Tag: antipsychotic

The Experts Guide to Treating Agitation 

Treating agitation is a big part of inpatient and emergency psychiatric treatment. In the emergency department agitation accounts for 2.6% of total patient encounters. Knowing which medications to use and how to use them is critically important. Today I’m going to discuss all the options for the treatment of acute agitation in clinical practice. 

What is Agitation?

Agitation is an extreme form of arousal that is associated with increased verbal and motor activity that poses a threat to themselves and others. Agitation needs to be recognized immediately and addressed due to the risk of harm to the patient and others. 

Verbal De-escalation is Always The First Step

Engaging the patient and attempting to elicit a reason for the agitation should always be attempted first. In many cases patients are hungry, tired, or overly stimulated by the busy inpatient or ED setting. If these interventions are unsuccessful and the patient remains agitated security staff lead by the physician should inform the patient that if the behavior continues medication will be administered for safety purposes.

Thinking About Medication

Sometimes using medication is unavoidable and is required to facilitate a medical evaluation. We need to be mindful of the potential adverse events associated with sedating medication. The most common adverse effects are hypoxia, airway obstruction, QTc prolongation, bradycardia, and hypotension. Patients over the age of 65, alcohol intoxication, and multiple medication administrations in a short period of time increases the risk of adverse events.

Routes of Administration

It’s always best to offer PO (oral) medication prior to using IM or IV medications. In the inpatient setting we do not allow IVs due to the potential risk of self-harm; IM medication is second route of administration commonly used. I will usually use risperidone 2 mg or olanzapine zydis 10 mg because it begins dissolving immediately once the person puts it in their mouth in both cases. Oral medications can be “cheeked” and will also take longer to start working. In general, it’s important to note the onset of PO medication will be slower. Antipsychotic medications and benzodiazepines are commonly used for sedation in acute agitation. 

First Generation Dopamine Blocking Medications

These medications have been around for a long time and have a good safety profile when used to treat acute agitation. Some antipsychotics have the risk for more side effects due to their ability to lower seizure threshold, cause hypotension, and have an increased anticholinergic burden. 

Haloperidol

This is the go-to antipsychotic for acute agitation. It works by blocking D2 receptors and can be given PO, IM, or IV. Typical dosing is 2.5 to 10 mg with a recommended maximum dose of 20 mg/day. The average time to sedation is 25-28 minutes and the mean total time sedated is 84-126 minutes. The main risk for haloperidol is EPS such as acute dystonic reactions. To avoid this situation, we usually combine Haldol with lorazepam or benztropine/diphenhydramine. Haldol is also well studied and relatively staff for those who are acutely intoxicated with alcohol. 

Chlorpromazine

I will usually go to chlorpromazine when I need someone to sleep such as cases of mania with acute agitation. I find it to be a little more sedating and it can be combined with diphenhydramine. Doses can range from 25 mg to 200 mg depending on the level of severity. The maximum dose is 400 mg/day. 

Second Generation Dopamine Blocking Medication

Second generation medications have the added advantage of lower risk for QTc prolongation, less sedation, and fewer extrapyramidal symptoms compared to the first-generation options. 

Olanzapine

Olanzapine comes in PO, IM, and IV forms, and the typical starting dose is 10 mg. Olanzapine reaches peak concentration in 15-45 minutes and its half-life is 2-4 hours. The incidence of EPS is much lower than injectable haloperidol. There is very rare incidence of QTc prolongation. There is some evidence that 10 mg of olanzapine is more effective than 5 mg of haloperidol for sedation and that most patients are adequately sedated at 15 minutes after administration of 10 mg olanzapine compared to 5 mg and 10 mg of haloperidol. 

It’s important to note that multiple studies have demonstrated adverse events when olanzapine is combined with benzodiazepines. Although the risk may be overstated it’s best to avoid this combination unless necessary. Olanzapine is highly anticholinergic and should be avoided in cases where anticholinergic overdose is suspected. 

Ziprasidone

Ziprasidone is a second-generation medication that is available in either PO or IM formulations. The PO form of the medication has little utility in acute agitation, but the IM version can be useful. Time to onset of effect is usually 15-20 minutes and it reaches peak concentrations in 30-45 minutes. The duration of sedation is at least 4 hours. Ziprasidone carriers the highest risk of second-generation medications for QTc prolongation

Risperidone

Data for risperidone in acute agitation is limitted. It does have the advantage of coming as an oral disintegrating tablet. In most cases I would administer 2-4 mg depending on the severity of symptoms. It can be a good option for patients with psychotic agitation due to paranoid delusions. It’s a good option for elderly patients and pregnant patients who can take PO medication. 

Benzodiazepines 

Benzodiazepines are another good choice when it comes to rapid treatment of acute agitation. Benzodiazepines do carry the risk of creating a paradoxical reaction in the elderly, but it’s relatively rare and seen in only 1% of cases. Flumazenil (benzodiazepine blocker) can be used to counteract this paradoxical reaction if needed. There is risk for respiratory depression especially in those who are already on central nervous system depressants. If withdrawal is suspected from benzodiazepines or alcohol, this is the first line option for treatment. 

Lorazepam

Lorazepam is available in IV, IM, and PO formulations. The typical dosing is 0.5-2 mg IM or PO. This medication can be given every 30 minutes up to a maximum dose of 12 mg/day. Lorazepam is longer acting than midazolam and has an average time to adequate sedation of 32 minutes. 

Midazolam

Midazolam is available in IM formulation and the typical dosing begins at 2-5 mg. The average time to sedation is 13-18 minutes for the IM formulation. When given IM the total time of sedation is between 82-105 minutes. Midazolam offers the advantage over lorazepam because it’s onset of action is faster. Midazolam also works faster than haloperidol or ziprasidone. The duration of sedation is also shorter. 

Medication Combinations

In most cases these medications will be used in combination to maximize their effects. The most well-known is the so called B52 which consists of Haloperidol 5 mg, Lorazepam 2 mg, and diphenhydramine 50 mg. The idea here being 50, 5, and 2 are the doses and B52 because it’s like the B52 bombers when it comes to sedation. I also often combine chlorpromazine and olanzapine with 50 mg of diphenhydramine in the IM formulations. For PO risperidone you can combine it with PO lorazepam and diphenhydramine if needed. With ziprasidone I will usually give this one alone without lorazepam or diphenhydramine. 

Physical Restraints

The utilization of physical restraints may be necessary when safety is a major concern. In some cases, verbal de-escalation, and medication are not enough. The problem is physical restraints can lead to injury for both the patient and staff. Patients who continue to fight against the restraints can have a complication known as rhabdomyolysis where the muscles are literally breaking down from the person fighting against the restraints. Sedation should always be provided when physical restraints are used. What happens if a person is given high doses of sedating medications and placed in psychical restraints but remains agitated?

Special Cases

It’s rare but I have had two clinical scenarios where an individual was placed in restraints given multiple doses of medications and remained severely agitated. Due to concern for the patient’s safety and risk of rhabdomyolysis I had to transfer each of these cases to the medical floor for IV dexmedetomidine (Precedex) which is commonly used to sedate patients in the intensive care unit who are intubated. After a short course of Precedex treatment each patient’s agitation resolved. There is now a rapidly dissolving film of dexmedetomidine available for acute agitation in bipolar disorder and schizophrenia, so I guess I was ahead of the times when I made these clinical decisions. 

Conclusion

Agitation is a complicated and multifactorial process that requires quick action. To maintain safety, agitation needs to be quickly identified and managed. Verbal de-escalation and comfort measures should always be the starting point. If medications are required there are several individual and combinations that can be selected based on the clinical situation. When all else fails physical restraints remain a possibility until medications have had time to reach peak concentrations and effectiveness. 

0

The Real Story Behind Using Two Antipsychotics For Schizophrenia

It wasn’t that long ago when I was sitting in lectures as a first-year psychiatry resident. I learned about the first- and second-generation antipsychotic medications in detail. One commandment that was always preached in my training was to never combine two antipsychotic medications because there is no additional benefit. Today we are here to explore this idea and see if there is truly no additional benefit to using two antipsychotics and explore why there is so much antipsychotic polypharmacy in serious mental illness.  

Introduction

While all training programs preach the use of mono-therapy when it comes to the use of antipsychotics in clinical practice, the reality is up to 50% of psychiatric inpatients are receiving antipsychotic polypharmacy. 

Since most guidelines discourage the use of multiple antipsychotic medications, why are many psychiatrists going against these guidelines? In most cases we are just trying to stabilize patients, get them better, and keep them out of the hospital as the goal is to provide most psychiatric care in the community. To reach these goals a single medication does not always produce the desired results. 

Patients that end up on multiple antipsychotics have some unique characteristics. They tend to have more severe psychotic symptoms, are male, unemployed, and younger. Those with frequent inpatient admissions on involuntary status are also more likely to end up on two medications. 

What To Do When a Single Medication Is Not Enough?

The use of multiple antipsychotics is an area of limitted research. However, there is a difference between rational polypharmacy and irrational polypharmacy.

We should start this discussion by saying a patient should be started on monotherapy titrated to an effective dose and continued on the medication for 6 weeks prior to making a change. If the first medications fails, then switching to another medication or long acting injectable is a reasonable next step. If after another 6 weeks of treatment the patient remains unstable and symptomatic the technical next step is to start clozapine. There are many reasons why clozapine may not be a good option for a particular patient including the strict requirements for weekly complete blood cell counts CBCs.

Assuming this process is followed and the patient is still symptomatic what’s the next step?

Consider Receptor Binding Profiles

This is the first step in prescribing two medications rationally. Most first-generation medications such as Haldol will bind tightly to D2 receptors and stay bound to the sites longer. Second-generation medications like quetiapine are known to bind to the receptors and quickly dissociate giving an on-off like effect. Tight binding and longer duration of binding can lead to extrapyramidal side effects (EPS), whereas quick on-off medications like quetiapine have limitted EPS risk. 

You should also consider other receptors the medication may target such as histamine and muscarinic cholinergic receptors. It would be best to avoid combining two medications that have high antihistamine and anticholinergic activity.

Let’s look at some scenarios where antipsychotic polypharmacy makes sense. 

Patients With Acute Agitation

This is a common problem on the inpatient unit. A patient is on a low-potency quick on-off medication like quetiapine but remains symptomatic and is engaging in dangerous behavior. 

The addition of a higher potency, higher affinity medication like Haldol makes some sense here. This will control the acute agitation, can be titrated until the psychotic aggression is controlled, and can be stopped as soon as the patient is stable on quetiapine. We can see how the receptor binding profile makes this combination reasonable.

Clozapine Refractory Patients

What do you do when a patient is on the best antipsychotic medication but remains symptomatic? 

We do have several lines of evidence that we can look at for this question. One option is to add low dose risperidone. This is a similar idea to adding Haldol to quetiapine. Clozapine has lower affinity for the D2 receptor than risperidone which has much higher affinity for D2 receptors. There were two placebo-controlled trials that support this combination. Before combining medications, I would suggest obtaining a clozapine level to make sure it’s therapeutic. 

There are two more recent studies that compared multiple antipsychotic medication combinations and used rehospitalization as a measure of effectiveness. Both studies found a significant reduction in rehospitalization for patients receiving polypharmacy compared to those receiving monotherapy. The best outcome was achieved when clozapine was combined with aripiprazole. 

Patient is On a Long Acting Injectable (LAI) but Remains Symptomatic at the Highest Dose 

This is a common problem because the doses of LAIs are limitted. For example, the LAI aripiprazole (Aristida) is limitted to a maximum dose of 20 mg/day. The oral formulations of aripiprazole allow for a maximum dose of 30 mg/day. One strategy is to give the injection early. This will usually be done on week 3 for formulations that last 4 weeks. Another option is to add another medication with a different receptor binding profile such as the clozapine aripiprazole combination that was shown to reduce the risk of rehospitalization.

Treatment of Insomnia 

The addition of low dose quetiapine to a medication like paliperidone is common in clinical practice. Once D2 receptor blockade has been maximized by reaching an effective dose of paliperidone, considering the addition of as need (PRN) quetiapine for its low potency and sedating properties is reasonable. The medication should be used PRN only and should be removed once the insomnia has resolved. Consider a sleep study if sleep apnea is possible and using other options such as short-term orexin antagonists, melatonin, and sedating antidepressant if appropriate. 

Treatment of Antipsychotic Induced Side Effects 

I know what you are going to say, adding a medication to treat a side effect of another medication doesn’t make sense. Let’s take an example to illustrate why this makes sense. If a patient is stable on risperidone and is discovered to have an elevated prolactin level you have an obligation to address it. The addition of low dose aripiprazole has been proven to reduce prolactin levels in these cases. Another possibility is using aripiprazole to reduce the metabolic burden of medications such as clozapine. There is much more limited data in this area and I would consider metformin a much better option to start with if antipsychotic induced weight gain is a problem.

In the process of Switching Medication the Patient Achieves Remission 

This is another common clinical scenario. A patient didn’t respond to a medication, and you begin decreasing the dose of the first medication while titrating the new medicine. Then suddenly they are better. You don’t know why but they are better than they have ever been and now you are afraid to make any additional changes. Ideally you would finish the process and appropriately titrate the new medicine while discontinuing the ineffective medication. There is no good data to support inadequate dosing of two antipsychotics, and it’s best to continue your taper/titration and reevaluate after it’s complete.

Conclusion

There is still limited data to support the use of multiple antipsychotic medications although it is often seen in clinical practice. There are a few places where the addition of a second medication makes sense, and we can use receptor profiles to help us make rational decisions and avoid excess side effect burden. 

0

Powered by WordPress.com.

Up ↑