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Pharmacotherapy of Depression

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Presentation on theme: "Pharmacotherapy of Depression"— 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, 2014 9:00 AM II. Slide 1

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 II. Slide 2 Weissman MM, et al. JAMA ;276:

5 Depression and Suicide
Up to 15% of patients with major depressive disorder requiring hospitalization commit suicide II. Slide 7 Risk of completed suicide death rate at 1% per year over the following 10 years Depression Guideline Panel. AHCPR publication

6 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 II. Slide 8 Depression Guideline Panel. AHCPR publication

7 Pharmacotherapy Reduces Risk of Suicide
300 259 Treated 250 Untreated 200 Suicides/100,000 person-years 150 141 100 II. Slide 9 50 Isacsson G, et al. J Affect Disord ;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 II. Slide 4 DSM-5. Washington, DC: American Psychiatric Association

9 DSM-5 Criteria for Major Depressive Episode
5 Symptoms in the same 2-week period 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 II. Slide 3 * Must include 1 of these DSM-5. Washington, DC: American Psychiatric Association

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

11 Psychological Symptoms
Hopelessness Low self esteem Denial, discounting, or explaining away stigmatized feelings Impaired memory, difficulty concentrating II. Slide 6 Low self esteem is highly predictive of depression DSM-5. Washington, DC: American Psychiatric Association Depression Guideline Panel. AHCPR publication

12 Continuum of Depression and Anxiety
Comorbid depression and anxiety Major depressive disorder Anxiety disorders II. Slide 16

13 Outcomes of Treatments of Major Depressive Disorder
Dropout Nonresponse/response w/residual symptoms Response Incomplete remission Complete remission Recovery VII. Slide 3

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 II. Slide 11 Rush AJ, et al. Psychiatr Ann ;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 II. Slide 12

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

17 Economics of Depression— Total Annual Cost
Lost productivity—55% Suicide—17% II. Slide 10 Pharmaceuticals—3% Outpatient care—6% Inpatient care—19%

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

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 Mood, Emotion, Cognitive function
Energy Interest Impulse Drive Norepinephrine Serotonin Dopamine Motivation Sex Appetite Aggression Anxiety Irritability Mood, Emotion, Cognitive function IV. Slide 4

22 Serotonergic Innervation of the CNS
Thalamus Cingulum Neocortex Cingulate gyrus Striatum Hippocampus Ventral striatum Hypothalamus Cerebellar cortex Amygdaloid body IV. Slide 5 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

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 Although serotonin is mainly attributed to its function in psychiatric disorders and the brain, it is actually predominantly located within the GI tract. An estimated 95% of all the serotonin in the body is in the digestive tract. 90% of this is in the cells in the GI mucosa, 10% is in the neurons of the GI tract which transmit signals contract the muscles and activate intestinal movement. And only about 5% of the body serotonin is in the central nervous system So often times, kids may complain of a stomach ache or some GI upset---and this is very well due to the fact that the antidepressants are stimulating the receptors within the GI tract. Also, serotonin has also been found to be actively taken up by blood platelets and stored. Here is functions as a vasoconstrictor and helps to regulate hemostasis/or the ability to stop bleeding and blood clotting. ----thus may also have a role in wound healing. This raises a concern in patients that may be taking warfarin/coumadin due to an increased risk of bleeding which should be monitored closely. *Also located in platelets to facilitate aggregation for blood clotting

24 Types of Receptors (5-HT1-7)
Function 1A, 1B , 1D, 1E, 1F Anxiety, aggression, sexual behavior, appetite, vasoconstriction 2A, 2B, 2C 2A: 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 3 Chemoreceptor trigger zone, emesis, GI/bowel motility, nausea, memory 4 Cardiac repolarization (seizure susceptibility), respiration, gastric emptying, oesophageal peristalsis, appetite, anxiety 5A, 5B Locomotion, anxiety, sleep, cognition, thermoregulation, respiration, mood, memory 6 7 Now that were aware of the various locations, its important to recognize the different types of receptors of serotonin as they have different functions within our bodies. Type 1 receptors: with subtypes A B D E F : function primarily with anxiety, aggression, sexual behavior, appetite, and vasocontriction. specifically 1A receptors: (like buspirone) relieve anxiety, impulsivity, aggression, depression; can increase dopamine release (partial agonist –abilify) to improve symptoms of schizophrenia Also, for example, the triptans target the 1D receptor which promote a greater degree of vasoconstriction --- thought to relieve the increased pressure in migraines. Type 2 receptors: with subtypes A B C : -2A: inhibits dopamine release: responsible for anxiety, agitation, hallucinations, sexual behavior, weight gain/loss,--- -so this is also a target for drugs used to treat schizophrenia (where there is a deficiency in dopamine) as they work to antagonize 5-ht2a receptors (clozapine, atypical antipsychotics) 2B: functions in smooth muscle (GI tract) and regulates cardiovascular function/structure 2C: affects appetite, anxiety, mood, GI motility, sexual behavior, thermoregulation and weight Type 3: is mainly associated with the chemoreceptor trigger zone---responsible for nausea and vomiting reflexes. ondansetron is an anti-emetic that works as a 5ht3 antagonist Types 1 and 2 are really the most relevant in terms of the antidepressant drugs we’ll be discussing today. Type 1 and 5: *inhibitory response; decrease in cAMP levels Acute stimulation of 2a or 2c can cause acute mental agitation, anxiety, or panic attacks 2a:motor mvmts due to inhibition of da neurotransmission----akathisia/restlessness, psychomotor retardation /// apathy //decreased libido 3: nausea, vomiting ¾ in GIT: increased bowel motility, GI cramps, diarrhea’ Fluoxetine actually antagonist at 5ht2c ---activating! Since increases NE and DA

25 Norepinephrine Innervation of the CNS
Thalamus Cingulate gyrus Cingulum Neocortex Hippocampus Hypothalamus Pituitary Amygdala Cerebellar cortex Olfactory and entorhinal cortices IV. Slide 6 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

26 Neurotransmitters—Mechanisms of Action Neurotransmitter receptor
Autoreceptor PRESYNAPTIC CELL SYNAPTIC CLEFT Neurotransmitter Reuptake transporter IV. Slide 16 Neurotransmitter receptor POSTSYNAPTIC CELL

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

28 Pharmacologic Effects of Antidepressants
DA reuptake inhibition Reduce depression Psychomotor activation Antiparkinsonian effects H1 block Sedation/drowsiness Hypotension Weight gain NE reuptake inhibition Reduce depression Tremors Tachycardia Erectile/ejaculatory dysfunction 5HT reuptake Antianxiety effects GI disturbances Sexual dysfunction ACh block Blurred vision Dry mouth Constipation Sinus tachyardia Urinary retention Cognitive dysfunction Antidepressant Alpha2 block Alpha1 block IV. Slide 3 Anxiety Postural hypotension Dizziness Reflex tachycardia Memory dysfunction

29 The Evolution of Antidepressants
MAOIs 1960s Tricyclics 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors IV. Slide 13 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
Type Selectivity Agent Brand Irreversible Nonselective Phenelzine Tranylcypromine Isocarboxazid Nardil Parnate Marplan MAO-A selective Clorgyline MAO-B selective Selegiline Eldepryl Reversible Moclobemide Brofaramine Toloxatone Befloxatone

32 Monoamine Oxidase Inhibitors
Drugs Brand Name Dosage Range (mg) Isocarboxazid Marplan 20-60 Phenelzine Nardil 45-90 Tranylcypromine Parnate Selegeline patch Emsam  6-12

33 The Evolution of Antidepressants
MAOIs 1960s Tricyclics 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors IV. Slide 13 Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

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

35 Pharmacologic Effects of TCA’s
block Sedation/drowsiness Hypotension Weight gain NE reuptake inhibition Reduce depression Tremors Tachycardia Erectile/ejaculatory dysfunction 5HT reuptake Antianxiety effects GI disturbances Sexual dysfunction ACh block Blurred vision Dry mouth Constipation Sinus tachyardia Urinary retention Cognitive dysfunction Antidepressant Alpha1 block IV. Slide 3 Postural hypotension Dizziness Reflex tachycardia Memory dysfunction

36 The Evolution of Antidepressants
MAOIs 1960s Tricyclics 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors IV. Slide 13 Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

37 Selective Serotonin Reuptake Inhibitors
Drugs Starting Maximum Range Fluoxetine 10 (QAM) 80 20-40 Paroxetine 10 (QHS) 50 Citalopram 10 40* Escitalopram 5 20 10-20 Fluvoxamine 300 (BID) Sertraline 25 200 50-200 *

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
MAOIs 1960s Tricyclics 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors IV. Slide 13 Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

41 Serotonin and Norepinephrine Reuptake Inhibitors
Drugs Starting Maximum Range Venlafaxine (Effexor) 25 375 BID/TID (Effexor XR) 37.5 225 75-225 QD Duloxetine (Cymbalta) 10 60 20-60 QD/BID Desvenlafaxine (Pristiq) 50 100 QD Levomilnacipran ER (Fetzima) 20 120 40 – 120 QD

42 The Evolution of Antidepressants
MAOIs 1960s Tricyclics 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors IV. Slide 13 Selective dopamine reuptake inhibitors 1990s Mixed Receptor Effects

43 Dopamine and Norepinephrine Reuptake Inhibitors
Drugs Starting Maximum Range Bupropion Wellbutrin 100mgBID 450mg(3-4 divided) WellbutrinSR 150mgQD 200mgBID WellbutrinXL 450mgQD Zyban 300mg For 7-12wks

44 The Evolution of Antidepressants
MAOIs 1960s Tricyclics 1970s Older heterocyclics 1980s SSRIs Newer dual reuptake inhibitors IV. Slide 13 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 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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