Managing Depression
in Primary Care
Primary Care Medicine: Principles
and Practice
October 2011
Educational Objectives:
By the end of the presentation, a participant
will be able to:
1)  Choose antidepressant based on side
effect profile
2) Manage common antidepressant related
side effects
Descartes Li, M.D.
Clinical Professor
University of California, San Francisco
[email protected]
3) Understand risks of Osteoporosis, GI
bleeding, QTc prolongation, and Suicide
with antidepressants
Outline
Relevant Disclosures
none
•  Current Controversies
•  Overview of Antidepressants
•  Antidepressants: Selection and Side
Effect Management
•  Non-pharmacological treatments
•  Osteoporosis, GI bleeding, QTc, and
Suicide
•  Questions and Summary
1
Outline
The Crazy State of Psychiatry,
by Marcia Angell
•  Current Controversies
•  Overview of Antidepressants
•  Antidepressants: Selection and Side
Effect Management
•  Non-pharmacological treatments
•  Osteoporosis, GI bleeding, QTc, and
Suicide
•  Questions and Summary
How generalizable are study
findings?
In one study of psychiatric outpatients,
only 41 (12%) of 346 patients
would have been eligible for typical
research studies.
Zimmerman M et al. Are subjects in pharmacological
treatment trials of depression representative of patients in
routine clinic practice? Am J Psychiatry. 2002;159(3):
469-473.
Turner E et al. Selective Publication of Antidepressant Trials
and Its Influence on Apparent Efficacy. NEJM 2008 358(3):
252
2
In Defense of Antidepressants
American Psychiatric Association
Practice Guidelines for Depression
Agency for Health Care Policy and Research,
Clinical Practice Guidelines
Cochrane Review
http://www2.cochrane.org/reviews/en/
ab007954.html
In Defense of Antidepressants , by Peter
Kramer (The New York Times, July 9, 2011)
Bottom Line: For mild depression,
watchful waiting is a reasonable option
SSRI s (selective serotonin
reuptake inhibitors)
• First line
• Fairly safe in OD
• 9m minimum duration of
treatment
Outline
•  Current Controversies
•  Overview of Antidepressants
– SSRIs
–  Other Antidepressants
– TCAs
– MAOIs
•  Antidepressants: Selection and Side
Effect Management
•  Non-pharmacological treatments
•  Osteoporosis, GI bleeding , QTc and
Suicide
•  Questions and Summary
SSRI: Side Effects
Categories
•  Early and frequently transient
•  Early and persist: sexual
dysfunction
•  Gradually and accrue: weight
gain
Fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil),
fluvoxamine (Luvox), citalopram (Celexa), escitalopram
(Lexapro)
3
Early and Transient
Examples:
•  Nausea or dull headache
•  Jitteriness
•  Gi upset
Early and Transient
Strategies:
•  Start low and go slow
•  Reassurance
•  For anxiety/nervousness: add lowdose benzodiazepines
•  For sedation: see later
Furukawa, T A, Streiner, D L, & Young, L T. (2001). Is
antidepressant-benzodiazepine combination therapy clinically
more useful? A meta-analytic study. Journal of affective
disorders, 65(2), 173-7.
Second Generation
Antidepressants
Second Generation
Antidepressants
Duloxetine (Cymbalta):
Buproprion (Wellbutrin):
– Low rate of sexual side effects or wt gain,
– Assoc. w/ increased rate of seizures, not
for pts w/ eating d/o or prior sz d/o
– mixed NE and 5HT activity,
– Alleviates pain of diabetic neuropathy and
fibromyalgia
Kajdasz DK et al, Clin
Ther 2007;29 Suppl:
2536-2546.
4
Second Generation
Antidepressants
Mirtazapine (Remeron):
– sedation and weight gain
Second Generation
Antidepressants
Second Generation
Antidepressants
Nefazodone (Serzone):
–  5-HT2 blocker, ?for anxious depression
–  black box for liver failure (1/250K pt-yrs)
–  low rate of sexual se s
Second Generation
Antidepressants
Trazodone (Desyrel):
–  usually prescribed as a hypnotic
–  Warn about priapism
Venlafaxine (Effexor):
–  Mixed NE and 5HT activity
–  increases BP
–  similar side effect profile to ssri s
–  significant withdrawal syndrome
5
Tricyclic Antidepressants
(TCA s )
•  NE reuptake inhibitors
•  anticholinergic side effects,
orthostatic hypotension, tremor,
weight gain, sexual side effects,
•  cardiac conduction delay (quinidine
like effect)
Note: Duloxetine, a newer dual action antidepressant, has more equal 5HT
and NE effects across its dosage range.
Monoamine-oxidase inhibitors
(MAOIs)
Who was
Libby
Zion?
http://en.wikipedia.org/wiki/Libby_Zion
Examples [not a complete list]: amitriptyline (Elavil),
doxepin (Sinequan), imipramine (Tofranil),
desipramine (Norpramin), nortriptyline (Pamelor,
Aventyl), maprotiline (Ludiomil)
Prevalence of MAOI usage
Psychiatrists who had
prescribed MAOIs
Percentage
(N=573)
Never
12
Not for at least three years
27
Between one to three years ago 17
Between three and 12 months
ago
14
Within last 3 months
30
Balon R et al. A Survey of Prescribing Practices for Monoamine
Oxidase Inhibitors. Psychiatric Services 50:945–947, 1999.
6
Monoamine-oxidase inhibitors
(MAOIs)
Important: dietary restrictions! (b/o
hypertensive crisis)
Also drug-drug interactions
Side effects: sedation, sexual side
effects, weight gain
phenelzine (Nardil), trancylopramine (Parnate),
[selegiline (Eldepryl) for Parkinson s]
MAOI Summary
Make sure you look up dietary
restrictions!
MAOI Diet
•  Avoid:
–  aged cheese
–  aged or cured meats (e.g., air-dried sausage);
–  any potentially spoiled meat, poultry, or fish;
–  broad (fava) bean pods;
–  Marmite concentrated yeast extract;
–  sauerkraut; soy sauce and soy bean
condiments;
–  and tap beer.
•  Wine and domestic bottled or canned beer are
considered safe when consumed in moderation.
•  Refer to article and give handout to patient
J Clin Psychiatry 1996 Mar;57(3):99-104 . The making of a user
friendly MAOI diet.
Antidepressants
•  SSRI s
•  SGA ( Other )
•  Tricyclics
•  MAOI s
7
Outline
•  Current Controversies
•  Overview of Antidepressants
•  Antidepressants: Selection and
Side Effect Management
– Sedation
– Sexual Dysfunction
– Weight Gain
•  Non-pharmacological treatments
•  Osteoporosis, GI bleeding , QTc and
Suicide
•  Questions and Summary
As you write that Rx…
•  Patients told to stay on ADs for at
least 6 months were three times
more likely to continue their meds
•  Discussing side effects was also
associated with staying the course
longer
Bull SA et al. Discontinuation of use and switching of
antidepressants: influence of patient-physician
communication. JAMA 2002;288 (11):1403-1409.
Case Vignette
Depressed for 2 months, No medical
problems, No comorbidities
Which ONE of the following is the best
medication intervention?
a.  Bupropion 150mg twice daily
b.  Duloxetine 40mg daily
c.  Fluoxetine 20mg daily
d.  Imipramine titrated up to 100mg at
bedtime
e.  Venlafaxine 300mg daily
How to pick
antidepressant?
8
Current evidence does not warrant the
choice of one … antidepressant over
another on the basis of differences in
efficacy and effectiveness.
Other differences with respect to onset
of action and adverse events may be
relevant for the choice of a
medication.
Gartlehner et al. Comparative Benefits and Harms of Second-Generation
Antidepressants. Ann Intern Med. 2008;149:734-750.
Do No Harm
Choosing an Antidepressant is Not
Based on Efficacy?
Clinically important differences exist …for
both efficacy and acceptability in favour
of escitalopram and sertraline.
Sertraline might be the best choice…
Cipriani et al. Comparative efficacy and acceptability of 12
new-generation antidepressants: a multiple-treatments
meta-analysis. Lancet 2009; 373: 746–58.
How to pick antidepressant?
SSRI s and SGA s
Safer than:
Tricyclics
MAOI s
•  Patient preference
•  Patient or Family history of response
•  Clinician familiarity
•  Comorbidities--Side effect profile
9
The Maze of Mood Medications
The person who takes medicine
must recover twice, once from
the disease and once from the
medicine.
Attributed to William Osler, MD
Of 401 out- patients taking SSRIs:
Most Common
Most Bothersome
drowsiness (38%)
dry mouth (34%)
sexual dysfunction
(34%)
drowsiness (17%)
sexual dysfunction
(17%)
weight gain (11%)
N.B. Good side effect management
means good follow-up!
How do you choose?
Food
– Fast
– Good
– Cheap
Meds
– Sedation
– Sexual dysfunction
– Weight gain
– (Cheap)
Choosing an Antidepressant
Side Effects
• Sedation/activation
• Sexual dysfunction
• Weight gain
• (Cost)
Hu, X H, Bull, S A, Hunkeler, E M, et al. (2004). Incidence and duration of side effects
and those rated as bothersome with selective serotonin reuptake inhibitor treatment for
depression: patient report versus physician estimate. J Clin Psychiatry, 65(7), 959-65.
10
Case Vignette
No medical problems
Depressed for 2 months
Hypersomnia
Insomnia or anxious
Relative activation vs. Sedation
modern antidepressants
Activating
psychostimulants
Bupropion
Fluoxetine, Sertraline
Neutral or
mixed
Mildly to
Moderately
Sedating
Strongly
sedating
Venlafaxine, Escitalopram
Citalopram
Paroxetine, Fluvoxamine
Nefazodone
Tricyclics
Trazadone
Mirtazapine
Kelly, K, Posternak, M, & Alpert, J E. (2008). Toward achieving optimal response:
understanding and managing antidepressant side effects. Dialogues in clinical
neuroscience, 10(4), 409-18.
Sedation Management
Strategies
•  Review other meds
•  Switch from am to hs dosing
•  Reduce dosage
•  Switch to another AD
•  ?Consider psychostimulant:
methylphenidate or
dextroamphetamine or modafinil
(this is off-label)
Choosing an Antidepressant
Side Effects
• Sedation/activation
• Sexual dysfunction
• Weight gain
• (Cost)
Fava M et al, Ann Clin Psychiatry 2007;19
(3):153-159.
11
Case Vignette
No medical problems
Depressed for 2 months
Sexual dysfunction is common
•  Women: 43% total, 22% low libido,
14% sexual arousal problems, 7%
pain
•  Men: 31% total, 21% premature
ejaculation, 5% erectile dysfunction,
5% low libido
Remember to ask about sexual
functioning beforehand
Fears loss of libido
Laumann EO et al, JAMA 1999;281(6):537-544.
SEXUAL DYSFUNCTION
Effect on sexual functioning
Increased?
Neutral or
mixed
DEPRESSION
DECREASED
LIBIDO
AROUSAL
DISORDER
Segraves. J Clin Psychiatry Monogr. 1993.
ANTIDEPRESSANT
ORGASM
DYSFUNCTION
Common
Psychostimulants
Bupropion
Nefazadone
Mirtazapine
Duloxetine
Tricyclics
Maoi’s
Ssri’s,Venlafaxine
Kelly, K, Posternak, M, & Alpert, J E. (2008). Toward achieving optimal response:
understanding and managing antidepressant side effects. Dialogues in clinical
neuroscience, 10(4), 409-18.
12
Sexual Dysfunction Strategies
Dose reduction
Timing of sexual activity
Drug holiday
Anti-dote therapy: (off-label)
Sexual Dysfunction Strategies
anti-dote therapy: (off-label)
buspirone 45mg qd
dopamine (DA) agonists: amantadine
bupropion 300mg qd
α2-adrenergic receptor antagonists: yohimbine
psychostimulants: methylphenidate 5-20mg
PDE-5 inhibitors: Sildenafil 50-100mg qd
Choosing an Antidepressant
Side Effects
• Sedation/activation
• Sexual dysfunction
• Weight gain
• (Cost)
Case Vignette
No medical problems
Depressed for 2 months
Obesity
Weight loss
13
Impact on weight
Weight loss
(?)
Neutral or
mixed
mild to
moderate
Significant
psychostimulants
Bupropion
Nefazadone
Ssri’s (fluoxetine <
paroxetine)
Weight Management strategies
Maoi’s
Tricyclics
mirtazapine
Kelly, K, Posternak, M, & Alpert, J E. (2008). Toward achieving optimal response:
understanding and managing antidepressant side effects. Dialogues in clinical
neuroscience, 10(4), 409-18.
Sample Year End Diary Entry
Alcohol units 3836 (poor)
Cigarettes 5277
Calories 11,090,265 (repulsive)
Fat units 3457 (approx.) (hideous idea in
every way)
Weight gained 74 lbs.
Weight lost 72 lbs (excellent)
Bridget Jones Diary, by Helen Fielding. Penguin Books 1996.
Weight Management strategies
(off label)
Life style interventions :
Eat healthy, exercise more
Get the right amount of sleep and reduce
stress*
Address dry mouth
Switch or add bupropion
Add psychostimulants
*Elder, C R, Gullion, C M, Funk, K L, et al. (2011). Impact of sleep,
screen time, depression and stress on weight change in the
intensive weight loss phase of the LIFE study. International
journal of obesity, 2011 Mar 29. [Epub ahead of print]
14
Weight Management strategies
(Off-Label)
•  Sibutramine (Meridia): removed from
US market b/o CV risks
•  Orlistat (Xenical): 120mg tid w meals
•  Bupropion + Naltrexone (Contrave):
also rejected b/o increased P and BP
(N16mg+B200mg BID)
•  Metformin, studied in patients on
atypical antipsychotics
•  Topiramate 100-150mg daily
Choosing an Antidepressant
Side Effects
• Sedation/activation
• Sexual dysfunction
• Weight gain
• Cost
Cost of some psychiatric meds
Case Vignette
No medical problems
Depressed for 2 months
No money
Drug & Strength
#
Budeprion XL 150MG Tabs
180 $295.93
Cost
$1.64
Wellbutrin SR 150MG Tab
180
$651.00
$3.62
Clonazepam 2mg tab
90
$23.99
$0.27
Citalopram Hydrobromide 20mg Tab 90
$89.97
$1.00
Diazepam 5mg tab
90
$13.97
$0.16
Escitalopram 10MG Tab
90
$314.97
$3.50
Fluoxetine HCl 20MG Cap
90
$50.97
$0.57
Mirtazapine 15mg Tab, 30mg
90
$149.98
$1.67
Sertraline HCl 100MG Tab*
90
$29.97
$0.33
Venlafaxine HCl 75mg Cap
90
$168.97
$1.88
Zolpidem Tartrate 10mg tab
90
$45.97
$0.51
Unit cost
from Drugstore.com 7/16/11, prices subject to change,
about 50% cheaper than local drugstore
*Descartes Li – Best Buy!
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Outline
•  Current Controversies
•  Overview of Antidepressants
•  Antidepressants: Selection and Side
Effect Management
•  Non-pharmacological treatments
•  Osteoporosis, GI bleeding, QTc and
Suicide
•  Questions and Summary
Case Vignette
Depressed for six
months
No medical hx, no
comorbidities
Wants meds, should
you recommend
psychotherapy?
No.
Case Vignette
Depressed for six
months
No medical hx, no
comorbidities
Wants
psychotherapy,
but can t afford
it
Okay to prescribe
meds? Yes
Mergl et al. Are treatment preferences relevant in response to serotonergic
antidepressants and cognitive-behavioral therapy in depressed primary care
patients? Results from a randomized controlled trial including a patients' choice
arm. Psychother Psychosom 2011;80:39-47.
Other options
•  Psychotherapy
•  Bibliotherapy
•  Self-help organizations
•  Exercise
•  Light therapy
•  Complementary/alternative
medications
Mergl et al. Are treatment preferences relevant in response to serotonergic
antidepressants and cognitive-behavioral therapy in depressed primary care
patients? Results from a randomized controlled trial including a patients' choice
arm. Psychother Psychosom 2011;80:39-47.
16
Bibliotherapy
• Feeling Good, by David Burns
Self Help
organizat
ions
• Mind Over Mood, by
Greenberger and Padefsky
Outline
•  Current Controversies
•  Overview of Antidepressants
•  Antidepressants: Selection and Side
Effect Management
•  Non-pharmacological treatments
•  Osteoporosis, GI bleeding, QTc
and Suicide
•  Questions and Summary
GI Bleeding
17
SSRIs and GI bleeding
What s the bottom line?
•  Two potential mechanisms: platelet
aggregation, gastric acidity
•  Overall risk is low: 1 per 8000 SSRI
prescriptions
•  Associated also with increased blood
loss during surgical procedures.
•  TCAs, mirtazapine, and bupropion
NOT associated with bleeding
You should mention this risk in the
following situations:
•  history of stomach ulcers or bleeding
disorders.
•  about to have surgery (consider
stopping SSRI a few days in
advance).
•  taking NSAIDs, aspirin, warfarin, or
antiplatelet drugs (clopidogrel).
SSRIs and osteoporosis
Osteoporosis
Two observational studies in Archives of Internal
Medicine:
Women on SSRIs lost double the bone
density of those either on tricyclics or on no
antidepressants
Diem SJ et al., 2007;167(12):1240-1245.
Haney EM et al. 2007;167(12):1246-1251.
18
SSRIs and osteoporosis
More recent study, with longer followup, found association with:
• wrist fracture (HR = 1.30, 95% CI
1.04–1.62),
The bottom line
Warn your elderly patients about
osteoporosis, even though the
findings are still preliminary.
• but not with first hip fracture (HR =
1.01, 95% CI 0.71–1.44)
Diem SJ et al. Use of Antidepressant Medications and Risk
of Fracture in Older Women. Calcif Tissue Int (2011)
88:476–484.
QTc and Citalopram
QTc and Citalopram
trial of 119 adults showed that QTc is
increased in a dose-dependent
fashion with citalopram
http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm
Dosage
QT prolongation
CI (msec)
20mg
8.5msec
6.2-10.8
60mg
18.5msec
16.0-21.0
40mg
12.6msec
inferred
19
Bottom Line
•  Check EKG before you go higher than
40mg, then again after they have been
on a higher dose
•  If they're already on a higher dose,
just check the EKG
•  If QTc in men over 450 and women
over 500, consider decreasing dosage
or switching to escitalopram
•  Review other risk factors for increased
QTc
Antidepressants and Suicide
Risk
Suicide Risk and
Antidepressants
Suicide Risk and
Antidepressants
•  In 2004, FDA issued a black box
warning for children and adolescents
warning of a risk of suicidal events.
•  In 2007, another black box warning
issued for adults up to 25 years of
age. (based on an odds ratio, 1.55; 95%
Furthermore, benefit of
antidepressants in pediatric patients
is controversial
confidence interval, 0.91 to 2.70)
Bridge JA et al. Clinical response and risk for reported suicidal
ideation and suicide attempts in pediatric antidepressant
treatment: a meta-analysis of randomized controlled trials.
JAMA 2007;297:1683-1696.
Friedman RA and Leon AC. Expanding the black box depression, antidepressants, and the risk of suicide. NEJM
2007 Jun 7;356(23):2343-6. Epub 2007 May 7.
20
Suicide Risk and
Antidepressants
Increase in suicidal ideation in children
up to age 18, but not actual suicide.
Probably suicide neutral or slightly
beneficial in 25-65 yr age range
Hammad et al. Suicidality in pediatric patients treated with
antidepressant drugs. Arch Gen Psychiatry
2006;63:332-339.
Stone M et al. Risk of suicidality in clinical trials of
antidepressants in adults: analysis of proprietary data
submitted to US Food and Drug Administration. BMJ 2009
Aug 11;339:b2880.
Bottom line
Odds Ratios for Suicidal Behavior and Ideation among Patients Treated
with Antidepressants for Psychiatric Indications, as Compared with
Placebo.
Data are from the Summary Comments of the December 13, 2006, meeting
of the FDA's Psychopharmacologic Drugs Advisory Committee. CI denotes
confidence interval.
Questions
In younger patients (<25years)
•  Suicide risk is increased
•  Risk decreases with increasing age
•  Warn younger patients (and their
families) to monitor for increased
suicidality
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Outline
•  Current Controversies
•  Overview of Antidepressants
•  Antidepressants: Selection and Side
Effect Management
•  Non-pharmacological treatments
•  Questions
•  Summary (Good Side Effect
Management means good follow
up)
22