depression studies

Antidepressant Augmentation Strategies in Unipolar Depressive Disorders

What is the evidence base?

This lecture focuses on Augmentation, adding a second treatment to ongoing antidepressant treatment.

David L. Fogelson, M.D.

Clinical Professor of Psychiatry

David Geffen School of Medicine at UCLA

Department of Psychiatry and Biobehavioral Sciences

Augmentation Strategies

  • Pharmaceuticals with and without FDA indication for antidepressant augmentation
  • Nutraceuticals
  • Psychostimulation
  • Psychotherapy

Principles of Pharmacotherapy Management

  • 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
  • Antidepressant selection individualized: symptom profile, comorbidity, tolerability profile, previous response, potential drug–drug interactions, patient preference, and cost.

Criteria for Level of Evidence and Line of Treatment

  • 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 meta-analysis 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

  • 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

  • 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 meta-analyses)
    • 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 meta-analysis. 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?

  • 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?

  • 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 mono-therapy trial?  RCT Data

  • 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 mono-therapy trial?  STAR*D Data

  • 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?

  • 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? 

  • 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
  • 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?

  • 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

  • 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

  • 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] -Fish Oil [Level 1]
    • Psychotherapy, IPT&CBT [Level 2]
  • Third-line
    • Buspirone [Level 2] -TMS [Level 3]
    • Modafinil [Level 2] -ECT [Level 2]
    • Stimulants [Level 3]
    • Ziprasidone [Level 3] -Folate [Level 2]

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


  • Lithium
  • Atypical Antipsychotics
  • T3
  • Antidepressants
  • Buspirone
  • Psychostimulants
  • Antiepileptic Drugs
  • Pindolol


  • 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

Lithium Augmentation in STAR*D

  • 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
  • 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

  • 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

  • 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
  • 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

  • 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)

  • Risperidone
    • 1.83, response; 2.63, remission; 1.08, discontinuation
  • Aripiprazole
    • 2.07, response; 2.09, remission; 1.24, discontinuation
  • Quetiapine
    • 1.60, response; 1.89, remission; 1.59, discontinuation
  • Olanzapine
    • 1.39, response; 1.83, remission; 1.23, discontinuation
  • All total
    • 1.69, response; 2.00, remission; 1.30, discontinuation
    • Total response rates 44.2%, compared with 29.9% Placebo
      • NNT 9
      • By comparison Lithium = 41%
    • Total remission rates 30.7%, compared with 17.2% Placebo
      • 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

  • 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

  • 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 (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 non-remitters 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. 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

  • 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

  • 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


  • 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

  • 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)
  • Remission Rates, HAM-D
    • Mirtazapine+venlafaxine, 13.7%
  • Response Rates
    • Mtz + Vlfx 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)

  • 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 & QIDS-SR
      • Bupropion-SR, 29.7% 39.0%
      • Buspirone, 30.1% 32.9%
    • Response Rates, QIDS-SR
      • Bupropion-SR, 31.8%
      • Buspirone, 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, 1243–1252.

Tricyclic Antidepressants

  • 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
  • prospective studies
    • 4 (31%) of 13 responded to addition of desipramine or imipramine to fluoxetine
    • 4 (36%) of 11 patients in another study

Tricyclic Antidepressants: Extreme Caution in Dosing!

  • Most SSRIs inhibit metabolism of TCAs
  • Marked elevations in TCA blood levels reported when TCAs and SSRIs are combined
  • TCAs have a narrow window of safety
  • Risk for arrhythmias
  • 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

  • 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 follow-up 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


  • Randomised controlled trials; 24 reviewed
  • 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, Psychostimulants for depression. Cochrane Database of Systematic Reviews 2008, Issue 2.

Psychostimulants, more research is needed

  • 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

  • 4 blinded, controlled trials (of 28–70 days), as augmentation
    • carbamazepine (1 trial), RCT, 1999, CBZ=28 & Lithium=31
      • Augmented SSRIs & TCAs
      • 28 days duration
      • Response, CBZ 57%, Lithium 68%, no Pb; equally effective
    • lamotrigine (2), RCT, 2002 & 2003, LTG=33 & Pb=30
      • 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
      • 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

  • 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


  • 11 RCTs; 2.5 mg TID
  • Antagonist of β-adrenoreceptors and 5-HT1A autoreceptors
  • The pooled odds ratios for dichotomous response to treatment
    • Week 1 2.39
    • Week 2 2.39
    • Week 3 1.94
    • Week 4 1.59 after four weeks separation from placebo is lost
    • Week 5 1.42
    • Week 6 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


  • S-adenosyl methionine (SAM-e)
  • Eicosapentaenoic acid (EPA, Fish Oils)
  • DHEA (dehydroepiandrosterone)
  • Trpytophan
  • Folate and Inositol

S-adenosyl methionine (SAM-e)

  • 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.


  • 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 first-line 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


  • Phototherapy
  • Vagal Nerve Stimulation
  • Transcranial Magnetic Stimulation
  • Electroconvulsive Therapy


  • 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 long-term 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


  • 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?

  • 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] -Fish Oil [Level 1]
    • Psychotherapy, IPT&CBT [Level 2]
  • Third-line
    • Buspirone [Level 2] -TMS [Level 3]
    • Modafinil [Level 2] -ECT [Level 2]
    • Stimulants [Level 3] -Carbamazepine [Level 3]
    • Ziprasidone [Level 3] -Folate [Level 2]
  • Not proven Effective
    • 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