Medical Management of Major Depressive Disorder

1
Medical Management of Major Depressive Disorder

• Boadie W. Dunlop, M.D.
• 6/19/2008

2
Common Mis-steps in the Primary Care Treatment of
Depression

• Incorrect Diagnosis
• Incomplete Diagnosis
• Sub-optimal medication selection
• Sub-optimal dosing
• Not treating to remission of illness
• Sub-optimal duration of therapy

3
General Approach to the patient presenting with
depressed mood

• 1) Rule out medical illness
• 2) Consider non-affective psychiatric disorders
  as primary illness
• 3) Consider patient, disease and treatment
  factors of the illness
• 4) Initiate treatment
• 5) Evaluate response and follow

4

• I. DIAGNOSTIC ACCURACY

5
DSM-IV Diagnosis of MDD

• 2 weeks, with 5/9 SIGECAPS sx nearly every day
• One of the sx MUST be
• A) Loss of Interest or Pleasure in or Activities
• B) Depressed Mood
• During the past month, have you
• 1) Had little interest or pleasure in doing
  things?
• 2) Been feeling down, depressed or hopeless
• Patient Health Questionnaire-9 (PHQ-9)
• (Free from Macarthur Foundation)

6
Diagnosis of MDE SIGECAPS

• Sleep Insomnia or Hypersomnia
• Interest Loss of pleasure/interest
• Guilt Excessive or inappropriate guilt, or
  feelings of worthlessness
• Energy Fatigue or loss of energy
• Concentration Poor or indecisiveness
• Appetite Change, or gt5 weight change in 1
  month
• Psychomotor Retardation or agitation
• Suicide Recurrent thoughts of death

7
Im Depressed does not MDD!

• Sadness
• Disappointment, Bummed
• Anhedonia
• Amotivation
• Anergia
• Frustration
• Loneliness

8
Mood Disorder due to General Medical Condition

• COMMON
• Hypothyroidism
• Stroke
• Parkinsons Disease
• AIDS
• Renal Failure
• Systemic Lupus Erythematosus
• Diabetes mellitus
• (Medications)

• RARE but LETHAL
• Neoplasm(CNSPancreas)
• CNS Infections
• Huntingtons Disease
• Electrolyte Disturbance
• Hepatic Encephalopathy
• Porphyria
• Wilsons Disease
• Cushings/Addisons
• Vitamin Deficiencies

9
Psychiatric Disorders Presenting with Depressed
Mood

• AFFECTIVE
• Major Depressive D/O
• Bipolar D/O I II
• Dysthymia

• NON-AFFECTIVE
• Substance Use D/O
• Anxiety D/O
• Adjustment D/O
• Bereavement
• Schizophrenia
• Dementia
• Delirium

10
Ruling Out Bipolar D/O

• Decreased Need for Sleep
• Have you ever gone several nights with very
  little sleep, and not missed it? That is,
  functioned normally, or better than normal?
• Speeded Up and Stimulus Seeking
• Have you had a time when you were very
  impulsive, risk-taking, or talking so quickly
  that people asked you to slow down?
• Grandiosity
• Have you ever felt you had special abilities
  that led you to feel superior to others in some
  way?

11
Assessing for Anxiety

• Panic Attacks
• Have you ever suddenly felt intensely
  frightened, fearing you were dying, going crazy
  or losing control, with many physical symptoms?
• PTSD
• Have you ever been in a situation where you were
  severely injured or thought you were going to
  die, or saw someone killed or severely injured?
• Social Phobia (Social Anxiety Disorder)
• Do you fear speaking in front of people you
  dont know well that you will say something that
  will say something embarrasing, or make a fool of
  yourself?

12
Panic/Agoraphobia
13
Assessing for Anxiety

• OCD
• Are you bothered by thoughts that keep coming
  back to you through the day that are distressing
  and that make no sense and you cant get rid of?
• Are there any rituals or habits you have to
  perform each day, even though they dont seem to
  make sense?

14
The Comorbidity Triangle
Anxiety
Depression
Substance Abuse
15

• II. Treatment Selection

16
Why bother to treat MDD?

• Response Rates Placebo 30
• Medication 60
• ECT 85
• Relapse Rates One episode 50
• Two episodes 70
• Three episodes 90
• Suicide Rate 10-15 complete suicide
• Medical Comorbidity MDD increases risk of death
  6 months post-MI by 3x (5 gt 15)

17
First-Line Treatments for Major Depressive
Disorder

• Psychotherapy
• Cognitive-Behavioral Therapy
• Marital Counseling
• Medication
• Selective Serotonin Reuptake Inhibitor (SSRI)
• Escitalopram, Sertraline, Fluoxetine, Paroxetine
• Serotonin Norepinephrine Reuptake Inhibitor
  (SNRI)
• Venlafaxine, Duloxetine
• Bupropion
• Mirtazapine
• Tricyclic Antidepressant (TCA)
• Amitriptyline, Desipramine, Nortriptyline

APA Practice Guideline for Treatment of Patients
with Major Depressive Disorder, 2nd ed., Am J
Psychiatry 2000 Apr157(4 Suppl)1-45.
18
Choosing the Treatment

• 3 Considerations
• The Patient
• The Illness
• The Treatments

19
Considerations in Selecting a Treatment

• Patient preference
• Treatment availability
• Therapists, Formularies, Cost
• Generics Fluoxetine, Sertraline, Citalopram,
  Paroxetine, Bupropion
• Prominent Symptoms
• Insomnia, Irritability
• Medical Comorbidity/Drug Interactions
• Hypertension, BPH, Coronary artery disease,
  Seizures
• Side effect profile
• Sexual dysfunction, Weight gain
• Personal and Family history of treatment response
• Psychiatric Comorbidities
• ADHD, Anxiety disorder
• (umm Efficacy?)

20
FDA-Indications for Depression and Anxiety
Disorders
Dx Fluox Sert Par (Es)Cit Ven Dulox Bup Mirtaz TCA MAOI
MDD
GAD
PD
Soc Phob
PTSD
OCD
Medications Bup bupropion Dulox duloxetine
Es(Cit) escitalopram/citalopram Fluox
fluoxetine MAOI monoamine oxidase inhibitor
Mirtaz mirtazapine Par paroxetine Sert
sertraline TCA tricyclic antidepressant Ven
venlafaxine Diagnoses GAD generalized anxiety
disorder MDD major depressive disorder OCD
obsessive compulsive disorder PTSD
post-traumatic stress disorder Soc Phob social
phobia.
21
Choice of Antidepressant if Anxiety is Present

• Must select SSRI or SNRI
• Do NOT start with bupropion (Wellbutrin) or
  mirtazapine (Remeron)
• DOSING Start at HALF usual starting dose for 4
  days
• Fluoxetine 10 mg, Sertraline 25 mg, Citalopram
  10 mg, Escitalopram 5 mg, Paroxetine 10 mg
  (Paroxetine CR 12.5 mg)
• Venlafaxine 37.5 mg, Duloxetine 30 mg

22
Concern About Side Effects

• Best Choice Psychotherapy
• Weight Gain
• Avoid Mirtazapine, paroxetine, TCAs
• Sexual Dysfunction
• Bupropion, mirtazapine, selegiline (MAOI patch -
  EMSAM)
• Anticholinergic Effects (BPH, Delirium)
• Avoid TCAs
• Hypertension
• Avoid MAOIs
• Use with caution Venlafaxine
• Cardiac Disease
• Avoid TCAs
• Seizures
• Avoid Bupropion gt 300 mg/d
• Note All antidepressants lower seizure threshold

23
Changes in Weight After 26-32 Weeks of Therapy
Paroxetine vs. Sertraline vs. Fluoxetine
30
30
Mean Change in Weight Baseline to endpoint
Percent of Patients with gt 7 Weight Gain at
Endpoint
25
20
20
Percent of Patients
10
Percent Change
10
7
4
3.5
1.0
-0.25
0
0
PAR(N47)
SERT (N48)
FLU (N44)
PAR
SERT
FLU
-10
PAR vs. baseline (Plt0.001) PAR vs. SERT (P
lt0.015) PAR vs. FLU (P lt0.001) at endpoint. PAR
vs. SERT (P 0.003) PAR vs FLU (P 0.016) at
endpoint. Fava M et al. J Clin Psychiatry.
200061863-867.
24
Additional Co-morbidities to Consider

• Chronic Pain Noradrenergic Agents
• TCAs Amitriptyline, Desipramine
• SNRIs Duloxetine Venlafaxine
• Attention Deficit Disorder
• Bupropion
• Nicotine Dependence
• Bupropion

25

• III. Treatment Monitoring

26
Response and Remissionin Depression

• Response
• significant improvement but not necessarily
  complete relief of symptoms
• often measured by ?50 decrease from baseline
  HAM-D score
• Remission
• minimal or no symptoms
• return to functional normality
• no longer meets diagnostic criteria
• often measured as HAM-D of 7 or less

Frank E et al. Arch Gen Psychiatry.
199148851-855. Rush AJ, Trivedi MH. Psychiatr
Ann. 199525704-709.
27
Phases of Treatment for Depression
Recovery
Remission
Normalcy
X
X
O
O
O
Response
Symptoms
Severity
X
Progression to disorder
Relapse
Recurrence
Syndrome
Acute (6-12 Weeks)
Continuation (6 Months)
Maintenance (?1 Year)
Treatment Phases
Time
Kupfer DJ. J Clin Psychiatry. 199152(suppl
5)28-34 Depression Guideline Panel. Clinical
Practice Guideline No. 5 Depression in Primary
Care, 2 Treatment of Major Depression.
Rockville, Md Agency for Health Care Policy and
Research, U.S. Department of Health and Human
Services 1993. AHCPR publication 93-0551.
28
Potential Consequences of Failing to Achieve
Remission

• Increased risk of relapse and treatment
  resistance1-3
• Continued psychosocial limitations4
• Decreased ability to work and decreased workplace
  productivity5,6
• Increased cost for medical treatment6
• Sustained depression may worsen
  morbidity/mortality of other conditions7-9

 1Paykel ES et al. Psychol Med.
1995251171-1180 2Thase ME et al. Am J
Psychiatry. 19921491046-1052 3Judd LL et al.
J Affect Disord. 19985997-108 4Miller IW et
al. J Clin Psychiatry. 199859608-619 5Simon GE
et al. Gen Hosp Psychiatry. 200022153-162
6Druss BG et al.Am J Psychiatry.
2001158731-734 7Frasure-Smith N et al. JAMA.
19932701819-18258Penninx BW et al. Arch Gen
Psychiatry. 200158221-227 9Rovner BW et al.
JAMA. 1991265993-996.
29
Level 1 Response and Remission Take Longer Than
Generally Appreciated
Of Ultimate Responders,35 Responded After Week 6
Of Ultimate Remitters, 47 Remitted After Week 6
53
30.0
25.0
65
22.1
24.5
25.0
47
22.9
19.4
20.0
20.0
35
17.8
14.5
15.0
12.9
12.9
15.0
Percent
11.4
Percent
10.0
11.5
11.0
10.0
10.0
7.6
5.0
4.9
5.0
0.0
0.0
2
4
6
8
10
12
gt13
2
4
6
8
10
12
gt13
Weeks
Weeks
36 remitters at or after week 10Mean daily dose
for remitters 42 mg
Trivedi MH et al. Am J Psychiatry. 200616328
30
Dose Titration

• Initial Treatment 4-6 weeks before raise from
  minimal effective dose.
• If no benefit by 4 weeks, raise dose, otherwise
  wait until patient has Plateau, then increase
  dose every 4 weeks.
• Continue raising dose until remission achieved,
  or to maximally tolerated dose.
• If lt30 better after one dose increase, switch to
  another medication

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Next Step Switch or Augment?

• If not remitted, make sure patient at maximally
  tolerated dose.
• If, at this level, patient clearly perceives
  benefit from medication, better to augment
• Good Combinations
• SSRI or SNRI Bupropion
• SSRI or SNRI Mirtazapine
• SSRI or SNRI sedative/hypnotic or benzo (if
  anxiety present)
• If benefit is low, or bad side effects, switch

32
Level 2 Treatment Outcomes (Remission)
(L-2 Switch)
Trivedi MH et al. N Engl J Med. 20063541243
Rush AJ et al. N Engl J Med. 20063541231
33
Conclusions From Levels 1 and 2

• Pharmacologic distinctions do not translate into
  large clinical differences in a non-selective
  population
• Cumulative remission rate is gt50 with first 2
  steps
• Predictors of response consistent with previous
  studies

34
Risk of Recurrence Following Recovery From an
Index Episode of Major Depression
N359

• Recurrence Risk
• Past history
• Residual
• symptoms
• Early or late onset
• Severe or chronic
• Women
• Untreated

Lavori PW et al. Int J Meth Psychiatr Res.
19944211
35
Case Example - Brittany

• 35 year-old woman, married x 8 years, homemaker
  with 3 children.
• No previous psychiatric history
• Medically healthy (TSH, CBC/Chem etc. normal)
• Onset of occasional sadness and crying about 9
  months ago.
• Over next two months, became more fatigued,
  irritable, socially withdrawn, forgetful, worried
  and self-critical, with difficulty falling
  asleep.
• Not actively suicidal, but does think shed be
  better off if a bus ran over her.
• Diagnosis Major Depressive Episode
• Next step?

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Case Example, contMore History!

• Review for other psychiatric symptoms
• Drinking 2 glasses of wine to help fall asleep
• No illicit drugs
• No history of hypomania or mania
• No hallucinations or delusions
• No obsessions/compulsions
• About 4 months ago, began having unexpected panic
  attacks. No other anxiety symptoms
• No family history of psychiatric problems
• Increasing distance from husband financial
  stressors, demanding children, rare intimacy
• No family in town to help.
• Lifelong difficulty asserting herself.

37
Case Example, contWhat to choose for Brittanys
Depression?

• CBT or Marital Therapy
• Pros No side effects Effective for panic
  Emotional support and help with assertiveness
• Cons Expensive Slow to improve Time demand
• Medication
• Pros Relatively rapid, Many effective for panic
• Cons
• Side effects (sexual, weight gain)
• Longer duration of treatment required
• Not as protective against relapse

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Case Example, contFinal Decision

• CBT (no side effects, help with assertion
  isolation)
• Medication
• SSRI Sertraline or Fluoxetine (panic efficacy)
• 2nd Citalopram/escitalopram (not approved for
  panic disorder)
• SNRI Venlafaxine or Duloxetine
• Less likely to cause sexual dysfunction
• Other options TCA, Selegiline patch
• Avoid Bupropion worsening anxiety
• Probably avoid Paroxetine and Mirtazapine
  (weight gain)

39
Getting to Yes Adherence

• Reduce stigma
• Educate patient about the symptoms and illness
• Identify target symptoms for treatment
• Educate and anticipate side effects
• Connect taking of medications with an existing
  daily habit
• Call doctor before deciding to stop the
  medication
• Give control and choices to patient as much as
  possible
• REMEMBER! At least 33 of patients are
  non-compliant

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Reasons for Non-Response

• Non-compliance
• Inadequate dosage
• Slow response
• Poor absorption (e.g. Ulcerative Colitis, Crohns
  Disease)
• Other drug effects (e.g. Carbamazepine inducing
  metabolizing enzymes)
• Incorrect Diagnosis
• Psychosocial Factors
• True Non-response