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Pharmacotherapy of Depression

Pharmacotherapy of Depression. Jerry Overman, Pharm.D., BCPP Clinical Pharmacy Specialist, Mental Health (NIMH) NIH Clinical Center Pharmacy Department WMSHP and DC-CCP Spring Meeting May 10, 2014 9:00 AM. Jerry Overman, Pharm.D., BCPP

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Pharmacotherapy of Depression

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  1. Pharmacotherapy of Depression Jerry Overman, Pharm.D., BCPP Clinical Pharmacy Specialist, Mental Health (NIMH) NIH Clinical Center Pharmacy Department WMSHP and DC-CCP Spring Meeting May 10, 2014 9:00 AM

  2. Jerry Overman, Pharm.D., BCPP • has no financial interest or relationships to disclose

  3. Objectives • Define major depressive disorder and list the core symptoms of the illness • Identify the various mechanisms and theories proposed for the pathogenesis of depression • List the medication classes used to treat depression • Discuss the pharmacology of the various classes of antidepressants and how these mechanisms relate to both efficacy and tolerability

  4. Epidemiology of Depression • Lifetime prevalence of a major depressive episode: 17% • Male: 13% • Female: 21% • Trends • Age at onset: Younger • Incidence: Increasing Weissman MM, et al. JAMA. 2011;276:293-299.

  5. Depression and Suicide • Up to 15% of patients with major depressive disorder requiring hospitalization commit suicide Depression Guideline Panel. AHCPR publication 93-0550.

  6. Additional Risk Factors for Suicide • Substance abuse (self or family) • Psychotic symptoms • Living alone • Insomnia • Anxiety • Hopelessness • Male gender • White race • Advanced age • History of attempts • Medical illnesses Depression Guideline Panel. AHCPR publication 93-0550.

  7. Pharmacotherapy ReducesRisk of Suicide 300 259 Treated 250 Untreated 200 Suicides/100,000 person-years 141 150 100 50 0 Isacsson G, et al. J Affect Disord. 1996;41:1-8.

  8. DSM-5 Criteria for Major Depressive Episode • ≥5 symptoms present during same 2–week period • Change from previous functioning • Functional impairment and/or distress • Symptoms not due to another cause DSM-5. Washington, DC: American Psychiatric Association. 2013.

  9. Sleep: Insomnia or hypersomnia Interest: Anhedonia - loss of interest or pleasure Guilt: Feelings of worthlessness Energy: Fatigue Concentration: Diminished ability to think or make decisions Appetite: Weight change Psychomotor: Psychomotor retardation or agitation Suicide: Recurrent thoughts of death DSM-5 Criteria forMajor Depressive Episode 5 Symptoms in the same 2-week period * Must include 1 of these DSM-5. Washington, DC: American Psychiatric Association. 2013.

  10. “Tired all the time”, “blahs” Headache, Pain Malaise Vague abdominal or joint pains Disturbed sleep Sexual or relationship problems Common Presenting Somatic Complaints DSM-5. Washington, DC: American Psychiatric Association. 2014.

  11. Hopelessness Low self esteem Denial, discounting, or explaining away stigmatized feelings Impaired memory, difficulty concentrating Psychological Symptoms DSM-5. Washington, DC: American Psychiatric Association. 2013. Depression Guideline Panel. AHCPR publication 93-0550.

  12. Continuum of Depression and Anxiety Comorbid depression and anxiety Major depressive disorder Anxiety disorders

  13. Outcomes of Treatments of Major Depressive Disorder • Dropout • Nonresponse/response w/residual symptoms • Response • Incomplete remission • Complete remission • Recovery

  14. Acute Recovery in Major Depression • HAM-D score 7 • Patient asymptomatic • No longer meets criteria for depression • Minimal or no symptoms • Psychosocial and occupational functioning restored Rush AJ, et al. Psychiatr Ann. 1995;25:704.

  15. Consequences of Failing to Achieve Recovery • Greater risk of relapse • Continued psychosocial limitations • Continued impairments at work • Worsens prognosis of other medical disorders • Increased utilization of medical services • Sustained elevation of suicide and substance abuse risks

  16. Response and Remission Remission Relapse Recurrence Euthymia + Relapse Increasedseverity Symptoms Response Progression to disorder + Syndrome Acute (6–12 wk) Continuation (4–9 mo) Maintenance (1 yr) Treatment Phases Time Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.

  17. Economics of Depression—Total Annual Cost Lost productivity—55% Suicide—17% Pharmaceuticals—3% Outpatient care—6% Inpatient care—19%

  18. Profile of the Ideal Antidepressant Rapid Onsetof Action Once DailyDosing Activity in a Range of Disorders IdealAntidepressant CostEffective MinimalSide Effects No DrugInteraction Safety inOverdose

  19. New Mechanisms • Various effects on: • Serotonin (5HT) • Dopamine (DA) • Norepinephrine (NE) • Gamma amino butyric acid (GABA) • NMDA Glutamate (N-Methyl-D Aspartate) • Tachykinins • NK1, NK2, NK3 • Corticotropin releasing factor • Glucocorticoid receptor antagonists • Neuropeptide Y • Brain Derived Neurotrophic Factor (BDNF) • Cannabinoid receptors

  20. Ascending Aminergic System Cortex Selective manipulation of these aminergic transmitters has been the common denominator for all currently marketed antidepressants These same systems are implicated in anxiety Midbrain NE DA 5-HT Brain Stem

  21. Serotonin Norepinephrine Anxiety Irritability Energy Interest Impulse Sex Appetite Aggression Motivation Drive Dopamine Mood, Emotion,Cognitive function

  22. Serotonergic Innervation of the CNS Cingulum Thalamus Neocortex Cingulate gyrus Striatum Hippocampus Ventral striatum Hypothalamus Cerebellar cortex Amygdaloid body Olfactory and entorhinal cortices Intracerebellar nuclei Caudal raphe nuclei Hippocampus Dorsal raphe nuclei To spinal cord From Kaplan HI, Sadok BJ. In: Synopsis of Psychiatry, Behavioral Sciences, Clinical Psychiatry, 6th ed. Revised. 1991.

  23. Physiologic Distribution of Serotonin 5% CNS: -regulates cognition, mood, appetite, sleep, sexual behavior 95% GI tract: -regulates intestinal movement -90% cells of the lining of GI tract -10% enteric neurons *Also located in platelets to facilitate aggregation for blood clotting

  24. Types of Receptors (5-HT1-7)

  25. Norepinephrine Innervation of the CNS Thalamus Cingulate gyrus Cingulum Neocortex Hippocampus Hypothalamus Pituitary Amygdala Cerebellar cortex Olfactory and entorhinal cortices Locus ceruleus To spinal cord Hippocampus Lateral tegmental NA cell system From Kaplan HI, Sadok BJ. In: Synopsis of Psychiatry, Behavioral Sciences, Clinical Psychiatry, 6th ed. Revised. 1991.

  26. Neurotransmitters—Mechanisms of Action Autoreceptor SYNAPTIC CLEFT PRESYNAPTIC CELL Neurotransmitter Reuptake transporter Neurotransmitter receptor POSTSYNAPTIC CELL

  27. Sexual dysfunction, CNS stimulation Nausea ? anxiety, insomnia, panic 5-HT Receptors Regulatory Processes 5HT 1A 5HT 1D 5HT 2A 5HT 1A 5HT 5HT synthesis storage release 5HT 2C Weight regulation ? 5HT 5HT ¯ Might food intake 1D Regulate vasculature Headache 5HT 3 5HT Transporter

  28. Reduce depression Psychomotor activation Antiparkinsonian effects Sedation/drowsiness Hypotension Weight gain DA reuptake inhibition H1 block Blurred vision Dry mouth Constipation Sinus tachyardia Urinary retention Cognitive dysfunction Reduce depression Antianxiety effects GI disturbances Sexual dysfunction Antidepressant 5HT reuptake inhibition ACh block NE reuptake inhibition Reduce depression Tremors Tachycardia Erectile/ejaculatory dysfunction Pharmacologic Effects of Antidepressants Alpha2 block Alpha1 block Anxiety Postural hypotension Dizziness Reflex tachycardia Memory dysfunction

  29. The Evolution of Antidepressants 1950s MAOIs Tricyclics 1960s 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

  30. Brief history of MAOI’s • Monoamine oxidase inhibitors first observed to have mood elevating properties (1950’s) • Limited prescribing • Acute hypertension reported from ingestion of dietary tyramine - “cheese reaction” • Interactions with other medications • Introduction of the newer antidepressants • Continued efforts have been made to develop MAOI’s that do not require restriction of dietary tyramine • One strategy has been to exploit the existence of multiple isoenzymes of MAO (MAOA and MAOB)

  31. Monoamine Oxidase Inhibitor Antidepressants

  32. Monoamine Oxidase Inhibitors

  33. The Evolution of Antidepressants 1950s MAOIs Tricyclics 1960s 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

  34. Amitriptyline (Elavil) Imipramine(Tofranil) Clomipramine (Anafranil) Amoxapine(Asendin) Doxepin (Sinequan) Nortriptyline (Pamelor ) Desipramine (Norpramin ) Maprotiline (Ludiomil) Protriptyline (Vivactil) Trimipramine (Surmontil) Tricyclic Antidepressants

  35. Sedation/drowsiness Hypotension Weight gain H1 block Blurred vision Dry mouth Constipation Sinus tachyardia Urinary retention Cognitive dysfunction Reduce depression Antianxiety effects GI disturbances Sexual dysfunction Antidepressant 5HT reuptake inhibition ACh block NE reuptake inhibition Reduce depression Tremors Tachycardia Erectile/ejaculatory dysfunction Pharmacologic Effects of TCA’s Alpha1 block Postural hypotension Dizziness Reflex tachycardia Memory dysfunction

  36. The Evolution of Antidepressants 1950s MAOIs Tricyclics 1960s 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

  37. Selective Serotonin Reuptake Inhibitors * http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm297624.htm?source=govdelivery

  38. 1.) The antidepressant effects of the drugs are known to be limited to the s-isomer2.) The difference between the effects of citalopram and escitalopram on the QT interval presumably means that the QT effects are not specific to the s-isomer http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm

  39. FDA Recommendations re; Citalopram • Not recommended at doses greater than 40mg due to prolongation of QTc interval • Not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute MI or uncompensated heart failure • Not recommended in patients who are taking other drugs that prolong QTc • The max recommended dose is 20mg per day for patients with hepatic impairment, patients > 60 years of age, patients who are CYP 2C19 poor metabolizers and patients who are taking another CYP219 inhibitor; these factors can lead to increased blood levels of citalopram, increasing the risk of QTc prolongation and Torsades de Pointes http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm

  40. The Evolution of Antidepressants 1950s MAOIs Tricyclics 1960s 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

  41. Serotonin and Norepinephrine Reuptake Inhibitors

  42. The Evolution of Antidepressants 1950s MAOIs Tricyclics 1960s 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

  43. Dopamine and Norepinephrine Reuptake Inhibitors

  44. The Evolution of Antidepressants 1950s MAOIs Tricyclics 1960s 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

  45. Mixed Receptor Effects • SRI, 5HT2 antagonist • Trazodone (Desyrel, Oleptro) • Nefazodone • Noradrenergic (alpha 2), 5HT2,5HT3 antagonist • Mirtazapine (Remeron) • SRI, 5HT1 partial agonist • Vilazodone (Viibryd) • SRI, 5HT1a agonist, 5HT1b partial agonist, 5HT3/7 antagonist • Vortioxetine (Brintellix)

  46. Some Augmentation Strategies • Lithium • Thyroid Supplementation • Atypical Antipsychotics • Buspirone • Modafanil • Lamotrigine • Stimulants • ………………………

  47. Discontinuation Syndrome • Withdrawal Syndrome • Can occur with most antidepressants • Symptoms: dizziness, nausea, paresthesias, anxiety/insomnia • Onset 36-72 hours • Duration 3-7 days

  48. Summary • Depression is a biologically based illness that responds to antidepressant therapy in the majority of patients • Appropriate choice of antidepressant therapy should be based on past response, patient characteristics and adverse event profile • Appropriate trial length and dosage is important when evaluating response to antidepressants

  49. Questions?

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