Calm After a Storm

Verbal de-escalation coupled with second-gen antipsychotics outperform benzodiazepines for treating agitation in patients with schizophrenia and bipolar disorder

Patients diagnosed with schizophrenia or bipolar disorder can experience agitation, which is defined as excessive motor or verbal activity. Textbook behavior typically includes:

  • Pacing
  • Fidgeting
  • Clenching fists or teeth
  • Prolonged staring
  • Picking at clothing or skin
  • Throwing objects
  • Responding to internal stimuli, such as auditory or visual hallucinations

This was the list presented by Leslie Citrome, MD, MPH, Clinical Professor of Psychiatry and Behavioral Sciences, New York Medical College, during his Psych Congress 2021 session titled Managing Agitation in Schizophrenia and Bipolar Disorder: What’s Available, What’s New, What’s Next.

Interestingly enough, Dr. Citrome explained, patient-perceived feelings and actions when agitated aren’t identical to the textbooks. Patients describe experiencing:

  • Explosive anger
  • Low frustration tolerance
  • Anxious, paranoid
  • Losing control/uncontrollable
  • Overwhelmed
  • Verbally abusive
  • Aggressive, violent, wanting to fight

Regardless of the words used to describe agitation associated with schizophrenia and bipolar disorder, Dr. Citrome emphasized that this state “is on a continuum and severity usually increases over time—unless we do something to stop someone from losing control.”

Studies report that for those with schizophrenia, the probability of an increase in serious aggression to violent behavior is fivefold higher than in persons without any diagnosed mental disorder.1 And when a person with schizophrenia or bipolar also exhibits substance dependence, the potential for violence escalates.  

That said, not everyone with schizophrenia is aggressive, violent, or hostile, which prompted Dr. Citrome to caution, “Let’s not stigmatize the mentally ill for being responsible for the world’s violence.” He did add, however, “You should anticipate agitation as a possible prelude to aggression, violence, or hostility, and you’d be a fool to ignore agitation.”

Assess before Prescribing

Before reaching for the prescription pad, Dr. Citrome recommends assessing an agitated patient to pinpoint causes. Here’s what should be considered:

Agitation may be caused by a medical condition.

History of violence is important to consider for safety.

Co-occurring substance use, dependence, and intoxication may be present.

Hallucinations and delusions can influence behavior.

Chaotic environments may destabilize a person.

Poor impulse control may result from neuropsychiatric deficits.

Iatrogenic causes include akathisia.

In addition, never underestimate how important it is to check and assess an agitated patient’s vital signs. “Sometimes we forget to do that because when someone is agitated and has a history of psychosis, we assume that this is part of their psychosis. But if the patient tells me they have symptoms that are unusual for them, including new onset psychosis, then I’m going to be concerned about a medical underlying cause of their altered mental status,” Dr. Citrome said.

Guiding Light

At this point in the doctor’s presentation, the patient has been evaluated, acute medical causes for agitation have been considered, and it’s time to review psychiatric etiology. Of note: Medication is not yet the primary concern.

To help identify those causes, Dr. Citrome gave a shout out to Project BETA (Best Practices in Evaluation and Treatment of Agitation). The project, created by a group of emergency department psychiatrists and research department physicians, addresses inconsistencies and unmet needs in the quality of the management of people who are agitated.

Project BETA’s golden goal: Rapidly calm without overly sedating the patient

And while BETA does not shun the use of medications, the recommendation is to try non-pharmacological calming strategies first.

Here are Project BETA suggestions:

The use of medication as a restraint should be discouraged.

Nonpharmacologic approaches, such as verbal de-escalation and reducing environmental stimulation, should be attempted first.

Medication should be used to calm patients, not to induce sleep.

Patients should be involved in the process of selecting medication to whatever extent possible.

If the patient is able to cooperate with taking oral medications, these are preferred over intramuscular (IM) medications.

These recommendations, Dr. Citrome said, are particularly pertinent when an agitated patient is brought into the emergency department. “It can be quite traumatic to be held down by five people, get an injection of one thing, and then an injection of something else. These patients are not happy campers. And then you have to deal with the aftermath, where they’re suspicious of anything else you have to offer.”

In particular, Dr. Citrome emphasized, verbal de-escalation techniques “work quite well and seem to limit harm to the patient as well as others.” He also advised paying close attention to volume, tone, and rate of speech. “It’s quite interesting how the patient will mimic you,” he added.

Another key non-pharmacological calming strategy is relaxed, non-aggressive body language. “This body language issue cannot be overemphasized,” Dr. Citrome said.

Adding Meds to the Mix

When medications are essential to treat psychosis-driven agitation in patients with known psychiatric disorders, such as schizophrenia, schizoaffective disorder, or bipolar disorder, Dr. Citrome spotlights second-generation antipsychotics with fast-acting IM formulations over benzodiazepines.

Fast-acting IM formulations not only address the patient’s underlying psychosis, but they also tend to rate patient approval. “No one ever came up to me and said, ‘Doc, give me a shot of haloperidol to calm me down.’ But they have asked me for second-generation IMs, simply because it’s a whole different experience. They know these SGAs are well-tolerated and work quickly. So, when they are in a hurry to get better and feel calmer, they know second-generation IMs do the trick,” Dr. Citrome said.

The FDA has approved two second-generation antipsychotic/fast-acting IM formulations: ziprasidone and olanzapine. Both are FDA-approved for the indication of agitation associated with schizophrenia. Olanzapane is also FDA-approved for agitation associated with bipolar.

Unlike haloperidol, akathisia and dystonia are largely avoided with these agents. Both also allow for a smooth transition to long-term therapy with the same agent.

Turning to future developments, BXCL501 is an agent currently under investigation. This is an orally dissolving film formulation of dexmedetomidine, a selective α-2A adrenergic receptor agonist. “This is interesting,” Dr. Citrome said. “It’s not an antipsychotic, and it does not block dopamine D2 receptors, so there is no acute drug induced parkinsonism, for example, and no chance of a dystonia.”

Dr. Citrome also mentioned that BXCL501 produced no drug related severe or serious adverse events and it worked quickly—in about 20 minutes—in the schizophrenia study.

A second investigational agent is intranasal olanzapine. This device has not yet been tested for agitation per se but results in rapid uptake and maximum concentration are similar to IM olanzapine.

While there are new, safer, and more effective options to treat agitation in patients with schizophrenia and bipolar disorder, Dr. Citrome concluded as he began—emphasizing that verbal de-escalation should typically be the go-to choice to create calm and build a connection with the patient.

1. Swanson JW. Mental disorder, substance abuse, and community violence: an epidemiological approach. In: Monahan J, et al., eds. Violence and Mental Disorder: Developments in Risk Assessment. University of Chicago Press; 1994:101-136.