Depression in Medicine

1
Depression in Medicine

• David Schilling, M.D.
• August 2, 2007

2
Major Teaching Points of this Lecture

• Remind you that depression is common in your
  patients.
• Convince you that depression is an important
  issue for your patients.
• Enable you to diagnose depressive disorders
  accurately according to the DSM-IV criteria.
• Give antidepressants adequate time to work.

3
Iceberg Phenomenon
Depressed Patients Seen By Psychiatrists
Depressed Patients Seen in Primary Care Practice
Watts, 1966 WPA/PTD Educational Program on
Depressive Disorders
4
Prevalence Of Major Depression
Percent of Population
Katon and Sullivan. J Clin Psychiatry.
198951(suppl 6)3.
5
RATES OF MAJOR DEPRESSION

• Point prevalence 45
• Women 56
• Men 3
• 1 year prevalence 11.3
• Lifetime incidence
• Women 20
• Men 10

6
Prevalence of Depressive Disorders in Various
Patient Populations
General population
5.8
Chronically ill
9.4
Hospitalized
33.0
Geriatric inpatients
36.0
Cancer outpatients
33.0
Cancer inpatients
42.0
Stroke
47.0
MI
45.0
Parkinsons disease
39.0
0
10
20
30
40
50
Prevalence
There is a range of percentages depending on
the study.
Adapted from WPA/PTD Educational Program on
Depressive Disorders
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Major Depression PrevalenceChronic Medical
Illness

• Heart disease 15 to 23
• Diabetes 11 to 12
• Chronic obstructive pulmonary disease (COPD) 10
  to 20

Katon W et al. Biol Psychiatry, 2003
8
RISK FACTORS FOR MAJOR DEPRESSION
Association
Risk Factor
9
Depression Prevalence Is Especially High in
Neurological Illness

• Lifetime prevalence
• Parkinsons disease 40-50 lifetime prevalence
• Huntingtons disease 40 lifetime prevalence.
  Depression may antedate chorea by years
• Multiple sclerosis 10-50 lifetime prevalence
• Alzheimers disease 15-55 prevalence
• CVAs 30-50 lifetime prevalence

Katon W et al. Biol Psychiatry, 2003
10
MAJOR DEPRESSIVE EPISODE

• Depressed mood or anhedonia either 1. or 2.
  below
• At least 5 of the following
• 1. Depressed mood most of the day nearly every
  day
• 2. Decreased interest or pleasure most of the
  day/every day
• 3. Insomnia or hypersomnia
• 4. Anorexia or hyperphagia or 5 weight
  gain/loss in month
• 5. Psychomotor agitation or retardation
• 6. Fatigue
• 7. Decreased concentration or thinking,
  indecisiveness
• 8. Negative thinking worthlessness,
  inappropriate guilt
• 9. Recurring thoughts of death or suicide
• Not organically caused
• Not uncomplicated bereavement

Adapted from DSM IV TR
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MAJOR DEPRESSIVE DISORDERCommon Presenting
Complaint in Medical Settings

• Anxiety 50 will have depression
• Insomnia
• Fatigue
• Chronic pain
• e.g., tension headaches, back pain, etc.
• Somatization
• e.g., increase in all medical complaints
• Cognitive impairment
• in elderly (pseudodementia)

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Not Organically Caused DDx of Depression


Mimicking Condition
Symptoms
Differentiators
Depression Mood changes Apathy Loss of
energy Fatigue Apathy Depression Apathy Depres
sion Depression Mood changes Loss of
appetite Apathy

• Substance abuse
• Alcohol
• Cocaine
• CNS stimulants
• Marijuana
• Anemia
• Hyperthyroidism/
• Hypothyroidism
• Neoplasia

Medical history Family history Blood screen Urine
screen Hemoglobin Hematocrit Thyroid
function tests Medical history CT
scan MRI Ultrasound
DSM-IV
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Not Organically Caused DDx of Depression


Symptoms
Differentiators
Mimicking Condition
Medical history Medical history Laboratory
findings Various imaging techniques Medical
history CT scan MRI PET scan Medical
history Neurologic exam CT scan MRI,EMG

• Medications
• Reserpine
• Corticosteroids
• Beta- blockers
• Estrogen
• Progesterone
• Benzodiazepines
• Chronic illnesses
• TB
• Neoplasia
• AIDS
• Arthritis
• Trauma
• Brain injury
• Left hemisphere
• Injuries

Depression Fatigue Mania Depression Fatigue L
oss of appetite Apathy Anxiety Major
depression Loss of appetite Apathy Major
depression Apathy
DSM-IV
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SUBSTANCE INDUCED DEPRESSIONMany Abused
Substance Have Been Proven to Cause Depression

• Alcohol
• Cocaine
• Heroin
• Marijuana
• Amphetamines
• Look for evidence of dependence, abuse,
  intoxication or withdrawal

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MEDICATION INDUCED DEPRESSIONVery Few
Medications Have Been Proven to Cause Depression

• Many cases reported of a med associated
  depression, but causality harder to prove
• Often a proper assessment for depression is not
  made before the drug is started
• many cases may have already had depression

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Not Uncomplicated Bereavement
Depression
Grief (Bereavement)
Impairment 2 mo
Relatively fixed anhedonia
Self-esteem decreased
Functioning severely impaired
Generalized guilt
Often actively suicidal
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MAJOR DEPRESSIVE DISORDER

• Presence of major depressive episode
• Not attributable to separate psychotic
  disorder or bipolar disorder or medical
  disorder or substance abuse disorder
  or uncomplicated bereavement

18
Impact Of Depression In Chronic Medical Illness
Morbidity And Mortality
Economic Impact
Treatment Implications
Maladaptive Effects
19
Economic Impact Of Mental Disorders High
Utilizers Of General Medical Care

• 29 of primary care visits
• 52 of specialty visits
• 40 of in-hospital days
• 26 of prescriptions
• Two-thirds have 1 or more chronic medical
  illnesses

The Top 10 Of Healthcare Utilizers Account For
Katon et al. Gen Hosp Psychiatry. 199012355.
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Economic Impact Of Mental Disorders Medical
Inpatients With Psychiatric Comorbidity

• Length of stay
• Use of medical services
• Medical costs
• ER costs
• Rehospitalization rates for at least 4 years
  after discharge

Increased Healthcare Utilization
Saravay and Lavin. Psychosomatics. 199435233.
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Impact Of Depression In Chronic Medical Illness
Morbidity And Mortality
Economic Impact
Treatment Implications
Maladaptive Effects
22
Depression Decreases Adherenceto Medical Regimens

• Depression may affect adherence by
• Adversely influencing expectations and benefits
  about efficacy of treatment
• Increasing withdrawal and social isolation
• Reducing cognitive functioningand memory
• Influencing dietary choices and reducing energy
  to exercise and follow self-management regimens
  (ie, checking blood glucose)

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Meta-Analysis of the Adverse Effect of Depression
on Patient Adherence

• Compared to nondepressed patients, the odds are 3
  times greater that depressed patients would be
  nonadherent with medical treatment recommendations

DiMatteo MR, et al. Arch Intern Med.
2000160(14)2101-2107.
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Depression Adversely Impacts Self-Management of
Chronic Medical Illness

• Depressed patients with MI are more likely to
  drop out of exercise programs1
• Smokers with history of depression are 40 less
  likely to succeed in quitting smoking over a
  9-year period compared to nondepressed smokers2
• Patients with major depression and coronary
  artery disease are less likely to adhere to
  low-dose aspirin therapy than nondepressed
  controls3
• Patients with history of depression compared to
  nondepressed are more likely to develop
  depression with smoking cessation4

1. Blumenthal JA, et al. Psychosom Med.
198244(6)529-536. 2. Anda RF, et al. JAMA.
1990264(12)1541-1545. 3. Carney RM, et al.
Health Psychol. 199514(1)88-90. 4. Dierker L,
Am J. Psychaitry 159947-953, 2002
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Depression Decreases Medication Adherence in
Patients With Diabetes
Nonadherent Days ()
Oral Hypoglycemic
Lipid LoweringMeds
ACE Inhibitors
Lin E et al., Diabetes Care, 2004
26
Depression Is Associated With an Increased
Percent of Smoking
pNone pNone N4225
Adjusted for demographics, medical comorbidity,
diabetes severity,diabetes type and duration,
treatment type,HbA1c and clinic. Katon et al,
Diabetes Care, 2004
27
Depression is Associated with an increased BMI
30 kg/m2 by
pNone pNoneN4225
Depression Group
Adjusted for demographics, medical comorbidity,
diabetes severity, diabetes type and duration,
treatment type,HbA1c and clinic Katon et al,
Diabetes Care, 2004
28
Depression Is Associated With Higher Percentage
with HbA1c 8
pNone pNone
N4225
Adjusted for demographics, medical comorbidity,
diabetes severity, diabetes type and duration,
treatment typeand clinic. Katon et al, Diabetes
Care, 2004
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Depression Is Associated With a Higher Number of
Cardiac Risk Factors
3 Cardiac Risk Factors ()
Diabetic Patients With CVD N3010
Diabetic Patients Without CVD N1215
Katon et al, J Gen Intern Med, 2004
30
Impact Of Depression In Chronic Medical Illness
Morbidity And Mortality
Economic Impact
Treatment Implications
Maladaptive Effects
31
Depression Is Associated With Increased Diabetes
Complications

• Meta-analysis of 27 studies showed a significant
  association between depression and a range of
  diabetes complications with effect sizes in the
  small to moderate range (95 CI 0.17 to 0.32)

DeGroot et al, Psychosom Med, 2001
32
Depression Effect on Risk of Diabetic
Complications

• Incidence of coronary artery disease was 3 times
  as common over a 10-year period in diabetics who
  were initially depressed vs nondepressed1
• In a prospective study of children with type 1
  diabetes, the risk of development of retinopathy
  was associated with duration of diabetes, time
  spent in poor glucose control, and time spent in
  major depression2

1. Carney et al. 1994. Psychosom Med 2.
Kovacs et al. 1997. Diabetes Care
33
Depression Associated With Increased Mortality
Post-Myocardial Infarction
Cox model hazard ratio for 6-month mortality
associated with depression 5.74 (95 CI
4.61-6.87)p.0006
Mortality
Time after MI (months)
Frasure-Smith N, et al. JAMA. 19932701819-1825.
34
Adverse Bidirectional Interaction

• Smoking
• Sedentary lifestyle
• Obesity
• Lack of adherenceto medical regimens

• Medical illnessat earlier age
• Poor symptom control
• Increased functional impairment
• Increased complications of medical illness

Major Depression
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Depressive DisordersTreatment Goals
Treatment
Minimize Relapse/ Recurrence Risk
Reduce/Remove Signs, Symptoms
Restore Role/ Function
Adapted from WPA/PTD Educational Program on
Depressive Disorders
36
Consider for Medication Referral

• Patient preference
• Previous positive response to medications
• Moderate to severe vegetative symptoms
• Significant residual symptoms after 6 weeks of
  psychotherapy
• 2 or more episodes

37
PHARMACOTHERAPYTHREE TREATMENT PHASES

• Acute 612 weeks
• Continuation 49 months
• Maintenance 1 or more years

38
Treatment with Antidepressant Acute Phase
Diagnosis
Initiate treatment
Intolerant
Monitor every 1-2 weeks
Reduce dose or switch
Assess Week 6
Noimprovement
Improvement
Adapted from WPA/PTD Educational Program on
Depressive Disorders
39
Selecting a Safe and Effective Antidepressant
Medication

• 1) Efficacy
• 2) Side effect profile relative to your patients
  needs
• 3) Dosing

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All Antidepressants Are Efficacious

• 70 - 80 efficacy with any marketed
  antidepressant
• SRIs or Bupropion are excellent first line
  choices
• TCAs may be superior for some severe
  depressions
• MAO-Is may be preferred for some atypical
  depressions

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SSRIs (Selective SRIs)

• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox)
• Paroxetine (Paxil)
• Sertraline (Zoloft)

42
Serotonin Reuptake Inhibitors A First Line
Choice for Treatment of Depression and Various
Anxiety Disorders

• Similar efficacy to earlier agents
• More acceptable side effect profile
• Relative medical safety/ease of use
• Reduced lethality with overdose

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PHARMACOLOGY OF SSRI ANTIDEPRESSANTS
Enzyme Inhibition Effects
Protein Binding
Half-Life
80 IID6
94
26 hr
Paroxetine
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Common SRI Adverse Effects

• GI disturbances
• Headache changes
• Sleep disturbances
• Appetite changes
• Sexual function changes
• Anxiety level changes
• Allergic reactions

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Unusual SRI Adverse Effects

• Withdrawal reactions
• Electrolyte disturbances
• Bruxism/myoclonus
• Hypotension/bradycardia
• Word-finding difficulties
• Photosensitivity
• Blunted emotional reactivity
• Paradoxical/unusual sexual effects
• Suicidal risk (a subject of controversy)

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LOW TOXICITY IN OVERDOSE

• Fluoxetine
• Sertraline
• Paroxetine
• Trazodone
• Venlafaxine

• Nefazodone
• Citalopram
• Escitalopram
• Mirtazapine
• Duloxetine
• Bupropion

Toxicity of newer antidepressants in overdose can
be significant. Venlafaxine and citalopram have
proconvulsant effects and citalopram has been
observed to cause QT prolongation. Nefazodone and
mirtazapine were considered safer in overdose in
one review.1 Bupropion has both adverse
proconvulsant and cardiac effects in overdose.
1. Kelly et al. J Toxicol Clin Toxicol
20044267-71
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General Dosing Strategy

• Avoid frequent dose increases but make contact
  with patient every 1-2 weeks
• Wait 2-4 weeks with total non-response (or
  partial response that has plateaued) before
  increasing. Change if no response after 4 weeks.
• When clinically necessary, may have to make above
  changes earlier than 4 weeks.
• Wait 8-12 weeks if gradual response that has not
  plateaued

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Fluoxetine Dosing

• Begin 10-20 mg/morning, 5-10 mg for age 60
  or if hx of unprecipitated panic attacks, or to
  avoid side effects.
• Increase to 20 mg after 1 week. Continue with
  20 for 4 weeks. If no response, increase in
  20 mg increments every 4 weeks as tolerated
  (Fava M et al. J Clin Psychopharmacol 2002
  22379-387)
• No improvement after 4 weeks at 60 mg/d? Stop
  trial.
• Partial response? Difficult to interpret. Get
  consult

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Citalopram Dosing

• Begin 20 mg in AM, 10 mg for elderly,
  unprecipitated panic attacks, etc.
• Increase to 40 mg after 1 week. Continue 40 mg
  for 4 weeks if tolerated.
• If no/partial response after 4 weeks, increase to
  60 mg.
• Change if no response to 60 mg in 4 weeks.

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Sertraline Dosing

• Start with 50 mg in AM (25 mg for elderly,
  and those with panic disorder)
• Maintain 50 mg/day for 2-4 weeks before
  increasing. If no/partial response
  increase in 50 mg increments every 4 weeks.
  Change if no response at 200 mg for 4 weeks.

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Bupropion (Wellbutrin)

• NDRI with comparable antidepressant efficacy
• Seizure risk up to 0.44/1,000 at higher doses
• Equally effective as SSRIs for the non-specific
  anxiety symptoms that typically are present in
  depressed patients. (Rush AJ et al.
  Neuropsychopharmacol 200125131-138)
• But, probably not effective for panic disorder.
• Contraindicated in patients with history of
  bulimia or anorexia nervosa because of increased
  seizure risk

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Bupropion II

• More costly than SSRIs even in generic SR form
  (e.g. 42 for 30 day supply at 300 mg/d)
• Minimal sedation
• May enhance sexual functioning
• Weight neutral or slight weight loss on average
• Minimal cardiac or other medical effects

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DOSING OF BUPROPION

• SR associated with lower seizure risk than
  regular release (0.1/1,000) in 150 mg bid dose.
  XL used when single daily dose administration is
  needed.
• Begin 100150 mg qAM X 4 days
• Increase to 100150 mg BID (at least 8 hours
  between doses)
• In patients with liver disease
• 50 increase in T1/2 of hydroxybupropion
• No effect on bupropion and other metabolites
• Start with 100 mg qAM

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Bupropion Adverse Effects

• More frequent
• Tremors
• Dry mouth
• Constipation
• Sweating
• Dizziness
• Insomnia
• Nausea

Preskorn S J Clin Psychiatry 199556(Suppl 6)
p.18
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Bupropion Dosing

• Caution with concurrent medications that lower
  seizure threshold
• Avoid if history of seizure disorder
• IR dosage Do not exceed 450 mg/d, 150 mg/dose
• SR dosage Do not exceed 400 mg/d, 200 mg/dose
• XR dosage Do not exceed 450 mg/d, single dose
• Avoid rapid dose increase

from PDR 2001-6
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Impact Of Depression In Chronic Medical Illness
Morbidity And Mortality
Economic Impact
Treatment Implications
Maladaptive Effects
57
Antidepressant Treatment Trials In Patients With
Chronic Medical IllnessMajor depression is
responsive to antidepressant treatment in
patients with

• Ischemic heart disease
• Parkinsons disease
• Rheumatoid arthritis
• Stroke
• HIV

• Cancer
• Chronic tinnitus
• COPD
• Diabetes
• Inpatient rehabilitation needs

Katon and Sullivan. J Clin Psychiatry.
199051(suppl 6)3.
58
Antidepressant Analgesia In Chronic, Nonmalignant
Pain

• Summary of 28 studies
• More effective than placebo
• A median of 58 of patients reported at least 50
  pain reduction
• Response is greater when a specific pain
  diagnosis is made
• Greater response for pain in the head region
• Response not dependent on presence of
  depression
• Doses similar to those used for depression

Onglena and Van Houdenhove. Pain. 199249205.
59
SSRIs In Chronic Pain

• Tricyclics heterocyclics
• Mixed drugs (venlafaxine, duloxetine) are more
  effective than selective drugs - further study
  warranted
• Both pure serotonergic and pure noradrenergic
  drugs may have less effect size than drugs with
  mixed effects

Onglena and Van Houdenhove. Pain. 199249205.
60
Suicide Rates Due to Depressive Disorders
Kaplan Sadock, 1991WPA/PTD Educational Program
on Depressive Disorders
61
Depression and Chronic Medical Illness

• Increased prevalence of major depression in the
  medically ill
• Depression amplifies physical symptoms associated
  with medical illness
• Comorbidity increases impairment in functioning
• Depression decreases adherence to prescribed
  regimens
• Depression is associated with adverse health
  behaviors (diet, exercise, smoking)
• Depression increases mortality