were present in >70% of the cases. Five (14%) of the patients died; however, only one of these died within the past two decades, and that was a 2-year-old who had ingested chlorpromazine accidentally. Croarkin et al. (2008) reported on 16 cases in subjects 18 years old
and younger from 1991 through 2007, mostly male, all of whom survived. These data suggest that the standard of care for these patients has improved, but do not address reporting bias.