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

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.

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

Neurotransmitters Dopamine Norepinephrine Serotonin Gamma aminobutyric acid Acetylcholine

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

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

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

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

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

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

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

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

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

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

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

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

The P450 system

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

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

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

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

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

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

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

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

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

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

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.