Transcript Antidepressant Augmentation Strategies: what is the

Antidepressant Augmentation
Strategies in Unipolar Depressive
Disorders:
What is the evidence base?
David L. Fogelson, M.D.
Clinical Professor of Psychiatry
David Geffen School of Medicine at UCLA
Department of Psychiatry and Biobehavioral Sciences
Augmentation Strategies
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Pharmaceuticals with and without FDA
indication for antidepressant
augmentation
Nutraceuticals
Psychostimulation
Psychotherapy
Principles of Pharmacotherapy
Management
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Diagnostic assessment: suicidality, bipolarity, co-morbidity,
concomitant medications, and special features (psychosis,
atypical features, seasonality).
Laboratory assessment: Dx concerns; Drug monitoring
Never medication alone: patient education, compliance issues,
self-management techniques, psychotherapy
Acutely, monitor every 1–4 weeks, period of greatest risk.
Depending on severity and response, follow up every 2–4
weeks or longer.
Monitoring requires routine use of validated outcome scales.
– HAMD
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Antidepressant selection individualized: symptom profile,
comorbidity, tolerability profile, previous response, potential
drug–drug interactions, patient preference, and cost.
2009 Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical
Guidelines for the Management of Major Depressive Disorder in Adults.
I. Classification, Burden and Principles of Management
Scott B. Patten et al, Journal of Affective Disorders 117 (2009) S5–S14
Criteria for Level of Evidence
and Line of Treatment
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Level Criteria
1 • At least 2 RCTs with adequate sample sizes, preferably
placebo-controlled, and/or meta-analysis with narrow
confidence intervals
2 • At least 1 RCT with adequate sample size and/or metaanalysis with wide confidence intervals.
3 • Non-randomized, controlled prospective studies or case
series or high quality retrospective studies.
4 • Expert opinion/consensus.
Line of Treatment Criteria
 First-line • Level 1 or Level 2 evidence, plus safety and
clinical judgment considerations
 Second-line • Level 3 evidence or higher, plus safety &
clinical
 Third-line • Level 4 evidence or higher, plus safety & clinical
2009 Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical
Guidelines for the Management of Major Depressive Disorder in Adults.
I. Classification, Burden and Principles of Management
Scott B. Patten et al, Journal of Affective Disorders 117 (2009) S5–S14
The preponderance of evidence does not
suggest one first line treatment is better
than another
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Three major systematic reports do not find
unequivocal efficacy or tolerability differences
among second-generation antidepressants
All have Level 1 evidence to support efficacy
There are no consistent predictors of outcome
Most second-generation antidepressants are
first line
*Gartlehner, G., et al 2007. Comparative effectiveness of second-generation antidepressants inthe pharmacologic
treatment of adult depression. Agency for Healthcare Research and Quality, Rockville, MD.
*Gartlehner, G., et al 2008. Comparative risk for harms of second generationantidepressants : a systematic review and
meta-analysis. Drug Safety 31, 851–865. *National Institute for Clinical Excellence, 2004. Depression: management of
depression in primary and secondary care. Clinical Guideline 23. London,NICE.
*Sartorius, N., et al 2007. Antidepressant medications and other treatments of depressive disorders: a CINP Task Force
report based on a review of evidence. Int. J. Neuropsychopharmacol. 10, S1–207.
Antidepressants with probable
evidence for minor superior efficacy
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A multiple comparisons network meta-analysis (in which both direct
and indirect comparisons are analyzed)
– 12 second-generation antidepressants
– identified a small superiority in response rates
– escitalopram, mirtazapine, sertraline and venlafaxine
An international expert consensus panel
– head-to-head RCTs of antidepressants
– clomipramine, escitalopram and venlafaxine evidence of
superiority (two or more good quality RCTs and supportive metaanalyses)
– Duloxetine and mirtazapine probable evidence (at least 2 RCTs
and/or supportive meta-analysis)
My opinion
– Fluoxetine trumps this data: better tolerability and lower risk for
severe withdrawal reactions
– Some of the authors have received large consulting fees from
pharmaceutical companies
Cipriani, A. et al, 2009. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments metaanalysis. Lancet 373, 746–758.
Montgomery, S.A., et al 2007. Which antidepressants have demonstrated superior efficacy?
A review of the evidence. Int. Clin. Psychopharmacol. 22, 323–329.
What are the first line treatments?
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First-line recommendations
– Bupropion [Wellbutrin] NDRI 150–450 mg
– Citalopram [Celexa, Cipramil] SSRI 20–60 mg
– Desvenlafaxine [Pristiq] SNRI 50–100 mg
– Duloxetine [Cymbalta] SNRI 60–120 mg
– Escitalopram [Cipralex,Lexapro] ASRI 10–20 mg
– Fluoxetine [Prozac] SSRI 20–80 mg
– Fluvoxamine [Luvox] SSRI 100–300 mg
– Levomilnacipran [Fetzima] SNRI 40-120
– Mirtazapine [Remeron] α2-adrenergic agonist; 5-HT2 antagonist 30–60 mg
– Paroxetine [Paxil] SSRI 20–60 mg, 25–50 mg for CR version
– Sertraline [Zoloft] SSRI 50–200 mg
– Venlafaxine [Effexor] SNRI 75–375 mg
– Vilazodone [Viibryd] SSRI+5HT1 40
– Vortioxetine [Brintellix] SSRI+5HT1 20
Second-line recommendations
– Amitriptyline, clomipramine, nortriptyline, desipramine and other TCAs
– Quetiapine [Seroquel] Atypical antipsychotic 150–300 mg
– Selegiline transdermal [Emsam] Irreversible MAO-B inhibitor 6–12 mg daily transdermal
– Trazodone [Desyrel] Serotonin reuptake inhibitor; 5-HT2 antagonist 150–300 mg
Third-line recommendations
– Phenelzine [Nardil] Irreversible MAO inhibitors 45–90 mg
– Tranylcypromine [Parnate] 30–60 mg
Why is augmentation
needed?
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Monotherapy in the largest naturalistic
outcome study
80% of 2,876 patients had chronic or
recurrent depression
Most had comorbid psychiatric and medical
conditions
Remission rates for HAM-D 28%, QIDS-SR
33%, quick inventory of depression Sxs
Evaluation of outcomes with citalopram for depression using measurement-based
care in STAR*D: implications for clinical practice. Trivedi MH, et al, STAR*D Study Team.
Department of Psychiatry, University of Texas Southwestern Medical Center, Am J Psychiatry. 2006
Jan;163(1):28-40
How long is an adequate monotherapy trial? RCT Data
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Over 6 weeks in drug group, HDRS improves by
13.05; Pb by 8.96
Largest Decrease for both groups occurs in week 1,
Drug=4.54, Pb=3.55
First 2 weeks account for 60.2% of total drug
improvement, 61.6% of PB
Drug effect = drug placebo difference
57% of the “drug effect” occurs in weeks 1 & 2,
43% during weeks 3-6
– The largest “effect” occurs during week 2
– Controlling for dropouts, 52% occurs during first 2 weeks
– Non sedating drugs, 45% occurs during first 2 weeks
Is there a delay in the antidepressant effect? A Meta-analysis.
Posternak MA, Zimmerman M, J Clin Psychiatry 2005;66:148-158
How long is an adequate monotherapy trial? STAR*D Data
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In real-world samples, response and remission may
take longer.
STAR*D
– patients who ultimately show clinical response
(open-label citalopram for 12 weeks) 56% first
achieved response after 8 or more weeks
– 40% of patients who ultimately remitted first
achieved remission after 8 or more weeks
Patients with minimal improvement (e.g., ≥20%
improvement in rating scale scores) after 4–6
weeks should continue on antidepressant for
another 2–4 weeks before considering additional
strategies.
Trivedi, M.H., et al, 2006 Evaluation of outcomes with citalopram for depression using
measurement-based care in STAR*D: implications for clinical practice. Am. J. Psychiatry 163, 28–40.
When is mono-therapy
deemed inadequate?
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The target goal for acute treatment should
be remission, a resolution of depressive
symptoms.
“Response” to treatment (a reduction in
symptom levels) is not an adequate
outcome
residual depressive symptoms are risk
factors for relapse and negative predictors
of long-term outcome
McIntyre, R.S., O'Donovan, C., 2004. The human cost of not achieving full
remission in depression. Can. J. Psychiatry 49 (3 Suppl 1), 10S–16S.
When is it time to begin
augmentation?
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After 6-10 weeks of treatment with
monotherapy at maximum dose that is well
tolerated
Switching is deemed likely to be less effective,
has already been attempted
– Further monotherapy trials are unjustifiable because of
Acuity
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Trials failed to achieve remission
Continue current agent: possesses partial
efficacy and is well tolerated
Re-evaluation does not change diagnosis
– e.g., bipolarity, depressive subtype, comorbidity including
substance abuse
Should you first switch to a drug
with a different mechanism?
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Overall, no conclusive evidence for
switching out of class over switching within
the class
Small differences in outcome may be a
result of enhanced efficacy of some
antidepressants, regardless of mechanism of
action
In STAR*D switching within class was just
as effective
Augmentation and
Combined Therapy are not
the same
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Augmentation is adding a second
treatment to ongoing antidepressant
treatment
Combined therapy is combining two
treatments from the onset of
treatment
This talk will focus on Augmentation
2009 Canadian Network for Mood and
Anxiety Treatments: ranking of strategies
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First-line
– Aripiprazole [Level 1]
– Lithium [Level 1]
– Olanzapine [Level 1]
– Risperidone [Level 2]
Second-line
– Bupropion [Level 2]
– Mirtazapine [Level 2]
– Quetiapine [Level 2]
– Triiodothyronine [Level 2]
– Other antidepressant [Level 3]
– Psychotherapy, IPT&CBT [Level
Third-line
– Buspirone [Level 2]
– Modafinil [Level 2]
– Stimulants [Level 3]
– Ziprasidone [Level 3]
Unranked
– Anti-epileptic medications
– Pindolol
Because of much greater safety,
if acuity allows, I rank first line,
above all others:
Antidepressants
Buspirone
Modafinil
Stimulants
Similar to recommendations
of TMAP group, unpublished data
-Fish Oil [Level 1]
2]
-TMS [Level 3]
-ECT [Level 2]
-Folate [Level 2]
Pharmaceuticals
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Lithium
Atypical Antipsychotics
T3
Antidepressants
Buspirone
Psychostimulants
Antiepileptic Drugs
Pindolol
Lithium
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meta-analysis (10 RCTs, N=269
participants) found significantly superior to
placebo in augmentation of antidepressants,
including TCAs and SSRIs
12% known to be bipolar
2 studies with SSRIs
8 studies, dose > 800 mg
41% response rate; 14% in placebo
Crossley, N.A., Bauer, M., 2007. Acceleration and augmentation of
antidepressants with lithium for depressive disorders: two meta-analyses of
Lithium Augmentation in STAR*D
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Lithium added after 2 previous trials: citalopram
then augmentation with bupropion or buspirone or
switch to sertraline or venlafaxine or bupropion
Single blind, randomized, no placebo
14 weeks of treatment
– Lithium (up to 900 mg/day) (n=69)
Started at 450 mg/day, at week 2 increased to
900, could decrease to 225 if not well tolerated
and then 1 week later increased to 450 mg/day
 Mean dose 859 mg, level = 0.6
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Remission Rates, HAM-D, 16%
A Comparison of Lithium and T3 Augmentation Following Two Failed Medication Treatments for
Depression: A STAR*D Report. Nierenberg AA, et al, Massachusetts General Hospital, 50 Staniford St.,
Boston, MA 02114. Am J Psychiatry. 2006 Sep;163(9):1519-30.
Atypical Antipsychotics:
Risperidone, Olanzapine,
Aripiprazole, and Quetiapine
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Canadian network ranks Risperidone,
Olanzapine, Aripiprazole first line
Canadian network ranks Quetiapine
second line
More Recent Meta-Analysis ranks them
equally effective and well tolerated
Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of
Placebo-Controlled Randomized Trials, J.C. Nelson & G.I. Papakostas, Am J Psychiatry
2009; 166:980–991
Meta-Analysis of AAP
Augmentation
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meta-analysis (16 RCTs, N=3,480
participants) found all significantly superior
to placebo in augmentation of
antidepressants, mostly SNRIs and SSRIs
– No significant differences between AAP
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Olanzapine, N=1,000; 4 trials
Risperidone, N=386; 3 trials
Quetiapine, N=1,029; 5 trials
Aripiprazole, N=1,065; 3 trials
Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of
Placebo-Controlled Randomized Trials, J.C. Nelson & G.I. Papakostas, Am J Psychiatry
2009; 166:980–991
Outcome Measure:
Odds Ratio and NNT
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The odds ratio is the ratio of the odds of an
event occurring in one group to the odds of
it occurring in another group
The NNT is the number of patients who
need to be treated in order to prevent one
additional bad outcome (i.e. the number of
patients that need to be treated for one
patient in the active treatment to benefit
compared with a control in a clinical trial).
Meta-Analysis of AAP Augmentation:
Response Rates, Remission Rates,
Discontinuation (Odds Ratio)
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Risperidone
– 1.83, response;
Aripiprazole
– 2.07, response;
Quetiapine
– 1.60, response;
Olanzapine
– 1.39, response;
All total
2.63, remission; 1.08, discontinuation
2.09, remission; 1.24, discontinuation
1.89, remission; 1.59, discontinuation
1.83, remission; 1.23, discontinuation
– 1.69, response; 2.00, remission; 1.30, discontinuation
– Total response rates 44.2%, compared with 29.9% Placebo
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NNT 9
By comparison Lithium = 41%
– Total remission rates 30.7%, compared with 17.2% Placebo
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NNT 9
– Total discontinuation for any reason 19.6%, compared
with15.5% Placebo
Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled
Randomized Trials, J.C. Nelson & G.I. Papakostas, Am J Psychiatry2009; 166:980–991
Meta-Analysis of AAP
Augmentation
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Duration of trial (4 to 12 weeks in duration)
was not correlated with overall effectiveness
Method of establishing treatment resistance
(historical or prospective) was not
correlated with overall effectiveness
– The trend suggested patients not responding to
prospective treatment were more treatment
resistant than not responding to historical
treatment
Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of
Placebo-Controlled Randomized Trials, J.C. Nelson & G.I. Papakostas, Am J Psychiatry
2009; 166:980–991
Weigh Risk Benefit of AAP
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The benefit is large
But the risk of serious adverse effects is also
large
– Metabolic syndrome
– Extrapyramidal symptoms
– Less frequent but serious symptoms such as
tardive dyskinesia and neuroleptic malignant
syndrome.
As a consequence the risk-benefit ratio may be
different than that of several alternatives
Triiodothyronine
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Triiodothyronine (T3, liothyronine)
– benefit in open trials and some RCTs
– A meta-analysis of eight studies (total N=292) weakly
supported the efficacy of T3 augmentation of TCAs,
 odds ratio of 1.53 in RCTs (n=4), not significant
 2.09 in all trials (n=8)
– TCA data is stronger than equivocal support for
augmentation of SSRIs; only one large RCT shows efficacy
 A STAR*D RCT, single blind-no placebo, of 73 nonremitters after 2 treatment trials found remission rates
of 24.7%
--Aronson R, Offman HJ, Joffe RT, Naylor CD: Triiodothyronine augmentation in the treatment of refractory
depression: a meta-analysis. Arch Gen Psychiatry 1996; 53:842–848.
-Cooper-Kazaz, R., Lerer, B., 2008. Efficacy and safety of triiodothyronine supplementation in patients with major
depressive disorder treated with specific serotonin reuptake inhibitors. Int. J.Neuropsychopharmacol. 11, 685–699.
-Nierenberg, A.A., et al 2006. A comparison of lithium and T(3) augmentation following two failed medication
treatments for depression: a STAR*D report. Am. J. Psychiatry 163, 1519–1530.
Triiodothyronine, Dosing
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25 mcg per day for one month
Followed by 50 mcg per day for one
month
Long term safety unknown
? Risk for permanent suppression of
thyroid function
Long term efficacy; poor data
Kelly, T.F., 2009. Long term augmentation with T3 in refractory major depression,
Journal of Affective Disorders 115 (2009) 230–233
T3, more research needs
to be conducted
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Larger high quality trials with longer
follow-up and evaluation of tolerance
and dependence are needed
to test the robustness of these
findings and, furthermore, to explore
when T3 may be beneficial and in
which clinical situations it is optimal.
How effective is the strategy of
“combining” two antidepressants?
– Mirtazapine
– Bupropion
– Tricyclic Antidepressants
– Buspirone, an anxiolytic
Mirtazapine
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1 RCT, Pb controlled
26 adults
bupropion (n 1), SSRI (n 22),
venlafaxine (n 3)
15 to 30 mg per day for 4 weeks
response rates 64%-MTZ and 20%-Pb
remission rates 45%-MTZ and 13%-Pb
Carpenter, L.L., et al 2002. A double-blind, placebo-controlled study of antidepressant augmentation
with mirtazapine. Biol. Psychiatry 51, 183–188.
STAR*D: Venlafaxine plus
Mirtazapine
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STAR*D, no placebo, single blind, randomized
– Venlafaxine plus mirtazapine after 3 failed antidepressant
trials
– Venlafaxine (mean dose = 210.3 mg, SD=95.2) 300 mg
max dose reached at 9 weeks, mirtazapine (mean dose =
35.7 mg, SD = 17.6) 45 mg max dose reached at 9 weeks
(N=51)
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Remission Rates,
– Mirtazapine+venlafaxine,
Response Rates
– Mtz + Vlfx
HAM-D
13.7%
23.5%
McGrath, P.J., et al 2006. Tranylcypromineversus venlafaxine plus mirtazapine following three failed
Antidepressant medication trials for depression: a STAR*D report. Am. J. Psychiatry 163, 1531–1541.
Buspirone (up to 60 mg) and
Bupropion (up to 400mg)
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No placebo controlled trials for Bupropion
Failed placebo controlled trials for Buspirone
STAR*D, single blind, randomized, no placebo
– Added to citalopram, 55 mg
– Remission Rates, HAM-D &
 Bupropion-SR, 29.7%
 Buspirone,
30.1%
– Response Rates,
 Bupropion-SR,
 Buspirone,
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QIDS-SR
39.0%
32.9%
QIDS-SR
31.8%
26.9%
Bupropion slightly better tolerated
Appelberg, B.G., et al 2001. Patients with severe depression may benefit from buspirone augmentation of selective
serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J.
Clin. Psychiatry 62, 448–452.
Trivedi, M.H., et al 2006. Medication augmentation after the failure of SSRIs for depression. N. Engl. J. Med. 354,
Tricyclic Antidepressants
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retrospective case reports or series
– low doses of TCAs added to SSRIs (fluoxetine or
sertraline)
– SSRIs (fluoxetine or citalopram) added to TCAs
– Typical study: low-dose TCA (25–50 mg/day) to
fluoxetine
– response in 13 (65%) of 20
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prospective studies
– 4 (31%) of 13 responded to addition of
desipramine or imipramine to fluoxetine
– 4 (36%) of 11 patients in another study
Weilburg JB, et al. Tricyclic augmentation of fluoxetine. Ann Clin Psychiatry 1991;3:209–13.
Levitt AJ, et al. Do depressed subjects who have failed both fluoxetine and a tricyclic antidepressant
respond to the combination? J Clin Psychiatry 1999;60:613–6.
Tricyclic Antidepressants:
Extreme Caution in Dosing!
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Most SSRIs inhibit metabolism of TCAs
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Marked elevations in TCA blood levels reported when TCAs
and SSRIs are combined
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TCAs have a narrow window of safety
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Risk for arrhythmias
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Use low doses of TCAs (25–50 mg/day)
– Monitor plasma levels
– May increase above 50 mg/day if level is low
Double-Blind Study of High-Dose Fluoxetine
Versus Lithium or Desipramine Augmentation
of Fluoxetine in Partial Responders and
Nonresponders to Fluoxetine
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101 outpatients
Partial responders (n 49) or nonresponders (n 52)
– 8 weeks of treatment with fluoxetine 20 mg/day
Randomized to 4 weeks
– Fluoxetine (40–60 mg/day)
– fluoxetine plus lithium (300–600 mg/day)
– fluoxetine plus desipramine (25–50 mg/day
no significant difference in response rates
– fluoxetine, 42.4%
– fluoxetine plus desipramine, 29.4%
– fluoxetine plus lithium, 23.5%
mean lithium level 0.37 mEq/L
mean desipramine level 104.7
Desipramine: 150 to 300 ng/mL, accepted therapeutic range
Lithium: 0.6-1.2 mEq/L, accepted therapeutic range
Fava, M., et al 2002. Double-blind study of highdose fluoxetine versus lithium or desipramine
augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. J. Clin.
Psychopharmacol. 22, 379–387.
Combining Antidepressants:
More research is needed
Larger high quality trials with longer followup and evaluation of tolerance and
dependence are needed
to test the robustness of these findings and,
furthermore, to explore when combined
therapy may be beneficial and in which
clinical situations optimal.
**Nevertheless Buspirone, Bupropion, and
Mirtazapine are relatively safe and deserve
early consideration in your treatment
algorithm
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Psychostimulants
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Randomised controlled trials; 24 reviewed
PSYCHOSTIMULANTS VERSUS PLACEBO AS
ADJUNCT TO ANTIDEPRESSANT TREATMENT
Four trials, 5 analyses
-short term trial of Methylphenidate, n=50, failed
to separate from placebo
-In two short term trials of modafinil, n=411, failed
to separate from placebo
-In two medium term trials of modafinil, n=443,
failed to separate from placebo
Candy B, et.al. Psychostimulants for depression.
Cochrane Database of Systematic Reviews 2008, Issue 2.
Psychostimulants, more
research is needed
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Larger high quality trials with longer
follow-up and evaluation of tolerance
and dependence are needed to test
the robustness of these findings and,
furthermore, to explore which PS may
be more beneficial and in which
clinical situations they are optimal.
Antiepileptic Medications
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4 blinded, controlled trials (of 28–70 days), as
augmentation
– carbamazepine (1 trial), RCT, 1999, CBZ=28 &
Lithium=31
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Augmented SSRIs & TCAs
28 days duration
Response, CBZ 57%, Lithium 68%, no Pb; equally effective
– lamotrigine (2), RCT, 2002 & 2003, LTG=33 & Pb=30
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Augmented Paroxetine
63 days duration
Response, LTG 66%, Pb 43%, not significant
Demonstrates why Pb control is important
– phenytoin (1), RCT, 2005, phenytoin=11, Pb=9
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Augmented SSRIs
28 days duration
Response, Phenytoin=18%, Pb=78%, Placebo was superior
Vigo DV & Baldessarini RJ, Anticonvulsants in the Treatment of Major Depressive Disorder:
An Overview, Harvard Rev Psychiatry, 2009, 17:231-241
Antiepileptic Medications
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The evidence base does not support
the use of AEDs as an augmentation
strategy for the relief of unipolar Major
Depression
There is suggestive evidence that
carbamazepine may be effective
Pindolol
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11 RCTs; 2.5 mg TID
Antagonist of β-adrenoreceptors and 5-HT1A autoreceptors
The pooled odds ratios for dichotomous response to
treatment
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Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
2.39
2.39
1.94
1.59 after four weeks separation from placebo is lost
1.42
1.28, deteriorating response is worrisome
Time-to-event analysis showed a greater response with pindolol
augmentation versus placebo
(P = 0.04).
By comparison, 1.69, pooled response to AAPs
May work to accelerate initial response
Whale, R., et al 2008. Pindolol augmentation of serotonin reuptake inhibitors for the
treatment of depressive disorder: a systematic review. J. Psychopharmacol OnlineFirst,
October 2, 2008 as doi:10.1177/0269881108097714
Nutraceuticals
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S-adenosyl methionine (SAM-e)
Eicosapentaenoic acid (EPA, Fish Oils)
DHEA (dehydroepiandrosterone)
Trpytophan
Folate and Inositol
S-adenosyl methionine
(SAM-e)
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SAM-e is a synthetic form of a dietary amino acid
functions as a methyl donor in biological processes
involving neurotransmitters
doses, ranging from 800 to 1600 mg/d, usually
divided doses with meals.
Length of treatment ranged from 2-8 weeks.
6 published systematic reviews since 2000
All concurred for mild to moderate depression, SAM-e
> placebo, and = efficacy to tricyclic antidepressants
There is no evidence for its use as an
augmenting agent
– its use as such should be considered carefully
given possibility of serotonin syndrome.
Williams, A.L., Girard, C., Jui, D., Sabina, A., Katz, D.L., 2005. S-adenosylmethionine (SAMe) as
treatment for depression: a systematic review. Clin. Invest. Med. 28, 132–139.
Omega-3 fatty acids
(EPA, DHA, Fish Oils)







polyunsaturated fatty acids integrated into cell
membranes
1–6 g of EPA
formulations with higher levels of EPA superior to
placebo, DHA was not
Duration of treatment ranged from 4–16 weeks.
Two meta-analyses (2006 & 2007) found significant
benefit as monotherapy and augmentation to
antidepressants, but included Bipolar depression
Subsequent studies have been published, with
mixed results
Level 1 evidence from published studies for efficacy
of omega-3 fatty acids as an augmentation in mild
to moderate MDD
Lin, P.Y., Su, K.P., 2007. A meta-analytic review of double-blind, placebocontrolled trials of
antidepressant efficacy of omega-3 fatty acids. J. Clin. Psychiatry 68, 1056–1061.
DHEA
(dehydroepiandrosterone)










DHEA (dehydroepiandrosterone) a natural steroid produced
by adrenal glands
metabolized to testosterone and estrogen
In Rx of depression, dosages varied from 30mg/day to
450mg/day.
Treatment duration 6–8 weeks
superior to placebo as monotherapy and augmentation
N=15; these are very preliminary findings
side effects include acne and hirsutism
Concerns remain regarding exacerbation of breast and
prostate cancer and increased clotting and liver damage
Data is weak for its benefit as an augmentation agent
Use as a third line treatment
Wolkowitz, O.M., et al., 1999. Double-blind treatment of major depression with
dehydroepiandrosterone. Am. J. Psychiatry 156, 646–649.
Tryptophan


A dietary amino acid converted to 5
hydroxytryptophan (5-HTP) and then into
serotonin (5-HT) centrally and peripherally
RCTs
– generally negative results with tryptophan
augmentation of SSRIs or TCAs

Side effects
– drowsiness, dry mouth, nausea, and other
gastrointestinal symptoms, but not serotonin
syndrome

insufficient evidence to confirm benefits of
tryptophan in augmentation of antidepressants
Levitan, R.D., et al, 2000. Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with
fluoxetine to treat major depressive disorder:antidepressant and hypnotic effects. J. Psychiatry Neurosci. 25, 337–346.
Turner, E.H., et al, 2006. Serotonin a la carte: Supplementation with the serotonin precursor 5-hydroxytryptophan.
Pharmacol. Ther. 109, 325–338.
Folate and Inositol

A meta-analysis of two studies noted the
efficacy of folic acid or folate, a form of
Vitamin B9, as adjunctive treatment to
antidepressants
– However, it was unclear whether this benefit
would be seen both in those with folate
deficiency and those with normal folate levels.

a meta-analysis found no clear benefit for
inositol, a carbocylic polyol, as monotherapy
or augmentation
Taylor, M.J., et al, 2004a. Folate for depressive disorders: systematic review and meta-analysis of
randomized controlled trials. J. Psychopharmacol. 18, 251–256.
Taylor, M.J., et al, 2004b. Inositol for depressive disorders. Cochrane Database Syst. Rev. 2,
CD004049.
Herbal Treatments: St.
John’s Wort




Level 1 evidence to support the firstline use of St. John's wort as
monotherapy in mild to moderate
MDD
dose ranges (500 mg/day to 1800
mg/day)
short-term studies (4–12 weeks)
Little or no data regarding use as an
augmentation strategy
–Cochrane Database Syst Rev. 2008 Oct 8;(4):CD000448.
–St John's wort for major depression. Linde K, Berner MM, Kriston L.
Nutraceuticals, Summary


Level 1 evidence from published
studies for efficacy of omega-3 fatty
acids as augmentation
Little evidence to justify use of other
agents
Psychostimulation




Phototherapy
Vagal Nerve Stimulation
Transcranial Magnetic Stimulation
Electroconvulsive Therapy
Phototherapy






standard daily “dose” = 10,000 lux (intensity) for
30 min
given in the early morning
Response usually occurs within 1–3 weeks
Level 1 evidence for efficacy of light therapy in
seasonal MDD
recommended as a first-line treatment
No studies have examined the combination of
light therapy and antidepressants in the
treatment of seasonal MDD
Even, C., et al, 2008. Efficacy of light therapy in nonseasonal depression:
a systematic review. J. Affect. Disord. 108, 11–23.
Vagal Nerve Stimulation







VNS
– implantation of a bipolar electrode around left vagus
nerve, accessed through an incision in lower neck
– Wire is connected to subclavicular pulse generator
– intermittent electrical signals sent to left vagus nerve
Lack of substantial evidence for short-term and longterm efficacy in acute severe depression
only one acute RCT, no maintenance RCTs
Appropriate place of VNS in the treatment algorithm
for TRD remains to be determined.
Most patients continued on pre-trial antidepressant
medications
Evidence of greater antidepressant effects accruing over time
with combination therapy [Level 3]
Insufficient evidence to recommend combination of VNS and
antidepressant medication.
C. Daban et al., Review: Safety and efficacy of vagus nerve stimulation in
treatment-resistant depression, Journal of Affective Disorders 110 (2008) 1–15
Transcranial Magnetic
Stimulation

A meta-analysis of rTMS for TRD
–
–
–
–



response and remission rates
25% and 17% for active treatment
9% and 6% for sham treatment
These are significant differences (Lam et al., 2008)
most evidence supports high-frequency rTMS applied to the
left DLPFC
Combined use of rTMS with antidepressant medication
accelerates response under sham-controlled conditions
(Bretlau et al., 2008)
Adding open-label mirtazapine increased the response to
rTMS monotherapy (Schule et al., 2003) [Level 3].
Lam, R.W., et al, 2008. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systemic
review and meta-analysis. Can. J. Psychiatry 53, 621–63
Bretlau, L.G., et al, 2008. Repetitive transcranial magnetic stimulation (rTMS) in combination with
escitalopram in patients with treatment-resistant major depression: a double-blind, randomised, sham-controlled trial.
Pharmacopsychiatry 41, 41–47.
Schule, C., et al, 2003. Effects of antidepressant pharmacotherapy after
repetitive transcranial magnetic stimulation in major depression: an open
follow-up study. J. Psychiatr. Res. 37, 145–153.
Electroconvulsive
Therapy



In patients who have failed one or more
adequate antidepressant medication trials, ECT
response rates are 50–60%
Combining ECT and antidepressant medication
does not increase the therapeutic effect of ECT
Augmentation of nortriptyline with ECT
increases the remission rate compared to ECT
and discontinuation of nortriptyline [Level 2]
Flint, A.J., Rifat, S.L., 1998. The treatment of psychotic depression in later life:
a comparison of pharmacotherapy and ECT. Int. J. Geriatr. Psychiatry 13, 23–28.
Prudic, J., et al, 1996. Resistance to antidepressant medications and short-term clinical response to
ECT. Am. J. Psychiatry 153, 985–992.
Sackeim, H.A., et al, 2009. Effect of concomitant pharmacotherapy on electroconvulsive therapy
outcomes: short-term efficacy and adverse effects. Arch. Gen. Psychiatry 66, 729–737.
Psychostimulation,
summary

Phototherapy
– No evidence for augmentation

Vagal Nerve Stimulation
– No evidence for augmentation

Transcranial Magnetic Stimulation
– Level 3 evidence favors combining with
medication for enhanced response

Electroconvulsive Therapy
– Level 2 evidence favors combining with
medication for enhanced remission
Psychotherapy





Most studies are of combined therapy vs. psychotherapy vs.
meds, level 1 evidence for combo, second line due to costs
One RCT of psychotherapy added to meds vs. usual Rx
158 patients, partially remitted with antidepressant
residual symptoms
clinical management or clinical management with cognitive
therapy
– With maintenance antidepressants during a 1-year follow-up

Relapse rate and Response
– 47% relapse rate in the clinical management group
– 29% relapse with CBT
– small statistically significant effect on residual symptom levels

At a 6-year follow-up effects of CBT in prevention of relapse
and recurrence persisted
Paykel, E.S., 1999. Prevention of relapse in residual depression by cognitive therapy:
A controlled trial. Arch. Gen. Psychiatry 56, 829–835.
2009 Canadian Network for Mood and
Anxiety Treatments: ranking of strategies
Has Anything Changed? Because of much greater safety,




First-line
– Aripiprazole [Level 1]
– Lithium [Level 1]
– Olanzapine [Level 1]
– Risperidone [Level 2]
– Quetiapine [Level 2]
Second-line
– Bupropion [Level 2]
– Mirtazapine [Level 2]
– Triiodothyronine [Level 2]
– Other antidepressant [Level 3]
– Psychotherapy, IPT&CBT [Level
Third-line
– Buspirone [Level 2]
– Modafinil [Level 2]
– Stimulants [Level 3]
– Ziprasidone [Level 3]
Not proven Effective
– Anti-epileptic medications
– Pindolol
if acuity allows, I rank first line,
above all others:
Antidepressants
Buspirone
Modafinil
Stimulants
Similar to recommendations
of TMAP group, unpublished data
-Fish Oil [Level 1]
2]
-TMS [Level 3]
-ECT [Level 2]
-Carbamazepine [Level 3]
-Folate [Level 2]