Adrienne Rosenbauer, PharmD April 10 th, 2015

Transcription

1 Adrienne Rosenbauer, PharmD April 10 th, 2015

2 Review general principles of psychopharmacology Describe the pharmacology of each of the major psychiatric drug classes in the context of common mental illnesses experienced by refugees Review common drug interactions and the role genetics plays Describe the role primary care providers can play in addressing mental health needs of refugees

3 Study of the effects that drugs have on neurobiology and their effects in mental illness Relatively young field Prior to 1970s, focus was on psychoanalysis and not biology Rapidly evolving Basic principles of pharmacology Pharmacodynamics Pharmacokinetics (1)

4 What drugs do to the body Dose-response relationship Drug binds to target Effect Agonism Antagonism Unwanted targets = side effects

5 Increase/decrease activity along neural pathways in brain Serotonin Norepinephrine GABA Dopamine Action at neuronal receptors Alter concentrations of neurotransmitters Act directly on postsynaptic neuron s receptors

6 (2)

7 What the body does to drugs Time course of drugs and metabolites Absorption Distribution Metabolism Elimination

8 Half life Time it takes for drug concentration to decline by 50% Large variability among drugs of the same class Steady-state Generally reached after 5 half lives

9 Cytochrome P450 (CYP) enzymes Large family of liver enzymes Metabolize a majority of drugs CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1, CYP3A4 Major source of drug-drug interactions Enzyme inhibition Enzyme induction Genetic variability

10 Major depressive disorder Post-traumatic stress disorder Generalized anxiety disorder Insomnia Somatic complaints Often the main focus of patients when visiting primary care provider (3)

11 Overlap in drug treatment options between disease states MDD SSRIs, SNRIs, TCAs, other antidepressants PTSD SSRIs, TCAs, prazosin GAD SSRIs, SNRIs, benzos, buspirone, hydroxyzine Insomnia Sedative-hypnotics, benzos Somatic complaints SNRIs, TCAs, anticonvulsants

12 Prevalence General US population: 9% (men), 17% (women) Refugee population: 30.8% Neurobiology Depletion of monoamine neurotransmitters Serotonin, norepinephrine, dopamine Current pharmacotherapy focuses on these Glutamate, GABA Upcoming research (4,6)

13 Drug treatments SSRIs SNRIs TCAs MAOIs Other antidepressants

14 Mechanism Inhibit reuptake of serotonin into the presynaptic neuron, increasing concentration of serotonin in the synaptic cleft Top choice for treating MDD Wide therapeutic index Potential for drug-drug interactions, but less so than older agents (4)

15 Serotonergic system (4)

16 Generic name Brand name Half-life Metabolism Pearls Citalopram Celexa 35 hours 2C19, 3A4 Half life doubles with hepatic impairment Escitalopram Lexapro hours 2C19, 3A4 Half life doubles with hepatic impairment Fluoxetine Prozac 4-6 days (active metabolite ~9 days) Paroxetine Paxil 21 hours 2D6 Sertraline Zoloft 26 hours Non-CYP 2C19, 2D6 Not as much need to taper off slowly due to long half life (5)

17 Noradrenergic system (4)

18 Mechanism Inhibit reuptake of both serotonin and norepinephrine into the presynaptic neuron Similar safety/side effect profile to SSRIs

19 Generic name Desvenlafaxine Brand name Pristiq, Khedezla Half-life Metabolism Pearls hours 3A4 (minor) Duloxetine Cymbalta 8-17 hours 1A2, 2D6 Analgesic effect beyond antidepressant effect alone Levomilnacipran Fetzima 12 hours Non-CYP Venlafaxine Effexor 5 hours (active metabolite 11 hours) 2D6 NE reuptake inhibition starts at higher doses (5)

20 Dopaminergic system (4)

21 Generic name Brand name Halflife Metabolism Mechanism of action Pearls Bupropion Wellbutrin 21 hours 2B6 DNRI (suspected) Lowers seizure threshold; avoid alcohol Mirtazapine Remeron hours 1A2, 2D6, 3A4 Increases 5-HT 1A receptor transmission Histamine blockade (drowsiness) Trazodone Desyrel 7-10 hours 3A4 Mixed serotonin receptor effects Used off-label for insomnia Vilazodone Viibryd 25 hours 3A4, 2C19, 2D6 Mixed serotonin receptor effects Vortioxetine Brintellix 66 hours 2D6 Mixed serotonin receptor effects (5)

22 aka MAOIs Tranylcypromine, phenelzine Last-resort option due to potential for severe interactions Tyramine-containing foods Cured meats, aged cheeses, fermented foods Supplements, OTC products, and illicit drugs that increase serotonin, norepinephrine, or dopamine activity St John s Wort, chlorpheniramine, dextromethorphan, amphetamines (4)

23 Prevalence General US population: 4% Refugee population: 30.6% Neurobiology Amygdala activation/exaggerated response seen in some studies (4,6)

24 Drug treatment FDA-approved Sertraline Paroxetine Off-label Other SSRIs Prazosin TCAs NOT benzos, surprisingly!

25 Used off-label for PTSD-related nightmares Mechanism Post-synaptic α 1 adrenergic antagonism Possible reasons behind effect: Reduce output of corticotropin-releasing hormone Suppress nightmare-generating non-rem stage 1 sleep Metabolism Half life: 2-3 hours Hepatic (non-cyp) (5)

26 Neurobiology Increased norepinephrine function and concentration Problems with feedback inhibition loop mediated by presynaptic α 2 -adrenergic receptor? Many other neurochemical messengers involved in fear/anxiety response to stimulus Large genetic factor (4)

27 Drug treatment FDA-approved SSRIs Escitalopram Paroxetine SNRIs Duloxetine Venlafaxine XR Benzodiazepines Alprazolam Diazepam Lorazepam Other anxiolytics Buspirone Hydroxyzine Off-label Other SSRIs TCAs

28 Mechanism Bind to α-subunit of GABA-A receptor on postsynaptic neuron Receptor has inhibitory effect on neuron when chloride channel opens Modulates receptor to produce greater effect when GABA binds Best for short-term use Initial treatment along with SSRI, then taper off after 6 weeks (4)

29 GABAergic system (4)

30 Generic name Brand name Half-life Metabolism Pearls Alprazolam Xanax 11 hours 3A4 Clonazepam Klonopin hours Non-CYP Panic disorder only Diazepam Valium hours (active metabolite 100 hours) 2C19, 3A4 Lorazepam Ativan 12 hours Non-CYP Temazepam Restoril 4-18 hours Non-CYP Insomnia only Triazolam Halcion hours 3A4 Insomnia only (5)

31 Generic name Brand name Buspirone Buspar 2-3 hours Hydroxyzine Atarax, Vistaril Half-life Metabolism Mechanism of action 20 hours 3A4 Partial agonism at 5-HT 1A? Hepatic Histamine / muscarinic blockade Pearls No concerns about abuse/dependence (5)

32 Primary chronic insomnia is rare Comorbidity is the rule, not the exception Non-pharmacological treatment first Sleep hygiene Drug treatment Benzodiazepines Non-benzo sedative-hypnotics Other agents (4)

33 Non-benzo sedative-hypnotics: Generic name Brand name Half-life Metabolism Eszopiclone Lunesta 6 hours 2E1, 3A4 Zaleplon Sonata 1 hour 3A4 (minor) Zolpidem Ambien 2.5 hours 3A4, 2C9, 1A2, 2D6 (minor), 2C19 (minor) Other agents: Generic name Brand name Half-life Metabolism Mechanism of action Diphenhydramine Benadryl 2-8 hours Hepatic Anticholinergic antihistamine Doxylamine Unisom hours 2D6 Anticholinergic antihistamine Ramelteon Rozarem hours 1A2 Melatonin receptor agonist (5)

34 Chronic pain reporting prevalence General US population: 22% Refugee population: 78%, 65%, 83% Physical or mental cause? Physical-only focus can lead to underrecognition/under-treatment of mental health problems Depression/anxiety can cause real physical symptoms (6)

35 Feel it s inappropriate to discuss psychosocial stressors with medical care providers High levels of cultural stigma associated with mental illness May use culture-specific bodily idioms (6)

36 Drug treatment FDA-approved Duloxetine Off-label TCAs Gabapentin

37 Generic name Brand name Half-life Metabolism Pearls Amitriptyline Elavil hours Non-CYP Off-label pain, insomnia, PTSD Desipramine Norpramin hours Hepatic Off-label pain Doxepin Sinequan 15 hours (active metabolite 31 hours) 2C19, 2D6 Mostly for psychosis + depression Imipramine Tofranil 8-21 hours 2D6 Off-label pain, PTSD Nortriptyline Pamelor hours Hepatic Off-label pain (5)

38 Generic name Brand name Half-life Metabolism Pearls Gabapentin Neurontin 5-7 hours Excreted unchanged in urine Neuropathic pain Other anticonvulsants are approved for use as mood stabilizers in bipolar disorders, but there is a lack of good evidence for use in pain, PTSD, or GAD (5)

39 Used as adjunctive treatment in major depression Aripiprazole Olanzapine Quetiapine Off-label for PTSD Risperidone

40 Potential for side effects Many cause sedation (anticholinergic properties) Atypical antipsychotics Weight gain Glucose intolerance Hyperlipidemia Typical antipsychotics Extrapyramidal side effects

41 Pharmacodynamic Additive effects from therapy duplication Opposition in mechanisms of action Pharmacokinetic CYP450 Protein binding

42 Not as many as you d think! Most clinically insignificant Largest concerns: Narrow therapeutic index drugs Anticoagulants/antiplatelets High risk of serotonin syndrome Any serotonergic agent + MAOI

43 St John s Wort Used for depression Effects on serotonin receptors Induces CYP3A4 and 2C19 Alprazolam Oral contraceptives Digoxin Warfarin HIV drugs Black seed Also known as black cumin Often used for asthma/allergies Unknown effectiveness Unknown mechanism of action (3,6,7)

44 Pharmacodynamics Polymorphic genes control transcription of proteins involved in drug transporters/drug targets Why some people respond to a drug and others don t (4)

45 Pharmacokinetics Inter-ethnic differences in CYP450 enzymes Poor metabolizers Intermediate metabolizers Extensive metabolizers Ultra-rapid metabolizers (4,8)

46 Protein (major polymorphisms) Frequency of poor metabolizers Clinical consequences Example substrates CYP2D6 5% 10% Caucasians 3% Blacks 1% Asians 1% Arabs High drug concentrations; possible toxicity Desipramine, nortriptyline, codeine, dextromethorphan CYP2C9 10% Caucasians 1% 3% Blacks 0% 2% Asians Reduced substrate clearance Warfarin, phenytoin CYP2C19 3% 5% Caucasians 15% 20% Asians High drug concentrations; increased sedation and possible toxicity Diazepam (8)

47 Refugees less likely to directly discuss mental health issues Often begin as physical complaints Hesitant to see mental health specialists Attentive listening, communication, empathy, respect Be flexible about cultural differences (3)

48 Employ non-pharmacological treatments also Drugs can treat symptoms, but will not change underlying maladaptive behavior patterns But don t be afraid of drug therapy! Most drug interactions are subclinical Understanding pharmacology helps guide treatment decisions (3)

49 1. Schatzberg AF, Cole JO, DeBattista C. Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing, Inc; p. 2. aan het Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. CMAJ. 2009;180(3): Kirmayer LJ, Narasiah L, Munoz M, et al. Common mental health problems in immigrants and refugees: general approach in primary care. CMAJ. 2011;183(12):E959-E Schatzberg AF, Nemeroff CB, editors. The American psychiatric publishing textbook of psychopharmacology. 4 th ed. Washington, DC: American Psychiatric Publishing, Inc; Lexi-Comp. Drug monographs. Accessed 2015 April Crosby SS. Primary care management of non-english-speaking refugees who have experienced trauma: a clinical review. JAMA. 2013;310(5): Natural medicines comprehensive database. Supplement monographs. Accessed 2015 April Bains RK. African variation at cytochrome P450 genes: evolutionary aspects and the implications for the treatment of infectious diseases. Evolution, medicine, and public health

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