Treatment of Depression in the

Primary Care Office Paul E.A. Glaser, MD, PhD

Departments of Psychiatry, Pediatricsand Anatomy & Neurobiology

University of KentuckyNovember 5, 2010

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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

Depression

MDD (Major Depressive Disorder, unipolardepression) 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.

Lifetime Prevalence of Common Psychiatric Disorders

Kessler 1994; Kessler 1995; DSM-IV-TR™ 2000.

*In menstruating women.

Lifetime prevalence (%)

0 2 4 6 8 10 12 14

7.8%Posttraumatic stressdisorder (PTSD)

5.1%Generalized anxietydisorder (GAD)

3.5%Panic disorder

2.5%Obsessive-compulsivedisorder (OCD)

16 18

Alcohol dependence 14.1%

Major depressive disorder 17.1%

13.3%Social anxiety disorder

5%*Premenstrual dysphoricdisorder (PMDD)

Depression—Somatic Presentation

Overall, 69% of depressed patients present with somatic complaints that can complicate diagnosis, such as Headaches Weakness Constipation

Simon 1999; Depression in Primary Care 1 (AHCPR), 1993.

Back pain

Joint pain

Abdominal pain

Depression—Anxiety Comorbidities

Many patients with anxiety disorders have depression at some time during their lives

*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.

Posttraumaticstress disorder Panic disorder

OCD

Depression

48% of patients with PTSD Up to 65% of patients with panic disorder*

67% of patients with obsessive-compulsive disorder

GADSocial anxiety

disorder

42% of patients with generalized anxiety disorder

34% to 70% of patients with social anxiety disorder

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?

Screening for Depression

PHQ-9 is a short screen patient can fill out themselves while waiting

http://www.phqscreeners.com/ Although only a screening test, can

rate severity of depression

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

Biopsychosocial Model

Models for Depression

3 Main Biological models Monoamine Hypothesis Neurotransmitter Receptor Hypothesis Dysfunction of the Hypothalamic-pituitary-

adrenal (HPA) axis

MDD – Major Depressive Disorder

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

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 these2 symptoms

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

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.

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

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

Books to recommend

CBT for adults

Books to recommend

CBT for adolescents

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?

Serotonin Receptors

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

SSRIs – Practical DosingFluoxetine (Prozac) – 10mg qam for 2-4 days,

increase to 20mgAverage dose range 20-40mg, max 80mgGeneric Tablets – $4 med (10,20, and 40mg)Liquid (20mg/5cc), mint flavor, mixed reviewsProzac Weekly (90mg q.week)

Sertraline (Zoloft) – 50mg qam for 2-4 days, increase to 100mg

Average dose range 75-100mg, max 200mgLiquid (20mg/ml) has 20% alcoholMust be mixed in juice, Ale 81, alcohol

SSRIs – Practical DosingCitalopram (Celexa) – start 10mg qam 2-4 days,

increase to 20mg qamAverage 20-40mg, max 60mg qdGeneric 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 50mgGeneric Tablets – $4 med (20 and 40mg)

http://www.madewithmolecules.com/

SSRIs - Common Side EffectsSSRIs 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 consentGI : Nausea, diarrhea, dyspepsia, anorexia (decreased with low starting doses)Sexual: ejaculation failure (primarily ejaculatory delay), libido decreased (decreased desire)Sleep: insomnia, somnolence

Less CommonFatigue, dry mouth, weight gain, induction of manic phaseTremor, increased sweating

Very low, but possible risk of suicide thoughts in adolescents

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

MDD Drug Interactions at Usual Effective Doses

1A2 2C9/10 2C19 2D6 3A3/4

Citalopram* • • • + •

Escitalopram† • • • ++ •

Fluoxetine* • +++ ++ +++ +

Nefazodone* • • • • +++

Paroxetine* • • • +++ •

Venlafaxine* • • • + •

Sertraline* • • • + •

Inhibitory effect of select antidepressants on specific cytochrome P450 isoenzymes

Preskorn 1999. Manufacturers’ product information 2003.

*Adapted from Preskorn 1999.†Manufacturer’s product information 2003.‡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.

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

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-HT2Areceptors

alterations in signal transduction modulation of gene transcription esp. BDNF,

trkB

Tricyclic Antidepressants

Amitriptyline (Elavil) – treats depression at a dosage range of 25-150mg qhs Drowsiness, dry mouth, weight gain Heart block in overdose Chronic pain Migraine Fibromyalgia Diabetic peripheral neuropathy

Imipramine (Tofranil) – 25-200mg qhs

Mixed Action Antidepressants

Nefazadone (Serzone): 5-HT reuptake inhibition and 5-HT2A & 5-HT2C 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

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 37.5-75 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

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 (o-

dealkylation) 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

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

Mixed Action Antidepressants

Mirtazapine (Remeron): a2-adrenergic antagonist (enhances NE (and 5HT) release); 5-HT2A, 5-HT3 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

SSRI Discontinuation SymptomsPharmacokinetic features may explain the relative

differences among SSRIs in the emergence of discontinuation effects, which include

• Dizziness • Vivid dreams• Irritability • Lowered mood• Lethargy • Paresthesia (shooting pains• Nausea up neck for some)

Discontinuation Effects

Coupland 1996.

In a retrospective analysis,

Frequency (%) of discontinuation cases during medically supervised withdrawal

30.8%

20.0%

14.0%

2.2%0

5

10

15

20

25

30

35

Perc

ent (

%)

Sertraline(n=45)

Clomipramine(n=13)

Paroxetine(n=50)

Fluvoxamine(n=43)

Fluoxetine(n=20)

0.0%

Newer Therapies CRF antagonists 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

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.

Treatment Goals for Patients With MDD

Adapted from Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.

Symptoms

Syndrome

Treatment phases Acute Continuation Maintenance

Recurrence

Response“Normalcy”

RecoveryRemission

Relapse

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) 15 – 30 mg dosed bid Quetiapine (Seroquel XR) 150-300mg usually qhs Buproprion (Wellbutrin) SR 150-300mg qam

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

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

Questions?