Principles of Psychopharmacology in Children And Adolescents

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Principles of Psychopharmacology in Children And
Adolescents

• Waqar Waheed
• University of Calgary

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Biochemical Neuroanatomy

• 100 billion neurons
• 1,000 to 10,000 connections with each other
• Neuronal networks are arranged to govern human
  behavior (Mesulam, 1998) and the brains 3 basic
  functions
• Environmental influences of psychotherapy and
  pharmacological intervention have impact on these
  networks

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4 Major Anatomical Systems

• Thalamus (S, A, V) and Primary Sensory Cortices
  (S1, A1, V1)
• Association Cortex (Primary cortex, subcortical
  structures, limbic system) ?creates an internal
  representation of sensory info.
• Medial Temporal Lobe-memory storage/retrieval,
  attaches limbic valence to sensory info.
• Basal Ganglia- modulate cortical activity, CSTC
  loop

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Major Excitatory Neurotransmitter

• Glutamic acid (glutamatergic pathways)

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Major Inhibitory Neurotransmitter

• GABA, via interneurons in each of the
  aforementioned areas

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Neurons modulating these 4 neuronal systems

• Cholinergic-Basal forebrain/brainstem
• Dopaminergic- S. Nigra/Ventral Teg. areas
• Noradrenergic- Locus coeruleus
• Serotonergic- Raphe Nuclei

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Neurotransmission at the synapse

• Receptor Types
• 1. Presynaptic vs. Postsynaptic
• 2. Ionotropic- fast, ion-gated-Class I
• vs. Metabotropic- slow G-protein
  coupled- Class II
• 3. Autoreceptors vs. heteroreceptors
• Influenced further by
• 1. Reuptake (not for neuropeptides)
• 2. Degradation

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Major Excitatory Neurotransmitter

• Glutamic acid (Glutamate, Glu)
• Glutamatergic neurons
• Projection fibers (C-C, C-T, C-S, T-C, C-spinal)
• Hippocampus (generation of memory, LTP)
• Cerebellum

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Glutamate Receptors

• Ionotropic (increased intracellular Na, Ca2)
• NMDA
• Agonist activity requires binding of glycine or
  glycine analogue to the receptors glycine site
• Blocked by PCP/ketamine at the receptors PCP
  site
• AMPA
• Kainate
• Metabotropic
• mGluR1-7

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Impact of Glutamate activity

• Excess stimulation of these neurons occurs in
  seizures/stroke resulting in neuronal death
• NMDAR PCP site blockade ---gt psychosis
• Hippocampus- NMDAR crucial for LTP
• Substances binding at the NMDAR glycine site,
  (glycine, d-cycloserine) are associated with
  reduction in psychosis/negative symptoms in
  schizophrenia

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? Intoxication

• Within an hour (less when smoked ,snorted,or
  used intravenously) ,two (or more) of the
  following signs
• (1) vertical or horizontal nystagmus
• (2) hypertension/tachycardia
• (3) numbness or diminished responsiveness to
  pain
• (4) ataxia (5) dysarthria (6) muscle rigidity (7)
  seizures or coma (8) hyperacusis

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Major Inhibitory neurotransmitter

• GABA comes from
• Glu by the action of enzyme
• GAD

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GABA Receptors

• GABAA-(ionotropic) BZD vs. Barbiturates/Ethanol
• Progabide binds between gamma and beta subunits ?
  increased intracellular Cl-
• BZD bind to the alpha subunit and open the ion
  channel if a gamma subunit is present and GABA is
  bound to the beta subunit
• Barbiturates/Ethanol bind near the ion channel
  and are not dependent on the presence of GABA
• GABAB-(metabotropic) pre and post synaptic
• Agonist - Baclofen

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Acetylcholine

• ACh is crucial for memory and cognitive function
• Choline Acetyl CoAcholine acetyltransferase?
  Ach
• ACh ---AChE(acetyl cholinesterase)--gt Choline
  acetate
• Muscarinic receptors metabotropic
• Nicotinic receptors - ionotropic

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Cholinergic Neurons

• Neurons in the basal forebrain (nucleus of
  Meynert/septal nuclei) project to frontal,
  parietal, and occipital cortex (modulate
  attention/novelty-seeking), as well as to the
  hippocampus/cingulate gyrus (modulate memory),
  providing virtually all of the acetylcholine
  (ACh) for the brain.
• Dorsal midbrain neurons project to thalamus
  (regulation of sleep-wake sycles)

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• Short range interneurons in striatum (modulate
  GABA-ergic neurons by opposing the effect of
  dopaminergic neurons)

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Serotonergic Neurotransmission

• Comes from tryptophan by the action of TPH
• 2 of the bodys serotonin is in the brain/spinal
  cord
• Project from the mid-brain raphe nuclei to the C,
  S, T, Cerebellum, Amygdala and Hippocampus

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Serotonin Receptors

• 5-HT1 -metabotropic
• Buspar (5 HT1A partial agonist), triptans (5 HT1D
  agonists)
• 5-HT2 -metabotropic
• LSD/psilocybin (5 HT2A partial agonists, in
  cortical neurons)
• Atypicals (5 HT2 antagonists)
• 5-HT3 - ionotropic

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Dopamine Neurotransmission

• 3 wide ranging projections
• Nigrostriatal (SN to Caudate and Putamen)
  modulates the neuronal excitability of GABAergic
  neurons
• Mesolimbic (VTA to Amygdala/Nucleus
  accumbens)-appetite/reward behavior
• Mesocortical (VTA to frontal, cingulate and
  entorhinal cortices) fine tuning of cortical
  neurons, increasing the s-n ratio
• 1 intermediate-length projection (HT-P)
• 2 ultra-short systems (retina, olfactory bulb)

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Dopaminergic Receptors

• D1 family includes D1 and D5 receptors
• D2 family includes D2,3,4 receptors
• D1 - SN, striatum, olfactory tubercle, cortex
• D2 - SN, striatum, olfactory tubercle, retina,
  pituitary (autoreceptors are D2)
• D3 - Nucleus Accumbens
• D4 on GABAergic neurons in SN, thalamus,
  hippocampus and cortex
• D5 Hippocampus, cortex and hypothalamus

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• All are metabotropic receptors
• DAT- blocked by cocaine/amphetamines/bupropion
• COMT in synapse
• MAO-B intraneuronally
• Dopamine comes from tyrosine by the action of TH

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Noradrenergic Neurotransmission

• Neurons are in the locus coeruleus (LC) and in
  the tegmentum (nearly 50 in each location)
• Functions
• Arousal/vigilance
• Selective attention/response to novel stimuli
• Sleep cycles/appetite/mood/cognition
• LC neurons project to the cortex, thalamus,
  hippocampus, cerebellum and spinal cord
• Tegmental neurons project to the basal forebrain,
  hypothalamus and spinal cord

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Noradrenergic Neurotransmission

• Alpha1 receptors primarily post-synaptic
• Alpha2 receptors primarily pre-synaptic
• Agonists clonidine, guanfacine
• Beta1 receptors are the primary beta receptor in
  the CNS
• Antagpnists- propranolol
• All receptors (alpha and beta are metabotropic)

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Noradrenergic Neurotransmission

• NE comes from dopamine by the action of DBH
  (release enhanced by stimulants)
• Metabolized intra-synaptically by COMT
• Metabolized intra-neuronally by MAO
• Uptake by the presynaptic neuron by NET (blocked
  by desipramine, nortriptyline, venlafaxine,
  atomoxetine)

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Pharmacokinetics

• What the body does to the drug
• Absorption
• Distribution
• Metabolism
• Elimination

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Factors Affecting Drug Movement/Availability

• Molecular size/shape
• Degree of ionization
• Lipid solubility in ionized v non-ionized states
• Binding to proteins
• transmembrane movement is usually limited to
  unbound drug)
• Paracelluar movement is usually possible except
  for areas with tight junction capillaries (B-B
  barrier)

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Cmax

• The peak plasma concentration achieved after the
  administration of a given dose of med (the
  crest level)

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Tmax

• The time it takes to reach Cmax after the med is
  administered

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t1/2

• The half-life of a med is the time it takes for
  the plasma concentration to be half of Cmax

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Clearance

• Rate at which the med is removed from the plasma

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Steady state concentration

• Dependent on the meds
• Cmax
• Tmax
• t1/2 (independent of dose)
• Clearance
• Exact dosage (the higher the dosage, the greater
  the Cmax)
• Frequency of dosing
• Typically achieved after 4-5 half-lives

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• If a med is dosed at intervals greater then the
  t1/2, then the med continues to hit peaks and
  troughs never reaching a SSC or plateau.
• Lack of SSC is not problematic for stimulant med
  dosing but is problematic for fluoxetine,
  lithium, etc.

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MEC

• Minimal Effective Concentration
• The minimal plasma concentration of a med which
  needs to be maintained to have some
  pharmacodynamic effect

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Orally administered med

• Absorption (passive or by active transport
  proteins)
• A poorly absorbed durg will have lower Cmax and
  longer Tmax
• Protein binding in circulation (no
  pharmacodynamic effect in this state)

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IV Med

• No first pass effect (no metabolism by liver
  before med gets in to the heart and onwards into
  the systemci circulation)

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Compared with adults

• Children have smaller body size
• Children have more liver parenchyma, relative to
  body size
• Children have relatively more body water and less
  adipose tissue
• Children have more renal parenchyma relative to
  body size

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Smaller body size

• Smaller volume of distribution which leads to a
  higher peak plasma concentration
• After a 20 mg dose of fluoxetine is administered
  to children, a twofold peak plasma concentration
  occurs as compared to adults (Wilens et al 2002)

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More liver parenchyma

• Greater first pass hepatic drug extraction
• Reduced Bioavailability
• Faster drug metabolism
• Shorter half-life
• Bupropion SR half-life in juveniles is
  approximately 12 hours as compared to 21 hours in
  adults (Daviss et al 2005) necessitating split
  dosing throughout the day

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Relatively more body water and less adipose tissue

• Less accumulation
• Faster elimination

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More renal parenchyma

• Greater clearance capacity
• Faster elimination
• Shorter half-life
• Lithium in children (Vitiello et al 1998)

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Metabolism

• Phase I oxidation/reduction/hydrolysis- to
  increase polarity CYP-450 enzymes
• Phase II conjugation, UGT enzymes
• Cytochrome P450 Enzymes
• Families (1-4)
• Subfamilies (A-E)
• Specific enzyme coded by a specific gene (1 and
  up)

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CYP 3A

• Chromosome 7
• Metabolizes 40-50 of all drugs

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CYP 3A4

• 6-12 months- 50 of adult levels
• Puberty- 100 (exceeds adult levels in
  childhood)
• Substrates
• Sertraline/citalopram/fluoxetine
• Zolpidem/trazodone/alprazolam/midazolam
• Risperidone/seroquel/aripiprazole/haldol
• Inhibitors (grapefruit juice, star fruit,
  fluvoxamine)
• Inducers (CBZ, phenytoin, St. Johns wort)

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CYP 2D6

• Chromosome 22 (other members of the CYP 2 family
  are coded by genes on other chromosomes)
• 1st month of life- 20 of adult activity
• 10 years of age- 100
• Substrates
• Amphetamines/atomoxetine
• Fluoxetine/fluvoxamine/paroxetine
• Mirtazipine/venlafaxine/TCAs
• Haldol/risperidone/aripiprazole

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CYP 2D6

• Inhibitors
• Bupropion/clomipramine/desipramine
• SSRIs
• Haldol/thioridazine/perphenazine
• Inducers
• None

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CYP 2D6 Polymorphisms

• Poor metabolizers
• White/African 10
• Asian- 1
• Ultrarapid metabolizers
• Ethiopian- 30
• White- 4

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UGT based DD interactions

• Uridine diphosphate glucoronyl transferases are
  the microsomal enzymes responsible for Phase-II
  glucuronidation
• VPA inhibits and ethinyl estradiol induces UGT2B7
  for which lamotrigine is a substrate

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Efflux Transporters (p-glycoproteins, p-gps)

• Substrates
• Nortriptyline
• Risperidone
• Sertraline
• Topiramate
• Inhibitors (fluoxetine, grapefruit juice,
  haloperidol, risperidone, olanzapine)
• Inducers (phenytoin, St, Johns wort)

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Other drugdrug Interactions

• Pharmacodynamic Interactions (which occur at
  active sites)
• Citalopram tramodol (serotonergic analgesic) ?
  Serotonin Syndrome
• Vs, the following non-CYP 450 pharmacokinetic
  interaction
• Lithium ibuprofen (deceased renal Li clearance)
  ? Lithium toxicity

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Indications for Therapeutic Drug Monitoring

• Inadequate response
• Higher than normal dose requirement
• Serious/persistent adverse effects
• Toxicity
• Suspected non-compliance
• Suspected drug-drug interactions
• Changing brands
• Other illnesses

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MEDICATION MANAGEMENT OF ADHD
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Medications for ADHD
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Stimulants Dosing/MOA

• Precise mechanisms have not been confirmed
• MPH? prevents DA and NE re-uptake
• Up to daily max of 2 mg/kg,
• Amphetamine based? promote pre-synaptic vesicle
  release of DA and NE
• Up to daily max of 1 mg/kg

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Response to stimulants

• 75 respond to the first stimulant
• Up to 90 respond if 2 stimulants are used
  consecutively

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Non-stimulants Dosing/MOA

• Strattera- increases NE
• 0.5 mg/kg/day x 3d then 1.2 mg/kg/day (qd or bid
• Bupropion- Increases NE and DA
• XR form, 150 mg qam (children) for adolescents,
  increase to 300 mg qam after 3-4 weeks if partial
  benefit
• Venlafaxine - Increases Serotonin (at low doses)
  and NE (at high doses) (37.5 mg- 300 mg qd, XR
  form)
• Clonidine- Central pre-synaptic alpha adrenergic
  receptor agonist (0.025 0.3 mg/d, usually tid)

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Common Side effects of Stimulants

• Loss of appetite/Weight loss
• Insomnia (less if taken early)
• Increased heart rate/blood pressure
• Affective flattening
• Nausea/vomiting/diarrhea (less if with food)

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Less Common Side Effects

• Triggering psychosis
• Making tics worse
• Increased risk of seizures
• Suppression of growth

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Comparison of Stimulants

• Short acting forms usually last 3-4 hours
• Associated with rebound effects
• Lower cost
• Greater abuse potential
• Multiple dosing through the day

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• Long acting forms usually last 8-10 Hours
• Usually are better tolerated
• Greater cost
• Relatively lesser abuse potential
• Ease of administration- No school doses required

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Abuse Potential

• Stimulants- High
• Short acting forms gt long-acting forms
• 29 of students taking prescribed stimulants in
  one study reported they gave away, were forced to
  give away, sold, or were robbed of their
  medication. (Poulin, 2001)
• Street Value of Dexedrine 5 for a 5 mg tab
• Non-Stimulants- Low

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Side Effects of Non-Stimulants
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MEDICATION MANAGEMENT OFANXIETY DISORDERS
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GAD, SAD, Sep Anxiety Disorder

• Fluvoxamine gt fluoxetinesertralineparoxetineven
  lafaxine (Birmaher 2003, RUPP 2001, Walkup et al
  2008, Rynn et al 2007)

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Selective Mutism

• Fluoxetine has shown benefit (Black and Uhde
  1994)

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Panic Disorder

• Paroxetine (Masi et al 2001) and citalopram
  (Lepola et al 1998) have shown benefit

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Specific Phobias

• Traditionally treated with targeted CBT

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OCD

• Meta-analysis (Geller et al 2003) indicates
  Clomipramine gt all SSRIs (mostly)

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PTSD

• RCTs (Cohen et al 2007 n24, Robb et al 2008
  n131) did not show superiority of sertraline
  over PBO, CBT Steiner et al 2007 showed
  superiority of high dose VPA (500-1500 mg) over
  low dose VPA (250 mg)
• Open label studies (n of 6-28) of clonidine,
  propranolol, CBZ, citalopram, risperidone,
  quetiapine and clozapine demonstrated benefit in
  symptom reduction.

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School refusal

• Imipramine (Gittelman-Klein and Klein 1971)

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MEDICATION MANAGEMENT OF PDD
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PsychoPharmacology PDD

• Risperidone , approved by the FDA for treatment
  of irritability and other behavioral symptoms in
  children with ASD.
• The serotonin system has been implicated, but a
  mechanism has not been defined
• SSRIs shown to reduce repetitive behaviors
  (adults/adolescents/children)
• TCAs, Alpha adrenergic agents have been shown to
  be helpful in HA, Inattention in pts.

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• Glutamate system
• Amantadine (NMDA blocker) shown to reduce HA,
  inappropriate speech in children (DBPC)
• D-cycloserine-(Partial NMDA agonist) shown to
  improve social responsiveness in children (SBPC)
• Lamotrigine-(glutamate release blocker), no
  effect
• Riluzole- (Glutamate antagonist) being studied,
  based on benefit in childhood onset OCD

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PsychoPharmacology PDD

• GABA-ergic system
• BZDs known to cause disinhibition
• GABA receptor blocker flumazenil has shown (Wray
  2000) benefit..
• We undertook a randomized, double-blind, placebo
  controlled pilot study of the behavioral effect
  of the benzodiazepine antagonist, flumazenil in
  two children with autism. In one participant,
  there was a mild increase in Interpersonal
  engagement between 2040 minutes

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OTHER FOCI OF MEDICATION TREATMENT
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Emergency management of aggression

• Lorazepam 0.5 mg 1 mg up to every hour, 4mg/24h
  max (children), 6 mg/24h max (adolescents)- main
  risk to monitor respiratory suppression
• Haloperidol 1-5 mg q 1-2 hours (12-20 mg max/24h)
• main risk- acute dystonia, managed with Cogentin
  0.5 mg PO/IM

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Emergency management of aggression

• Risperidone M-tab
• lt20 kg 0.25 mg x 1, repeat after1h
• 20 kg - 0.5 mg x 1, repeat after 1h
• Olanzapine (Zydis)
• 2.5 mg per hour up to max 10 mg per day
• Olanzapine (IM)
• 3 doses max per day of 2.5 5 mg, spaced at
  leats 2 h apart main risk hypotension
• Avoid IM lorazepam IM olanzapine (at least 1h
  apart)

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Insomnia

• Antihistamines (diphenhydramine 25-50 mg qhs, PK
  interaction with fluoxetine)
• Melatonin 3 mg (children) 6 mg (adolescents)- 1
  hour before bedtime
• If delayed sleep phase is the concern, 0.5 mg 6-7
  hours before bedtime is recommended instead
• NBzRAs Zaleplon/Zolpidem/Zopiclone
• Rebound insomnia if used intermittently

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Insomnia

• Alpha 2 agonists- Clonidine- 2-3 hours before
  bedtime (0.025 - 0.1 mg), usually recommended
  daily, risk of rebound htn
• avoid in DM, Raynauds
• Other medications
• Atypical antipsychotics/ Chloral hydrate prn
• SSRIs/TCAs continuous daily administration

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Enuresis

• Desmopressin- Tablets only (nasal spray has a
  black box warning, risk of hyponatremia/seizures/d
  eath)
• 0.2 mg po at bedtime (mandatory fluid
  restriction)
• increase by 0.2 mg increments every 4 days up to
  a max of 0.6 mg in children, 0.8 mg in
  adolescents
• stop after 1 week of max dose if no benefit
• Imipramine- 0.5 mg/kg po qhs
• Increase by 0.5-1 mg/kg/day up top a max of 2.5
  mg/kg/day
• Stop after 2 weeks of max dose if no benefit

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Drug induced Syndromes

• Serotonin, Neuroleptic malignant and
  anticholinergic syndromes have a number of common
  features
• Hypertension
• Tachycardia
• Tachypnea

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Onset/Mental status
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Temperature/Pupils
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Skin/Muscle Tone
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Reflexes
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FDA Risk Categories
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• Most are Pregnancy Category C
• Except bupropion, clozapine, buspirone (B)
• Except paroxetine, classic mood stabilizers (D)
• Beenzodiazepines (D or X)