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In this episode, we venture into the psychopharmacology of agitation, with a special focus
on psychotic agitation. Dr. Michael Jibson (University of Michigan) and Dr. David Osser
(Harvard Medical School) shared clinical pearls to treat this challenging situation.
 Contents

Here is the summary of the podcast .................................................................................................................... 2

Transcript .................................................................................................................................................................... 2
Key Points .................................................................................................................................................................... 7
References ................................................................................................................................................................... 8

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Here is the summary of the podcast

Today’s question is: How to manage an agitated patient?

Here is a summary of this episode:

• Antipsychotics are the mainstay of treatment; addressing psychotic agitation as well as treating
delirium. Haloperidol is best combined with a benzodiazepine, showing both high efficacy and low
side effect profile.

• There are currently no FDA-approved oral regimens for agitation. However, there are orally
disintegrating formulations of olanzapine, aripiprazole and risperidone. Asenapine is available in a
sublingual formulation which requires more patient cooperation.

• Benzodiazepines have anxiolytic and sedating effects but can produce behavioral disinhibition and
cognitive impairment in patients with dementia.

Transcript

Hello everyone and welcome to the Psychopharmacology Institute podcast. I’m your host, Dr. Wegdan
Rashad. In this series we will be discussing topics that matter to you in your clinical practice, sharing
expert opinions and the latest research.

So, in our practice we may come across a patient who can be described as agitated, meaning that they
may be uncooperative, difficult to interact with or who is potentially violent or even aggressive. This
episode’s question is how to manage an agitated patient from a psychopharmacological aspect.

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But first, what are the defining features of agitation? Dr. Michael Jibson, Professor of Psychiatry at
Michigan University answers this from his lecture on emergency psychopharmacology.

Dr. Jibson:
Agitation is an episodic state of intense anxiety, heightened arousal, increased motor activity. It’s a
distinctive condition in which these things come together and bring about a significant disturbance of a
patient’s behavior and ability to interact in a meaningful way with the environment and the people
around them.

There are many causes of agitation. Drug intoxication or withdrawal, delirium, affective and psychotic
disorders, cognitive impairment and personality disorders can all be associated with agitation.

Today we will zoom in on psychotic agitation, which is often found in a manic episode with psychotic
features, positive symptoms like command hallucinations and delusions of persecution and thought
disorganization.

Now, let’s say you are assessing your agitated patient, Dr. Jibson raised an important pearl to keep in
mind:

Dr. Jibson:
One of the things to think about with psychotic agitation is akathisia. We find with antipsychotic
medications that restlessness, a subjective sense of restlessness that constitutes akathisia is a common
phenomenon. We often overlook it and are not thinking about perhaps a treatment that we’re giving to
address psychosis or even agitation as having the potential via akathisia of making it somewhat worse.
But we should look at that patient’s pattern of motor behavior and see if there’s a pattern of restlessness
separate from the purposeful movements that are sometimes associated with agitated behavior.

Right, so we should consider akathisia and treat it promptly. So, now that you’ve carefully assessed your
patient, what’s the first measure you’re going to take? Over to Dr. Jibson.

Dr. Jibson:
Number one by far is to maintain the safety of the patient and staff who are involved in the patient’s
care. This is absolutely critical. All other considerations are secondary to this one. Second thing to do is
to identify and address the underlying pathology. If there are cognitive problems to the degree that it’s
possible to bring about an improvement in that cognitive condition, to try to do that and to treat any
underlying medical problems that might be going on.

So, clearly, safety comes in first, then identifying and managing the underlying pathology. In his lecture,
Dr. Jibson stated that one should start with the least intrusive approach first and progress if there is no
response. We can start by verbal de-escalation, if not responsive to it, we can offer medications if that too
fails, room seclusion and eventually physical restraint may be utilized, but obviously under very regulated
conditions, beyond the scope of this podcast. And now, regarding medications:

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 Dr. Jibson:
Antipsychotics are usually the mainstay of treatment. They come in a couple of forms, oral or sublingual
or injectable forms. The second line agents for treatment are benzodiazepines also coming in oral and
injectable forms. It’s worth thinking about which of these medications is most appropriate for each
situation and what form of administration is going to be best for the patient or work most effectively.
Antipsychotics are at the top of the list generally because they’re going to address the underlying
problems of mood elevation, of psychotic symptoms directly as well as having a calming effect on the
patient for the agitation itself. They will address some other causes such as delirium, not as effectively as
removing offending agents that cause delirium but they are an approved and accepted treatment for
delirium.
The benzodiazepines are going to provide sedation. They’re very effective at reducing anxiety and do it
quickly. And they’re the appropriate agent for controlling withdrawal symptoms from alcohol or
sedatives, the only agents where withdrawal is a medically dangerous syndrome. So the
benzodiazepines are often going to be complementing what’s happening with the antipsychotics but
they do not reproduce all of the things that the antipsychotics can do.

And then there’s the combination of an antipsychotic and benzodiazepine together. There’s not a lot of
published literature on this, but this combination has been shown to work better than either agent alone.
We have a clip from Dr. David Osser’s lecture on schizophrenia algorithms. Dr. Osser is a Professor of
Psychiatry at Harvard Medical School.

Dr. Osser:
Now, of the comparison of the relative effectiveness, we have a number of older studies where they
looked at haloperidol and lorazepam either separately and combined. And the studies clearly showed
that the combination is more effective than either treatment alone.
And also there’s a very low risk of acute extrapyramidal side effects when you combine haloperidol with
lorazepam, indeed so low that it appears unnecessary to add an anticholinergic or antiparkinsonian
med even though I know a lot of clinicians use that, the triple therapy of anticholinergic, haloperidol and
lorazepam is used a lot but actually has no evidence supporting that it is better than just plain
haloperidol and the lorazepam which can be combined in the same syringe by the way safely.

So what to do if, after you administer the medication and the patient doesn’t calm down immediately?
Shall we give him or her another dose? Dr. Jibson addresses some important questions to ask yourself
when deciding on the right medication, and answers the question I just posed.

Dr. Jibson:
First is: How long does it take the medication to get absorbed, to get into the bloodstream and to arrive
at the brain? Second is: How long does it take for the level in the bloodstream and at the brain to hit its
peak concentration? And then the third thing is: When do we actually expect it to work? When do we
expect it to start working? And when do we expect its full effect to be manifest?
Be aware also that higher doses of medication do not work faster. It’s really tempting if the patient is not

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 responding immediately to just keep going back with more and more medication. That makes sense up
to the time that you hit the maximum recommended dose. And after that, there’s really no alternative to
simply waiting for the medicine to do its job.

So, we should allow time to also help us in controlling this patient’s agitation.

Now for oral medications, which include antipsychotics and benzodiazepines. Dr. Osser gives us his views
on the use of PRN medications for agitation.

Dr. Osser:
Now, oral PRNs are used for very agitated people who will take PRN. They’re usually not necessary for
the less severe agitation. A benzodiazepine is just as effective. Oral antipsychotics do not work for
psychosis in one hour. The only thing they’re doing in one hour is nonspecific sedation and that can be
accomplished as well and probably safer with a PRN benzodiazepine. I know that PRN antipsychotics
are very widely used but they don’t make a heck of a lot of sense.

The antipsychotics we have are oral haloperidol, orally disintegrating olanzapine, aripiprazole, and
risperidone as well as the sublingual asenapine. Remember, none of those drugs are actually FDA
approved for agitation.

Dr. Jibson:
There are several of the antipsychotic medications that are available in orally disintegrating tablets. This
requires a lower level of cooperation and it’s difficult to cheek or discard the medication. The amount of
time that it takes for these medications to dissolve is somewhat different among them. The fastest
dissolving of them dissolves almost completely within about 3 to 5 seconds. And if you simply flick the
medication, the patients are willing to open their mouth, have to be cooperative to that degree but you
flick the medication into their mouth and it hits the oral mucosa. There’s usually enough saliva there
that by the time they get their tongue around to locate the medicine it’s already well on its way to
dissolving. Some of them take a little bit longer, 10 to 15 seconds. And so there is time for the patient to
fiddle with the medication. But in general, you can be fairly assured that the medication is going to go
where it’s supposed to go.

We might be tricked into assuming that orally disintegrating tablets are absorbed faster, Dr. Jibson
clarifies an important point:

Dr. Jibson:
The thing to be aware of though with orally disintegrating medication is that they are not absorbed
transmucosally. They have to be swallowed just like any other medication and they are not more rapid
than standard oral formulations. There is no difference in those that dissolve in the mouth versus those
that have to be swallowed as a pill in how long it takes them to get into the bloodstream. And it’s
important to keep those things in mind.

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Sure! Very good point.
So asenapine has the shortest time to peak concentration at 30 minutes to an hour. Olanzapine is the
slowest to reach peak concentration taking 5 to 6 hours.

Regarding oral benzodiazepines, here’s Dr. Jibson’s summary on what they have in common, what makes
each different and what’s the best option to use. Yes, I know that you already know which one is
preferred for agitation.

Dr. Jibson:
All the benzodiazepines work by the same mechanism but the differences among them are in how much
you have to give, how you can give it and what the pharmacokinetics are, how long it takes to work and
how long it sticks around. Generally, lorazepam is going to have a superior overall profile for acute
agitation in the prescribed dose range. And lorazepam works well in conjunction with the antipsychotics.
When given orally, it can be used with any of them. Looking at these desirable points, lorazepam clearly
has a superior overall profile for acute agitation even though it is not approved for that. We typically use
1 to 2 mg at doses of 30 minutes to two hours with an average dose of 2 to 4 mg a day. But interestingly
enough, there are studies out there that show that this medicine continues to be safe and effective even
at doses as high as 12 mg in 12 hours. Time to peak concentration is about two hours. The medication
begins to work at about 15 to 20 minutes but it does take a while for it to reach that peak concentration.

However, benzodiazepines don’t address psychosis and they have been found to produce behavioral
disinhibition in some patients in particular with those with cognitive impairment. Benzos themselves can
cause cognitive impairment and should be avoided in patients with dementia.

Now, if the patient is not responding to oral medications and other approaches, you may need to resort
to the more intrusive, parenteral medications. But which one to chose? We have an option of
intramuscular and intravenous formulations of haloperidol, intramuscular olanzapine and ziprasidone as
well. Dr. Osser sheds some light on this matter.

Dr. Osser:
Now the largest and best controlled study of IM treatments was fairly recently. It was done in 2013 by
Mantovani. It was a study of 100 patients in Brazil who went into an ER who were extremely agitated.
Most had schizophrenia but about 1/3 of them had bipolar mania or schizoaffective disorder. So the
four treatments were haloperidol plus a benzodiazepine; haloperidol plus an antiparkinson, olanzapine
alone and ziprasidone alone, all IM. So the results were the haloperidol plus the benzo was tied for the
best with the olanzapine alone for best efficacy in one hour and all the other time points. But, the side
effects were 60% greater with the olanzapine alone versus the haloperidol plus the benzodiazepine. And
by the way, if you use the haloperidol and the antiparkinson, EPS were 3.6 times greater with that
combination compared to the haloperidol plus the benzo again demonstrating that the benzo works
well to counter the parkinsonian side effects of the haloperidol. And so it still came out in this Mantovani
study as the best of those four treatments to use. So we still advocate it as our number one choice.

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 Typically, you would use 5 of haloperidol, 2 of lorazepam and you can repeat it once or twice every 30 to
60 minutes. It’s rapid. It’s safe. It’s cost effective.

So we return to the concept of combination parenteral therapy. However, let me remind you that there is
a warning about combining parenteral olanzapine and benzodiazepines together, Dr. Jibson elaborates
further.

Dr. Jibson:
Among the second generation medications, olanzapine is available for intramuscular administration
only. Big issue with olanzapine is that there is a recommendation that it not be simultaneously
administered with intramuscular benzodiazepines. It is okay if either medicine is given orally. The data
that suggest that there is a big problem with simultaneous use of olanzapine and benzodiazepines
intramuscularly are not particularly strong but it is high enough that there are a lot of settings where
the recommendation is against it. And it is easy enough to avoid that combination that we generally just
say whether the risk is high or not, there is no reason to do those together.

Ziprasidone intramuscular injection is also FDA approved and has proved to be effective. However,
special care needs to taken regarding QT prolongation which can occur with this drug.

And that about concludes our quick overview of how to manage patient agitation.

Key Points

Now for the key points:

• After ensuring safety of the patient and health care staff, assessment of the underlying pathology
is important. Also, you should keep in mind the possibility that akathisia might be the cause of
agitation.
• Antipsychotics are the mainstay of treatment. Why? Because they address the cause in psychotic
agitation as well as playing a role in the treatment of delirium. The antipsychotic haloperidol, is
best combined with benzodiazepines, showing both high efficacy and low side effect profile.
• There are currently no FDA-approved oral regimens for agitation specifically. However, there are
orally disintegrating formulations of olanzapine, aripiprazole and risperidone. Asenapine is
available in a sublingual formulation which requires more patient cooperation.
• Benzodiazepines have anxiolytic and sedating effects but can produce behavioural disinhibition
and cognitive impairment in patients with dementia.
• Parenteral olanzapine should not be used with a parenteral benzos and look out for QT
prolongation in intramuscular ziprasidone.

The following people participated in this episode: Dr. Flavio Guzman as the general editor, Rosario Anon
Suarez as the audio engineer, Pamela Gonzalez as the project manager and myself Dr. Wegdan Rashad
as the host.

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Thank you for joining us in today’s podcast until the next episode, goodbye!

References

1. Mantovani, C., Labate, C. M., Sponholz Jr, A., de Azevedo Marques, J. M., Guapo, V. G., Pazin-Filho,
A., & Del-Ben, C. M. (2013). Are low doses of antipsychotics effective in the management of
psychomotor agitation? A randomized, rated-blind trial of 4 intramuscular interventions. Journal of
clinical psychopharmacology, 33(3), 306-312.