T. Lau, MD, FRCPC, MSc., Assistant Professor, UNIVERSITY OF OTTAWA

1. T. Lau, MD, FRCPC, MSc., Assistant Professor, UNIVERSITY OF OTTAWA Objectives To discuss some underlying neurobiological correlates of psychiatric conditions including the connection with the biogenic amines and faster neurotransmitter systems To review the some basic psychopharmacologic principles To review drug interactions and serious adverse drug reactions Geriatrics, Royal Ottawa Mental Health Centre Back to Basics MS 4. April 15, 2010

2. “We have to ask ourselves whether medicine is to remain a humanitarian and respected profession or a new but depersonalized science in the service of prolonging life rather than diminishing human suffering” Elisabeth Kubler-Ross (Swiss-American psychiatrist and author )

3. To help prepare for the LMCC exam Part 1. • To review the biogenic amine neurotransmitter systems • To review the pharmacologic management of depression, bipolar disorder and schizophrenia • To discuss each of the medication classes and representative examples. • To review drug interactions and serious adverse drug reactions

4. At the end of this lecture, you should know: • Names and classes of medications • Pathways and actions of biogenic amine neurotransmitters • Mechanism of action of the common medications (eg SSRI’s, TCA’s, Antipsychotics etc.) • Generally be aware of the different pharmacological options for the three most common psychiatric conditions • Principles on how to start medications and follow their management over time. • Be aware of some significant adverse side effects

5. Psychopharmacology Review • SECTION 1. Intro • History of Psychopharmacology • Neurons & Neurotransmitters • SECTION 2. Specific Disorders and Algorithms • Depression and Anxiety • Bipolar Disorder • Schizophrenia • SECTION 3. Specific Medications • Antidepressants • Mood stabilizers • Antipsychotics • SECTION 4. Drug Interactions

6. History of Psychopharmacology Some Principles of Pharmacology Neurons & Neurotransmitters

7. NaSSA Psychopharmacology Noradrenergic and specific serotonergic antidepressant Atypical Antipsychotic Mono-amine oxidase inhibitor CPZ AAP MAOI AP VPA 1950 1960 1970 1980 1990 200I Li TCA SSRI SNRI Non-selective tricyclic AD Selective serotonin re-uptake inhibitor Serotonin noradrenaline re-uptake inhibitors Librium

8. Antipsychotics • “major tranquilizers” • Typical (1st generation) • Atypical (2nd generation) • Sedative/hypnotics • “minor tranquilizers” • Benzos • barbiturates • Cognitive Enhancers • AchEI • NMDA receptor antagonists • Antidepressants • TCAs (tertiary, secondary) • MAOIs/RIMAs • SSRIs • SNRIs • SARI • DRI • Mood stabilizers • Lithium • Anticonvulsants • Atypical APs Psychopharmacopeia

9. How effective are psychotropics? Pinson and Gray Psychiatric Services 2003

10. Pharmacology • is the study of how drugs interact with living organisms to produce a change in function. • Pharmacokinetics describes the effect of the body on the drug (e.g. half-life and volume of distribution). • Pharmacodynamics describes the drug's effect on the body (desired or toxic). • Psychopharmacology • is the study of how substances that crosses the blood-brain barrier affect behavior, mood or cognition.

11. Downstream signal transduction

12. Complicated because… • Different receptors for same ligand • Different effects at dendritic soma and axon • Different effects pre and post synaptically • Receptor desensitization and localization- changes over TIME. • Different pathways and function

13. If, in a disease state, there is too little, the treatment goal is to raise it. • Eg. Depression with serotonergic/noradrenergic underactivity, antidepressants increase • If, in the disease state, there is too much, the treatment goal is to block it • Eg. Psychosis with overactivity of the mesolimbic pathways, antipsychotics decrease, (dopamine antagonists)

14. Neurotransmitters • Monoamines • Catecholamines: • Dopamine, Norepinephrine • Indolamines: Serotonin, • Histamine • Acetylcholine • Amino acids: • glutamate, GABA, glycine • Steroid hormones • estrogen, androgen, corticosteroids • Gases: nitric oxide • Feedback: cannabinoids • Peptides and proteins: • opioids, endorphins, GH, CCK, PRL, angiotensin II, oxytocin, calcitonin, insulin, glucagon.

15. “Top down” Sleeping pills Sedatives Anti-convulsants Mood stabilizers Alcohol “Bottom up” Antidepressants Antipsychotics Two Types Of PsychoactiveMedications/Substances

17. NA, DA and 5HT Synthesis

18. Noradrenaline Deficiency Sydrome • Deficiency syndrome • Impaired attention • Problems concentrating • Deficiencies in working memory • Slowness of information processing • Depressed mood • Psychomotor retardation • Fatigue

19. Noradrenaline Deficiency Sydrome

20. Serotonin deficiency syndrome • Deficiency Syndrome • Sleep problems, • anxiety, • obsessions, • irritability, • impulse control problems, • appetite disturbance

22. 4 pathways in the brain • Mesocortical • Mesolimbic (pleasure pathway) • Tubero-infundibular • SubstantiaNigra

24. Dopamine deficiency • Depressed. • Anhedonia, no motivation, procrastination and the inability to feel pleasure. Difficulty getting up in the morning. Problems concentrating • Hypersomnia • Parkinson’s • Prone to form addictions, • a need for caffeine or other stimulants, and gaining weight.

25. Dopamine Excess • Psychosis • Aggression • Hypervigilance

27. Differential Diagnosis • Mood disorders • Anxiety • Psychosis • Treatment Algorithms • Depression • Bipolar Disorder • Schizophrenia

28. Differential Diagnosis of Mood disorders • Major depressive disorder • Dysthymic disorder • Depressive disorder NOS • (PMDD, Minor depressive disorder, RBDD, postpsychotic depressive disorder of schizophrenia, etc.) • Bipolar I disorder • (including mixed episodes) • Bipolar II disorder • Cyclothymia • Mood disorder due to a GMC • Substance induced mood disorder

29. Differential Diagnosis of Anxiety • Social phobia • Specific phobia • Generalized Anxiety Disorder • Post Traumatic Stress Disorder • OCD • Panic with and without agoraphobia • Separation anxiety disorder • Associated w depression / psychosis • Somatoform / Dissociative disorders • Personality disorder • Substance and general medical exclusion

30. Differential Diagnosis of Psychosis • Mood D/O • Depression or Mania with psychosis • SCZ • Schizophrenia, Schizoaffective, Schizophreniform • Brief Psychotic Episode • Delusional disorder • Dissociative D/O • Delirium • Personality Disorder • Substance and General Medical Exclusion

31. Initiate treatment with SSRI, SNRI, NRI, other Partial or no response after 4-6 wks of tx at adequate dosages R/A Diagnosis. Optimize dose Inadequate response Augment 1st Lithium 2nd atypical antipsychotic 3rd Lamotrigine 4th Thyroid T3 Switch to new antidepressant from a different class Combine 2 antidepressants from different classes Consider ECT at any time particularly when Very severe depression Not eating or drinking Catatonia Psychosis Suicide Risk Med Intolerance / Pregnancy Consider psychotherapy at any point particularly with early childhood trauma Mann NEJM 2005

32. Determine Phase of illness MANIA MIXED DEPRESSION EUTHYMIA 1) Lithium (for Cade’s disease) 2) Mood Stabilizer (Li, VPA, AAP) plus Antidepressant 3) Lamotrigine 4) Seroquel Monotherapy 5) ECT Lithium AAP ?Lamictal Lithium Epival Typical and Atypical Antipsychotics ECT AAP CMZP Consider ECT at any time particularly when Very severe depression or uncontrolled mania Not eating or drinking Catatonia Psychosis Suicide Risk Med Intolerance / Pregnancy BIPOLAR ALGORITHYM

33. APA Schizophrenia Guidelines 2004. Schizophrenia Tx Algorithm

34. Schizophrenia Tx Algorithm

38. Antidepressants SSRI’s SNRI’s SARI’s NaSSA’s NDRI TCA’s MAOI RIMA’s Novel Agents Mood stabilizers Lithium Epival Lamotrigine Antipsychotics Clozapine Olanzapine Risperidone Quetiapine Ziprasidone

39. SSRIs (Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram) SNRIs (Venlafaxine, Des-Venlafaxine, Duloxetine) SARIs (Trazodone) TCAs (Clomipramine, Amitriptyline, etc) MAOIs (Nardil, Parnate) RIMAs (Moclobemide) Dopamine agonist (Mirapex)

42. 5HT reuptake inhibition Increased availability of 5HT in synapse (and somatodendritic areas) Increased activity of 5HT 1A autoreceptors acutely and decreased firing rate (negative feedback loop) Desensitization of presynaptic 5HT1A autoreceptors Return of normal firing rate with ongoing decreased reuptake. Increased 5HT release and neurotransmission Mechanism of action: SRIs

43. NE reuptake inhibition Increased availability of NE in synapse (and somatodendritic areas) Increased activity of alpha2 autoreceptors acutely and decreased firing rate (negative feedback loop) Desensitization of presynaptic alpha 2autoreceptors Return of normal firing rate with ongoing decreased reuptake. Increased NE release and neurotransmission Downregulation of beta adrenergic receptors Sensitization of alpha 1 adrenergic receptors Mechanism of action: NRIs

44. Prozac (Fluoxetine) [Bech BJP 2000, Beasley JCP 2000] Longest t ½, ~15 days, active metabolite, elderly watch for SIADH, EPS. Inhibitor of 2D6. Norfluoxetine 6 week washout. Can be problematic b/o of this. Paxil (Paroxetine) [Wagstaff CNS drugs 2002] Shortest half life, some anticholinergic ASE, no metabolites, high risk of discontinuation syndrome. Substrate and inhibitor of 2D6 leading to non-linear pharmacokinetics Luvox (Fluvoxamine) [Edwards BJP 1994] Interacts with coumadin. Least protein bound, no metabolites, no chiral center, weakest potency, sedating. Inhibitor of 1A2 and 3A/4 Zoloft (Sertraline) [Perry CNS Drugs 1997, DeVane Clin Pharmaco 2002] Needs to be taken w food, DA activity: EPS and active metabolite, few drug interactions, can cause diarrhea and heartburn. Dose dependent variable neurotransmitter effects. Celexa (Citalopram) [Keller JCP 2000, de Lima EBMH 2001] Most selective. Few drug interactions. Doesn’t effect INR (coumadin). Cipralex [Burke JCP 2002] escitalopram S-enantiomer of Celexa. More of a dose dependent response curve due to differential binding at the allosteric and active drug site

45. Pharmacodynamics Blocks 5 HT reuptake 5HT 1A antidepressant anxiolytic 5HT 1B food intake/temp regulation 5HT 1C sensory 5HT 1D anti migraine 5HT 2A sleep disruption/sexual ASE, suicide R-changes, EPS, 5HT 3 nausea Indications: MDD, dysthymia, OCD, PD, SP, PTSD, GAD, BN, Pain d/o, migraine, FM, selective mutism, autism/Tourette’s

46. T Tremors H H/A’s 20-30% E Euphoria 8% MDD, 50% BAD N Nervousness (agitation, dizziness, restlessness) E Endocrine (SIADH, galactorrhea) W weight gain A anorgasmia and other sex problems 20-50%) G GI upset, GI bleed (age>85, prev GI bleed) E Excretions S Sleep disturbance (REM suppression except luvox, inc awakenings, nocturnal myoclonus), sedation 75% tolerate SSRI’s w no ASE’s 25% ASE disappear by day 14 (most w/I 3-4d). ~10% do not develop tolerance 5HT syndrome, discontinuation syndrome • GASH: • GI (upset, N/D/C, bleed 1:8000) • Activation / Anxiety, • Sexual dysfxn / Sleep disturbance / Sedation / Seizure 0.2%, • Head ache • In the elderly, >85 or previous GI bleed increased risk of GI bleed [Dalton CNS Drugs 2006]. Retrospective data base reviews limited by confounders including NSAID use. • Increased risk of fracture in those over 50 OR=2.1, falls OR 2.2 [Richards AIM 2007]

49. Pharmacology of 1, 2 or all 3 monoamines, depending on the dose (Harvey AGP 2000) At low doses 5HT (same ASE’s: nausea, agitation, sexual dysfxn, insomnia) At medium to high both 5HT and NE Reuptake blockade Watch for HTN, severe insomnia, agitation, nausea, H/A, EPS At very high doses all three May be useful in melancholic, severely depressed inpatients and those refractory to other antidepressants Steady state [ ] ~3d, t ½ ~5hrs, ~11h for active metabolite (ODV ~56% of any given dose), unless XR. Metabolized by 2D6, weak inhibitor of 2D6 Few drug interactions May be safer if combined with coumadin Mirtazapine or Nefazadone may block some 5HT effects ASE’s (E vs placebo) [ISDNSSH]: Insomnia(18vs10%), somnolence 17-23 vs. 8-9%), dizziness (19vs 8%), anxiety (XR better), dry mouth (22 vs 11%, 12 vs. 6% XR), nausea (31-37 vs. 11-12%), h/a (24% comparable to placebo), sweating (<75: 5-6% =placebo, 225: 12.4%, 375 19.3%), sexual dysfxn (12-16 vs <1%), sustained HTN (<75: 1%=placebo, 225: 2.2, 375: 4.5%), withdrawal effects common

50. Desvenlafaxine (Pristiq) AKA, O-desmethylvenlafaxine, • Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine (Effexor) • It is being targeted as the first non-hormonal based treatment for menopause. • Theoretically useful for slow 2D6 metabolizers • The most commonly observed ASE (incidence >= 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, priapism, night terrors, anxiety, and delayed ejaculation. • Nausea was consistently the most common complaint (30-50% vs placebo 9-11%) and the most common reason for discontinuation.