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Pharmacotherapy of Depression Jerry Overman, Pharm.D., BCPP Clinical Pharmacy Specialist, Mental Health (NIMH) NIH Clinical Center Pharmacy Department.

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Presentation on theme: "Pharmacotherapy of Depression Jerry Overman, Pharm.D., BCPP Clinical Pharmacy Specialist, Mental Health (NIMH) NIH Clinical Center Pharmacy Department."— Presentation transcript:

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

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

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

7 Pharmacotherapy Reduces Risk of Suicide Treated Untreated Isacsson G, et al. J Affect Disord. 1996;41:1-8. Suicides/100,000 person-years

8 DSM-5. Washington, DC: American Psychiatric Association 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

9 * Must include 1 of these DSM-5. Washington, DC: American Psychiatric Association DSM-5 Criteria for Major Depressive Episode S leep: Insomnia or hypersomnia I nterest: Anhedonia - loss of interest or pleasure G uilt: Feelings of worthlessness E nergy: Fatigue C oncentration: Diminished ability to think or make decisions A ppetite: Weight change P sychomotor: Psychomotor retardation or agitation S uicide: Recurrent thoughts of death  5 Symptoms in the same 2-week period

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

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

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

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

14 Rush AJ, et al. Psychiatr Ann. 1995;25:704. 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

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

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

18 Ideal Antidepressant Rapid Onset of Action Once Daily Dosing Activity in a Range of Disorders Cost Effective Minimal Side Effects Safety in Overdose No Drug Interaction Profile of the Ideal Antidepressant

19 New Mechanisms Various effects on: –Serotonin (5HT) –Dopamine (DA) –Norepinephrine (NE) –Gamma amino butyric acid (GABA) –NMDA Glutamate (N-Methyl-D Aspartate) Tachykinins –NK 1, NK 2, NK 3 Corticotropin releasing factor Glucocorticoid receptor antagonists Neuropeptide Y Brain Derived Neurotrophic Factor (BDNF) Cannabinoid receptors

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

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

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

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-HT 1-7 ) ReceptorFunction 1A, 1B, 1D, 1E, 1FAnxiety, aggression, sexual behavior, appetite, vasoconstriction 2A, 2B, 2C2A: inhibits dopamine release; mediates anxiety, agitation, hallucinations, sexual behavior, weight gain/loss 2B: Smooth muscle (GI tract), cardiovascular function 2C: inhibits dopamine and norepinephrine release; mediates appetite, anxiety, mood, GI motility, sexual behavior, thermoregulation, weight gain/loss 3Chemoreceptor trigger zone, emesis, GI/bowel motility, nausea, memory 4Cardiac repolarization (seizure susceptibility), respiration, gastric emptying, oesophageal peristalsis, appetite, anxiety 5A, 5BLocomotion, anxiety, sleep, cognition, thermoregulation, respiration, mood, memory 6 7

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

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

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

28 DA reuptake inhibition Reduce depression Reduce depression Psychomotor activation Psychomotor activation Antiparkinsonian effects Antiparkinsonian effects NE reuptake inhibition Reduce depression Reduce depression Tremors Tremors Tachycardia Tachycardia Erectile/ejaculatory dysfunction Erectile/ejaculatory dysfunction 5HT reuptake inhibition Reduce depression Reduce depression Antianxiety effects Antianxiety effects GI disturbances GI disturbances Sexual dysfunction Sexual dysfunction Alpha 1 block Postural hypotension Postural hypotension Dizziness Dizziness Reflex tachycardia Reflex tachycardia Memory dysfunction Memory dysfunction Anxiety Anxiety ACh block Blurred vision Blurred vision Dry mouth Dry mouth Constipation Constipation Sinus tachyardia Sinus tachyardia Urinary retention Urinary retention Cognitive dysfunction Cognitive dysfunction H 1 block Sedation/drowsiness Sedation/drowsiness Hypotension Hypotension Weight gain Weight gain Pharmacologic Effects of Antidepressants Antidepressant Alpha 2 block

29 The Evolution of Antidepressants 1950s 1960s 1970s 1980s 1990s MAOIs Tricyclics Older heterocyclics SSRIs Newer dual reuptake inhibitors Selective dopamine reuptake inhibitors 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 TypeSelectivityAgentBrand IrreversibleNonselectivePhenelzine Tranylcypromine Isocarboxazid Nardil Parnate Marplan MAO-A selectiveClorgyline MAO-B selectiveSelegilineEldepryl ReversibleMAO-B selectiveMoclobemide Brofaramine Toloxatone Befloxatone

32 Monoamine Oxidase Inhibitors DrugsBrand NameDosage Range (mg) IsocarboxazidMarplan  PhenelzineNardil  TranylcypromineParnate  Selegeline patchEmsam  6-12

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

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

35 NE reuptake inhibition Reduce depression Reduce depression Tremors Tremors Tachycardia Tachycardia Erectile/ejaculatory dysfunction Erectile/ejaculatory dysfunction 5HT reuptake inhibition Reduce depression Reduce depression Antianxiety effects Antianxiety effects GI disturbances GI disturbances Sexual dysfunction Sexual dysfunction Alpha 1 block Postural hypotension Postural hypotension Dizziness Dizziness Reflex tachycardia Reflex tachycardia Memory dysfunction Memory dysfunction ACh block Blurred vision Blurred vision Dry mouth Dry mouth Constipation Constipation Sinus tachyardia Sinus tachyardia Urinary retention Urinary retention Cognitive dysfunction Cognitive dysfunction H 1 block Sedation/drowsiness Sedation/drowsiness Hypotension Hypotension Weight gain Weight gain Pharmacologic Effects of TCA’s Antidepressant

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

37 Selective Serotonin Reuptake Inhibitors DrugsStartingMaximumRange Fluoxetine 10 (QAM) Paroxetine 10 (QHS) Citalopram 1040*20-40 Escitalopram Fluvoxamine (BID) Sertraline *

38 1.) The antidepressant effects of the drugs are known to be limited to the s-isomer 2.) 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

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

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

41 Serotonin and Norepinephrine Reuptake Inhibitors DrugsStartingMaximumRange Venlafaxine (Effexor  ) BID/TID Venlafaxine (Effexor XR  ) QD Duloxetine (Cymbalta  ) QD/BID Desvenlafaxine (Pristiq  ) QD Levomilnacipran ER (Fetzima  ) – 120 QD

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

43 Dopamine and Norepinephrine Reuptake Inhibitors DrugsStartingMaximumRange Bupropion Wellbutrin  100mgBID450mg(3-4 divided) Bupropion WellbutrinSR  150mgQD200mgBID Bupropion WellbutrinXL  150mgQD450mgQD Bupropion Zyban  150mgQD300mgFor 7-12wks

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

45 SRI, 5HT 2 antagonist –Trazodone (Desyrel , Oleptro  ) –Nefazodone Noradrenergic (alpha 2), 5HT 2, 5HT 3 antagonist –Mirtazapine (Remeron  ) SRI, 5HT 1 partial agonist –Vilazodone (Viibryd  ) SRI, 5HT 1a agonist, 5HT 1b partial agonist, 5HT 3/7 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 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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