PATIENT FILE
The Case: The man whose antidepressants stopped working
The Question: Do depressive episodes become more difficult to treat and
more recurrent over time?
The Dilemma: When can you stop antidepressant treatment and what do
you do if medications that worked in the past no longer work?
Pretest Self Assessment Question (answer at the end of the case)
When should antidepressant maintenance become indefinite?
A. Following remission from one episode of major depression
B. Following remission from two episodes of major depression
C. If there is a particularly severe episode or one with suicidality,
especially if a positive family history for depression
D. Following remission from three episodes of major depression
E. On a case by case basis
Patient Intake
• 63-year-old man with the worst depression and anxiety he has ever
felt
Psychiatric History: First Episode
• Age 42, became depressed and anxious after his episode of atrial
fibrillation
• Felt vulnerable and afraid of death
• After his hospitalization for atrial fibrillation, which resolved with
medications, he felt depression, anxiety, “butterflies in his stomach”
and felt like his whole body was “plugged into an electrical circuit”
• Began having suicidal thoughts
• This episode also coincided with the death of his mother
• Treatment with alprazolam (Xanax) and clonazepam (Klonopin): no
improvement
• Sertraline (Zoloft) treatment 100 mg/day and he was much improved
within 2–3 months, functioning normally at work but had sexual side
effects
• Felt totally normal after 6 months and discontinued sertraline
Social and Personal History
• Married 33 years, 3 children
• Non smoker
• No drug or alcohol abuse
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PATIENT FILE
Medical History
•
•
•
•
•
Atrial fibrillation age 42, resolved with medication
Hypercholesterolemia
BP normal
BMI normal
Normal fasting glucose and triglycerides
Family History
•
•
•
•
Mother: depression and alcohol abuse
Maternal uncle: alcohol abuse
Son: depression
Daughters: one with mild depression, one with postpartum
depression
Medications One Year Following the First Episode of Depression
•
•
•
•
Antiarrhythmic
Statin for cholesterol
Antihypertensive
Aspirin
Psychiatric History: Second Episode
• Relapsed into his second episode of major depression at age 52, 10
years after his first episode and 9 ½ years after stopping sertraline
• Symptoms same as last time
• Fear, anxiety, depression, “plugged into a circuit”
• Suicidal thoughts
• Symptoms worse in the morning
• Unable to function and wife had to drive him to work for 3 months
• Depression could have been triggered in part by his taking partial
early retirement just before this episode, and feeling vulnerable again
and worried about whether this meant his life was over
• For some reason, not given sertraline again at first, but paroxetine
(Paxil) which showed no benefit
• Switched to sertraline 150 mg/day with supplemental clonazepam
(Klonopin) prn anxiety, and symptoms resolved within 2–3 months
but with recurrent sexual dysfunction, same as the first time
• Discontinued sertraline after 1 year
Psychiatric History: Third Episode
• Relapsed into a third episode of major depression at age 58, 6 years
after his last episode, and 5 years after stopping sertraline the second
time
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PATIENT FILE
• Symptoms exactly the same again, with fear, anxiety, suicidal
thoughts, unable to function, symptoms worse in the morning
• Was not started on sertraline again because of prior sexual
dysfunction, but given bupropinon SR (Wellbutrin SR), but no
improvement after 8 weeks
• Added sertraline again, and helped after 8 weeks (completely normal)
and stopped bupropion but continued sertraline for a year and then
discontinued it
Psychiatric History: Fourth Episode
• Relapsed into a fourth episode of major depression at age 61, 3 years
after his last episode and 2 years after discontinuing sertraline for the
3rd time
• The patient had gone back to work, had been very successful again,
and retired again
• Brought up worries about his mortality again
• However, doing volunteer work and this helps a bit
• This time, given venlafaxine XR (Effexor XR) and this worked even
faster than before and he did not have sexual dysfunction, but
discontinued it after less than a year
Based on just what you have been told so far about this patient’s history
and recurrent episodes of depression, do you think it was a mistake to
allow him to discontinue his antidepressant after
– this last fourth episode?
– after his third episode?
– after his second episode?
Psychiatric History: Fifth Episode
• Patient has been suffering with fifth episode for 15 months
• New psychosocial factors from marital difficulties seem to have
triggered this episode
• Same symptoms as before
• The referring psychiatrist has given venlafaxine 75–150 mg, which
worked for his last (fourth) episode, but no response this time to 8
weeks of treatment at this dose, plus another 8 weeks at 375 mg/day
(4 months total treatment)
• This is very atypical for him, where antidepressants worked quickly
and robustly in the past
• Has severe psychomotor retardation and strong thoughts but no
active plans for suicide
• For months 5 through 11, venlafaxine was augmented with
– Dextroamphetamine (Dexedrine) 20 mg/day
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PATIENT FILE
•
•
•
•
•
– Buspirone (Buspar) 30 mg/day
– Clonazepam 2 mg in the morning and 2 mg at night
– Lorazepam (Ativan) 2 mg in the morning and 2 mg at night
This treatment regimen associated with only a partial response,
and continuing depression, anxiety, guilt, hopelessness and suicidal
ideation
Switched the venlafaxine back to sertraline 200 mg/day which had
worked in the past, along with continuing the same augmentation
medications above, but no response for months 12 through 15 of
treatment of this fifth episode
He seems to have developed treatment resistant depression
Would this have happened in any event, or could this have been
prevented by earlier maintenance treatment?
He now presents to you 15 months into his fifth episode of major
depression, not responding to standard treatments
Attending Physician’s Mental Notes: Initial Psychiatric
Evaluation
• Patient has been suffering through fifth episode of depression for 15
months
• Here is a case that indeed is linked to psychosocial stressors, but
seems to have new episodes of depression coming closer and closer
together following discontinuation of his antidepressant
• First recurrence 9½ years after stopping sertraline the first time
• Second recurrence 5 years after stopping sertraline the second time
• Third recurrence 2 years after stopping sertraline the third time
• He is now here only a year after stopping his venlafaxine following his
fourth episode of depression
• Treatment guidelines are consistent with discontinuing antidepressants
9 to 12 months after remission from a first episode of depression,
with long term maintenance after the second episode reserved
perhaps for very severe cases. Clearly the third episode of major
depression should be treated indefinitely with antidepressant
maintenance, and no doubt, after a fourth episode, indefinite
antidepressant maintenance is indicated
• One wonders if the fourth episode and the current fifth episode could
have been prevented if he had been treated in maintenance after his
third episode
• Now, attending physician is a bit worried that the medications will not
work as well this time
• Perhaps changes have occurred in the brain, with shrinkage of the
hippocampus and/or prefrontal cortex due to 4 previous and now
a fifth episode of depression, and that might make the current fifth
episode very difficult to treat
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PATIENT FILE
• Is this the natural history of treatment resistant depression in the
making?
How would you treat him?
–
–
–
–
–
–
–
–
–
Increase the dose of dextroamphetamine
Increase the dose of buspirone
Augment with bupropion
Augment with L-methylfolate (Deplin), or thyroid or SAMe
Augment with an atypical antipsychotic, especially aripiprazole or
quetiapine
Refer for TMS
Refer for ECT
Augment with mirtazapine (Remeron)
Switch to an MAOI
Attending Physician’s Mental Notes: Initial Psychiatric
Evaluation, Continued
• Has not responded to bupropion in the past, and not clear his
buspirone or amphetamine is helpful, and he does not need two
different benzodiazepines
• Maybe too treatment resistant for a natural product
• He has anxiety and is quite depressed, so suggest an anxiolytic/
sedating/sleep inducing antidepressant like mirtazapine, while
discontinuing his dextroamphetamine, buspirone, and consolidating
his two benzodiazepines into one
• Could have added an atypical antipsychotic, but because of his
cardiovascular status, patient wished to try mirtazapine first
• Patient willing to do all of this but discontinue his amphetamine,
although he does agree to reduce the dose
• Mirtazapine 15 mg/day added and given at night
• Lorazepam discontinued and clonazepam increased to 2.5 mg in the
morning and 1 mg at night
• Buspirone discontinued
• Dextroamphetamine decreased to 10 mg/day in the morning
Attending Physician’s Mental Notes: First Interim Followup,
Month 18 (3 months after initial psychiatric evaluation)
• Referring psychiatrist maintained the above medication treatment,
and patient finally started feeling better at month 18, which the patient
attributed to sertraline
• Far from well yet
• Feels worst in the morning, his usual pattern (disorganized, lacking
energy, anxious)
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PATIENT FILE
• Suggested his mirtazpine dose be increased and to add quetiapine
(Seroquel)
• Maintained sertraline 200 mg/day
• Increased mirtazapine to 30 mg/day at night
• Maintained dextroamphetamine 10 mg in the morning
• Maintained clonazapem 2.5 mg in the morning and 1 mg at night
• Added quetiapine, tapered up to 300 mg/day
Attending Physician’s Mental Notes: 2nd Interim Followup,
Month 22
• Referring psychiatrist maintained the above medication treatment, but
no improvement
• Still very depressed in the morning
• Recommended starting MAOI
• Washed out of sertraline, mirtazapine, dextroamphetamine
• Continued clonazapam, quetiapine
• MAOI started in 7 days (equals 7 half lives of sertraline, mirtazapine;
only 5 half life washout of these is required before starting an MAOI)
• Transdermal selegilene 6 mg/24 hours prescribed
Attending Physician’s Mental Notes: 3rd Interim Followup,
Month 24
• Referring psychiatrist made the changes suggested above, but
discontinued quetiapine because of excessive daytime sedation and
some initial worsening of psychomotor retardation
• No side effects attributable to transdermal selegilene
• 4–5 weeks after starting MAOI, began to feel better
• Now he looks, if anything, a bit hypomanic, but upon close
examination, patient is somewhat exhuberant about getting well,
having waited 2 years to respond from this fifth episode
• Let’s hope he does not stop his antidepressant this time
Case Debrief
• The patient has a 13 year history of recurrent unipolar major depressive
episodes
• His first 4 episodes were readily treated to full remission and he
discontinued treatment each time several months to a year after remitting
• His subsequent episodes came in an ever escalating pattern, with less
and less time between them
• By the time of his fifth episode, he had become treatment resistant, and
took two years to get better
• He responded to a single action agent several times (SSRI), then a dual
action agent the fourth time (SNRI) and finally, after failing SSRI and SNRI
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PATIENT FILE
treatment plus multiple augmentation strategies the fifth time, required an
MAOI
Take-Home Points
• Major depression can be recurrent, and recurrences can possibly
indicate disease progression potentially manifested as shorter and
shorter periods of wellness between subsequent episodes, with
eventually poor interepisode recovery, and ultimately, treatment
resistance
• This may be linked to changes in brain structure and neurotrophic
factors
• Patients with 3 or more episodes of depression should be treated
indefinitely with antidepressant maintenance
• Antidepressant-induced sexual dysfunction can be a powerful reason
to discontinue antidepressants, despite the risks of recurrence and
treatment resistance
Performance in Practice: Confessions of a
Psychopharmacologist
• What could have been done better here?
– There is no question the patient should have been treated with
maintenance antidepressants after his third episode of depression,
possibly preventing his fourth and fifth episodes, and possibly
preventing the development of treatment resistance
– The patient was very religious and did not believe in
psychotherapy, but perhaps more efforts should have been made
to get him into psychotherapy to deal with his issues about his
own mortality and his reactions to psychosocial stressors
• Possible action item for improvement in practice
– Make a concerted effort to see that patients with recurrent
episodes of major depression and who need maintenance
treatment are not lost to followup
Tips and Pearls
• MAO inhibitors have fallen out of favor in the United States and are
not used at all in many countries
• These agents remain powerful alternatives for cases like this one,
with treatment resistance
• Some myths about dangers, side effects, diet and drug interactions
regarding MAOIs can be dispelled with re-study of the facts about
these agents, such as those shown below
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PATIENT FILE
Two-Minute Tute: A brief lesson and psychopharmacology
tutorial (tute) with relevant background material for this case
– How MAOIs work
– Tips on how to use MAOIs
– Brain changes in recurrent depression
– See also Case 10, Two Minute Tute, p 113
Table 1: Currently approved MAO inhibitors
Name (trade name)
Inhibition of
MAO- A
Inhibition of
MAO-B
Amphetamine
properties
phenelzine (Nardil)
+
+
tranylcypromine (Parnate)
+
+
isocarboxazid (Marplan)
+
+
amphetamines (at high doses)
+
+
+
brain
+
+
+
gut
+/-
+
+
selegiline low dose oral (Deprenyl, Eldepryl)
–
+
+
rasaligine (Agilect/Azilect)
–
+
–
moclobemide (Aurorix, Manerix)
+
–
–
+
selegiline transdermal system (Emsam)
Table 2: MAO inhibitors with amphetamine actions or amphetamines
with MAO inhibitions
Drug
Comment
amphetamine
MAOI at high doses
tranylcypromine (Parnate)
also called phenylcyclopropylamine, structurally related to
amphetamine
Selegiline
metabolized to L-methamphetamine
metabolized to L-amphetamine
less amphetamine formed transdermally
Table 3: MAO enzymes
Substrates
MAO-A
MAO-B
5-HT
Phenylethylamine
NE
DA
DA
Tyramine
Tyramine
Tissue distribution
Brain, gut, liver, placenta, skin
Brain, platelets, lymphocytes
Table 4: Suggested tyramine dietary modifications for MAO inhibitors*
Food to avoid
Dried, aged, smoked, fermented, spoiled,
or improperly stored meat, poultry, and fish
Broad bean pods
Aged cheeses
cheese, yogurt
Tap and nonpasteurized beers
Food allowed
Fresh or processed meat, poultry, and fish
All other vegetables
Processed and cottage cheese, ricotta
Canned or bottled beers and alcohol (have
little tyramine)
Brewer’s and baker’s yeast
Marmite, sauerkraut
Soy products/tofu
*No dietary modifications needed for low doses of transdermal selegiline or for low oral doses of
selective MAO-B inhibitors.
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PATIENT FILE
MAO-A
destroying NE
A
inactive
substance
NE
NE transporter
(NET)
A
MAO-A
destroying NE
no vasoconstriction
no ↑ BP
alpha 1
receptors
Figure 1: Normal NE Destruction
Tyramine, as in cheese,
increases the release
of NE (1) and the
excess is destroyed
by MAO-A (2)
in NE neurons
22
A
1
1
22
1
NE transporter
(NET)
A
no vasoconstriction
no BP
alpha 1
receptors
= 40mg high
tyramine meal
12–69
Figure 2: Tyramine increases norepinephine release
Here, the tyramine
increases the release of
NE(1) and the irreversible
MAO-A enzyme to stop
destroying NE(2).
This increase in
NE(3) can lead
to dangerous
elevations of
blood pressure.
2
MAO-A inhibitor
stops the enzyme
from destroying NE
A
2
2
2
A
NE transporter
(NET)
3
alpha 1
receptors
vasoconstriction
and hypertension
Figure 3: Inhibition of MAO-A and tyramine
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PATIENT FILE
Table 5: Potentially dangerous hypertensive combos: agents when
combined with MAOIs that can cause hypertension (theoretically via
adrenergic stimulation)
Decongestants
phenylephrine (alpha 1 selective agonist)
ephedrine* (ma huang, ephedra) (alpha and beta agonist; central NE and DA releaser)
pseudoephedrine* (active stereoisomer of ephedrine – same mechanism as ephedrine)
phenylpropanolamine* (alpha 1 agonist; less effective central NE/DA releaser than ephedrine)
Stimulants
amphetamines
methylphenidate
Antidepressants with NRI (norepinephrine reuptake inhibition)
TCAs
NRIs
SNRIs
NDRIs
Appetite suppressants with NRI
sibutramine*
phentermine
*withdrawn from markets in the United States and some other countries
Table 6: Potentially lethal combos: agents when combined with MAOIs
that can cause hyperthermia/serotonin syndrome (theoretically via
SERT inhibition)
Antidepressants
SSRIs
SNRIs
TCAs (especially clomipramine)
Other TCA structures
cyclobenzaprine
carbamazepine
Appetite suppressants with SERT inhibition
sibutramine*
Opioids
dextromethorphan
meperidine
tramadol
methadone
propoxyphene
*withdrawn from markets in the United States and some other countries
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PATIENT FILE
Table 7: Tyramine content of cheese
Cheese
mg per 15g
serving
English
STILTON
17.3
Kraft®
grated
PARMESAN
0.2
Philadelphia®
CREAM
CHEESE
0
Table 8: Tyramine content of commercial chain pizza
mg per
serving
Serving
1/2 medium
double cheese,
double
pepperoni
1.378
TM
1/2 medium
double cheese,
double
pepperoni
0.063
1/2 medium
double cheese,
double
pepperoni
0
Table 9: Tyramine content of wine
Wine
mg per 4-oz
serving
Ruffino
CHIANTI
0.36
Blue Nun®
WHITE
0.32
Cinzano
VERMOUTH
0
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PATIENT FILE
Table 10: Are brain changes progressive in depression?
• A frontal-limbic function disconnection is present in depression
and correlates with the duration of the current depressive
episode
• Hippocampal volume loss is greater with longer periods of
untreated depression
• The likelihood that a life stress precipitates a depressive episode
is greatest for the first episode of depression and declines with
each subsequent episode, although the risk of subsequent
episodes increases as though prior episodes of depression as
well as life stressors are causing subsequent episodes
• More episodes as well as residual symptoms both predict poorer
outcome in terms of more relapses
• Antidepressants may boost trophic factors, normalize brain
activity, suggesting that successful and early treatment may
attenuate progressive maladaptive brain changes and improve
the clinical course of the illness
• Symptomatic remission may be the clinician’s benchmark for
enhancing the probability of arresting disease progression
• Sustained remission may be a clinician’s benchmark for
reversing the underlying pathophysiology of major depression
Posttest Self Assessment Question: Answer
When should antidepressant maintenance become indefinite?
A. Following remission from one episode of major depression
– Guidelines suggest this is not necessary unless particularly severe
and other risk factors such as suicidality and a highly positive
family history
B. Following remission from two episodes of major depression
– This is ambiguous, with non complicated cases not requiring
indefinite maintenance but complex, severe or suicidal cases
probably needing maintenance
C. If there is a particularly severe episode or one with suicidality,
especially if a positive family history for depression
– Yes
D. Following remission from three episodes of major depression
– Definitely yes
E. On a case by case basis
– No, should be more systematic than this as shown in the answers
above
Answer: C and D
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PATIENT FILE
References
1. Stahl SM, Mood Disorders, in Stahl’s Essential
Psychopharmacology, 3rd edition, Cambridge University Press, New
York, 2008, pp 453–510
2. Stahl SM, Antidepressants, in Stahl’s Essential
Psychopharmacology, 3rd edition, Cambridge University Press, New
York, 2008, pp 511–666
3. Stahl SM, Selegilene, in Stahl’s Essential Psychopharmacology The
Prescriber’s Guide, 3rd edition, Cambridge University Press, New
York, 2009, pp 489–96
4. Stahl SM, Sertraline, in Stahl’s Essential Psychopharmacology The
Prescriber’s Guide, 3rd edition, Cambridge University Press, New
York, 2009, pp 497–502
5. Stahl SM, Venlafaxine, in Stahl’s Essential Psychopharmacology The
Prescriber’s Guide, 3rd edition, Cambridge University Press, New
York, 2009, pp 579–584
6. Trivedi MH, Rush AJ, Wisniewski SR et al. Evaluation of outcomes
with citalopram for depression using measurement-based care in
STAR*D: implications for clinical practice. Am J Psychiatry 2006;
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7. Rush AJ, Trivedi MH, Wisniewski SR et al. Bupropion-SR, sertraline,
or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med
2006; 354(12): 1231–42
8. Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longerterm outcomes in depressed outpatients requiring one or several
treatment steps: a STAR*D report. Am J Psychiatry 2006; 163:
1905–17
9. Warden D, Rush AJ, Trivedi MH et al. The STAR*D Project results: a
comprehensive review of findings. Curr Psychiatry Rep 2007; 9(6):
449–59
10. Judd LL, Akiskal HS, Maser JD et al. Major depressive disorder: a
prospective study of residual subthreshold depressive symptoms as
predictor of rapid relapse. J Affect Disord. 1998; 50(2–3): 97–108
11. Kendler KS, Thornton LM, Gardner CO Stressful life events and
previous episodes in the etiology of major depression in women: an
evaluation of the “kindling” hypothesis. Am J Psychiatry 2000; 157:
1243–51
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