Psychopharmacotherapy of Aggression & Psychiatric Emergencies in Children & Adolescents Mental...

Psychopharmacotherapy of Aggression &

Psychiatric Emergencies in Children & AdolescentsMental Health Services

Elham SalariChild & Adolescent Psychiatrist

Psychiatric Emergencies

• Aggression

• Delirium

Aggression

PRN Sedation–patterns

• Aggressive behaviors, may be associated with a variety of psychiatric disorders and are often the reason for referral to psychiatric treatment.


• Acute episodes of aggression or agitation are common in children and adolescents receiving inpatient psychiatric treatment.


• Although behavioral techniques are usually first-line interventions, psychotropic medications with sedative effects are widely used on an ‘as needed’, or prn (Pro Re Nata) basis to treat acute aggressive episodes.

The use of p.r.n medication

to control aggression

in child and adolescent

mental health inpatient services

France, 2009

• The study was carried out on the psychiatry ward of a paediatric teaching hospital in Paris, France.

• P.r.n prescriptions were written, for 27% of the patients (51) but only 14% (26) received a total of 76 administrations.

France, 2009

• Anxiety was the reason given for 67% of the p.r.n administrations, with hydroxyzine used in 69% of these cases.

France, 2009

• Disruptive behaviour accounted for 22% of prn administrations, with antipsychotic drugs accounting for 88% of these administrations.

Australia, 2006

• A retrospective chart review examined 122 medical charts from a child and youth mental health inpatient service in South Brisbane.

Australia, 2006

• 71.3% of patients were prescribed prn sedation and 50.8% were administered prn sedation.

• Patients received an average of 8.0 doses of prn sedation, with 9.8% receiving 10 or more doses.

Australia, 2006

• Chlorpromazine and

• diazepam

were the most commonly utilised agents.

Drugs prescribed and administered for prn

sedationDrugs prescribed and administered for prn sedation

Dose range (mg)

Diazepam 2-20Chlorpromazine 10-100

Temazepam 10–20Droperidol IM 2.5–10Haloperidol 2–2.5 (oral)

2.5–5 (IM)Olanzapine 2.5–10Quetiapine 25–100

Others

Comparison with other studies

• The nature of drugs utilized for prn sedation varies with other studies reporting predominance of

• thioridazine,• thioridazine or

lorazepam• or chlorpromazine in

combination with chloral hydrate

Comparison with other studies

• The lower rate of use of atypical antipsychotics is noteworthy as it contrasts with other reports describing escalating utilization rates of atypical antipsychotics for nonprn use in children and adolescents

Antihistamines

Antihistamines

• Antihistamines, particularly first generation (older) antihistamines, are known to have effects on the central nervous system by causing rapid sedation and slowing down psychomotor performance and cognitive function.

Antihistamines

• Despite the common use of antihistamines for aggression and agitation, there is only one published, controlled study for an antihistamine (diphenhydramine) on managing child and adolescent aggression on psychiatric inpatient units on acute basis.

Diphenhydramine

• In this double-blind, placebo-controlled, pilot study of an antihistamine for 21 male patients (aged 5–13 years old), PRN diphenhydramine was not superior to placebo in reducing aggression, as there was a significant placebo effect.

Typical

Antipsychotics

Atypical

Antipsychotics

Atypical Antipsychotics

• For acute treatment of aggression on child and adolescent inpatient units, ziprasidone is the most extensively studied atypical antipsychotic medication.

Ziprasidone

Ziprasidone

• Ziprasidone was the first atypical antipsychotic available in IM form and this might be the reason that it was observed as the most extensively studied antipsychotic for managing aggression in inpatient children and adolescents.

Ziprasidone

• A case report of youths treated with IM ziprasidone reported an immediate beneficial effect on controlling the aggressive episode on the inpatient child psychiatry unit.

• Ziprasidone has been found to be beneficial in treating aggression in child and adolescent inpatients as well as adolescents in the emergency room

Ziprasidone vs haloperidol

ZiprasidoneHaloperidol

with Lorazeoam


• Both treatment groups had similar outcomes in regards to restraint time and use of rescue medications.

• The Behavior Activity Rating Scale(BARS) scores in subjects started decreasing immediately after the IM ziprasidone injection and had a significant decrease after one half hour and continued to decrease up to two hours.


• Although no severe side effects were found, side effects may not have been monitored or documented carefully.

• Nonetheless, the authors conclude that IM ziprasidone should be considered since it leads to a similar clinical outcome while avoiding potential severe adverse events associated with typical antipsychotic medications such as haloperidol.

Olanzapine

(Zyprexa)

olanzapine vs ziprasidone

olanzapine ziprasidone


• A retrospective study comparing the efficacy of IM ziprasidone and IM olanzapine PRN in 100 juvenile (younger than 18 years) psychiatric inpatients found that these medications were similar in terms of their ability to address inpatient Aggression.


• However, patients taking IM ziprasidone received significantly more doses of IM ziprasidone, as well as other potentially calming medications, such as antihistamines or lorazepam.


• Somnolence was the most common side effect noted during this study for either IM ziprasidone or IM olanzapine.

• Neither medication had any documented significant effect on QTc interval, blood pressure, or heart rate.

Risperidone

(Risperdal)

Risperidone

• Most of the risperidone studies were conducted in outpatient settings and are targeted to treat chronic aggression rather than acute inpatient aggression.

• As per our search, only one study has attempted to observe the effects of risperidone in treating the aggression in an inpatient unit.

Risperidone

• In this study, 38 aggressive adolescent inpatients with CD and other oppositional problems were randomly assigned to risperidone or placebo treatment for six weeks in a doubleblind, placebo-controlled, randomized clinical trial.

• Risperidone was superior to placebo in reducing aggression.

Orally Dissolvable Form

Risperidone

Zyprexa Zydis

Olanzapine

Orally disintegrating tablet

Risperdal m-tab

Orally disintegrating tablet


• Orally Disintegrating Tablets (ODTs) which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take it water.


• Absorption through the cheek allows the drug to bypass the digestive tract for rapid systemic distribution.

• Drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be significantly greater than those observed from conventional dosage forms.


• The need for non-invasive delivery systems persists due to patients’ poor acceptance of, and compliance with, existing delivery regimes, limited market size for drug companies and drug uses, coupled with high cost of disease management.


• A patient in a psychiatric institutional setting who may try to hide a conventional tablet under his or her tongue to avoid their daily dose of a psychotropic drug.

• Patients who are unwilling to take solid preparation due to fear of choking.

• Pediatric and geriatric patients who have difficulty in swallowing or chewing solid dosage forms.


• Risperidone and olanzapine, both are available in an orally dissolvable form (Risperdal M-tab and Zyprexa Zydis),

• Risperidone is also available as a liquid concentrate, again broadening the clinical situations in which it may be of benefit.

Risperidone

• Risperidal

Oral Solution

Quetiepine

(seroquel)

Quetiepine

• In one short-term (eight week), open-label, outpatient study (including 6–12 year old children with CD), quetiepine was found to be helpful and well tolerated when targeting aggression.

Aripiprazole

(Abilify)

Aripiprazole

• Although the inpatient studies on aripiprazole for pediatric aggression are also lacking, one open-label study of 15-day duration suggests that it is effective and safe in reducing aggression in children and adolescents with CD

Benzodiazepines

Benzodiazepines

• Although these agents are generally safe, several clinical caveats should be kept in mind with their use.

• It is found that the use of benzodiazepines in children and adolescents can be associated with a paradoxical reaction including agitation and other adverse side effects.

Benzodiazepines

• When used for longer durations, habituation to and physiologic dependence on any of the benzodiazepines may occur.

Benzodiazepines

• Despite these risks, benzodiazepines are still being preferred to treat pediatric agitation,

• even though standardized studies assessing the usefulness and adverse effects of benzodiazepine monotherapy in treating inpatient aggression in children or adolescents are lacking.

Comparison of the most commonly used benzodiazepines

for acute agitation and aggression.

Agent Routes Doseequivalency

(mg)

Typical dose (mg)

Alprazolam PO, SL

0.5 0.25–0.5 t.i.d. to q.i.d.

Clonazepam PO 0.25 0.125–0.5 q.d. to t.i.d

Diazepam PO, IM, IV

5 1–5 b.i.d. to t.i.d

Lorazepam PO, IM, IV

1 0.25–2 b.i.d. to t.i.d

Oxazepam PO 15 15–30 b.i.d. to t.i.d

Pharmacological Treatment of Aggression

in Children & Adolescent

Guidelines

Summary

• Medication must be appropriate to the severity of the aggression.

• Mild aggression can be managed with psychosocial interventions.

• A weight-based dose of diphenhydramine PRN can be considered for mild aggression but it should be noted that the beneficial effect may be due to a placebo effect.

Summary

• Moderate-to-severe aggression or threatening behavior with severe distress can be treated with either IM ziprasidone (20mg for both children and adolescents)

• or

• Olanzapine

(5mg for children and 10mg for adolescents)

American Academy of

Child and Adolescent Psychiatry

If patient is already taking psychiatric medications

General agitation treatments (PO preferred over IM)

Symptom-specific treatments (PO preferred over IM)

Suggested dose ranges

Diazepam 0.04 - 0.2 mg/kg/dose PO/IM/IV (max 10 mg/dose)

Diphenhydramine 1 mg/kg/dose to max 50 mg PO/IM/IV

Haloperidol 0.025-0.075 mg/kg/dose IM (max 5 mg/dose)

Lorazepam 0.05 mg/kg/dose PO/IM/IV (max 2 mg/dose)

Olanzapine 2.5 mg (school age) to 10 mg (late adolescence) PO

Risperidone 0.25 mg (school age) to 2 mg (late adolescent) PO

Ziprasidone 10 mg IM if 12-16 y10-20 mg IM if ≥16 y

The Royal Children`s Hospital Melbourne

If the patient can tolerate oral medications

Diazepam oral 0.2mg - 0.4mg/kg (Max 10mg/dose

if benzodiazepine naive)

Lorazepam Oral 0.5mg - 1mg (<40kg)1mg - 2.5mg (>40kg)

Olanzapine wafer

sublingual (SL)

2.5mg - 5mg (<40kg)5mg - 10mg (>40kg)

If oral medication not possible

Midazolam IM / IV 0.1mg - 0.2mg/kg(Max 10mg/dose)

Olanzapine IM only

5mg (<40kg)10mg (>40Kg

Haloperidol IM / IV 0.1mg - 0.2mg/kg (Max 5mg/dose,

usually 2.5mg - 5mg/dose)

Midazolam / Haloperidol

Combination

IM Give above doses combined in one syringe

Delirium

Mortality

• As with adult and elderly patients, delirium in children and adolescents in consultation–liaison psychiatry settings is associated with high mortality rates,

• ranging from 12.5%, through 20% to 29%.

Prevalence

• The paucity of epidemiological data is striking given the children represent a population at heightened risk of Delirium.

Symptom profile of delirium

in children and adolescent:

does it differ from

adults and elderly?

Symptom profile of delirium in children and adolescent

• In India: children and adolescents (age 8–18 years) diagnosed with delirium by the consultation–liaison psychiatry team were rated on the Delirium Rating Scale-Revised-98 (DRS-R-98) and compared with DRS-R-98 data on adults and elderly patients, 2012.


• Severity of symptoms, compared to adults, the children and adolescents had lower severity of sleep–wake disturbances, abnormality of thought, motor agitation, orientation, attention, short-term memory, long-term memory and visuospatial abilities impairment.


• When compared to elderly patients,

• children and adolescents had higher severity of lability of affect

• and lower severity of language disturbances, short-term memory and visuospatial abilities.


• Compared to adults, children and adolescents had lower frequency of long-term memory and visuospatial disturbances.

• Compared to the elderly, children and adolescents had higher frequency of lability of affect.


• certain features (irritability, affective lability, agitation, sleep–wake disturbance, fluctuation of symptoms) were reported more commonly in children.


• while other features (delusions, speech disturbance, memory deficits) were reported less commonly.


• Although studies suggest strong continuity in the clinical manifestations of the syndrome across the age span, additional features of delirium in children were identified by the systematic literature review, which have not been described in adults.


• Developmental regression with transient loss of previously acquired skills


• The inability of a usual carer to console the child,

• reduced eye contact with the usual carer,

• and other subtle changes in the quality of the parent–child interaction have been suggested as relatively unique features of delirium in children and adolescents.

Delirium subtypes in children and adolescents

• Schieveld et al. reported that only 35% of children and adolescents presenting with delirium in the setting of a PICU conformed to the hyperactive subtype.

• 22.5% of patients were classified as hypoactive,

• while the remaining 42.5% patients were classified as having a subsyndromal “emerging delirium.”

Delirium subtypes in children and adolescents

• The authors noted that the different forms were not always clear-cut and that some cases fluctuated markedly over time.

Possible predisposing factors

• young age are particularly at risk of emergence delirium, with those aged 2 to 5 years being most vulnerable,

• male gender,• mental retardation,• caregiver factors such as

carer anxiety or absence

Possible predisposing factors

• preexisting emotional and behavioral problems:

• children with higher levels of preoperative anxiety

• temperamentally more impulsive,• less social, and less adaptable to

environmental changes have also been identified as being at higher risk of emergence delirium

Management of delirium in children and adolescents

• “two-track” treatment approach using both psychosocial and pharmacological interventions

• in conjunction with attempts at reversing the cause(s) of the delirium.


• Stoddard et al. (2006) have suggested that brief use of intravenous haloperidol with later substitution of an atypical antipsychotic was increasingly becoming the case with children presenting with a delirium in the United States.


• In children with marked agitation, haloperidol at a loading dose of 0.15 to 0.25 mg/dose intravenously was used,

• followed by a maintenance dose of 0.05 to 0.5 mg/kg per 24 h.


• Review article:

• Individual haloperidol doses in these studies ranged from 0.02 to 0.67 mg/kg per dose.


• If children were able to tolerate oral, nasogastric, or gastrostomy tube medications,

• these authors suggested that after 24 to 48 h of intravenous haloperidol, substitution of an atypical antipsychotic such as risperidone, olanzapine, or quetiapine might be appropriate.


• In less acute situations, and when an enteral route of administration was possible, risperidone at a loading dose of 0.1 to 0.2 mg/dose by mouth, followed by a total daily maintenance dose of 0.2 to 2.0 mg/24 h, was the treatment of choice.


• The reports of Karnik et al. and Scharko et al. raise the possibility that risperidone may be less effective in hyperactive/agitated cases of delirium among adolescent patients,

• while having a particular role in hypoactive cases of pediatric delirium, based on wider receptor effects and potential to selectively increase dopamine in the prefrontal area.


• Karnik et al. proposed a theoretical framework to account for the apparent better response of hyperactive delirium to haloperidol and of hypoactive/mixed delirium to risperidone.


• Ratcliffe et al. assessed the effectiveness and safety of haloperidol using a retrospective chart review of acutely ill children who received haloperidol for “marked agitation and restlessness” or delirium.

• Although 43% had an excellent response,


• 23% had adverse reactions to the medication including dystonic reactions and hyperpyrexia.

• The authors concluded that the use of haloperidol was accompanied by an unacceptably high incidence of side effects in the critically ill pediatric population.

Droperidol• Droperidol, an analog

of haloperidol, has also been suggested to have a role in the treatment of agitated, violent, or psychotic pediatric patients and in adults with delirium.

Droperidol

• Droperidol is more sedating and has a faster onset of action than haloperidol, an effect that may have added benefit in extremely agitated and combative patients.

Droperidol

• A great deal of controversy has surrounded droperidol since the US Food and Drug Administration issued a “black box” warning in relation to droperidol's dose-dependent prolongation of the QT interval on the electrocardiogram.

• However, since then, several published studies have disputed this point

Droperidol

• For children two to 12 years of age:

• the maximum recommended initial dose is 0.1 mg/kg.


• Other psychotropic medications:

• Benzodiazepines

• Psychostimulants

Benzodiazepines

• Stoddard et al. suggested a role for

• intravenous benzodiazepines in the management of delirium in the pediatric critical care setting.

• They warned of the risk of sedation, paradoxical disinhibition, and worsening delirium significantly compromising the assessment and management in some cases.

Benzodiazepines

• Schieveld et al. reported that 55% of their cases of PICU delirium were associated with a recent increase or decrease in benzodiazepines and/or opioids.

Benzodiazepines• Williams has suggested that

benzodiazepines generally be reserved for childhood delirium due to sedative-hypnotic withdrawal,

• other than those cases in which lorazepam is used as an adjunct to haloperidol for persistent agitation and insomnia.

Psychostimulants

• A number of authors have described the successful use of psychostimulants such as methylphenidate for the treatment of hypoactive delirium in adults.

Psychostimulants

• However, there is no literature relating to the treatment of hypoactive delirium in children and adolescents with psychostimulants.

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