Antidepressant Augmentation Strategies in Unipolar Depressive Disorders: Evidence Base

1. 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

2. Augmentation Strategies • Pharmaceuticals with and without FDA indication for antidepressant augmentation • Nutraceuticals • Psychostimulation • Psychotherapy

3. 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. 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

4. 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

5. 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.

6. 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.

7. 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

8. 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-basedcare 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

9. 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

10. 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.

11. 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.

12. 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

13. 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

14. 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

15. 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] 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

16. Pharmaceuticals • Lithium • Atypical Antipsychotics • T3 • Antidepressants • Buspirone • Psychostimulants • Antiepileptic Drugs • Pindolol

17. Lithium • 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 randomized, placebo-controlled trials. J. Clin. Psychiatry 68, 935–940.

18. 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.

19. 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

20. 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

21. 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).

22. 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

23. 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

24. 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 tardivedyskinesia and neuroleptic malignant syndrome. • As a consequence the risk-benefit ratio may be different than that of several alternatives

25. Triiodothyronine • 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. 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.

26. 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

27. 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.

28. How effective is the strategy of “combining” two antidepressants? • Mirtazapine • Bupropion • Tricyclic Antidepressants • Buspirone, an anxiolytic

29. Mirtazapine • 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.

30. 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.

31. 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.

32. 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 13responded 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.

33. 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

34. 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.

35. 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

36. Psychostimulants • 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.

37. 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.

38. 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

39. 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

40. Pindolol • 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

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

42. 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.

43. 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.

44. 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.

45. 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.

46. 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.

47. 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.

48. 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

49. Psychostimulation • Phototherapy • Vagal Nerve Stimulation • Transcranial Magnetic Stimulation • Electroconvulsive Therapy

50. 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.