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Acute dystonic reactions are associated with antipsychotic use,

especially with high-potency first-generation antipsychotics. About 90%
of these reactions occur either in the first four days of treatment or after
an increase in dose.
Risk factors include large muscle mass, younger age and being male.
Acute dystonic reactions are class effects, not individual antipsychotic
effects. It is not appropriate to tell patients that they are allergic to a
particular medication because they had an acute dystonic reaction.
The drugs used to address the acute dystonic reaction are the
anticholinergics (benztropine or trihexyphenidyl) or the antihistamine
diphenhydramine. This presentation discusses dosing for each
medication.

Michael D. Jibson, MD, PhD

Professor of Psychiatry
Director of Residency Education
University of Michigan
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Acute dystonic reactions are one of the things that we think of in emergency psychiatry.
The definition of acute dystonic reaction is that it is a sudden, sustained, involuntary muscle
spasm anywhere in the body in response to an antipsychotic medication.

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It can occur in any muscle group but the most common places are small muscles in the
head and neck area.

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And some of these are so common that they have their own names. Like muscle cramps in
the eyes is oculogyric crisis in which gaze is deviated in a particular direction and usually
way out at the extreme of how far they can move by the nature of the muscle cramping.

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Cramp in the neck muscles called torticollis is usually represented by the chin being twisted
clear over to where it is touching a shoulder. It is quite scary and painful. All of these are.

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The most dangerous of them, however, is spasm of the throat. People feel like they are
going to choke. Laryngospasm is in fact the possibility. And so there is a medical danger
here. It’s quite rare but it does occur.

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Jaw cramping, trismus, has been described and also can occur. These aren’t the only places
where things happen. One can get cramping in any of the extremities. Back muscles are
fairly common, occasionally abdominal muscles. And one shouldn’t assume that it is going
to be in one place versus another.

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As we look at the risk factors, class of medication is at the top of the list. About 20% to 40%
risk of this occurring with the first generation antipsychotics. That’s an incredibly high risk
compared with the others.

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The lower potency first generation antipsychotics, chlorpromazine, for example, or
thioridazine, are less likely to cause this but all of them still more likely than the second
generation drugs.

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Even with the highest risk of the second generation drugs, risperidone and paliperidone,
acute dystonic reactions are relatively rare.

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The others, but I have just listed some, there are some additional second-generation drugs
that would fit on this list at this point, the acute dystonic reactions are quite rare but should
not be ruled out if you see someone having cramping. They have not been reported with
quetiapine or clozapine. And so one would not expect these things to be seen with these
drugs.

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Other risk factors to consider are time and dose. The large majority, about 90%, of these
reactions occur either in the first four days of treatment or after first four days after an
increase in dose.

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You can see people who have been maintained for a long time on a lower dose of medicine
who if the dose is increased by a large amount suddenly go into a period of high risk. And
so you can see this during those times. Generally, it is a time when there is a rapid
escalation of dose as well as being early in treatment.

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The most interesting thing that we see in the timing of the reaction is that the reactions are
most likely to occur during a trough serum level, not during the high level, the peak level
that would follow a dose. This is why when we’d be rounding on our inpatient unit we do
this first thing in the morning before the morning medications were given out. Some of the
less experienced staff would sometimes think this was malingering on the part of our
patients claiming they have one of these reactions to avoid getting more of the
antipsychotic. We cannot rule that out but in fact, most of the time, it was simply that they
were at the trough level of the medication.

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Patient risk factors. Larger muscle mass. It’s not clear if they actually have more cramping
or if the cramping is simply harder to control with the large muscle mass. This is a centrally
mediated phenomenon. It is not occurring at the level of the muscles but this was a risk
factor that we observed.

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Younger patients and male patients are more likely to have the acute dystonic reaction than
women or older patients. The usual rule with the older female patients, this is where you
want to start low and go slow. And you get some young buffed up men that are otherwise
healthy and you think you’ll just blast them with whatever medication you want and it is
going to be okay. Just the opposite is true in the case of acute dystonic reactions. The older
female patients tolerate the medications better than the younger otherwise healthy
patients.

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There are some studies that have indicated that patients with Asian genetics may be more
likely to experience an acute dystonic reaction. That hasn’t been systematically studied as it
might be.

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In making the diagnosis, you want to look for the overall setting in which the cramping is
occurring.

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So you’re going to expect that it is relatively early in treatment or after a change in
treatment.

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The onset is going to be rapid. Generally, these cramps occur very quickly rather than over
long period of time. Certainly, they would be likely to occur within one day rather than over
weeks.

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They tend to be localized. This is critical. They tend to be localized to one or just a few
muscles generally in the same area and that’s rather a generalized rigidity and that’s going
to be one of the key diagnostic features.

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Other things to look for: no alteration in consciousness, no alteration in vital signs.

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Now, these last three items are to distinguish an acute dystonic reaction from neuroleptic
malignant syndrome, a far more serious and dangerous disorder that requires
discontinuation of the medication over a substantial period of time and monitoring in an
intensive care unit. Acute dystonic reactions do not require that level of care.

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Treatment is straightforward, injectable benztropine or trihexyphenidyl. Right now,
benztropine is usually going to be a little bit more available in most hospital settings. But
either one of these medications is perfectly appropriate as an anticholinergic. Benztropine 2
mg, trihexyphenidyl 5 mg can be given at intervals from 15 to 30 minutes. And in each case,
up to four doses can be given safely. One expects to see a response within minutes of the
injection. So at 15 minutes, it is reasonable to expect to have seen some response. At 30
minutes, you’re probably seeing about as much as you are going to see with that dose. And
if things haven’t cleared up substantially, then another dose is appropriate. The average
number of doses that’s given with these medications is two but you can give up to four and
may still see a response at that point.

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The second option for acute treatment is an antihistamine. And the one that’s most
commonly used is diphenhydramine which is also anticholinergic. So you want to be a little
bit cautious using this particular antihistamine together with the anticholinergics. But 50 mg
doses IM again at intervals of 15 to 30 minutes and up to four doses can be used. Not listed
here but some other secondary treatments that can be used to at least relax the muscles
not necessarily addressing what is going on centrally but to relax the muscles would be a
benzodiazepine or a muscle relaxant. But those would clearly be second-line agents. The
anticholinergics or antihistamines are generally going to control things pretty well.

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After this occurs, you’re probably going to want to implement maintenance treatment.

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And so the same medications can be used at a somewhat lower dose range, 1 or 2 mg of
benztropine every six hours up to a maximum of 8 mg a day, trihexyphenidyl same thing 2
to 5 mg every six hours up to 20 mg a day. So again, maximum six-hour dosing will be
effective at heading this off. It does come with the side effects that go with anticholinergic
medications. So we don’t always want to do this prophylactically. But if a patient has had an
acute reaction, then it is a good idea to have this medication on board.

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Other alternatives, diphenhydramine 25 to 50 mg every six hours or a dopaminergic agent
such as amantadine at 100 mg every six to eight hours up to 300 mg a day would all be
reasonable options.

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Other treatment considerations, reduce the medication dose. You’re almost certainly going
to want to do that.

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Slow down the rate of titration.

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Consider an alternative medication.

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Be aware that acute dystonic reactions are class effects, not individual medicine effects. It is
not appropriate to tell a patient that they are allergic to a particular medication because
they had an acute dystonic reaction. In fact, they are prone to acute dystonic reactions and
they are going to be prone to those reactions with any medication that is comparable on
the list of risks. What we should say is that with this class of medicines, the reaction is at
higher risk.

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So consider an alternative class, a lower risk medication and consider gradually decreasing
or rather be aware that the risk is gradually decreasing with time and that the patient may
well tolerate a medication later that they had a reaction with early in treatment.

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So take home points here. Acute dystonic reactions are associated with antipsychotics and
especially with high potency first generation antipsychotics especially early in treatment.

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The drugs to use to address the acute dystonic reaction are the anticholinergics,
benztropine or trihexyphenidyl or the antihistamine, diphenhydramine. And the responses
to these medicines tend to be brisk and very effective.

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