Treatment of Depression in the Primary Care Office

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1 Treatment of Depression in the Primary Care Office Paul E.A. Glaser, MD, PhD Departments of Psychiatry, Pediatrics and Anatomy & Neurobiology University of Kentucky November 5, 2010

2 Disclosures of Potential Conflicts Source Consulta nt Advisor y Board Stock or Equity >$10,00 0 Speaker s Bureau Researc h Support Honorariu m for this talk or meeting Expenses related to this talk or meeting NIMH X NIDA X NARSAD X Lilly X Shire X

3 Objectives To learn about common presentations of depression in a primary care office To understand the depression in the context of other illnesses To review common treatments and management of depression

19.7% Women twice as affected as men First-degree relatives

4 Depression MDD (Major Depressive Disorder, unipolar depression) has a lifetime prevalence of 15%, recent Canadian study found 19.7% Women twice as affected as men First-degree relatives have a 2-3 fold increased risk of MDD compared to general population.

5 Lifetime Prevalence of Common Psychiatric Disorders Major depressive disorder 17.1% Alcohol dependence 14.1% Social anxiety disorder 13.3% Posttraumatic stress disorder (PTSD) Generalized anxiety disorder (GAD) Premenstrual dysphoric disorder (PMDD) 5.1% 5%* 7.8% Panic disorder Obsessive-compulsive disorder (OCD) 2.5% 3.5% Lifetime prevalence (%) *In menstruating women. Kessler 1994; Kessler 1995; DSM-IV-TR 2000.

6 Depression Somatic Presentation Overall, 69% of depressed patients present with somatic complaints that can complicate diagnosis, such as Headaches Weakness Constipation Back pain Joint pain Abdominal pain Simon 1999; Depression in Primary Care 1 (AHCPR), 1993.

Depression Anxiety Comorbidities Many patients with anxiety disorders have depression at some time during their lives 48% of patients with PTSD Up to 65% of

anxiety disorder 34% to 70% of patients with social anxiety disorder 67% of patients with obsessive-compulsive disorder *Figures for panic disorder and

7 Depression Anxiety Comorbidities Many patients with anxiety disorders have depression at some time during their lives 48% of patients with PTSD Up to 65% of patients with panic disorder* Posttraumatic stress disorder Panic disorder Social anxiety disorder Depression OCD GAD 42% of patients with generalized anxiety disorder 34% to 70% of patients with social anxiety disorder 67% of patients with obsessive-compulsive disorder *Figures for panic disorder and depression not specified as lifetime in DSM-IV-TR. Kessler 1995; DSM-IV-TR 2000; Brawman-Mintzer 1993; Rasmussen 1992; Stein 2000; Van Ameringen 1991; Wittchen 1999.

8 Screening for Depression PRIME-MD screening, two question with high sensitivity (96%) During the past month have you been bothered by feeling down, depressed, or hopeless? During the past month have you been bothered by little interest or pleasure in doing things?

9 Screening for Depression PHQ-9 is a short screen patient can fill out themselves while waiting Although only a screening test, can rate severity of depression

11 Evidence for biological basis of depression Strong genetic loading Family History: Twin concordance Monozygotic twins: 75% Dizygotic twins: 38% Biological Models of Depression in Animals Early Stressful events in animals cause changes in biological measures in the brain, e.g. altered HPA axis, altered neurotransmitter levels

12 Biopsychosocial Model

13 Models for Depression 3 Main Biological models Monoamine Hypothesis Neurotransmitter Receptor Hypothesis Dysfunction of the Hypothalamic-pituitaryadrenal (HPA) axis

14 MDD Major Depressive Disorder Five or more of the following symptoms are present most of the day, nearly every day, during a period of at least 2 consecutive weeks and cause significant dysfunction (DSM-IV-TR 2000) At least 1 of these 2 symptoms 1. Depressed mood (Note: In Children or Adolescents, can be irritable mood) 2. Loss of interest or pleasure in all, or almost all, usual activities 3. Significant weight loss or weight gain (Note: In Children, consider failure to make expected weight gains) 4. Insomnia or hypersomnia 5. Psychomotor agitation or retardation 6. Fatigue or loss of energy 7. Feelings of worthlessness or excessive or inappropriate guilt 8. Diminished ability to think or concentrate or indecisiveness 9. Recurrent thoughts of death or suicide

15 Depression (DSM-IV-TR) B-The symptoms do not meet criteria for a Mixed Episode. C- The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D - The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). E - The symptoms are not better accounted for by Bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

16 Depression effects Health Doubles rate of sudden cardiac death in women Depression increases illness and mortality post heart attack Worsens outcome in stroke Slows recovery in many illnesses Graph of completed suicide rates for 2004 by age

17 Depression Evidence Based Treatments Antidepressant medications Cognitive behavioral therapy (CBT) Interpersonal therapy (IPT) ECT (Electroconvulsive Therapy) Light therapy for SAD Vagal Nerve Stimulation Exercise Transcranial magnetic stimulation

18 Books to recommend CBT for adults

19 Books to recommend CBT for adolescents

20 Problems in Treatment Large percentage of people are not diagnosed or receive inadequate treatment Full remission of depressive symptoms is only reached in about 40% of people Recurrence is common (67% in depression, almost 100% in bipolar) Are we overtreating?

21 Serotonin Receptors

23 5-HT selective reuptake inhibitors (SSRI s) Selectively inhibit reuptake of 5-HT Induce compensatory changes in 5-HT neurotransmission including desensitization of autoreceptors which leads to greater 5-HT neurotransmission Induce compensatory changes in gene transcription (e.g. BDNF, trkb, CREB) which most likely lead to therapeutic effects

24 SSRIs Practical Dosing Fluoxetine (Prozac) 10mg qam for 2-4 days, increase to 20mg Average dose range 20-40mg, max 80mg Generic Tablets $4 med (10,20, and 40mg) Liquid (20mg/5cc), mint flavor, mixed reviews Prozac Weekly (90mg q.week) Sertraline (Zoloft) 50mg qam for 2-4 days, increase to 100mg Average dose range mg, max 200mg Liquid (20mg/ml) has 20% alcohol Must be mixed in juice, Ale 81, alcohol

25 SSRIs Practical Dosing Citalopram (Celexa) start 10mg qam 2-4 days, increase to 20mg qam Average 20-40mg, max 60mg qd Generic Tablets $4 med (20 and 40mg) Liquid (10mg/5cc), peppermint flavor (best) Escitalopram (Lexapro) start 5mg qam 2-4 days, increase to 10mg, max 20mg Most expensive (only non-generic SSRI) Liquid (5mg/5cc), peppermint flavor (best) Paroxetine (Paxil or Paxil CR), start 20mg (25 mg CR) qam, increase to 40mg (37.5mg for Paxil CR) Average 37.5 mg, max 50mg Generic Tablets $4 med (20 and 40mg)

27 SSRIs - Common Side Effects SSRIs are contraindicated until at least 14 days have passed since discontinuing a monoamine oxidase inhibitor (MAOI) and an MAOI is contraindicated for at least 14 days after discontinuation of an SSRI. Common Use in gaining consent GI : Nausea, diarrhea, dyspepsia, anorexia (decreased with low starting doses) Sexual: ejaculation failure (primarily ejaculatory delay), libido decreased (decreased desire) Sleep: insomnia, somnolence Less Common Fatigue, dry mouth, weight gain, induction of manic phase Tremor, increased sweating Very low, but possible risk of suicide thoughts in adolescents

28 Approved Indications for SSRIs in Adults Mood disorders Major depressive disorder: acute and long term Premenstrual dysphoric disorder Anxiety disorders Social anxiety disorder: acute and long term Posttraumatic stress disorder: acute and long term Panic disorder: acute and long term Obsessive-compulsive disorder: acute and long term

29 MDD Drug Interactions at Usual Effective Doses Inhibitory effect of select antidepressants on specific cytochrome P450 isoenzymes 1A2 2C9/10 2C19 2D6 3A3/4 Citalopram* + Escitalopram ++ Fluoxetine* Nefazodone* +++ Paroxetine* +++ Venlafaxine* + Sertraline* + *Adapted from Preskorn Manufacturer s product information Percent increase in plasma levels of a coadministered drug dependent on this CYP enzyme for its clearance. Sertraline has the potential for clinically important 2D6 inhibition. Consequently, concomitant use of a drug metabolized by P450 2D6 with sertraline may require lower does than usually prescribed for the other drug. Furthermore, whenever sertraline is withdrawn from cotherapy, an increased dose of the coadministered drug may be required. Preskorn Manufacturers product information 2003.

31 Noha Sadek, MD; Charles B Nemeroff, MD, PhD, 2000

32 Antidepressants: TCA s Tricyclic antidepressants are oldest Inhibit NE and 5-HT reuptake via inhibition of NET and SERT Mechanisms of action: down-regulation of β-adrenergic/5-ht 2A receptors alterations in signal transduction modulation of gene transcription esp. BDNF, trkb

mouth, weight gain Heart block in overdose Chronic pain Migraine

33 Tricyclic Antidepressants Amitriptyline (Elavil) treats depression at a dosage range of mg qhs Drowsiness, dry mouth, weight gain Heart block in overdose Chronic pain Migraine Fibromyalgia Diabetic peripheral neuropathy Imipramine (Tofranil) mg qhs

34 Mixed Action Antidepressants Nefazadone (Serzone): 5-HT reuptake inhibition and 5-HT 2A & 5-HT 2C receptor blockade; some NE-uptake inhibition sedating; perhaps less effective; good antipanic/antianxiety Brand name discontinued 2004 due to 1 in 300,000 liver failure Start 50mg bid, increase 100mg per week to max of 300mg bid The first SNRI Advantage much less sexual side effects Would not use first line due to rare liver effects

35 Mixed Action Antidepressants Venlafaxine (Effexor XR): 5-HT and NE reuptake inhibition; perhaps faster onset of action; fewer side-effects than TCA s At low doses, mostly an SSRI At higher doses, also some DA uptake inhibition Effexor XR 37.5, 75, and 150mg Start mg qday, titrate up every 4-7 days to 150mg and 225 mg qday Nausea, HA, dizziness common at first, or at higher doses Sexual dysfunction, orthostatic hypotension, even akathesia at higher doses Chronic pain, diabetic neuropathy Bad discontinuation syndrome for some

36 Mixed Action Antidepressants Duloxetine (Cymbalta): 5-HT and NE reuptake inhibition FDA approvals for Depression, GAD, Fibromyalgia, and diabetic peripheral neuropathy Start 30mg qhs, increase to 60mg qhs after a few days (max 90mg) Nausea, dry mouth headache, dizziness common Sexual side effects Less risk of discontinuation syndrome Safe in overdose The most popular SNRI currently

Mixed Action Antidepressants Desvenlafaxine (Pristiq) SNRI metabolite of venlafaxine (odealkylation) Slightly different potencies of blockade Ratio of 5HT to NE blockade is different for

37 Mixed Action Antidepressants Desvenlafaxine (Pristiq) SNRI metabolite of venlafaxine (odealkylation) Slightly different potencies of blockade Ratio of 5HT to NE blockade is different for each of the SNRIs, question is: what is the best for each patient? Do in vitro assays portray in vivo efficacy? Start 50mg qday, stay on 50mg qday, max 100mg Should have chronic pain usefulness

38 Mixed Action Antidepressants Buproprion (Wellbutrin): NE and DA reuptake inhibitor XL lasts slightly longer than SR, SR is cheaper Start 150 mg SR/XL qam, after few days increase to 300mg qam (max 450mg qam) fewer sexual side-effects maybe activating (do not dose at night) Insomnia, weight loss, dry mouth, tremor Adjunctive therapy for SSRI, or if sexual side effect Some benefit in smoking cessation, ADHD Seizure risk, increases with dose, poorly documented

39 Mixed Action Antidepressants Mirtazapine (Remeron): a 2 -adrenergic antagonist (enhances NE (and 5HT) release); 5-HT 2A, 5-HT 3 antagonist Start 15mg qhs, move to 30mg qhs after a few days (max 45mg) Comes as both pills and ODT Anti-histamine sedation, weight gain Very little sexual side effects

40 SSRI Discontinuation Symptoms Pharmacokinetic features may explain the relative differences among SSRIs in the emergence of discontinuation effects, which include Dizziness Irritability Lethargy Nausea Vivid dreams Lowered mood Paresthesia (shooting pains up neck for some)

41 Discontinuation Effects In a retrospective analysis, Frequency (%) of discontinuation cases during medically supervised withdrawal % Percent (%) % 14.0% Clomipramine (n=13) Paroxetine (n=50) Fluvoxamine (n=43) 2.2% Sertraline (n=45) 0.0% Fluoxetine (n=20) Coupland 1996.

42 CRF antagonists Newer Therapies glucocorticoid receptor antagonists substance P receptor antagonists NMDA receptor antagonists transdermal selegiline (EMSAM) "triple" reuptake inhibitors augmentation of typical antidepressant medications with atypical antipsychotics Omega 3 fatty acids

44 Somatic Therapies Electroconvulsive therapy (ECT): leads to robust acute enhancement of neurotrasmission Alterations in receptor activities Alterations in gene transcription occur quicker with ECT than medications Transcranial magnetic stimulation (TMS): unclear mechanism of action; may be less effective than ECT.

46 Treatment Goals for Patients With MDD Remission Recovery Normalcy Response Symptoms Syndrome Relapse Recurrence Treatment phases Acute Continuation Maintenance Adapted from Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.

47 MDD Treatment Augmentation Adjunctive to SSRI, SNRI Lithium 150mg bid Levothyroxine 25-50mcg qam Abilify 2-15mg (FDA approved) Trazodone 50mg-150mg qhs (helps insomnia, not FDA approved) Buspirone (Buspar) mg dosed bid Quetiapine (Seroquel XR) mg usually qhs Buproprion (Wellbutrin) SR mg qam

treatment-emergent switching are around 5% for SSRIs

48 Depression Is It BAD? Bipolar Affective Disorder much less common, but depressive phase often indistinguishable from MDD Rates of BAD (all types) around 1-4% Rates for treatment-emergent switching are around 5% for SSRIs and 10-15% for Tricyclic Antidepressants Take a good history in new patients about history of manic symptoms

49 Practical Tips for Treating Depression in Primary Care Screen for depression when you get red flags, or anyone with chronic illness Chose Evidence Based treatments Use adequate doses and duration of treatment Minimize side effects Learn augmenting treatments Refer for psychotherapy whenever possible

50 Questions?

Diagnosis & Management of Major Depression: A Review of What s Old and New. Cerrone Cohen, MD

Diagnosis & Management of Major Depression: A Review of What s Old and New Cerrone Cohen, MD Why You re Treating So Much Mental Health 59% of Psychiatrists Are Over the Age of 55 AAMC 2014 Physician specialty