Case Studies in Depression Care:
Treatment Non-Response, Medication
Side-Effects and Office Counseling*
Steven Cole, MD
Professor of Psychiatry
Stony Brook University Medical Center and
Thomas Oxman, MD
Professor of Psychiatry
Dartmouth School of Medicine
PHARMACOTHERAPY
• Effective
– Major depression
– Dysthymia (chronic depression)
• Possibly effective
– Minor depression
Initial Acute Phase Treatment
•
•
•
•
•
•
•
•
Elicit patient preference
Assess suicidality
Generally start with SSRI
Provide educational messages
Elicit commitment to take medication regularly
Arrange early follow-up (1 to 3 weeks)
Repeat PHQ-9 every month until remission
Start at or increase dose every week up to
adequate dose
• Once at adequate dose, re-evaluate dose q/month
www.ahrq.gov; www.depression-primarycare.org; APA
CHOOSING AGENTS:GENERIC SSRIs
• Citalopram (Celexa)/sertraline (Zoloft)
– effective for anxiety ( in short term)
– may need to increase dose (60 mg/200 mg) for efficacy
– low-moderate drug interactions
• Fluoxetine (Prozac)
–
–
–
–
long half-life
P450 inhibition at low doses
effective for anxiety (but  anxiety in short term)
Possible  insomnia (short term)
–
–
–
–
–
–
possibly sedating
effective for anxiety
possible weight gain
P450 inhibition at low doses
more frequent withdrawal symptoms
measurable anti-cholinergic activity
• Paroxetine (Paxil)
OTHER GENERIC NEW AGENTS
• Bupropion SR, XL (Wellbutrin)
–
–
–
–
–
–
–
–
100/200 mg (SR); 150/300 mg (XL)
somewhat activating; don’t give HS
do not give if there is seizure risk
unless using XL, don’t give >200 mg /dose
don’t prescribe >450 mg/day
XL can be prescribed once/day
fewer sexual side-effects
once day dosing available (XL)
• Mirtazapine (Remeron)
–
–
–
–
frequent appetite / weight gain
very sedating at low dose
few drug interactions
Sol-tabs available
CASE #1
• A 40-year-old male reports a little (but
not marked) improvement after 2 weeks
on escitalopram (Lexapro) 10 mg a day.
• What do you do next?
CASE #1
• POINTS TO CONSIDER
• Usually takes 3-4 weeks to attain maximal
clinical effects from one dosage of an
antidepressant
• Probably because of prolonged time needed
to effect receptor architecture or function
Post-Synaptic Signal
Transduction Effects
Oxman, 2005
neurogenesis
TIME COURSE OF BIOLOGICAL
CHANGES WITH ANTIDEPRESSANTS
Hours
Synaptic
Signaling
Days
Days
Receptor/
Transporter
Regulation
Weeks
Months
Years
Intracellular
Neuroplasticity/
Gene
Signaling & Expression Neurogenesis
Posttranslational
Modification
Oxman, 2005
KEY EDUCATIONAL MESSAGES
 Antidepressants only work if taken every day.
 Antidepressants are not addictive.
 Benefits from medication appear slowly.
 Continue antidepressants even after you feel better.
 Mild side effects are common, and usually improve with
time.
 If you’re thinking about stopping the medication, call
me first.
 The goal of treatment is complete remission; sometimes
it takes a few tries.
CASE #2
• After 8 weeks on sertraline (Zoloft) 50
mg bid, a patient is considerably better,
but not back to baseline.
• What do you do?
CASE #2
POINTS TO CONSIDER
• Treat patients aggressively until they reach
remission
• Increase dose as tolerated to 200 mg
• Patients who do not attain remission (even
those who experience a 50% or greater
response) are at greater risk for relapse and
continued functional impairment
OUTCOME TARGETS USING THE PHQ-9
• Clinically significant improvement (CSI)
= 5 point decrease in PHQ-9 score
• Response
= 50% decrease in PHQ-9 score
• Remission
= PHQ-9 score < 5 for two months
SIDE EFFECTS,
DRUG INTERACTIONS, AND
COMORBIDITIES
CASE #3
• A 30-year-old female complains of
anorgasmia on citalopram (Celexa)
40 mg/day
• What should you do and when?
CASE #3
POINTS TO CONSIDER
• Sexual dysfunction with all SSRIs approaches
50% prevalence (anorgasmia, decreased libido,
erectile problems)
• Does not improve over time
• RCT indicates sildenafil can be helpful for male
sexual problems
• Consider lower dose, switch medications, add
bupropion (limited, inconsistent data)
CASE #4
• After three days of treatment, this 30 yearold female on fluoxetine (Prozac) 20mg a
day complains of agitation and insomnia.
• What do you do?
CASE #4
POINTS TO CONSIDER
• Fluoxetine (and other SSRIs) often cause
increased anxiety and/or insomnia in
early stages of treatment
• This usually resolves within several days
or a week or two
• Consider starting at low doses in patients
with anxiety
• Consider prescribing “escape” medicine
SIDE EFFECTS
(SSRIs)
• Agitation/insomnia
• GI distress
• Sexual dysfunction
SIDE EFFECTS
(OTHER NEW AGENTS)
•
bupropion - agitation;  seizure risk
•
duloxetine - nausea (up to 40%)
•
mirtazapine - sedation; weight gain
•
venlafaxine - SSRI effects; 1-3%  BP
MANAGING SIDE EFFECTS
• Sedation
– Give medication HS
• GI distress
– Give medication with meals
• Anticholinergic effects
– Bulk in diet, lemon drops
• Postural hypotension
– Hydration, change position slowly,
support hose
MANAGING SIDE EFFECTS
(con’t)
• Insomnia/agitation
– Use adjunctive sedating agent
– Switch to mirtazapine
• Sexual dysfunction
– Switch to bupropion, mirtazapine
– Consider bupropion, sildenafil,
yohimbine, cyproheptadine
Case #5
• 70 year old female, widow of one year, complains of
depression, with PHQ9=21
• History of previous depression, age 51, responded well to
paroxetine (Paxil)
• Patient has AF, anxiety, migaine HA
• S/p MI, breast cancer
• Current meds
–
–
–
–
–
Tamoxifen
Aspirin
Risperidone
Metoprolol,
Sumatriptan
• In view of past history, should paroxetine be prescribed?
Paroxetine Drug Interactions
• Paroxetine inhibits P450
• All SSRIs inhibit platelet function
• All SSRIs are highly protein-bound
• All SSRIs have warning about triptans and
serotonin syndrome
Paroxetine Drug Interactions
• Tamoxifen
– pro drug requires P450
– paroxetine lowers drug levels of active metabolite
• Risperdal
– paroxetine increases blood levels of most psychotropics 2-4 x
(eg atomoxetine)
– adjust dose of psychotropic
• Metoprolol
– paroxetine may increase blood level (no data)
– observe
SSRI Drug Interactions
• Sumatriptan
– Potential risk of serotonin syndrome - observe
• Aspirin
– concern about increased bleeding; consider PPI
PUTATIVE ALTERNATIVES BASED ON
CYTOCHROME P450 INTERACTIONS
• Inter-individual and clinical variability
• Monitor effects and blood levels when
available
• Consider the antidepressants with relatively
lower effect on metabolic enzymes
–
–
–
–
citalopram (and escitalopram)
sertraline
mirtazapine
venlafaxine (and desvenlafaxine)
GENERAL DRUG INTERACTIONS
• Obtain medication history
• Be aware that all drugs can
affect the action and serum levels
of other drugs
• Monitor the clinical effects and
serum levels of all medications
• Use electronic data base
CASE #6
• You decide to start antidepressants
for a 30-year-old female who has
major depression, panic attacks, and
significant anxiety.
• Which medication(s) would you use
and how?
PREVALENCE OF MAJOR DEPRESSION
IN PATIENTS WITH ANXIETY
65% (Panic + MD)
42%
48%
Panic
Specific
Phobia
PTSD
(PTSD + MD)
(phobia +MD)
42%
(GAD + MD)
SAD
GAD
Depression
34-70%
(SAD + MD)
OCD
67% (OCD + MD)
Kessler, Arch Gen Psych 1995
COMORBID ANXIETY DISORDERS
• Educate patient: SSRIs have efficacy but
increase anxiety in short-term
• Start with low dose SSRI, titrate slowly
• Consider adjunctive meds for sleep or ‘escape’
(trazodone/hydroxyzine/benzodiazepine)
• Consider buspirone for GAD (not panic)
• Bupropion is not effective for Rx Of anxiety
• Consider monotherapy
– venlafaxine/mirtazapine/paroxetine
5-HT DRUGS-OTHER APPROVED INDICATIONS
Dep
citalopram
x
escitalopram
x
fluoxetine
Adult and
children
Panic OCD
GAD
PTSD
xx
x
fluvoxamine
paroxetine
SAD
X
x
BN
PDD
x
Adult
sertraline
x
venlafaxine
x
x
Adult
x
x
Adult and
children
x
x
x
x
PDD
x
PDD
x
DEP=major depression; OCD= Obsessive-compulsive disorder; SAD=social anxiety disorder; GAD=generalized anxiety disorder;
PTSD=post-traumatic stress disorder; BN=bulemia nervosa; PDD=premenstrual dysphoric disorder
CASE #6
POINTS TO CONSIDER
• Many antidepressants approved for the
treatment of anxiety disorders may
increase anxiety in the short term
• Use low doses and increase slowly
• Educate/warn patients
• Consider use of “escape” medication
CASE #7
• Two weeks ago, you started a 60-year-old
female with diabetes on nortriptyline (e.g.
Pamelor) 50 mg h.s. She now complains
of lightheadedness when she stands up.
• What should you do?
CASE #7
POINTS TO CONSIDER
• Dizziness does not = postural BP changes
• Nortriptyline (NTP) causes the least
postural BP change of all the TCAs
• Starting dose of NTP should be 10-25mg
• Best predictor of postural BP change
with TCA is prior postural BP changes
• Postural BP changes secondary to TCA
do not resolve with time
CASE #8
• This 46 year old female has had diabetes
for 20 years and now has depression and
painful peripheral neuropathy. She was
tried on amitriptylene which caused
severe constipation and sedation.
• What do you do now for the depression
and the pain?
CASE #8
POINTS TO CONSIDER
• Dual action tricyclics (amitriptyline,
nortriptyline, imipramine) useful for pain
• TCA risk of hypotension, gastroparesis
• Consider duloxetine (has indication for
depression and diabetic neuropathy)
• Consider venlafaxine or desvenlafaxine (dual
action)
ANTIDEPRESSANTS IN DIABETES
• Tricyclics
– useful for diabetic neuropathy
– watch for postural hypotension & gastroparesis
– may impair glycemic control
• SSRIs shown to improve depression/GHb
• Evidence of efficacy of new dual agents for
neuropathic pain
CASE #9
• This 66 year old male has depression and
unstable angina. He had been treated with
sertraline several years ago and it didn’t
work.
• Which antidepressant do you choose now?
CASE #9
POINTS TO CONSIDER
• Sertraline is a good choice for post-MI
patients because of safety data and probable
anti-platelet aggregation activity
• Review doses used previously (if inadequate
doses, repeat trial is reasonable)
• Other antidepressants studied post-MI
include citalopram and mirtazepine
ANTIDEPRESSANTS IN CAD / CVD
• Tricyclics
– prolong conduction
– cause postural hypotension
• SADHART (Glassman et al, JAMA 2002)
– Sertraline is safe & effective
– Sertraline inhibits platelet aggregation
• ENRICHD (Taylor et al, Arch Gen Psychiatry 2005)
– Patients on SSRIs have  death &  repeat MI (OD=.53-.59)
TREATMENT RESISTANCE:
What To Do When
the First Drug Does Not Work
CASE #10
• A 43 y.o. male
PHQ-9
11%
18
16
14
• 20 mg citalopram
for 4 weeks, then
40 mg for 4 weeks
12
10
8
6
4
2
0
Baseline 4 Weeks 8 Weeks
QUESTIONS TO ALWAYS ASK
• Is Depression the right / only diagnosis?
• Are there psychosocial stressors?
• Is this treatment failure?
If adequate dose
If adequate adherence
If adequate duration
If inadequate response (PHQ-9)
OPTIONS
• Adjust medication
– Maximally tolerated dose
• Change medications
– If PHQ-9 does not drop ≥ 5 points after four to six
weeks at adequate dose
• Add medications
– If partial response
• Add psychological counseling
–
–
–
–
CBT
IPT
PST
Office Counseling
Psychological issues
Available
Willing
Case # 10
POINTS TO CONSIDER
• Patient has experienced change in PHQ9
of > 5 points
• With partial response, continue
increasing dose to maximal dose
• Increase dose of citalopram to 60 mg
CASE #11
• A 37 y.o. female
• escitalopram 10 mg
for 4 weeks
• then escitalopram 20
mg for 8 weeks
• otherwise healthy
PHQ-9
25
24%
20
15
10
5
0
Baseline
4 Wks
12 Wks
38%
PRINCIPLES OF COMBINATION
ANTIDEPRESSANT TREATMENT
• Combine mechanisms, not just drugs
• Pharmacologic synergies may promote efficacy
• Opposing side-effect profiles may promote
tolerability
Pre-Synaptic
Neurotransmitter
Effects
Oxman, 2005
NON-SSRIs
Dose
Range
Drug
Starting
Dose
Advantages
DisAdvantages
Serotonin and Norepinephrine Antagonist
7.5 - 15 mg Few
interactions; less Sedation at low
sex dys;
mirtazapine 15 - 45 mg h.s.
dose; increased
sedation;
appetite
appetite
Norepinephrine and Dopamine Reuptake Inhibitor
Bupropion
SR
300- 450
mg
150 mg
q. a.m.
Stimulating; less Stimulating; cost;
unless XL;
sex dysfunction Bid
not for hx of
seizures
Serotonin and Norepinephrine Reuptake Inhibitor
Venlafaxine
XR
75 - 375
mg
37.5 75mg
Anxiety dx; less
P450
Possible BP; cost
for 1 / day XR
Dose
Range
Drug
Starting
Dose
Advantages
DisAdvantages
TCA Norepinephrine Reuptake Inhibitors
desipramine
100 300 mg
50 mg
25 - 150 10 -25
mg
nortriptyline mg
Less sedating, Anticholinergic;
generic
Not for
cardiac
disease
AntiLess
cholinergic;
orthostatic
Not for
BP; generic; cardiac
blood levels
disease
SIMULTANEOUS ACTIONS
5-HT
reuptk
5HT1
5HT2-
NE
NE
reuptk a2-
DA
SSRI
venlafaxine
bupropion
mirtazapine
activating
sedating at low doses
Oxman, 2005
AUGMENTATION OPTIONS
• Lithium (600-800 mg/d)
• T3 (25-50 mg/d)
•
•
•
•
•
•
Bupropion
Pindolol
Buspirone
Stimulants (methylphenidate)
Anticonvulsants (lamotrigine)
Antipsychotics
WHEN TO COMBINE
OR AUGMENT
•
•
•
•
Partial response (rather than No response)
Tolerating current antidepressant
Current antidepressant at maximal dose
More severe illness
– Time urgency
– Willingness to take multiple medications
DUAL ACTION MEDICATIONS?
SSRI’S VS. TCA’S:
HEAD TO HEAD (META-ANALYSES)
Relative Effect Size
N (Patients)
All studies
Favors SSRIs
101(10,496)
Inpatients
Outpatients
25 (1,377)
58 (7,834)
High HAM-D
Low HAM-D
38 (3,336)
39 (4,045)
Serotonergic TCAs
Noradrenergic TCAs
Favors TCAs
P<0.02
48 (5,317)
53 (5,179)
P<0.04
-0.4
Anderson IM. Depress Anxiety. 1989;7(suppl 1):11-17.
-0.2
0
0.2
STAR*D
Sequenced Treatment
Alternatives to Relieve Depression
Rush J et al…
Summary of studies prepared by Steven Cole, MD
Publications
46 publications to date
Primary and secondary outcomes
• Trivedi et al: Am J Psychiatry, January 2006
• Rush et al: NEJM, March 2006
• Trivedi et al: NEJM, March 2006
• Fava et al: Am J Psychiatry, July 2006
• Nierenberg et al: Am J Psychiatry, September 2006
• McGrath et al: Am J Psychiatry, September 2006
Study Design
•
•
•
•
4000 patients
23 psychiatric settings
18 primary care settings
3 sequenced levels of randomization for nonresponders to first level treatment
Levels
• Level One Treatment
– Citalopram (up to 60 mg)
• Level Two Treatment
– Switch
• bupropion SR, venlafaxine ER, sertraline, or CBT
– Augment
• bupropion SR, buspirone, or CBT
• Level Three Treatment
– Switch
• mirtazapine or nortriptyline
– Augment
• Lithium or T3 (with bupropion SR, sertraline, or venlafaxine XR
• Level Four Treatment
– Switch
• Tranylcypromine or (mirtazapine + venlafaxine XR)
Remission (Ham-D); Response (QIDS)
Level One (N=2876; 80% chronic or recurrent depression)
• citalopram (28%,47%; mean dose = 42 mg.)
Level Two (N=727)
Switch strategy
• bupropion SR (21%,26%; mean dose = 283 mg)
• sertraline
(18%,27%; mean dose = 136mg)
• venlafaxine XR (25%,28%; mean dose = 194; 33% > 225 mg)
• no significant differences among groups
Augmentation (mean dose = 55mg citalopram)
• buproprion SR (30%,32%; mean dose = 267 mg)
• buspirone
(30%,27%; mean dose = 41 mg)
• no significant differences between groups on primary outcome
measure, but bupropion group had greater reductions in QIDS and
lower attrition due to intolerance
Remission (HAM-D); Response (QIDS)
Level Three (N=235)
Switch strategy
• Mirtazapine (12%,13%; mean dose = 42 mg)
• Nortriptyline (20%;17%; mean dose = 97 mg)
• no significant differences between groups
Augmentation strategy (with bupropion SR, sertraline, or venlafaxine XR)
• Li (16% remission; mean dose = 860 mg)
• T3 (25% remission; mean dose = 45 micrograms)
• no significant differences between groups on primary outcome measure,
but Li was associated with more frequent side-effects and more attrition
due to intolerance
Level Four (N = 109)
• Tranylcypromine: (7%,12%; mean dose = 37 mg)
• Ven + Mir:
(12%,24%; mean dose 210 mg/36 mg)
• no significant differences between groups on primary outcome measure,
but (ven + mir) had greater symptom reduction and less attrition due to
intolerance
CONTINUATION & MAINTENANCE
PHASE TREATMENT
CASE #12
• A 40-year-old male with good response to
paroxetine 20 mg a day for depression
and panic disorder reports that he missed
several doses and feels extremely anxious,
with nausea, and tingling sensations in
arms and legs.
• What do you do next?
CASE #12
POINTS TO CONSIDER
• Discontinuation/withdrawal effects can
occur with all antidepressants, but seem
more common with shorter half life
medications (e.g. paroxetine and
venlafaxine)
CASE #13
• A 40-year-old female is back to
baseline functioning after 3 months on
desipramine (e.g. Norpramin) 150 mg a
day. She has no side effects and has
started to decrease the dose because she
feels fine.
• What should you do?
CASE #13
POINTS TO CONSIDER
• Patients who attain remission should
remain (continuation phase of treatment)
on full active dose of antidepressant
medication for at least 6-12 months after
they reach remission
• The end of an episode of depression is not
reached until after the continuation
phase of treatment is complete
THREE PHASES OF TREATMENT
Normal
Remission
Relapse
Recovery
Recurrence
Response
Relapse
> 50%
STOP
Rx
65 to 70%
STOP
Rx
Acute
Continuation
Maintenance
Phase (3 months+) Phase (4-9 months) Phase (years)
Time
Oxman, 2001
RISK FACTORS FOR RECURRENCE &
THUS MAINTENANCE RX
• Maintain dose 6-12 months after remission
• Chance of relapse
– 50% if 1 prior episode
– 75% if 2 prior episodes
– 90% if 3 prior episodes
• Dysthymia
• Severe episode with suicidality
• Patient may need lifetime therapy
• Maintenance should be full dose
CASE #14
• An 80 year old male regained full
functioning after taking citalopram (Celexa)
20mg each morning. After 6 months, he is
complaining of insomnia and depressive
feelings again.
• What do you do now?
CASE #14
POINTS TO CONSIDER
• “poop-out” or tachyphylaxis is now a wellrecognized, but little studied phenomenon
thought to occur more commonly with the SSRIs
than other antidepressant medications
• “poop-out” seems to respond well to a one-time
increase in dosage (or augmentation/switch of
medication if already at maximum dose)
RESIDUAL SYMPTOMS IN MAJOR
DEPRESSION PREDISPOSE TO….
•
•
•
•
•
•
Greater risk of relapse
Continued psychosocial limitations
Continued impairments at work
Worsens prognosis of Axis III disorders
Increased utilization of medical services
Sustained elevation of suicide and
substance abuse risks
Thase. J Clin Psych. 1999.
Hirschfeld et al. JAMA. 1997.
OFFICE COUNSELING
• Use TACCT
• SELF-MANAGEMENT SUPPORT
– UB-PAP (ultra-brief personal action planning)
• OFFICE PSYCHOTHERAPY
– “BATHE”
– “SPEAK”
Use T.A.C.C.T.
• T ell – provide basic information about illness
• A sk – about concerns/beliefs
(cognitive/emotional)
• C are – develop rapport; respond to emotions
• C ounsel – provide information relevant to
concerns and explanatory model
• T ailor – develop plan collaboratively
“C are”
• Reflection:
– “I can see you’re upset about this diagnosis.”
• Legitimation (validation):
–
“I can understand why this would be upsetting…
– “You came in with stomach pain and come out with a
diagnosis about depression…that’s upsetting”
– “Many of my patients feel the same way...”
C are (con’t)
• Support:
– “I want to do what I can…”
• Partnership:
– “Together, we…”
• Respect:
– “I am really impressed by how well you are
coping under the circumstances...”
UB-PAP
Ultra-Brief Personal Action Planning
Three question framework:
1. “Is there anything you would like to do for your health
before we talk again?” (what, when, where, how often?)
(Ask patient to restate plan.)
2. “We all have trouble meeting our goals, what is your level
of confidence you will be able to carry out this plan?” (if
<7, help patient problem-solve)
3. “When would you like to come back to discuss how the plan
has gone?”
Cole, unpublished document, 2005
OFFICE COUNSELING:
USE “BATHE”
• B Background: “What is going on …”
• A Affect: “How do you feel about…”
• T Trouble: “What’s troubling you …”
• H Handling: “How are you handling..”
• E
Empathy: “That must be difficult...”
Stuart M, Lieberman J: The Fifteen-Minute Hour, 2002
OFFICE COUNSELING:
USE “SPEAK”
•
•
•
•
•
S
P
E
A
K
schedule regular activities
plan pleasant events
exercise
assertiveness
kind thoughts about yourself
Cole S, Christensen J. Depression. In Behavioral Medicine in Primary Care, 2008