olanzapine intramuscular in Acute-Agitation-2019.pptx

ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY
Psychiatrists Providing Collaborative Care Bridging Physical and Mental Health
The Medical Management of Acute Agitation
APM Resident Education Curriculum
Revised 2019: Ariadna Forray, MD, Naomi Schmelzer, MD
Original version: R. Scott Babe, M.D., Clinical Assistant Professor of Psychiatry, Western University of Health Sciences,
Samaritan Mental Health, Corvallis, Oregon
Thomas W. Heinrich, MD, Associate Professor of Psychiatry & Family Medicine, Chief, Psychiatric Consult Service at Froedtert Hospital,
Department of Psychiatry & Behavioral Medicine, Medical College of Wisconsin
Version of March 15, 2019

Academy of Consultation-Liaison Psychiatry
Objectives
 Identify the behavioral spectrum of agitation
 Describe the broad differential diagnosis behind the symptoms of agitation and
aggression.
 Apply non-pharmacologic and pharmacologic approaches to management of the
agitated patient in the general medical setting.
2

The Case
 A 47 year-old male with a history of substance use disorder and bipolar disorder along with morbid
obesity, DM and COPD presents to the ED at 0200 after calling 911 and reporting chest pain.
 He is cooperative in the ED, but observed to be mumbling to himself and staring at staff suspiciously.
He is given lorazepam 1mg PO to calm him.
 Since arriving to the floor to rule out an MI, he has become increasingly restless, irritable, and
confrontational. He is increasingly uncooperative with medical care, then becomes verbally and
physically threatening to the staff.
 His primary team calls a psychiatry consult for help managing these behaviors.
3

Definitions
 Agitation
– Excessive motor or verbal activity
– “an emergent situation that is temporary, breaks the therapeutic alliance, and is in need of a
prompt and immediate intervention” (Garriga et al. 2016)
 Aggression
– Hostile, injurious, or destructive behavior. Can be verbal or physical.
 Violence
– Denotes physical aggression by people against other people
– 2 general types:
 Impulsive/reactive
 Instrumental/premeditated –goal-oriented violence
(Siever L. (2008) Neurobiology of aggression and violence. Am J Psychiatry 165: 429-42.
Garriga M., Pacchiarotti, I., Kasper, S. et al. (2016) Assessment and Management of Agitation in Psychiatry: Expert
consensus. World J Biol Psychiatry. 17, 170-185.)
4

Component Behaviors of Agitation
 Nonaggressive behaviors
– Restlessness (akathisia, fidgeting)
– Wandering
– Loud, excited speech
– Pacing or frequently changing body positions
– Inappropriate behavior (disrobing, intrusive, repetitive questioning)
 Aggressive behaviors
– Physical
 Combativeness, punching walls
 Throwing or grabbing objects, destroying items
 Clenching hands into fists, posturing
 Self-injury (repeatedly banging one’s head)
– Verbal
 Cursing
 Screaming
5

Larkin GL. et al. Trends in US Emergency Department Visits for Mental Health Conditions, 1992-2001. Psychiatric Services, June 2005. 56; 671-677.
Marco, C. A., & Vaughan, J. (2005). Emergency management of agitation in schizophrenia. The American journal of emergency medicine, 23(6), 767-776.
 There is little direct data on the prevalence, clinical impact, or financial consequences
of agitation
 Behavioral emergencies responsible for 6% of all ED visits (Larkin et al 2005)
 4.3 million psychiatric emergency visits/year (Marco and Vaughan, 2005)
 21% (900,000) agitated patients with schizophrenia
 13% (560,000) agitated patients with bipolar disorder
 5% (210,000) agitated patients with dementia
6
Epidemiology

Epidemiology
 Studies for health care workers
– California:
 465 assaults per 100,000 hospital workers vs. 82.5 assaults per 100,000 for all workers
(Peek-Asa et al 1997)
– Minnesota Nurses Study (Gerberich et al 2004):
 13.2 per 100 persons per year for physical assaults
 38.8 per 100 persons per year for non-physical assaults
 Greatest risk for persons working in/with:
 Long term care facility
 Intensive care
 Psychiatric unit
 Emergency department
 Geriatric patients
7
Peek-Asa, C., Howard, J., Vargas, L., & Kraus, J. F. (1997). Incidence of non-fatal workplace assault injuries determined from employer's reports in California. Journal of
Occupational and Environmental Medicine, 39(1), 44-50.
Gerberich, S. G., Church, T. R., McGovern, P. M., Hansen, H. E., Nachreiner, N. M., Geisser, M. S., ... & Watt, G. D. (2004). An epidemiological study of the magnitude and
consequences of work related violence: the Minnesota Nurses’ Study. Occupational and environmental medicine, 61(6), 495-503.

Etiology of Agitation
 A. Disease-related: three major categories
– Psychiatric manifestations of general medical conditions
– Substance intoxication/withdrawal
– Primary psychiatric illness
 B. Instrumental: unlikely to benefit from medical intervention (e.g., criminal
behavior)
– Consider short trial of verbal de-escalation
– Depending on severity, consider involving security or law enforcement
These are not mutually exclusive
8

Etiology of Agitation: A Sample of the Varied Conditions
that may Present with Pathologic Agitation
 Dementia
 Huntington's disease
 Brain injury or trauma
 Delirium (Organic Brain Syndrome)
 Korsakoff’s psychosis
 Brain tumors
 Seizure
 Hypoglycemia
 Stroke
 Thyroid disease
 Antisocial behavior
9
 Substance intoxication or withdrawal
 Bipolar disorder
 Major Depressive Disorder
 Psychosis
 PTSD
 Anxiety Disorders
 Personality Disorders
 Autism
 Intellectual Disability

Etiology of Agitation: Medical Causes
 Head trauma
 Encephalitis, meningitis, other
infection
 Encephalopathy (e.g., liver or renal
failure)
 Environmental toxins
 Metabolic abnormalities (sodium,
calcium, glucose)
10
 Hypoxia
 Thyroid disease
 Seizure (including post-ictal state)
 Toxic levels of medications
Nordstrom, K., Zun, L. S., Wilson, M. P., Stiebel, V., Ng, A. T., Bregman, B., & Anderson, E. L. (2012). Medical evaluation and triage of the agitated patient: consensus statement of the American Association for Emergency Psychiatry Project BETA Medical Evaluation
Workgroup. Western Journal of Emergency Medicine, 13(1), 3.

Etiology of Agitation: Delirium
Diagnostic Features
 Disturbance of consciousness
 A change in cognition or development of perceptual disturbance
 Not accounted for by a dementia
 Disturbance develops over a short period of time and tends to fluctuate
(“waxing and waning”)
 Caused by a general medical condition
11

Etiology of Agitation: Substances
 Substance intoxication –
– Alcohol, cocaine, amphetamines, cannabis, ketamine, ecstasy, bath salts, inhalants
 Substance withdrawal –
– Alcohol withdrawal delirium/DTs
 CNS effects of non-psychiatric medications (steroids)
12

Etiology of Agitation: Primary Psychiatric disorders
 Schizophrenia
 Bipolar Disorder
 Neurocognitive Disorder (Dementia)
 Personality Disorders
 Agitated depression
 Anxiety disorder
 Autism spectrum disorder
13

Etiology of Agitation: Common Triggers
 Akathisia from antipsychotic or antidepressant use
 Comorbid substance use or intoxication
 Poor impulse control or other comorbid cognitive deficits
 Chaotic or disruptive environment
 Medical illness
 Exacerbation of symptoms of primary illness
 Psychosocial trigger
14
Garriga, M., Pacchiarotti, I., Bernardo, M., & Vieta, E. (2017). Psychiatric Causes of Agitation: Exacerbation of Mood and Psychotic Disorders. The Diagnosis and Management
of Agitation, 126..

Etiology of Agitation: Schizophrenia
–Patients may present to the ED with acute psychosis
 Hallucinations
 Delusions
 Disorganized speech and/or behavior
 Lack of insight
 Bizarre behavior
–Fertile conditions for the development of agitation
 Psychosis and agitation have a reciprocal relationship
15

Etiology of Agitation: Schizophrenia
– Patients at highest risk for violence
 More suspicious and hostile
 More severe hallucinations
 Less insight into delusions
 Greater thought disorder
 Poor impulse control
– Risk factors for being targeted for violence by person with schizophrenia
 Parent or immediate family member
 Cohabitation
 Patient financially dependent on you
16
Sachs, G. S. (2006). A review of agitation in mental illness: burden of illness and underlying pathology. The Journal of clinical psychiatry, 67, 5-12.

Etiology of Agitation: Personality Disorders
Some personality disorders are more prone to agitation
 Decreased stress tolerance
 Poor impulse control
E.g., Borderline personality disorder, Antisocial personality disorder
17

Etiology of Agitation: Major Neurocognitive Disorder
– Overall, the incidence of agitation is estimated to be between 60-80% (median 44%)
(Bartels et al 2003)
 50% become frankly physically aggressive
 24% become verbally aggressive
– Burden of institutionalization
 Residents with dementia complicated by agitation have the highest 3-month rate of ED visits and
greatest use of restraints (Sachs, 2006)
 Despite use of restraints, over 40% receive no psychiatric medications
18
Bartels, S. J., Horn, S. D., Smout, R. J., Dums, A. R., Flaherty, E., Jones, J. K., ... & Voss, A. C. (2003). Agitation and depression in frail nursing home elderly patients with
dementia: treatment characteristics and service use. The American journal of geriatric psychiatry, 11(2), 231-238.
Sachs, G. S. (2006). A review of agitation in mental illness: burden of illness and underlying pathology. The Journal of clinical psychiatry, 67, 5-12

Etiology of Agitation: Dementia
–Agitation may be a final common pathway for the expression of…
 Depression
 Anxiety
 Psychosis
 Pain
 Delirium
– While agitation may be of multifactorial etiology in patients with dementia, it is
also true that many patients have only agitation as a target symptom for
treatment (Madhusoodanan, 2001)
19
Madhusoodanan, S. (2001). Introduction: antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric patients. The American Journal of
Geriatric Psychiatry, 9(3), 283-288.

Etiology of Agitation: Psychodynamic Perspectives
 A Psychodynamic framework can be used to complement treatment strategies
- Helps temper counter-transference
 Psychodynamic perspectives of agitation and violence
- In contemporary psychoanalytic thought, “the capacity for aggression is innate and universal,
aggressive behavior occurs in response to threats that the self perceives in relation to internal and
external objects.”
- Crisis can be defined as an assault on the person’s sense of self (Bernstein 2007)
20
Yakeley, J. (2018). Psychodynamic approaches to violence. BJPsych Advances, 24(2), 83-92.

Back to the Case (continued)
 Potential etiologies for our gentleman’s growing agitation
–Substance intoxication or withdrawal
–Delirium
–Bipolar disorder
–Personality disorder
21

Assessment of Agitation
–Decisions regarding diagnostic tests must be made in the context of
available history and physical examination
–Goal is to evaluate patient’s risk for medical comorbidities
–Many questions involve forced decisions based on…
 Assumptions
 Information available
 Diagnostic confidence
 Patient’s individual risk factors
22

Assessment of Agitation
 For a patient with known diagnosis of schizophrenia presenting with behavioral
features of typical decompensation:
– Expectant management is appropriate
 For patients with atypical features additional diagnostic tests may be required
– Atypical presentations
 Delirium
 History of trauma
 Overdose
 Headache
 Fever
– Diagnostic tests to consider
 Toxicology screens
 CT of brain
 BMP, CBC, and LFTs
 Urinalysis
 Endocrine tests
 Lumbar puncture
23

The Case (continued)
 Examination of the patient
– The patient is febrile with normal vitals
– Disheveled and malodorous
– Heart, lungs and abdomen are benign
– No tremor, diaphoresis, nystagmus or asterixis
– Mental status examination reveals:
 Appearance/behavior: middle-aged unkempt male in hospital johnny and socks,
uncooperative, pacing the room, poor eye contact, posturing with fists
 Speech: spontaneous, loud, nonpressured, use of profane language
 Mood: “I’m lousy!”, Affect: labile, irritable
 TP: tangential, TC: paranoia towards hospital staff, no SI/HI, no perceptual
disturbances. Does not participate in formal cognitive exam questions.
24

The Case (continued)
 Laboratory evaluation of the patient
– CBC, BMP are normal except for a glucose of 211
– LFTs are normal except for a low albumin
– TSH, B12, Folate, and RPR are also normal
– U/A is positive for glucose and trace ketones
– CT of head is read as “negative”
– EKG shows QTc < 400msec
– UDS and serum toxicology are negative
– Valproate, carbamazepine, and lithium levels are all negative
25

Before the Acute Intervention
 The staff on Med/Surg units are often less informed about what feelings and
behaviors their actions may elicit in patients
 Studies indicate that staff training and education can change this lack of appreciation
 Psychiatric consultants should provide education about
– Establishing goals from the patient’s perspective
– Interventions that support a structured setting
 Private or semi-private room
 Establish clear set of expectations with a written schedule
 Identify staff that are responsible for the patient’s care
– Attempting to enlist the patient in the treatment, i.e. which route of medication has worked the
best in the past as a “choice” which retains some patient control
26

Goals of Intervention
 Acute agitation or a violent patient modifies the normal caregiver-patient
relationship
 The first goal of treatment is to do only what is necessary to assure the safety of the
patient and others while facilitating the resumption of more normal interpersonal
relations
– Calming without over-sedation
27

Agitation Management
 Medical evaluation and triage
 Psychiatric evaluation
 Verbal de-escalation
 Environmental intervetions
 Psychopharmacologic interventions
 Use of seclusion/restraint
28
Holloman Jr, G. H., & Zeller, S. L. (2012). Overview of Project BETA: best practices in evaluation and treatment of agitation. Western Journal of Emergency Medicine, 13(1), 1.

Environmental Interventions
 Examples of effective non-pharmacological treatments
– Clearing the room
– Removing dangerous objects
– Having staff available as a “show of force”
– Close observation
– Calm conversation
– Decreasing sensorial stimulation
29

Communication/Behavioral Interventions
 Nonverbal
– Maintain a safe distance
– Maintain a neutral posture
– Do not stare; eye contact should convey sincerity
– Do not touch the patient
– Stay at the same height as the patient
– Avoid sudden movements
 Verbal
– Speak in calm, clear tone
– Personalize yourself
– Avoid confrontation; offer to solve the problem
30
Onyike, C., & Lyketsos, C. (2011). Aggression and violence. Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically, 101, 153-174..

Communication/Behavioral Interventions
 Aligning Goals of Care
– Acknowledge the patient’s grievance
– Acknowledge the patient’s frustration
– Shift the focus to discussion of how to solve the problem
– Emphasize common ground
– Focus on the big picture
– Find ways to make small concessions
 Monitoring Intervention Progress
– Be acutely aware of progress
– Know when to disengage
– Do not insist on having the last word
31
Onyike, C., & Lyketsos, C. (2011). Aggression and violence. Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically Ill, 101, 153-174..

Back to the Case (continued)
 You assist the team and the nursing staff:
– Clear the room
– Keep dangerous objects out of reach
– Call security
 You approach the patient using verbal de-escalation techniques that you have
learned and practiced
 Despite these interventions the patient makes further threats, rips-off telemetry
lines, and starts to pace with clenched fists while mumbling incoherently
32

A little bit of history…
33

Serotonin-Dopamine Model of Regulation of Agitation
 Dynamic interaction between the amygdala, nucleus accumbens, and the
prefrontal cortex
34
Nucleus
Accumbens
Amygdala
activation
Prefrontal Cortex
agitation
Serotonin
Suppression
Dopamine Released
Ryding et al. The role of dopamine and serotonin in suicidal behavior and aggression. Prog Brain Res 2008;172:307-15
Provides a basis for the response to certain medications

 Ideally pharmacotherapy for acute agitation should:
– Be easy to administer, non-traumatic
– Provide rapid tranquilization without excessive sedation
– Have a fast onset of action and a sufficient duration of action
– Have a low risk for significant adverse events and drug interactions
35

 Definition of psychopharmacologic treatment endpoint: rapid
tranquilization
– Calming process separate from total sleep induction
– Allows patient to participate in care
– Enables clinician to gather history, initiate a work-up, and begin treatment of
unidentified conditions
– Better therapeutic endpoint
– Sleep is not the desired outcome
 It conflicts with goal of patient participation
 Has not been found to be essential to improvement in agitation or decrease in psychotic
symptoms
36
Vieta et al. Protocol for the management of psychiatric patients with psychomotor agitation. BMC Psychiatry 2017;17:328

Pharmacologic Considerations
 Ease of preparation/administration
 Rapid onset of action: IV > IM > PO
 Sufficient duration of effect
 Low risk of adverse reactions or drug interactions
 What is known about the patient’s underlying condition(s)?
– Age
– Comorbid conditions
– Medication/other substance exposure
37
Zeller et al. Systematic Reviews of Assessment Measures and Pharmacologic Treatments for Agitation. Clin Therapeutics 2010; 32:405-425

Pharmacologic Treatment
 Most important factors in medication selection
– Etiology of agitation
– Acute effect on behavioral symptoms
– Multiple means of administration
– Limited side effects
– Ease of administration
– Patient preference
– History of response
 Goal is a balance between effectiveness and tolerability
38
Marder SR. A review of agitation in mental illness: treatment guidelines and current therapies. J Clin Psychiatry 2006;67:13-21

 Route of administration
–Oral (PO) administration
 Preferred if patient accepts
 Liquid or orally dissolving tablets
–Intramuscular (IM) administration
 Rapid elevation of plasma level
 Higher transient concentration
 Faster reduction in agitated behavior
39

 Route of administration (continued)
–Intravenous (IV) administration
 Similar to IM but more rapid elevation of plasma level
 Should be limited to when immediate tranquilization is essential
 Requires appropriate monitoring of vital signs for respiratory depression and
cardiovascular compromise
40

 Most studies of pharmacologic treatment in agitation were done in
patients with KNOWN psychiatric diagnosis
 No randomized, controlled studies have examined the use of medications
in populations with…
– Severe agitation
– Drug-induced agitation
– Significant medical comorbidity
 Results difficult to extrapolate to the undifferentiated agitated patient in
the general ED or medical/surgical unit
41

Association for Emergency Psychiatry Recommendations
 Undifferentiated Agitation/Suspected intoxication with stimulant or withdrawal from
alcohol/benzodiazepine
– Oral benzodiazepines (e.g. lorazepam 1-2 mg)
– Parenteral benzodiazepines (e.g. lorazepam 1-2 mg IM or IV)
 Acute intoxication with CNS depressant (e.g., alcohol)
– Avoid benzodiazepine if possible
1. Oral 1st generation antipsychotic (e.g. haloperidol 2-10 mg )
2. Parenteral 1st generation antipsychotic (e.g. haloperidol 2-10 mg IM)
 Delirium (not associated with alcohol or benzodiazepine withdrawal)
1. Oral 2nd generation antipsychotic (e.g. risperidone 2 mg, olanzapine 5-10 mg)
2. Oral 1st generation antipsychotic (e.g. low dose haloperidol)
3. Parenteral 2nd generation antipsychotic (e.g. olanzapine 10 mg IM)
4. Parenteral 1st generation antipsychotic (e.g. haloperidol low dose IM or IV)
 Schizophrenia or Mania
1. Oral 2nd generation antipsychotic alone (e.g. risperidone 2 mg, olanzapine 5-10 mg)
2. Oral 1st generation antipsychotic (e.g. haloperidol 2-10 mg with benzodiazepine)
3. Parenteral 2nd generation antipsychotic (e.g. olanzapine 10 mg IM)
4. Parenteral 1st generation antipsychotic (e.g. haloperidol 2-10 mg IM) along with benzodiazepine (e.g. lorazepam 1-2 mg)
42
Wilson M.P. et al. The Psychopharmacology of Agitation. Consensus Statement of the
American Association for Emergency Psychiatry, Western J Emerg Med. 2012;13(1):26-34.

Benzodiazepines
 Benzodiazepines (BZDs) act by facilitating the activity of GABA
– GABA is a major inhibitory neurotransmitter
 Therapeutic effects appears linked to decreased arousal
– Little benefit for psychiatric symptoms other than anxiety
 Long history of use in the management of acute agitation
– Individually
– Combination with antipsychotics (except IM olanzapine)
– Preferred in a patient in whom agitation is secondary to alcohol or sedative
withdrawal
43
Zaman et al. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2017;12:Cd003079

Benzodiazepines
 Lorazepam
– Only BZD with complete and rapid IM absorption
– No involvement of P450 system
– IM or sublingual administration
 60-90 minutes until peak plasma concentration
 8-10 hour duration of effect
 12-15 hour elimination half-life
– Studies suggest that lorazepam 2 mg is at least as effective as haloperidol in
controlling acute agitation1-2
44
1Allen MH. Managing the agitated psychotic patient: a reappraisal of the evidence. J Clin Psychiatry 2000;61(S14):S1-S20
2Battaglia et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind,
emergency department study. Am J Emerg Med 1997;15:335–340

Benzodiazepines
 Side effects
– Excessive sedation
 Additive with other CNS depressants
– Respiratory depression
 BZDs avoided in patients at risk for CO2 retention
– Paradoxical disinhibition
 More likely with high doses in patients with structure brain damage, mental
retardation or dementia
– Ataxia
45

Typical Antipsychotics
–Dopamine antagonist
 Positive
 Antipsychotic
 Anti-agitation
 Negative
 Extrapyramidal symptoms (EPS)
 Neuroleptic Malignant Syndrome (NMS)
– Many authors consider typical antipsychotics the treatment of choice in acute
agitation, especially in the setting of delirium
46

 Low potency
– Not recommended
 High potency - Haloperidol
– Virtually no anticholinergic properties
– Little risk of hypotension
– Does not suppress respiration
– Can be given IV
 Not FDA approved
– Fast acting
 Onset of action: 30 minutes
 Duration of action up to 12-24 hours
47
Powney et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of Systematic Reviews 2012;11:CD009377

 Side effects
– Extrapyramidal symptoms
 Dystonia
 Akathisia
 Parkinson-like effects
– QTc prolongation
 Rare at low doses
 Haloperidol and droperidol with “Black Box” warnings
– Lower seizure threshold
 Low-potency > high-potency antipsychotics
48
Powney et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of Systematic Reviews 2012;11:CD009377

 Loxapine
– 5 – 10 mg, inhaled
– Inhaled Loxapine has been recently endorsed by FDA for treatment for agitation in
Bipolar I disorder
– Efficacy supported in multiple trials when compared to placebo, has not been
compared to other active medication
– Need to monitor for bronchospasm, especially in patients with asthma
49
Owen RT. Inhaled loxapine: a new treatment for agitation in schizophrenia or bipolar disorder. Drugs of Today. 49(3):195-201, 2013
Garriga et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016;17:86-128

Atypical Antipsychotics
–Major advance in psychiatry
 Broader spectrum of response
 Different side effect profile
 Less EPS and akathisia
 QTc concern remains
 Metabolic syndrome
–No randomized, controlled studies have examined the use of
medications in populations with…
 Severe agitation
 Drug-induced agitation
 Significant medical comorbidity
50

– Olanzapine
 Intramuscular
 Oral tablet
 Oral tablet, disintegrating
– Aripiprazole
 Oral solution
 Oral tablet
 Intramuscular (immediate-release no longer available in US)
– Risperidone
 Oral solution
 Oral tablet
– Quetiapine
 Oral tablet
– Ziprasidone
 Intramuscular
 Oral tablet
51

 Olanzapine
– IM dose range of 5-10mg
 Maximum of 30mg/day
 15-45 minutes until peak plasma concentration
– PO dose range 5-10mg
 Flexible dose up to 40 mg/day better than fixed 10 mg/day dose
 1-3 hours until peak plasma concentration, but benefits often occur in less
time
52

 Olanzapine
– Adverse events
 Concern of orthostasis
 Long-term use has been associated with the development of metabolic
syndrome
 IM olanzapine should NOT be administered with BZDs or CNS depressants
given reports of adverse events and 8 deaths in Europe
 Patients were also suffering from medical comorbidities
 Cardiopulmonary depression, hypotension, and bradycardia reported
53

 Risperidone
– 2 - 6 mg PO or ODT
 Oral risperidone concentrate 2mg + oral lorazepam 2mg equivalent to IM
haloperidol 5mg + IM lorazepam 2mg
 Oral risperidone 2 mg equally effective as oral haloperidol 5 mg
 Overall not thought to be superior to other antipsychotics
54

 Aripiprazole
– It is unique in that it is a partial dopamine agonist
 Decreases dopamine in hyper-dopaminergic areas of the brain
 Increases dopamine in hypo-dopaminergic areas of the brain
– Oral aripiprazole 15 mg as effective as oral olanzapine 20 mg
– Low risk for QT interval prolongation (<1%)
– Immediate-release IM aripiprazole is effective in the management of agitation in
psychiatric illness; recommended IM dose is 9.75mg (discontinued in the US)
55
Kinon BJ, et al., J Clin Psychopharmacology. 28(6):601-607, 2008
Gonzalez D, et al. Current Medical Research & Opinion. 29(3):241-50, 2013

 Quetiapine
– 1-3 hours to peak plasma concentrations
– Very low risk of EPS
– Sedation and orthostasis are side effects
– Superior to placebo in 3 randomized trials, but not more efficacious when
compared to haloperidol
56

 Ziprasidone
– First atypical with an IM formulation
– IM dose range of 10-20mg
 10mg q2 hour; 20mg q4 hour; maximum of 40mg IM/day
– 30-40 minutes to peak plasma concentrations (9x faster than PO); 2-4 hour
elimination half-life; 4-6 hour duration of effect
– Adverse events: QTc interval prolongation
 Appears to prolong the QT to a greater degree than haloperidol, risperidone,
or olanzapine; no clinically relevant ECG changes observed in agitation studies
57

Combination Therapy
 Individual medications can be targeted to the different components of
agitation
– Anxiety and arousal  benzodiazepine
– Psychosis  antipsychotic
 Combining medications at low doses may reduce individual side effects
(decrease Cmax), while obtaining desired effect
58

Combination Therapy
 Most common combination
– Haloperidol 5mg IM
– Lorazepam 2mg IM
– Benefits
 Faster reduction in agitation
 Less injections required
 Simple to administer
 Lower incidence of EPS
59
Wilson et al. A comparison of the safety of olanzapine and haloperidol in combination with benzodiazepines in emergency department patients with acute
agitation. J Emerg Med 2012;43(5):790-7

Combination Therapy
 Side effects
– Overall, very well tolerated
– Side effect profiles of both the BZDs and antipsychotics apply
– Excess sedation most common adverse reaction
 However, recent studies suggest sedation rates appear similar to lorazepam
treatment alone
60

Onset of Action
Medication Dose Formulation Onset to Efficacy
Loxapine 5-10 mg Inhaled 10-20 minutes
Olanzapine 5-10 mg Intramuscular 15-30 minutes
Ziprasidone 10-20 mg Intramuscular 15-30 minutes
Lorazepam 2 mg Intramuscular 15-45 minutes
Haldol 5-15 mg Intramuscular 30-60 minutes
Aripiprazole 9.75-15 mg Intramuscular 45-90 minutes
Olanzapine 10-20 mg Oral 15-120 minutes
Risperidone 2-6 mg Oral 30-120 minutes
61
Adapted from Zun LS. J Emergency Medicine. 54(3):364-74, 2018

Summary for Acute Term
62
Medication Class Medication Dosing Side Effects/Considerations
Benzodiazepine Alprazolam Only available PO
Initial dose is 0.5-4 mg/day
•Paradoxical reactions can be seen in character-disordered patients
and can worsen symptoms in the elderly
Diazepam PO, IM, IV
Start at 5 mg
•Calming/sedating effect with rapid onset
•Use cautiously with elderly patients because of the long half-life
Lorazepam PO, SL, IM, IV
Start at 1 mg, moderate half-life (10-20 hr)
•No active metabolites; therefore, there is a small risk of drug
accumulation
•Metabolized only via gluconuronidation; therefore, it can be used in
most patients with impaired hepatic function
•Drug of choice within this class due to moderately long half-life
Typical antipsychotics Haloperidol PO, IM, IV
Start at 5-10 mg IM, IV*
*IV formulation is not FDA approved
•High-potency neuroleptic with favorable side-effect profile and
cardiopulmonary safety.
•IV form less likely to cause EPS
•ECG monitoring needed to assess torsades de pointes or QTc
prolongation
•Risk of NMS increases in patients who are poorly hydrated,
restrained, and kept in poorly aerated rooms while given large doses
of antipsychotics
•Frequent vital sign checks and testing for muscular rigidity are
recommended
•Can cause hypotension
Adapted from Allen M, Currier G, Carpenter D: The expert consensus guideline series: treatment of behavioral emergencies, J Psychiatr Pract 11:1-112, 2005
CVD, Cardiovascular disorder; ECG, electrocardiogram; EPS, extrapyramidal symptoms; IM, intramuscular; IV, intravenous; NMS, neuroleptic malignant syndrome; PO, per os (by mouth, orally); PR, per rectum;
SL, sublingual.

Summary for Acute Term (cont.)
63
Medication Class Medication Dosing Side Effects/Considerations
Atypical antipsychotics Risperidone PO, orally disintegrating tablet (OTD)
Starting dose 0.5-2 mg acutely
•No IM form is available
•Offers calming effect with treatment of underlying condition
•Orthostatic hypotension with reflex tachycardia.
•Increased risk of stroke in the elderly with CVD
Olanzapine PO, OTD, IM;
Starting dose 2.5-5 mg, max 30 mg/24 hr with doses 2-4
hours apart
•Useful in patients with poor reaction to haloperidol
•Calming medication with treatment of underlying disorder
•Avoid IM combination with lorazepam
•Increased risk of stroke in the elderly with CVD
Ziprasidone PO, IM
Max of 40 mg/24 hr of IM formulation
•Use caution in patients with preexisting QT prolongation
•Less sedating medication; therefore, good choice if desire tranquilization
without sedation
Aripiprazole PO, OTD
Starting PO dose 5-10 mg, max 30 mg/day
(currently IM formulation only for extended-release
maintenance therapy)
•Akathisia risk
•Less sedating than other medications
•Increased risk of stroke in the elderly
•Good choice for patients with QT interval prolongation
Combinations Haloperidol, lorazepam,
diphenhydramine, or benzatropine
5 mg IM, 2 mg IM, 50 mg IM, 1 mg IM •Most commonly used in the acute setting
•Young athletic men are at increased risk for dystonia
•Akathisia must be considered if agitation increases after administration
CVD, Cardiovascular disorder; ECG, electrocardiogram; EPS, extrapyramidal symptoms; IM, intramuscular; IV, intravenous; NMS, neuroleptic malignant syndrome; PO, per os (by mouth, orally); PR, per rectum;
SL, sublingual.
Adapted from Allen M, Currier G, Carpenter D: The expert consensus guideline series: treatment of behavioral emergencies, J Psychiatr Pract 11:1-112, 2005

Cost
64

Disposition
 Disposition depends on etiology of agitation and current condition
– Delirium  General medical hospital
– Psychosis  Psychiatric admission
– Don’t have a clue  General medical hospital to determine cause of agitation
65
Riker RR, Fraser GL. The new practice guidelines for pain, agitation, and delirium. Am J Critical Care. 22(2):153-7, 2013

Special Population: ICU patients
 Mechanically ventilated ICU patients: analgesia and sedation are
recommended
 Dexmedetomidine, rather than benzodiazepines
 No evidence haloperidol decreases the duration of delirium
 Atypical antipsychotics may decrease the duration of delirium in ICU
patients
66
Riker RR, Fraser GL. The new practice guidelines for pain, agitation, and delirium. Am J Critical Care. 22(2):153-7, 2013

Special Population: Weaning of Ventilation
 Dexmedetomidine (alpha 2 adrenergic sedative)
– Better than midazolam ( hypertension and tachycardia, time intubated)1
– Better than haloperidol ( time intubated, length of stay)2
67
1Ricker et. al, JAMA.2009;301(5):489–499
2Reade et. al, Critical Care 2009;13:R75

Recommended Readings
 Garriga M, Pacchiarotti I, Kasper S, et al. Assessment and management of agitation in
psychiatry: Expert consensus. World J Biol Psychiatry 2016;17:86-128.
 Marder SR. A review of agitation in mental illness: treatment guidelines and current
therapies. J Clin Psychiatry. 2006;67 (Suppl 10):13-21.
 Ryding E, Lindström M, Träskman-Bendz L. The role of dopamine and serotonin in
suicidal behaviour and aggression. Prog Brain Res. 2008;172:307-15.
 Wilson M.P. et al. The Psychopharmacology of Agitation. Consensus Statement of the
American Association for Emergency Psychiatry, Western J Emerg
Med. 2012;13(1):26-34.
68

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