1. Basic Science of Psychopharmacology Stephen R. Luber MD
Clinical Associate Professor Pediatrics
University of Washington
Rockwood Clinic

2. Disclosures
Research support: Merck/Schering Plough, Shire, Novartis, Sanofi Pasteur
Speaker’s Bureau: Eli Lilly, Novartis, Sanofi Pasteur
Consultant: Eli Lilly, Novartis
Off label use: fluoxetine, escitalopram on label MDD, lithium, aripiprazole, risperidone quetiapine, olanzapine, ziprasodone, straterra, naltrexone, sertraline.

3. Objectives
Understand the chemical properties and physiologic activity of various neurotransmitters (dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, acetylcholine
Know how to apply the principles of pharmacodynamics
Know how to apply the principles of pharmacokinetics
Know how common psychotherapeutic agents are metabolized and excreted
Understand the issues related to the combined use of psychopharmacologic agents

4. Neurotransmitters Dopamine Norepinephrine Serotonin
Gamma aminobutyric acid
Acetylcholine

5. Monoamine Hypothesis in MDD
Classicl antidepressants increase norepinephrine, dopamine and serotonin levels
So antidepressants either block the reuptake ie TCA, SSRI, SNRI, NERI (none for MDD in US) or
Stop the breakdown of the monoamine once back in cell MAOI
No real deficit in amount or receptor density for MAO BUT systems that regulate the interaction are impaired is signal transduction

6. Dopamine MonoAmine neurotransmitter
Implicated in ADHD via the mesocortical pathway ventral tegmental area to mesocortical and dorsolateral prefrontal areas
MDD bupropion dopaminergic AD works for MDD in adults
High levels can cause OCD like behavior esp. in those with tics
Psychosis postulated excessive levels in mesolimbic system lead to delusions, hallucinations, and thought disorder. Treat with agents to block dopamine

7. Norepinephrine MA Neurotransmitter involved in MDD
ADHD via the prefrontal pathway locus coeruleus to frontal lobes
Tricyclic antidepressants block NE transporter so remain at synapse longer
Atomoxetine NERI blocks norepinephrine reuptake
SNRI block both serotonin and norepinephrine reuptake

8. Serotonin MA neurotransmitter involved in MDD, anxiety
Metabolite 5-HIAA 5 hydroxy-indole acetic acid reduce in CSF of MDD with violent suicide attempts

9. Gamma aminobutyric acid
Neurotransmitter universally inhibits most neurons
GABA neurons have presynaptic transporters to remove GABA from synaptic cleft
Benzodiazepines bind nearby and modulate GABA 1 reducing anxiety

10. Acetylcholine
All antipsychotics block muscarinic cholingergic receptors
Cholinergic disruption associated with memory deficits including Alzheimer's
Newer trials targeted at improving cognition/social interaction in ASD are examining medications associated with acetylcholine such as cholinesterase inhibitors donepezil, galantamine, rivastigmine

11. Pharmacokinetics
Def. study of how drugs are taken up, biologically transformed, distributed, metabolized, and eliminated from the body
Age, disease, timing of a meal, other medications can all change how the medication is absorbed and eliminated

12. Pharmacokinetics Entry into body Transformation
Oral almost everything we use
Sublingual disc melt antipsychotic medications ascenapine needs sublingual stomach no bioavailability
Topical clonidine and methylphenidate patches
Intramuscular immediate and long acting antipsychotic medications, form of divalproex sodium, benzodiazepines
Transformation
Cleavage in gut of pro-drug lisdexamfetamine to dexamphetamine
Hepatic metabolism both primary compound and metabolite may be active

13. Pharmacokinetics Distribution Metabolism Elimination Based on water
Fat soluble
Ability to cross into CNS
Metabolism
Most drugs metabolized in liver
Several are not including lithium, topiramate, paliperidone
Elimination
Via the kidneys in urine
Via the gut in stool

14. Pharmacodynamics
Def. A study of a pharmacological or clinical effect of a medicine in individuals to describe the relation of the effect to dose or drug concentration
For instance fluoxetine is at steady state in approximately 5 days but efficacy is in 4-6 weeks
Stimulant for ADHD peaks as early as 1 hour and biological effect starts shortly after that
Onset and duration of action and side effects

15. Metabolism and Excretion
Majority of CNS active drugs discussed today are either glucuronidated or passed through the cytochrome P450 system
Other drugs primarily excreted through kidneys unchanged including lithium, paliperidone and topiramate

16. Polypharmacy and Drug-drug Interactions
Caution in general when co-administering carbamazepine with anything including birth control pills and methylphenidate
Caution when co-administering lithium and topiramate for increased risk of renal calculi
More drugs usually means more adverse effects try to change one at a time so efficacy and changes in tolerability can be managed

17. The P450 system

18. Cytochrome P450 Enzymes 1A2 Inhibitors Substrates Inducers
Fluvoxamine
Inducers
Cigarettes
Omeprazole
Substrates
Amitriptyline
Caffeine
Clomipramine
Clozapine
Haloperidol
Imipramine
Olanzapine
Tacrine
Theophylline

19. 2C19 Substrates Inhibitors Inducers Amitriptyline Atomoxetine
Citalopram
Clomipramine
Diazepam
Ibuprofen
Imipramine
Naproxen
Omeprazole
Phenytoin
Warfarin
Inhibitors
Fluoxetine
Fluvoxamine
Ketoconazole
Omeprazole
Sertraline
Inducers
Rifampin

20. 2D6 Substrates Amitriptyline Atomoxetine Clomipramine Codeine
Desipramine
Dextromethorphan
Encainide
Flecainide
Fluoxetine
Haloperidol
Imipramine
Maprotiline
Metoprolol
Nortriptyline
Paroxetine
Perphenazine
Propanolol
Risperidone
Thioridazine
Timolol

21. 2D6 Inhibitors No inducers of 2D6 Fluoxetine Haloperidol Paroxetine
Perphenazine
Quinidine
Sertraline
Thioridazine
No inducers of 2D6

22. 2E1 Substrates Inhibitors- none Inducers Acetaminophen Ethanol
Chronic ethanol use
Isoniazid
Acetaminophen
Ethanol

23. 3A4 Substrates Alprazolam Amiodarone Amitriptyline Carbamazepine
Citalopram
Clarithromycin
Clomipramine
Cyclosporine
Diltiazem
Disopryamide
Erythromycin
Imipramine
Lidocaine
Midazolam
Nefazodone
Nimodipine
Omeprazole
Quinidine
Sertraline
Triazolam
Verapamil
Vinblastine

24. 3A4 Inducers Inhibitors Carbamazepine Clarithromycin Phenobarbital
Phenytoin
Rifampin
Clarithromycin
Erythromycin
Fluoxetine
Fluvoxamine
Ketoconazole
Nefazodone

25. Combination Treatment
Can alter side effect profiles and toxicity
Lithium +topiramate lithium toxicity and renal stones
Lithium + antipsychotic higher rates of neuroleptic malignant syndrome
Fluoxetine + aripiprazole increased aripiprazole levels and toxicity

26. Combination Treatment
May lead to better symptom control
Stimulant +alpha agonist better control ADHD in stimulant partial responders
Add on of lamotrigine to other mood stabilizer improved mood control
May lead to lack of efficacy in previously well controlled child
Carbamazepine + aripiprazole lower levels and lack of efficacy

27. Combination Treatment
Look at non-psycho-tropics too
Carbamazepine + low dose OCP pregnant
Citalopram + linezolid (reversible MAO inhibitor) serotonin syndrome

28. Changes You May Wish To Make In Practice
Routine checks of all patients on psychopharmacologic agents for interaction with commonly used pediatric agents including birth control, antibiotics and asthma medications.
Select two medications from each main psychopharmacologic group and being using them in your practice.