building connections: management strategies for...

Copyright © 2014 Neuroscience Education Institute. All rights reserved.

Leslie L. Citrome, MD, MPH

Clinical Professor, Department of Psychiatry and Behavioral

Sciences, New York Medical College, Valhalla, NY

Sponsored by the Neuroscience Education Institute

Supported by educational grants from Teva Pharmaceuticals and Alkermes, Inc.

Building Connections:

Management Strategies for

Acute Agitation


Faculty Presenter

Leslie L. Citrome, MD, MPH, is a clinical professor in the

department of psychiatry and behavioral sciences at New York

Medical College in Valhalla, NY.

Consultant/Advisor: Alexza, Bristol-Myers Squibb, Forest, Forum,

Genentech, Janssen, Jazz, Lilly, Lundbeck, Merck, Mylan, Novartis,

Noven, Otsuka America, Pfizer, Reckitt Benckiser, Reviva, Shire,

Sunovion, Takeda, Teva

Speakers Bureau: AstraZeneca, Forest, Lundbeck, Novartis, Otsuka

America, Sunovion, Takeda

Stockholder: Bristol-Myers Squibb, Johnson & Johnson, Lilly, Merck,

Pfizer

Individual Disclosure Statement


Learning Objectives

• Utilize evidence-based guidelines to determine the

cause of agitation in patients who present with

behavioral emergencies

• Apply evidence-based strategies to optimally treat

and manage agitation due to psychiatric illnesses

such as schizophrenia and bipolar disorder


Pretest Question 1

A 45-year-old patient with schizophrenia presents

at the emergency department in a highly agitated

state. Which of the following agents is FDA-

approved for the treatment of acute agitation in

schizophrenia?

1. Intramuscular haloperidol

2. Inhaled loxapine

3. Sublingual asenapine

4. 1 and 2 only

5. All of the above


Pretest Question 2

Michael is a 25-year-old man who presents with

acute agitation, tremor, and dilated pupils. He

has a history of alcoholism but no other

psychiatric history. Standard screens reveal no

alcohol in his blood. Which of the following

treatment strategies is recommended for patients

with agitation due to alcohol withdrawal?

1. Lorazepam

2. Haloperidol

3. Asenapine


Pretest Question 3

Donna is a 45-year-old patient who was brought

to the emergency room due to severe agitation.

The patient's husband reports that he found his

wife in this state with an empty bottle of whiskey

in her hand. Standard screens reveal a very high

blood alcohol level. Which of the following

treatments is recommended for agitation due to

acute alcohol intoxication?

1.Lorazepam

2.Haloperidol

3.Asenapine


Agitation

• Characterized by behaviors such as:

– Explosive or unpredictable anger

– Intimidating behavior

– Hostile verbal behavior

– Restlessness

– Pacing

• May progress to violence and aggression if not

effectively managed

Bostwick JR, Hallman IS. Medsurg Nurs 2013;22(5):303-7;

Knox DK, Holloman GH. West J Emerg Med 2012;13(1):35-40.


Epidemiology of Agitation

• Agitation is present in:

– 50% of adults needing emergency psychiatric care

– 40% of pediatric patients needing emergency psychiatric care

– 50% of patients aged 65+ admitted to intensive care

– 92% of patients with dementia

Bostwick JR, Hallman IS. Medsurg Nurs 2013;22(5):303-7;


1.62 2.19

6.82

0

1

2

3

4

5

6

7

8

Physicians Nurses Mental Healthcare Professionals

Ris

k o

f W

ork

pla

ce

V

iole

nc

e (

%)

Healthcare workers

are at a very high

risk of workplace

violence compared

to other

professionials


Owen C et al. Psychiatr Services 1998;49(11):1458-61.

Victims of Serious Assault

587

137 113

30 15 15 8

0

100

200

300

400

500

600

700

Nursing Staff Other Patients Property Physicians Psychologists Family Domestic Staff

During the 7-month study, 174 patients

perpetrated 1289 incidents,

of which staff members rated 58% as serious

Copyright © 2014 Neuroscience Education Institute. All rights reserved. Copyright © 2014 Neuroscience Education Institute. All rights reserved.

RATING AGITATION


Behavioral Activity Rating Scale (BARS)

Swift RH et al. J Psychiatr Res 2002;36:87-95.

1 Difficult or unable to rouse

2 Asleep but responds normally to verbal or physical

contact

3 Drowsy, appears sedated

4 Quiet and awake (normal level of activity)

5 Signs of overt (physical or verbal) activity, calms down

with instruction

6 Extremely or continuously active, not requiring restraint

7 Violent, requires restraint


Overt Aggression Scale (OAS)

Yudofsky et al. J Neuropsychiatr Clin Neurosci 2997;9:541-8.


Overt Agitation Severity Scale (OASS)

Yudofsky et al. J Neuropsychiatr Clin Neurosci 2997;9:541-8.


Agitated Behavior Scale (ABS)

Bogner J. Agitated Behavior Scale 2000; http://www.tbims.org/combi/abs.


PANSS-EC (Excited Component)

Lindenmayer et al. Schizophr Res 2004;68(2-3):331-7.

Poor Impulse Control

Disordered regulation and control of action on inner urges,

resulting in sudden, unmodulated, arbitrary, or misdirected

discharge of tension and emotions without concern for

consequences

Tension

Overt physical manifestations of fear, anxiety, and agitation,

such as stiffness, tremor, profuse sweating, and

restlessness

Hostility

Verbal and nonverbal expressions of anger and

resentment, including sarcasm, passive-aggressive

behavior, verbal abuse, and assaultiveness

Uncooperativeness

Active refusal to comply with the will of significant others,

including the interviewer, hospital staff, or family, which may

be associated with distrust, defensiveness, stubbornness,

negativism, rejection of authority, hostility, or belligerence

Excitement

Hyperactivity as reflected in accelerated motor behavior,

heightened responsivity to stimuli, hypervigilance, or

excessive mood lability


Cohen-Mansfield Agitation Inventory (CMAI)

Cohen-Mansfield. J Am Geriatr Soc 1986;34:722-7.


ETIOLOGY OF AGITATION


Psychiatric Causes of Agitation

• Agitated depression

• Schizophrenia

• Personality disorder

• Bipolar disorder

• Extreme anxiety

Marzullo LR. Pediatric Emerg Care 2014;30:269-78.


Neurological / Structural

Causes of Agitation

• Parenchymal contusion (especially frontal)

• Subarachnoid hemorrhage

• Subdural or epidural hematoma

• Space-occupying lesions or tumors

• Hydrocephalus

• Seizure/postictal state

• Stroke



Infectious Causes of Agitation

• Meningitis

• Encephalitis

• Brain abscess

• Sepsis



Metabolic / Endocrine

Causes of Agitation

• Hypoglycemia or hyperglycemia

• Hyponatremia

• Hypercalcemia

• Renal failure

• Hypercarbia

• Acute hypoxemia

• Hypothermia or hyperthermia

• Hepatic encephalopathy

• Hypertensive encephalopathy

• Thyrotoxicosis or hypothyroidism Marzullo LR. Pediatric Emerg Care 2014;30:269-78.


Toxic Causes of Agitation

• Adrenergic agonists

• Alcohol

• Amantadine

• Amphetamines

• Anticholinergic agents

• Antidepressants

• Antiemetics

• Antihistamines

• Antipsychotics

• Antispasmodics

• Aspirin

• Atropine

• Bromide

• Carbon monoxide

• Cimetidine

• Cocaine

• Cycloserine

• Dextromethorphan

• Disulfiram

• Ephedrine

• -hydroxybutyrate

• Hallucinogens

• Hydrocarbons

• Lead and other heavy

metals

• Levodopa

• Lidocaine and other

local anesthetics

• Lithium

• Lysergic acid

diethylamide (LSD)

• Marijuana

• Mercury

• Opiates

• Phencyclidine (PCP)

• Procaine

• Pseudoephedrine

• Salicylates

• Sedative hypnotics

• Serotonin syndrome

• Steroids

• Theophylline

• Withdrawal from ethanol

or sedative drugs

• Xanthenes

Poisoning & Drug Overdose, 6e. Retrieved from http://www.accessmedicine.com/content.aspx?alD=55970001;


http://www.accessmedicine.com/content.aspx?alD=55970001


Possible Etiologies of Agitation With

Fever and Hyperdynamic Vital Signs

Medical Substance-Induced Toxidromes

GABA-mediated receptor

withdrawal

Cocaine Serotonin syndrome

Head injury PCP Neuroleptic malignant

syndrome

Systemic inflammation Ketamine Anticholinergic toxicity

Encephalitis Methamphetamine Malignant hyperthermia

Malignant catatonia MDMA

Tryptamines

Synthetic cathinones

(ie, bath salts)

Keary CJ et al. Primary Care Companion CNS Disord 2013;15(3); Epub ahead of print.


What Are Bath Salts?


What Are Bath Salts?

• Street name for the latest class of designer drug

• Often available on the Internet and in smoke shops,

head shops, and gas stations

– Sold under a variety of names

• Relatively cheap

– $20-50 per 50-mg packet

• Labeled "bath salts," "plant food," "pond water

cleaner," "novelty collector's items," and "not for

human consumption" to circumvent detection and

law enforcement

CDC. MMWR 2011;60(19):624-7;

Faas JA et al. Ann Pharmacother 2012;46:436-41.


Bath Salts Components:

Synthetic Cathinones MDMA Methylone

Mephedrone Methamphetamine

Cocaine MDPV

MDMA Methylone

SERT ++ ++

DAT ++ +++

NET ++ ++

METH Mephedrone

SERT + ++

DAT +++ +++

NET +++ ++

COC MDPV

SERT ++++ +++

DAT ++++ ++++

NET +++ ++++

Baumann MH et al. Eur J Pharmacol 2013;698:1-5; Dybdal-Hargreaves NF et al. Eur J Pharmacol

2013;714:32-40; Eshleman AJ et al. Biochem Pharmacol 2013;85:1803-15.

DAT: dopamine reuptake transporter

NET: norepinephrine reuptake transporter

SERT: serotonin reuptake transporter


Bath Salts: What To Look For

• Bath salts toxicity may mimic a psychiatric disorder

– Only 46% of users have a history of mental illness

• Most common signs of bath salts toxicity

– Patients are usually disoriented and agitated

– Dilated pupils with prominent nystagmus (involuntary eye

movements)

– Lockjaw and teeth grinding

– Rapid, inappropriate, incoherent speech

– Emotionally, verbally, and physically abusive

– Elevated liver enzymes and/or liver failure

McGraw M et al. J Emerg Nurs 2012;38(6):582-8; Penders TM. J Fam Pract 2012;61(4):210-2;

CDC. MMWR 2011;60(19):624-7; Jerry J et al. Cleve Clin J Med 2012;79(4):258-64;

Warrick BJ et al. Ann Emerg Med 2013; Epub ahead of print.


Bath Salts Detection

• Negative results on standard urine drug toxicology

screens

• Specialized labs can detect bath salts components

via chromatography-mass spectrometry

– Results may take several days

– Bath salts components vary and are constantly tweaked by

manufacturers to avoid detection

• Some newer, cheaper urine toxicology assays have

recently been developed

– Screen for 21 designer stimulants

Imam SF et al. J Emerg Med 2013; Epub ahead of print; Jerry J et al. Cleve Clin J Med

2012;79(4):258-64; Slomski A. JAMA 2012;308(23):2445-7.


Delirium

• Delirium is a group of symptoms indicative of a

disease process

• 3 key signs

– Sudden onset

– Change in cognition despite no history of dementia or

psychiatric disorder

– Change in level of consciousness or ability to focus

• Numerous causes include toxicity, medication

interactions, withdrawal, infection, hypoxia,

intracranial pressure, metabolic imbalances

Somes et al. J Emerg Nurs 2010;36:486-8.


DIFFERENTIAL DIAGNOSIS

As many as 80% of patients discharged to a psychiatric facility are

found to have a medical issue causing agitation

Rossi et al. Emerg Med Clin N Am 2010;28:235-56.


Evaluate for…

• Preexisting medical conditions

• Psychiatric history

• Current medications

• Drug exposure

• Alcohol exposure

• Allergies



Assess for Medical Causes of Agitation

• Vital signs, including O2 saturation and temperature

• Plasma glucose

• Plasma calcium

• White blood cell count to rule out sepsis

• Infectious disease screens as clinically indicated

• Plasma sodium to rule out hyponatremia or hypernatremia

• Oxygen saturation as clinically indicated

• Serum ammonia as clinically indicated

• Thyroid status

• Sedimentation rate if history of inflammatory disease

• Hydration level

• ECG Marzullo LR. Pediatric Emerg Care 2014;30:269-78;

Stahl et al. CNS Spectrums 2014; Epub ahead of print.


Also Evaluate for Adverse Medication Effects

• Extrapyramidal symptoms

(EPS)

– Akathisia

– Dystonia

– Parkinsonism

• Sedation

• Orthostasis

• Adverse anticonvulsant

effects

– Ataxia

– Tremor

– Cognitive impairment

• Adverse lithium effects

– Polyuria

– Tremor

– Cognitive impairment

• Adverse beta blocker effects

– Hypotension

– Bronchospasm

– Bradycardia

Stahl et al. CNS Spectrums 2014; Epub ahead of print.


Antipsychotic Motor Side Effects

• Tardive dyskinesia

– Rapid, repetitive movements

– Increasing dose of antipsychotic may IMPROVE tardive

dyskinesia

• Akathisia

– Subjective sense of restlessness or inability to sit still

– Treatment with antipsychotics may WORSEN akathisia

• Parkinsonism

– Tremor, hypokinesia, rigidity, postural instability

• Acute dystonia

– Sustained muscle contractions resulting in twisting and repetitive

movements or abnormal posture

Battaglia et al. CNS Spectrums 2007;12(8)(suppl 11):1-16.


Agitation due to Metabolic / Endocrine

Causes • Hypoglycemia is the most common metabolic cause of agitation

• Small, poorly reactive pupils (metabolic encephalopathies)

• Assess sodium status

• Acid-base status (indicating hypercarbia)

• Anion gap

• Renal function

• Liver function

• Thyroid function

• Urinalysis

• Creatine phosphokinase levels

• Potassium levels

Keary et al. Primary Care Companion CNS Disord 2013;15(3): Epub ahead of print;



Agitation due to Metabolic / Endocrine

Causes (continued)

• Recent weight loss

• Polyuria

• Polydipsia

• Vomiting

• Recent weight loss

• Tachycardia

• Diaphoresis

• Poor sleep

Indicate possible diabetes

Indicate possible thyroid dysfunction




Agitation due to Toxicological Causes

• Sudden onset

• Elevated heart rate and blood pressure

• Includes:

– Serotonin syndrome

– Neuroleptic malignant syndrome

– Anticholinergic excess

– Adrenergic excess

– Alcohol and drug intoxication




Agitation due to Withdrawal

Alcohol Withdrawal

• Dilated pupils

• Tremor

• Hypertension

• Tachycardia

• Tachypnea

• Hyperthermia

• Diaphoresis

Opiate Withdrawal

• Dilated pupils

• Preserved mental status

• Hypertension

• Tachycardia

• Normal respiration

• Normal temperature

• Nausea, vomiting, and

diarrhea




Agitation due to Infection / Inflammation

• Systemic inflammatory response syndrome (SIRS)

– Sepsis when due to infection

– Noninfectious causes include trauma, burns, pancreatitis, and hemorrhage

• Encephalitis (inflammation of brain parenchyma)

– Most common cause is herpes simplex virus

• Look for:

– Fever

– Hypoxia

– Meningeal irritation

– Stigmata of petechiae or purpura

– Cutaneous signs of IV drug use

– History of immunosuppression

– Recent treatment of sinusitis




Agitation due to Brain Injury

• Including TBI, hydrocephalus, brain tumor,

subarachnoid hemorrhage, or intracerebral

hemorrhage

• Often display autonomic asynchrony

– High blood pressure but low heart rate

• Look for signs of head trauma

– Brain contusions, subdural hematoma, subarachnoid bleeds,

or space-occupying lesions

• Consider tumor if:

– No sign of trauma

– Suspicious neurological examination

– New-onset changes in mood or behavior




Agitation due to Delirium

• Acute onset

• Lack of orientation

• Waxing/waning consciousness

• Often no psychiatric history

• Often impairment in some vital signs

• Often labile mood

• Hallucinations usually visual




Agitation Due to Psychosis

• Alertness, orientation, and cognition usually

not affected

• Vital signs and mood are usually stable

• Hallucinations are usually auditory




Medical

• Age >40 years

• No psychiatric history

• Abnormal vital signs

• Abnormal physical exam

• Sudden onset

• Visual hallucinations

• Emotional lability

• Unable to sustain attention

• Decreased consciousness

Primary Psychiatric

• Age <40 years

• Psychiatric history

• Normal vital signs

• Normal physical exam

• Gradual onset

• Auditory hallucinations

• Flattened affect

• Able to redirect

• Alert

Marx J et al. Rosen's Emergency Medicine: Concepts and Clinical Practice. Philadelphia, PA:

Elsevier Health Sciences; 2013.

How to Distinguish Primary Psychiatric Disorder

From Other Medical Causes and Behaviors


TREATING AGITATION


Project BETA

Key Elements in Evaluation

1. Medical evaluation and triage of the agitated patient

2. Psychiatric evaluation of the agitated patient

3. Verbal de-escalation of the agitated patient

4. Psychopharmacological approaches to agitation

5. Use and avoidance of seclusion and restraint

Holloman GH et al. West J Emerg Med 2012;13(1):1-2;

Nordstrom K et al. West J Emerg Med 2012;13(1):3-10.

BETA = Best Practices in Evaluation and Treatment of Agitation.


Acute Intervention: Goals

• Calm the patient as rapidly as possible

• Decrease likelihood of harm to self or others

• Allow diagnostic tests or procedures

• Attenuate psychosis

• Decrease need for seclusion/restraint decrease risk of

staff and patient injury that can occur when placing a

patient into restraints

• Sleep is not desirable when evaluating excessive

sedation that results in the need for constant observation

and assistance in toileting also places an excessive

burden on nursing staff's time

Citrome L. In: Glick RL et al, eds. Emergency Psychiatry: Principles and Practice. Baltimore, MD:

Lippincott Williams & Wilkins, Wolters Kluwer Health; 2008.


4 Main Objectives of

Verbal De-escalation

• Ensure the safety of the patient, staff, and

others in the area

• Help the patient manage his or her emotions

and distress and maintain or regain control of

his or her behavior

• Avoid the use of restraint whenever possible

• Avoid coercive interventions that escalate

agitation

Richmond et al. West J Emerg Med 2012;13(1):17-25.


10 Domains of De-escalation

1. Respect personal space

2. Do not be provocative

3. Establish verbal contact

4. Be concise

5. Identify wants and feelings

6. Listen closely to what the patient is saying

7. Agree or agree to disagree

8. Be clear about the rules and set clear limits

9. Offer choices and optimism

10. Debrief the patient and staff



Broaching the Topic of Medication

Invite the Patient's

Ideas

State a Fact

Persuade

Induce

Coerce (last resort)

"What helps you at times like this?"

"I think you would benefit from medication."

"I really think you need a little medicine."

"You're in a terrible crisis. I'm going to get you some

emergency medication. If you have any serious

concerns, let me know."

"I'm going to have to insist."



Pharmacotherapy for Agitation:

General Recommendations

• Attempt to identify the cause of agitation and

target medication to the most likely underlying

cause

• Use medication to calm, not sedate, patients

• Oral preparations are preferred over

intramuscular preparations

• Patients should be involved whenever possible

in the selection of medication

– Including route of administration

Wilson MP et al. West J Emerg Med 2012;13(1):26-34.


Pharmacotherapy for Agitation

• 3 general classes of medication

– First-generation antipsychotics (FGAs)

– Second-generation antipsychotics (SGAs)

– Benzodiazepines (benzos)

Commonly Used Agents for Treating Acute Agitation

Benzos FGAs SGAs

Lorazepam Haloperidol Aripiprazole * †

Oxazepam Droperidol Olanzapine * †

Chlordiazepoxide Loxapine * † (inhaled) Ziprasidone *

Diazepam Risperidone

Quetiapine

Clozapine

Asenapine

* FDA-approved for the treatment of acute

agitation associated with schizophrenia

† FDA-approved for the treatment of acute

agitation associated with bipolar disorder



Remembrances of

Things Past…

• Acute dystonia

• Oversedation

• Akathisia

• Parkinsonism

• Hypotension

• Tardive dyskinesia

Citrome L. Postgrad Med 2002;112(6):85-96.


First-Generation Antipsychotics:

Frequently Used, but…

• Universally cause sedation (or oversedation) with high

enough dose

• Several IM preparations available

• Low-potency agents (eg, chlorpromazine): watch for

hypotension, anticholinergic effects, seizure threshold

• High-potency agents (eg, haloperidol): watch for acute

dystonia, akathisia

• Continued use of the oral formulation is generally

suboptimal, especially if anticholinergic medications (eg,

benztropine) are required

Powney MJ et al. Cochrane Database Syst Rev 2012;11:CD009377;

Ahmed U et al. Cochrane Database Syst Rev 2010;(4):CD007445;

Volavka J et al. Expert Opinion Pharmacother 2009;10(12):1917-28.


Formulation

• Oral tablets and capsules

• Oral disintegrating tablets

• Oral liquid

• Sublingual

• Intranasal

• Inhaled

• Intramuscular (IM)

• Intravenous (IV)

Keating GM. CNS Drugs 2013;27:479-89; Nordstrom, Allen. Drugs 2013;73:1783-92.


Benzodiazepines

• Sedating

• Advantageous for agitation due to alcohol or sedative withdrawal

• Not recommended for long-term use due to tolerance, dependence, and withdrawal

• Use the lowest effective dose for the shortest period of time

• Lorazepam – Tablet

– Liquid

– IM Battaglia et al. CNS Spectrums 2007;12(8)(suppl 11):1-16;

Citrome, Volavka. CNS Drugs 2011;25(12):1009-21.


Second-Generation Antipsychotics

• As a class, more favorable EPS profile than

FGAs

• Some SGAs (eg, olanzapine, clozapine) carry

a greater risk of cardiometabolic side effects

Wilson MP et al. West J Emerg Med 2012;13(1):26-34; Bostwick, Hallman. Medsurg Nurs

2013;22(5):303-7; Citrome, Volavka. CNS Spectrums 2014; Epub ahead of print.


Ziprasidone:

First SGA FDA-Approved for Agitation

Available Formulations Capsules

IM

Typical IM Dose (mg) 10-20

Half-Life (hours) 2.2-3.4

Advantages Favorable EPS profile

Favorable cardiometabolic profile

Disadvantages Label warning for QTc prolongation

Use caution in patients with impaired renal

function

Oral formulation must be taken with food




BARS = Behavioral Activity Rating Scale.

Lesem MD et al. J Clin Psychiatry 2001;62(1):12-8;

Daniel DG et al. Psychopharmacology 2001;155(2):128-34.

Ziprasidone IM and

Improvement on the BARS


Adverse Event 2 mg

(N = 92)

10 mg

(N = 63)

20 mg

(N = 41)

Somnolence 8% 8% 20%

Nausea 4% 8% 12%

Dizziness 3% 3% 10%

Headache 3% 13% 5%

Postural hypotension 0 0 5%

Safety concerns noted in product labeling include caution in patients

with impaired renal function because the cyclodextrin excipient is

cleared by renal filtration

Pfizer. Geodon (ziprasidone) prescribing information. 2012.

Ziprasidone 10 and 20 mg IM: Adverse Events

With Incidence ≥5% and ≥2x vs. 2-mg Dose


Quantifying Differences

Number Needed to Treat (NNT)

How many patients would you need to treat with

Intervention A instead of Intervention B before you would

expect to encounter 1 additional positive outcome of

interest?

Number Needed to Harm (NNH) How many patients would you need to treat with

Intervention A instead of Intervention B before you would

expect to encounter 1 additional outcome of interest that

you would like to AVOID?


Calculating NNT (or NNH) Is Easy

What is the NNT for an outcome for Drug A vs. Drug B?

fA = Frequency of outcome for Drug A

fB = Frequency of outcome for Drug B

Attributable risk (AR) = fA – fB

NNT= 1/AR

By convention, when not presenting fractions,

we round up the NNT to the next whole number

For example, Drug A results in remission 50% of the time,

but Drug B results in remission 20% of the time

NNT = 1/[0.50-0.20] = 1/0.30 = 3.33 round up to 4


Response defined as ≥2-point decrease in BARS score at 2 hours after the first dose

**P = .01, ***P < .001 vs. control.



Ziprasidone IM for Agitation:

Responder Rates


NNT 4 NNT 2

Ziprasidone IM for Agitation:

Responder Rates

**P = .01, ***P < .001 vs. control.



Response defined as ≥2-point decrease in BARS score at 2 hours after the first dose


Citrome L. J Clin Psychiatry 2007;68(12):1876-85.

NNT for Response at 2 Hours vs.

Placebo?

Responders at 2 hours as defined a priori by each manufacturer


Olanzapine



Available Formulations Tablets

Orally disintegrating tablets

IM

Long-acting depot

Typical IM Dose (mg) 10

Half-Life (hours) 34-38


Superior to haloperidol (schizophrenia) and

lorazepam (bipolar disorder)

Disadvantages Do not coadminister with lorazepam

High cardiometabolic risk


Wright P et al. Am J Psychiatry 2001;158(7):1149-51.

Olanzapine 10 mg IM vs. Placebo

aSignificant differences

between olanzapine and

haloperidol were observed at

15 minutes (t = –3.67, df =

298, P < .001), 30 minutes (t

= –3.91, df = 298, P < .001),

and 45 minutes (t = –2.50, df

= 298, P = .01).

bSignificant differences

between olanzapine and

placebo were observed at 15

minutes (t = –4.13, df = 298,

P < .001), 30 minutes (t = –

5.75, df = 298, P < .001), 45

minutes (t = –5.87, df = 298,

P < 0.001), 60 minutes (t = –

5.98, df = 298, P < .001), 90

minutes (t = –6.07, df = 298,

P < .001), and 120 minutes (t

= –4.86, df = 298, P < .05).


Adverse Event Placebo (N = 415) 10 mg (N = 150)

Somnolence 3% 6%

Using IM olanzapine and parenteral benzodiazepines

simultaneously is NOT recommended

Lilly USA. Zyprexa (olanzapine) prescribing information. 2001.

Olanzapine 10 mg IM: Adverse Events

With Incidence ≥5% and ≥2x vs. Placebo


0

10

20

30

40

50

60

70

80

90

Response: 40% decrease in PANSS-EC from baseline to 2 hours post first IM injection

PBO

IM OLZ 2.5 mg

IM OLZ 5.0 mg

IM OLZ 7.5 mg

IM OLZ 10 mg

IM HAL 7.5 mg

% o

f P

ati

en

ts W

ho

Resp

on

ded

*P < .05 vs. all active doses †P < .05 vs. IM OLZ 7.5 mg and 10 mg

*

†

PBO = placebo.

FDA. Intramuscular Olanzapine for the Rapid Control of Agitation. Rockville, MD: U.S. Department

of Health and Human Services; February 12, 2001. NDA 21-253.

Olanzapine IM vs. Placebo

Dose Finding: Responder Rates

PANSS-EC Response Rate 2 Hours Post First IM Injection



Placebo?




Aripiprazole



Oral solution

IM

Long-acting depot

Typical IM Dose (mg) 9.75

Half-Life (hours) 75



Disadvantages Monitor for excessive sedation and orthostatic

hypotension if given with a benzo




Andrezina R et al. Psychopharmacology 2006;188(3):281-92.

Aripiprazole 9.75 mg IM vs. Placebo


Adverse Event Placebo (N = 220) 9.75 mg (N = 501)

Nausea 3% 9%

Safety concerns noted in product labeling include greater sedation

and orthostatic hypotension with the combination of lorazepam and

aripiprazole than with aripiprazole alone

Otsuka. Abilify (aripiprazole) prescribing information. 2012.

Aripiprazole 9.75 mg IM: Adverse Events



Tran-Johnson TK et al. J Clin Psychiatry 2007;68(1):111-9.

Aripiprazole IM vs. Placebo

Dose Finding: Responder Rates

PEC = Positive and Negative Syndrome Scale-Excited Component.



Placebo?




Loxapine

(FGA With 5-HT2A Antagonism)

Citrome. Ther Clin Risk Manage 2013;9:235-45; Citrome, Volavka. CNS Drugs 2011;25(12):1009-21.

Available Formulations Capsule

Oral liquid

IM

Inhaled

Typical Inhaled Dose (mg) 10


Advantages Favorable EPS profile compared to other FGAs


For inhaled formulation, speed and degree of reduction

in agitation are similar to those with IM antipsychotics

and lorazepam (onset of effect within 10 minutes)

Disadvantages Bronchospasm

Risk Evaluation and Mitigation Strategy (REMS)

program must be followed

Some degree of patient cooperation is required for

inhaled formulation


Citrome L. Int J Clin Pract 2011;65(3):330-40.

Inhaled Loxapine

(D)


*P ˂ .001.

Lesem MD et al. Br J Psychiatry 2011;198(1):51-8.

Schizophrenia: Inhaled Loxapine vs.

Placebo Over Time

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

0 30 60 90 120

Placebo 5 mg (n = 116) 10 mg (n = 112)

*

*

*

* *

*

*

*

*

*

*

*

*

*

Time After Dose 1 (min)

PA

NS

S-E

C S

co

res

, C

ha

ng

e F

rom

Ba

se

lin

e

10


Adverse Event Placebo (N = 263) 10 mg (N = 259)

Dysgeusia 5% 14%

FDA. [email protected]. www.accessdata.fda.gov/Scripts/cder/drugsatfda/index.cfm.

Loxapine Inhaled 10 mg: Adverse Events


Safety concerns noted in product labeling include a bolded

boxed warning regarding bronchospasm



Placebo? N

NT


Citrome L. Int J Clin Pract 2011;65(3):330-40.


Inhaled Loxapine: REMS Program

• Bolded boxed warning regarding bronchospasm

• Prior to administering inhaled loxapine, patients must be

screened for a history of pulmonary disease and examined

by chest auscultation for respiratory abnormalities such as

wheezing

• After administration, patients are required to be monitored for

signs and symptoms of bronchospasm at least every 15

minutes for at least 1 hour

• Inhaled loxapine is to be made available in the United States

only in an enrolled healthcare facility that has immediate on-

site access to equipment and personnel trained to manage

acute bronchospasm, including advanced airway

management (intubation and mechanical ventilation)

Citrome L. Curr Psychiatry 2013;12(2):31-6.

REMS = Risk Evaluation and Mitigation Strategies.


Asenapine

Available Formulations Sublingual tablet

Typical Dose (mg) 10



Disadvantages Unpleasant taste and numbing of the tongue

Must not be taken with food or liquids




Statistically significant differences at 15 min after study medication

administration (P < .002), the earliest assessment time, and

significant differences (P < .001) at all subsequent assessments

(intent-to-treat population)

Pratts M et al. Acta Psychiatr Scand 2014;130:61-8.

Sublingual Asenapine 10 mg vs. Placebo

Over Time

(N=60)

(N=60)


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

PANSS-EC Responders CGI-I Responders

Placebo Sublingual Asenapine 10 mg

NNT 3,

95% CI 2–4

NNT 2,

95% CI 2–3

PANSS-EC responders defined as ≥40% decrease from baseline;

CGI-I responders defined as those with a CGI-I score of 1 (Very Much Improved) or 2 (Much Improved).

CGI-I = Clinical Global Impression-Improvement Scale.

Pratts M et al. Acta Psychiatr Scand 2014; Epub ahead of print.

PANSS-EC Responders and

CGI-I Responders

(N=60) (N=60)


Risperidone


2013;22(5):303-7; Citrome, Volavka. CNS Spectrums 2014; Epub ahead of print;

Stahl. Prescriber's Guide. 4th ed. 2013.



Liquid

Long-acting depot

Typical Dose (mg) 2

Half-Life (hours) 3-20

Advantages May be augmented with a benzo or FGA

Often used to treat agitation in elderly patients

with dementia

Disadvantages May have more sedation and weight gain in

pediatric populations than in adult populations


Quetiapine


Extended-release tablets

Typical Dose (mg) 400-800

Half-Life (hours) 6


Disadvantages May be more sedating than other SGAs




Project BETA

• For psychosis-driven agitation in a patient with a

known psychiatric disorder (eg, schizophrenia,

schizoaffective disorder, bipolar disorder),

antipsychotics are recommended over

benzodiazepines because they address the

underlying psychosis

• Second-generation antipsychotics with supportive

data for their use in acute agitation are preferred over

haloperidol alone or with an adjunctive medication

• If the patient cannot cooperate with oral medications,

IM ziprasidone or IM olanzapine is preferred for acute

control of agitation



After Short-Acting IM Antipsychotics

• Oral antipsychotics

• Same antipsychotic used for acute control is a logical choice for

continued treatment

• Useful to have multiple formulations, such as regular tablets and orally

disintegrating tablets, for covertly noncompliant patients

• Long-acting injectable (depot) antipsychotics

• If available, same antipsychotic used for acute control is a logical

choice for continued treatment

• Useful with overt and covert noncompliance (including medication

administration over objection)

• Supported by a recently conducted prospective study of paliperidone

palmitate vs. oral antipsychotics in patients with schizophrenia, recent

incarceration, and substance use

– Paliperidone palmitate significantly delayed time to first treatment failure

(including arrest/incarceration) vs. daily oral antipsychotics

Citrome L et al. CNS Drugs 2011;25(12):1009-21;

Starr HL et al. Presented at APA 2014. Poster NR8-150.


Receiving Medication Lowers Risk of

Violence

• Swedish national registers: N = 82,647 patients

prescribed antipsychotics or mood stabilizers

• Compared with periods when participants were not on

medication, violent crime fell by 45% in patients

receiving antipsychotics (HR 0.55, 95% CI 0.47–0.64)

and by 24% in patients prescribed mood stabilizers

(0.76, 0.62–0.93)

• Mood stabilizers were associated with a reduced rate of

violent crime only in patients with bipolar disorder

Fazel S et al. Lancet 2014; Epub ahead of print.


Persistent Aggressive Behavior:

Treatments in Schizophrenia

• Second-generation antipsychotics (best

evidence)

• Beta blockers (second best evidence)

• Mood stabilizers (weak evidence)

• Antidepressants (weak evidence)

• Benzodiazepines (negative evidence)

Citrome L et al. CNS Drugs 2011;25(12):1009-21; Volavka J et al. Schizophr Bull 2011;37(5):921-9;

Volavka J et al. Int J Clin Pract 2008;62(8):1237-45.


Clozapine

Stahl. Prescriber's Guide. 4th ed. 2013.

Available Formulations Tablet

Orally disintegrating tablet

Typical IM Dose (mg) 12.5

Half-Life (hours) 8


Effective for the treatment of violent behavior

Disadvantages High risk of cardiometabolic effects

Not recommended first line due to high risk of

agranulocytosis

Requires frequent monitoring



Algorithm for the Treatment of Agitation

Associated

with

delirium

Associated

with

intoxication

Associated

with

psychosis

Unknown or

complex

presentation

Withdrawal

NOT

suspected

Withdrawal

suspected

CNS

stimulant

CNS

depressant

Oral SGA

Oral FGA

IM SGA

IM FGA

Oral benzo

IM benzo

Oral FGA

IM FGA

Oral SGA

Oral FGA

w/ benzo

IM SGA

IM FGA

w/benzo

Psychosis

evident

Psychosis

absent

Oral

benzo

IM benzo


RESTRAINT AND SECLUSION


Forced Medication, Restraint, and

Seclusion

• Increases incidence of injury to both patient and

staff

• Increases length of hospitalization

• Reinforces patient's idea that violence is necessary

to resolve conflict

• Should only be used when less restrictive

interventions have been ineffective in protecting

patient, staff, and others from harm

• Should never be used as a means of coercion,

discipline, convenience, or retaliation by staff

Knox DK, Holloman GH. West J Emerg Med 2012;13(1):35-40; Richmond et al. West J Emerg Med

2012;13(1):17-25; Holloman, Zeller. West J Emerg Med 2012;13(1):1-2.


Seclusion and Restraint Algorithm for Patients

Presenting With Agitation


Attempt verbal de-escalation and offer medication

(if indicated)

Place patient in

restraints

Administer medication

Continue verbal

de-escalation Place patient in a

quiet, locked

seclusion room

Place patient in a

quiet, unlocked

room

Medication (if indicated) and verbal de-escalation

Monitor patient, complete evaluation, and plan treatment

Verbal de-escalation and medication effective?

Is patient a danger to self or others?

Will patient sit in a quiet, unlocked room?

YES NO

NO

YES

YES NO


Summary

• Assessment of the etiology of agitation will help

prevent overlooking an underlying medical condition,

using inappropriate treatment strategies, and

unnecessarily using restraints

• When verbal de-escalation efforts are unsuccessful,

there are 3 main categories of medication used to

treat agitation: first-generation antipsychotics,

second-generation antipsychotics, and

benzodiazepines

• Antipsychotics come in a variety of formulations that

vary in invasiveness and rapidity of action

• Whenever possible, medication selection should

take into account patient preference


Posttest Question 1

A 45-year-old patient with schizophrenia presents

at the emergency department in a highly agitated

state. Which of the following agents is FDA-

approved for the treatment of acute agitation in

schizophrenia?

1. Intramuscular haloperidol

2. Inhaled loxapine

3. Sublingual asenapine

4. 1 and 2 only

5. All of the above


Posttest Question 2

Michael is a 25-year-old man who presents with

acute agitation, tremor, and dilated pupils. He

has a history of alcoholism but no other

psychiatric history. Standard screens reveal no

alcohol in his blood. Which of the following

treatment strategies is recommended for patients

with agitation due to alcohol withdrawal?

1. Lorazepam

2. Haloperidol

3. Asenapine


Posttest Question 3

Donna is a 45-year-old patient who was brought

to the emergency room due to severe agitation.

The patient's husband reports that he found his

wife in this state with an empty bottle of whiskey

in her hand. Standard screens reveal a very high

blood alcohol level. Which of the following

treatments is recommended for agitation due to

acute alcohol intoxication?

1. Lorazepam

2. Haloperidol

3. Asenapine

building connections: management strategies for...

Documents