Acute Dystonic Reaction

An acute dystonic reaction (ADR; involuntary, intermittent, sustained muscle contractions) is an early-onset EPS and can occur after a single dose of an antipsychotic, particularly in antipsychotic-naïve patients. Half of cases occur within 2 days of starting treatment and almost all within 1 week. While an ADR is much more likely with high-potency FGAs, this side effect can occur with all antipsychotics, including loose D2-binding ones like clozapine or quetiapine.

Patients complain about “cramping,” their “head turning,” problems with their eye “rolling back,” or a “thick” or protruding tongue. More dramatic manifestations, such as opisthotonus (body arching), torticollis, oculogyric crises (eyes rolling backwards), or trismus (lockjaw), can occur. Patients can be distressed and overwhelmed with anxiety, but are not confused. Although distressing, dystonia is usually not dangerous except in the cases of laryngeal-pharyngeal dystonia, which can result in respiratory compromise.

The clinical presentation of an ADR is usually acute and dramatic, and the diagnosis should not be difficult. Treatment with parenteral benztropine or diphenhydramine is highly effective.

ADR is preventable by giving prophylactic anticholinergics to high-risk patients [6]. Do not forget to discharge patients who had an acute dystonic reaction that brought them to the emergency room (ED) with a brief course of anticholinergics. If no further antipsychotic treatment is planned, 2 or 3 days of benztropine (Cogentin) 1–2 mg qid or diphenhydramine (Benadryl) 25–50 mg qid is sufficient. I have seen patients return to the ED the next day with another episode of ADR because they did not receive prophylaxis. The Pisa syndrome is a variant of dystonia that you should consider in a sideways-leaning patient due to persistent truncal dystonia.

Akathisia

Akathisia literally means “unable to sit still.” It is an extremely unpleasant sense of inner restlessness that compels patients to move about to relieve tension. As akathisia becomes more severe, you can observe the motor restlessness as patients may pace around and jiggle their feet or are unable to sit in your office or watch television for more than a few minutes at a time. It is one of the acute side effects, and I expect it to occur early in the course of treatment, sometimes as early as after the first antipsychotic dose. Although FGAs, particularly high-potency antipsychotics like haloperidol or fluphenazine, can easily bring on akathisia, higher doses of second-generation antipsychotics and the third-generation antipsychotics (partial agonists) can also cause it. The antipsychotics least likely to cause akathisia include quetiapine, iloperidone, and clozapine. Among the third-generation antipsychotics, brexpiprazole seems to have a very low akathisia risk [7].

The diagnosis of akathisia is usually straightforward. In the right clinical setting (i.e., after initiation of an antipsychotic), you should be alert for evidence of motor restlessness and always ask about an inner sense of restlessness. Some patients (usually more impaired patients with chronic disease) are objectively restless but deny the subjective component. In these circumstances I prefer to treat presumptively for akathisia. Note that the Barnes Akathisia Rating Scale (BARS) which is considered the gold standard in clinical trials labels such patients as having “pseudoakathisia” [8]. A diagnostic dilemma can occur when agitation in a very psychotic patient is either due to akathisia, requiring a reduction in antipsychotic treatment, or psychotic agitation, where increased medication is needed.

Akathisia is not a side effect that patients should have to live with in the long run. You have some fiduciary responsibility to recognize akathisia in impaired patients who cannot describe their inner distress. If possible, lower the antipsychotic and hope the akathisia resolves. Otherwise, you might have to switch antipsychotics, including switching to clozapine in patients who are very sensitive to extrapyramidal symptoms. Whatever you do, always treat akathisia symptomatically as well. Beta-blockers are considered the treatment of choice, and patients should be followed closely after initiation in case higher doses are required (start with propranolol 10 mg twice daily and titrate upward to up to 120 mg total daily dose). Mirtazapine which is a strong 5-HT2a antagonist antidepressant may be as effective as propranolol but easier to use and better tolerated [9, 10]. Simply add 15 mg at night. You should see a rapid effect, without the need to increase the dose. If there is marked distress, you can add a benzodiazepine (e.g., diazepam 5–15 mg/day). In cases with concurrent Parkinsonism, anticholinergics may be tried although they are probably not particularly good antiakathisia agents.

Parkinsonism

In its extreme form, drug-induced Parkinsonism is difficult to miss: patients can be observed shuffling along the corridor, almost falling, without arm swing. During a visit to your office, they may sit with their mouth open, drool, have a coarse resting tremor, or need help getting out of the chair. Parkinsonism is usually symmetrical in the drug-induced form and is characterized by a triad of resting tremor, cogwheel rigidity, and akinesia/bradykinesia, just like idiopathic Parkinsonism. Subtle manifestations, however, are easy to overlook or misdiagnose, such as an apparent lack of facial expression being described as “blunted affect” and attributed to primary negative symptoms instead of the masked facies of Parkinsonism, a secondary negative symptom. Signs and symptoms of Parkinsonism usually appear within the first month of treatment, and, as this side effect is often dose-related, reducing the dose of antipsychotic may solve the problem. If not, anticholinergic medications can be used, but attempts should be made to taper them after 3 months (see Chap. 19 for a more detailed discussion of why).

In clinical trials, the gold standard for the assessment of drug-induced Parkinsonism is the Simpson-Angus Rating Scale (SARS) [11]. Using the scale will help you assess a patient systematically for evidence of EPS, including examining a patient for clinical manifestations of rigidity and bradykinesia (e.g., drooling).

Tardive Dyskinesia

The most feared, long-term (hence “tardive,” which means late) consequence of treatment with dopamine-blocking agents is TD, a potentially irreversible movement disorder characterized by involuntary, choreiform movements. Less common, tardive akathisia or tardive dystonia is seen. Clinicians need to appreciate that TD is almost always irreversible once it develops, contrary to the hopeful view held by some clinicians that it remits if detected early and antipsychotics are stopped [12].

Depending on the clinical population treated with antipsychotics, you can expect to find a cross-sectional TD prevalence of around 20–30% [14]. The lowest prevalence (less than 10%) was seen in populations who had never been exposed to first-generation antipsychotics. These rates suggest two possibilities: (a) not all patients are at risk for TD (they are somehow protected biologically) and/or (b) TD can remit (which occurs in a small minority of patients, around 5%). One long-term study of 20 years found that most patients had TD at some time point during the course of their illness and it remains of concern to all patients. It is also notable that abnormal movements were present in 10% of patients with schizophrenia who had never been exposed to antipsychotic medications [15] suggesting that some cases of presumed drug-induced TD might be from the disease process itself, as already noted by Kraepelin in the pre-neuroleptic era. Taken together, these studies suggest that TD is a dynamic disorder, with the natural course interacting with antipsychotics in susceptible individuals. Risk factors for TD include non-modifiable risk factors like age (older patients are more sensitive), female gender, and a history of early EPS [16]. Some modifiable risk factors are diabetes, smoking, alcohol use, and the cumulative exposure to antipsychotics.

Diagnosis

TD is an iatrogenic disorder, and treatment with a dopamine-blocking agent (usually antipsychotics but do not forget antiemetics like metoclopramide) is a condition sine qua non. “Tardive” implies a sufficient duration of exposure, in most cases at least a few months, but I would still diagnose TD after briefer antipsychotic exposure if a patient develops new-onset motor symptoms consistent with TD.

Tardive movements from antipsychotics are choreiform (rapid and irregular; you cannot predict when the next movement is coming, like in chorea Huntington), although athetoid (slow and writhing) or even dystonic movements (more sustained postures) are sometimes seen. Movements can be confined to the face (e.g., tongue protrusions, chewing movements, eye blinking, or “grimacing”), but other areas can also be affected. Patients may seem to be moving their fingers as if playing the piano or truncal involvement can give patients the appearance of “dancing.” A tremor is not a symptom of TD! Most cases of TD are mild with a waxing and waning course, and as noted earlier, around 5% even remit spontaneously despite ongoing treatment. Severely afflicted patients can be incapacitated by constant, severe movements that interfere with talking, eating, breathing (respiratory TD affecting the diaphragm), or walking. Dramatic withdrawal dyskinesias can occur when patients are abruptly withdrawn from chronic antipsychotics, possibly due to the mechanism of dopamine receptor supersensitivity [17]. Those movements can last a few weeks but should eventually remit as the dopamine system resets itself.

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