Antidepressant Augmentation Strategies: what is the evidence ...

Antidepressant Augmentation Strategies: what is the evidence ...

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

Principles of Pharmacotherapy Management Diagnostic assessment: suicidality, bipolarity, comorbidity, 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 14 weeks, period of greatest risk. Depending on severity and response, follow up every 24 weeks or longer. Monitoring requires routine use of validated outcome scales. HAMD Antidepressant selection individualized: symptom profile, comorbidity, tolerability profile, previous response,

potential drugdrug 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 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 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 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 *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. areG.,first line *Gartlehner, et al 2008. Comparative risk for harms of second generationantidepressants : a systematic review and meta-analysis. Drug Safety 31, 851865. *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 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 multipletreatments meta-analysis. Lancet 373, 746758. Montgomery, S.A., et al 2007. Which antidepressants have demonstrated superior efficacy? A review of the evidence. Int. Clin. Psychopharmacol. 22, 323329. What are the first line treatments? First-line recommendations Bupropion [Wellbutrin] NDRI 150450 mg Citalopram [Celexa, Cipramil] SSRI 2060 mg Desvenlafaxine [Pristiq] SNRI 50100 mg

Duloxetine [Cymbalta] SNRI 60120 mg Escitalopram [Cipralex,Lexapro] ASRI 1020 mg Fluoxetine [Prozac] SSRI 2080 mg Fluvoxamine [Luvox] SSRI 100300 mg Levomilnacipran [Fetzima] SNRI 40-120 Mirtazapine [Remeron] 2-adrenergic agonist; 5-HT2 antagonist 3060 mg Paroxetine [Paxil] SSRI 2060 mg, 2550 mg for CR version Sertraline [Zoloft] SSRI 50200 mg Venlafaxine [Effexor] SNRI 75375 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 150300 mg Selegiline transdermal [Emsam] Irreversible MAO-B inhibitor 612 mg daily transdermal Trazodone [Desyrel] Serotonin reuptake inhibitor; 5-HT2 antagonist 150300 mg Third-line recommendations Phenelzine [Nardil] Irreversible MAO inhibitors 4590 mg Tranylcypromine [Parnate] 3060 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 46 weeks should continue on antidepressant for another 24 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, 284 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), 10S16S. 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 Because of much greater safety Aripiprazole [Level 1] if acuity allows, I rank first line, Lithium [Level 1] Olanzapine [Level 1] above all others: Risperidone [Level 2] Antidepressants Second-line Buspirone Bupropion [Level 2]

Mirtazapine [Level 2] Modafinil Quetiapine [Level 2] Stimulants Triiodothyronine [Level 2] to recommendations Other antidepressant [Level 3] -Fish Similar Oil [Level 1] Psychotherapy, IPT&CBT [Level 2] of TMAP group, unpublished dat 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 Pharmaceuticals

Lithium Atypical Antipsychotics T3 Antidepressants Buspirone Psychostimulants Antiepileptic Drugs Pindolol 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- 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 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; 166:980991 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 MetaAnalysis of Placebo-Controlled Randomized Trials, J.C. Nelson & G.I. Papakostas, Am J 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; Aripiprazole 2.07, response; Quetiapine 1.60, response; Olanzapine 1.39, response; 2.63, remission; 1.08, discontinuation 2.09, remission; 1.24, discontinuation 1.89, remission; 1.59, discontinuation 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; 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; 166:980991 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 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; 53:842848. -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, 685699. -Nierenberg, A.A., et al 2006. A comparison of lithium and T(3) augmentation following two failed 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) 230233 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

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, 183188. 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, Mirtazapine+venlafaxine, 13.7% Response Rates Mtz + Vlfx 23.5% HAM-D McGrath, P.J., et al 2006. Tranylcypromineversus venlafaxine plus mirtazapine following three failed 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, 448452. Trivedi, M.H., et al 2006. Medication augmentation after the failure of SSRIs for depression. N. Engl. J. 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 (2550 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 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 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 (2550 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 (4060 mg/day) fluoxetine plus lithium (300600 mg/day)

fluoxetine plus desipramine (2550 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, 379387. 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 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. 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 2870 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 Pindolol 11 RCTs; 2.5 mg TID Antagonist of -adrenoreceptors and 5-HT1A autoreceptors The pooled odds ratios for dichotomous response to treatment

Week Week Week Week Week Week 1 2 3 4 5 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 Nutraceuticals 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, SAMe > 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 16 g of EPA formulations with higher levels of EPA superior to placebo, DHA was not Duration of treatment ranged from 416 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, 10561061. 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 68 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 wi dehydroepiandrosterone. Am. J. Psychiatry 156, 646649. 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. Psychiat Neurosci. 25, 337346. Turner, E.H., et al, 2006. Serotonin a la carte: Supplementation with the serotonin precursor 5- 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 metaanalysis of randomized controlled trials. J. Psychopharmacol. 18, 251256. Taylor, M.J., et al, 2004b. Inositol for depressive disorders. Cochrane Database Syst. Rev. 2, CD004049. Herbal Treatments: St. Johns 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 (412 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 13 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, 1123. 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 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, 62163 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, shamcontrolled trial. Pharmacopsychiatry 41, 4147. 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, 145153. Electroconvulsive Therapy In patients who have failed one or more adequate antidepressant medication trials,

ECT response rates are 5060% 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 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, 2328. [Level 2] Prudic, J., et al, 1996. Resistance to antidepressant medications and short-term clinical response to ECT. Am. J. Psychiatry 153, 985992. Sackeim, H.A., et al, 2009. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. Arch. Gen. Psychiatry 66, 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, 829835. 2009 Canadian Network for Mood and Anxiety Treatments: ranking of strategies Because of much greater Has Anything Changed? safety, First-line if acuity allows, I rank first Aripiprazole [Level 1] line, Lithium [Level 1] above all others: Olanzapine [Level 1]

Antidepressants Risperidone [Level 2] Quetiapine [Level 2] Buspirone Second-line Modafinil Bupropion [Level 2] Stimulants Mirtazapine [Level 2] Similar to recommendations Triiodothyronine [Level 2] of TMAP group, unpublished Other antidepressant [Level 3] -Fish Oil [Level 1] Psychotherapy, IPT&CBT [Level 2] data 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

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    Departamento do Tesouro Nacional IN-DTN 16/91, incorporada no Manual do Sistema de Controle Interno IN SFC 01/2001, Cap. VII, Seção VIII ... incluindo o Controle Externo, com responsáveis definidos para tal mister, de maneira a contemplar suas expectativas na atuação....
  • Period 5: Industrialization and Global Integration, c. 1750 ...

    Period 5: Industrialization and Global Integration, c. 1750 ...

    -www.worldbook.com. A Push for Women's Suffrage. Lucretia Mott. Elizabeth Cady Stanton . and Susan B. Anthony. Key Concept 5.1. VI. The ways in which people organized themselves into societies also underwent significant transformations in industrialized states due to the fundamental...
  • Corporate Template 4:3 for External Use

    Corporate Template 4:3 for External Use

    What About the CO 2. Incubator? Use an incubator with a design that helps prevent contamination. They come from . YOU - normal flora on hands, breath, hair. Start with a clean, sterile incubator. All contaminants in a cell culture...
  • The Rule of Thirds - Jessamine County

    The Rule of Thirds - Jessamine County

    The paper is divided into thirds each way equally. The subject is now in the correct place. This photo is composted by the Rule of Thirds. Not the best use of the Rule of Thirds: That's better! Imagine the grid...