Principles of Psychopharmacology in Children And Adolescents

Waqar WaheedUniversity of Calgary

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 brain’s 3 basic functions

• Environmental influences of psychotherapy and pharmacological intervention have impact on these networks

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

Major Excitatory Neurotransmitter

• Glutamic acid (glutamatergic pathways)

Major Inhibitory Neurotransmitter

• GABA, via interneurons in each of the aforementioned areas

Neurons modulating these 4 neuronal systems

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

Neurotransmission at the synapse

• Receptor Types1. 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

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

Glutamate Receptors

• Ionotropic (increased intracellular Na+, Ca2+)– NMDA

• Agonist activity requires binding of glycine or glycine analogue to the receptor’s glycine site

• Blocked by PCP/ketamine at the receptor’s PCP site

– AMPA– Kainate

• Metabotropic– mGluR1-7

Impact of Glutamate activity

• Excess stimulation of these neurons occurs in seizures/stroke resulting in neuronal death

• NMDAR PCP site blockade ---> 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

? 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

Major Inhibitory neurotransmitter• GABA comes from

– Glu by the action of enzyme – GAD

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

Acetylcholine

• ACh is crucial for memory and cognitive function

• Choline + Acetyl CoA—choline acetyltransferase Ach• ACh ---AChE(acetyl cholinesterase)--> Choline + acetate • Muscarinic receptors – metabotropic• Nicotinic receptors - ionotropic

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)

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

Serotonergic Neurotransmission

• Comes from tryptophan by the action of TPH• 2% of the body’s serotonin is in the

brain/spinal cord• Project from the mid-brain raphe nuclei to the

C, S, T, Cerebellum, Amygdala and Hippocampus

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

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)

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

• 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

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

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)

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)

Pharmacokinetics

• “What the body does to the drug”

– Absorption– Distribution– Metabolism– Elimination

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)

Cmax

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

Tmax

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

t1/2

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

Clearance

• Rate at which the med is removed from the plasma

Steady state concentration

• Dependent on the med’s– 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

• 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.

MEC

• Minimal Effective Concentration• The minimal plasma concentration of a med

which needs to be maintained to have some pharmacodynamic effect

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)

IV Med

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

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

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)

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

Relatively more body water and less adipose tissue

• Less accumulation • Faster elimination

More renal parenchyma

• Greater clearance capacity• Faster elimination• Shorter half-life

– Lithium in children (Vitiello et al 1998)

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)

CYP 3A

• Chromosome 7 • Metabolizes 40-50% of all drugs

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. John’s wort)

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/TCA’s– Haldol/risperidone/aripiprazole

CYP 2D6

• Inhibitors– Bupropion/clomipramine/desipramine – SSRI’s– Haldol/thioridazine/perphenazine

• Inducers– None

CYP 2D6 Polymorphisms

• Poor metabolizers– White/African – 10%– Asian- 1%

• Ultrarapid metabolizers– Ethiopian- 30%– White- 4%

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

Efflux Transporters (p-glycoproteins, p-gps)

• Substrates– Nortriptyline– Risperidone– Sertraline– Topiramate

• Inhibitors (fluoxetine, grapefruit juice, haloperidol, risperidone, olanzapine)

• Inducers (phenytoin, St, John’s wort)

Other drug–drug 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

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

MEDICATION MANAGEMENT OF ADHD

Medications for ADHD

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

Response to stimulants

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

consecutively

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)

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)

Less Common Side Effects

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

•Suppression of growth

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

• 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

Abuse Potential

• Stimulants- ++ High –Short acting forms > 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

Side Effects of Non-Stimulants

MEDICATION MANAGEMENT OFANXIETY DISORDERS

GAD, SAD, Sep Anxiety Disorder• Fluvoxamine >

fluoxetine=sertraline=paroxetine=venlafaxine (Birmaher 2003, RUPP 2001, Walkup et al 2008, Rynn et al 2007)

Selective Mutism

• Fluoxetine has shown benefit (Black and Uhde 1994)

Panic Disorder

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

Specific Phobias

• Traditionally treated with targeted CBT

OCD

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

PTSD

• RCTs (Cohen et al 2007 n=24, Robb et al 2008 n=131) 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.

School refusal

• Imipramine (Gittelman-Klein and Klein 1971)

MEDICATION MANAGEMENT OF PDD

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– SSRI’s shown to reduce repetitive behaviors

(adults/adolescents/children)

• TCA’s, Alpha adrenergic agents have been shown to be helpful in HA, Inattention in pts.

• 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

PsychoPharmacology PDD• GABA-ergic system

– BZD’s 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 20–40 minutes “

OTHER FOCI OF MEDICATION TREATMENT

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

Emergency management of aggression

• Risperidone M-tab– <20 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)

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

• NBzRA’s – Zaleplon/Zolpidem/Zopiclone– Rebound insomnia if used intermittently

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, Raynaud’s

• Other medications– Atypical antipsychotics/ Chloral hydrate – prn– SSRIs/TCAs – continuous daily administration

Enuresis• Desmopressin- Tablets only (nasal spray has a black

box warning, risk of hyponatremia/seizures/death) – 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

Drug induced Syndromes

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

–Tachycardia

–Tachypnea

Onset/Mental status

Temperature/Pupils

Skin/Muscle Tone

Reflexes

FDA Risk Categories

•Most are Pregnancy Category C

• Except bupropion, clozapine, buspirone (B)

• Except paroxetine, classic mood stabilizers (D)

• Beenzodiazepines (D or X)