Most patients with major depressive disorder (MDD) do not reach symptom remission. These patients with residual symptoms have worse function and worse prognosis than those who remit. Several augmentation and combination treatments are used to either increase the chances of achieving remission or to eliminate/minimize residual depressive symptoms. Evidence for these pharmacological approaches rests primarily on open, uncontrolled studies, and there are clearly not enough controlled studies. Clinicians should carefully weigh these different treatment options to increase their patients’ chances of achieving and sustaining remission from depression. This paper will review the pertinent studies and will propose a novel approach to improve practice involving the use of augmentation or combination strategies at the outset of initial treatment to primarily enhance the chances of remission through synergy and/or a broader spectrum of action. This novel approach could potentially enhance retention and/or increase remission rates since the lack of response with antidepressant monotherapy may lead many depressed patients with little or no benefit to drop out of treatment, precluding the subsequent use of augmentation or combination strategies altogether. In addition, the emergence of certain side-effects (e.g., agitation, insomnia) or the persistence of some initial baseline symptoms (e.g., anxiety, insomnia) may lead to premature discontinuation from monotherapy in the absence of concomitant use of augmenting pharmacological options targeting these symptoms.

1.
Fava M: Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003;53:649–659.
2.
Fava M, Davidson KG: Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996;19:179–200.
3.
Thase ME, Entsuah AR, Rudolph RL: Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001;178:234–241.
4.
Nierenberg AA, Keefe BR, Leslie VC, Alpert JE, Pava JA, Worthington JJ 3rd, Rosenbaum JF, Fava M: Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry 1999;60:221–225.
5.
Fava M, Kaji J: Continuation and maintenance treatments of major depressive disorder. Psychiatr Ann 1994;24:281–290.
6.
Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A: Residual symptoms after partial remission: an important outcome in depression. Psychol Med 1995;25:1171–1180.
7.
Ramana R, Paykel ES, Cooper Z, Hayhurst H, Saxty M, Surtees PG: Remission and relapse in major depression: a two-year prospective follow-up study. Psychol Med 1995;25:1161–1170.
8.
Judd LL, Paulus MJ, Schettler PJ, Akiskal HS, Endicott J, Leon AC, Maser JD, Mueller T, Solomon DA, Keller MB: Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness? Am J Psychiatry 2000;157:1501–1504.
9.
Wells K, Sherbourne C, Schoenbaum M, Ettner S, Duan N, Miranda J, Unutzer J, Rubenstein L: Five-year impact of quality improvement for depression: results of a group-level randomized controlled trial. Arch Gen Psychiatry 2004;61:378–386.
10.
Unützer J, Katon W, Callahan CM, Williams JW, Hunkeler E, Harpole L, Hoffing M, Della Penna RD, Noel PH, Lin EH, Arean PA, Hegel MT, Tang L, Belin TR, Oishi S, Langston C. IMPACT Investigators: Improving mood-promoting access to collaborative treatment: collaborative care management of late-life depression in the primary care setting: a randomized controlled trial. JAMA 2002;288:2836–2845.
11.
Crismon ML, Trivedi M, Pigott TA, Rush AJ, Hirschfel RM, Kahn DA, DeBattista C, Nelson JC, Nierenberg AA, Sackeim HA, Thase ME: The Texas medication algorithm project: report of the Texas consensus conference panel on medication treatment of major depressive disorder. J Clin Psychiatry 1999;60:142–156.
12.
Quitkin FM, McGrath PJ, Stewart JW, Ocepek-Welikson K, Taylor BP, Nunes E, Deliyannides D, Agosti V, Donovan SJ, Petkova E, Klein DF: Chronological milestones to guide drug change. When should clinicians switch antidepressants? Arch Gen Psychiatry 1996;53:785–792.
13.
Nierenberg AA, McLean NE, Alpert JE, Worthington JJ, Rosenbaum JF, Fava M: Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry 1995;152:1500–1503.
14.
Anonymous: Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group. J Affect Disord 1990;18:289–299.
15.
Fava GA, Rafanelli C, Grandi S, Conti S, Belluardo P: Prevention of recurrent depression with cognitive therapy: preliminary findings. Arch Gen Psychiatry 1998;55:816–820.
16.
Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC, Nemeroff CB, Russell JM, Thase ME, Trivedi MH, Zajecka J: A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000;342:1462–1470.
17.
Fava M: Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 2001;62(suppl 18):4–11.
18.
Fava M, Alpert J, Nierenberg A, Lagomasino I, Sonawalla S, Tedlow J, Worthington J, Baer L, Rosenbaum JF: Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. J Clin Psychopharmacol 2002;22:379–387.
19.
Fava M, Rosenbaum JF, McGrath PJ, Stewart JW, Amsterdam JD, Quitkin FM: Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression: a double-blind, controlled study. Am J Psychiatry1994;151:1372–1374.
20.
Baumann P, Nil R, Souche A, Montaldi S, Baettig D, Lambert S, Uehlinger C, Kasas A, Amey M, Jonzier-Perey M: A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol 1996;16:307–314.
21.
Cournoyer G, De Montigny C, Oulette J, et al: Lithium addition in tricyclic-resistant unipolar depression: a placebo-controlled study. Presented at the XIVth Congress of the Collegium Internationale Neuropsychopharmacologicum, Florence, Italy, June 19–23, 1984.
22.
de Montigny C, Cournoyer G, Morissette R, Langlois R, Caille G: Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry 1983;40:1327–1334.
23.
Heninger GR, Charney DS, Sternberg DE: Lithium carbonate augmentation of antidepressant action: An effective prescription for treatment-refractory depression. Arch Gen Psychiatry 1983;40:1335–1342.
24.
Joffe RT, Schuller DR: An open study of buspirone augmentation of serotonin reuptake inhibitors in refractory depression. J Clin Psychiatry 1993;54:269–271.
25.
Kantor D, McNeven S, Leichner P, Harper D, Krenn M: The benefit of lithium carbonate adjunct in refractory depression: fact or fiction? Can J Psychiatry 1996;31:416–418.
26.
Katona CL, Abou-Saleh M, Harrison DA, Nairac BA, Edwards DR, Lock T, Burns RA, Robertson MM: Placebo-controlled trial of lithium augmentation of fluoxetine and lofepramine. Br J Psychiatry 1995;166:80–86.
27.
Schopf J, Baumann P, Lemarchand T, Rey M: Treatment of endogenous depressions resistant to tricyclic antidepressants or related drugs by lithium addition. Pharmacopsychiatry 1989;22:183–187.
28.
Stein G, Bernadt M: Double-blind trial of lithium carbonate in tricyclic-resistant depression; in NJ Birch (ed): Lithium: Inorganic Pharmacology and Psychiatric Use. Oxford, IRL Press, 1988, p 35.
29.
Stein G, Bernadt M: Lithium augmentation therapy in tricyclic-resistant depression: a controlled trial using lithium in low and normal doses. Br J Psychiatry 1993;162:634–640.
30.
Zusky PM, Biederman J, Rosenbaum JF, Manschreck TC, Gross CC, Weilberg JB, Gastfriend DR: Adjunct low dose lithium carbonate in treatment-resistant depression: a placebo-controlled study. J Clin Psychopharmacol 1988;8:120–124.
31.
Nierenberg AA, Papakostas GI, Petersen T, Montoya HD, Worthington JJ, Tedlow J, Alpert JE, Fava M: Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol 2003;23:92–95.
32.
Januel D, Poirier MF, D’alche-Biree F, Dib M, Olie JP: Multicenter double-blind randomized parallel-group clinical trial of efficacy of the combination clomipramine (150 mg/day) plus lithium carbonate (750 mg/day) versus clomipramine (150 mg/day) plus placebo in the treatment of unipolar major depression. J Affect Disord 2003;76:191–200.
33.
Bauer M, Forsthoff A, Baethge C, Adli M, Berghofer A, Dopfmer S, Bschor T: Lithium augmentation therapy in refractory depression-update 2002. Eur Arch Psychiatry Clin Neurosci 2003;253:132–139.
34.
Joffe RT, Singer W: A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatry Res 1990;32:241–251.
35.
Aronson R, Offman HJ, Joffe T, Naylor CD: Triiodothyronine augmentation in the treatment of refractory depression: A meta-analysis. Arch Gen Psychiatry 1996;53:842–848.
36.
Agid O, Lerer B: Algorithm-based treatment of major depression in an outpatient clinic: clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation. Int J Neuropsychopharmacol 2003;6:41–49.
37.
Clayton AH, Shen C: T4 augmentation in partial responders with major depression. NCDEU Annu Meet, Boca Raton, Fla., USA, June 2002.
38.
Iosifescu DV, Nierenberg AA, Mischoulon D, Perlis RH, Papakostas GI, Ryan JL, Alpert JE, Fava M: An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. J Clin Psychiatry 2005;66:1038–1042.
39.
Appelhof BC, Brouwer JP, Van Dyck R, Fliers E, Hoogendijk WJ, Huyser J, Schene AH, Tijssen JG, Wiersinga WM: Triiodothyronine addition to paroxetine in the treatment of major depressive disorder. J Clin Endocrinol Metab 2004;89:6271–6276.
40.
Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, Leight KL, Whybrow PC: Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry 2001;158:1617–1622.
41.
Bouwer C, Stein DJ: Buspirone is an effective augmenting agent of serotonin selective reuptake inhibitors in severe treatment-refractory depression. South Afr Med J 1997;87(suppl 4):534–537, 540.
42.
Dimitriou EC, Dimitriou CE: Buspirone augmentation of antidepressant therapy. J Clin Psychopharmacol 1998;18:465–469.
43.
Jacobsen FM: A possible augmentation of antidepressant response by buspirone. J Clin Psychiatry 1991;52:217–220.
44.
Landen M, Bjorling GB, Agren H, Fahlen T: A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry 1998;59:664–668.
45.
Appelberg BG, Syvalahti EK, Koskinen TE, Mehtonen OP, Muhonen TT, Naukkarinen HH: 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 2001;62:448–452.
46.
Onder E, Tural U: Faster response in depressive patients treated with fluoxetine alone than in combination with buspirone. J Affect Disord 2003;76:223–227.
47.
Cohn JB, Rickels K: A pooled, double-blind comparison of the effects of buspirone, diazepam and placebo in women with chronic anxiety. Curr Med Res Opin 1989;11:304–320.
48.
Fava M, Alpert JE, Carmin CN, Wisniewski SR, Trivedi MH, Biggs MM, Shores-Wilson K, Morgan D, Schwartz T, Balasubramani GK, Rush AJ: Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D. Psychol Med 2004;34:1299–1308.
49.
Martinez D, Broft A, Laruelle M: Pindolol augmentation of antidepressant treatment: recent contributions from brain imaging studies. Biol Psychiatry 2000;48:844–853.
50.
Perez V, Gilaberte I, Faries D, Alvarez E, Artigas F: Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 1997;349:1594–1597.
51.
Tome MB, Isaac MT, Harte R, Holland C: Paroxetine and pindolol: a randomized trial of serotoninergic autoreceptor blockade in the reduction of antidepressant latency. Int Clin Psychopharmacol 1997;12:81–89.
52.
Zanardi R, Artigas F, Franchini L, Sforzini L, Gasperini M, Smeraldi E, Perez J: How long should pindolol be associated with paroxetine to improve the antidepressant response? J Clin Psychopharmacol 1997;17:446–450.
53.
Bordet R, Thomas P, Dupuis B: Effect of pindolol on onset of action of paroxetine in the treatment of major depression: intermediate analysis of a double-blind, placebo-controlled trial. Am J Psychiatry 1998;155:1346–1351.
54.
Blier P, Bergeron R: The use of pindolol to potentiate antidepressant medication. J Clin Psychiatry 1998;59(suppl 5):16–23.
55.
Isaac MT, Isaac MB, Gallo F, Tournoux A: Milnacipran and pindolol: a randomized trial of reduction of antidepressant latency. Hum Psychopharmacol 2003;18:595–601.
56.
Berman RM, Anand A, Cappiello A, Miller HL, Hu XS, Oren DA, Charney DS: The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial. Biol Psychiatry 1999;45:1170–1177.
57.
Sacristan JA, Gilaberte I, Boto B, Buesching DP, Obenchain RL, Demitrack M, Perez Sola V, Alvarez E, Artigas F: Cost-effectiveness of fluoxetine plus pindolol in patients with major depressive disorder: results from a randomized, double-blind clinical trial. Int Clin Psychopharmacol 2000;15:107–113.
58.
Maes M, Libbrecht I, van Hunsel F, Campens D, Meltzer HY: Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance. J Clin Psychopharmacol 1999;19:177–182.
59.
Moreno F, Gelenberg AJ, Bachar K, Delgado P: Pindolol augmentation of treatment-resistant depressed patients. J Clin Psychiatry 1997;58:437–439.
60.
Perez V, Soler J, Puigdemont D, Alvarez E, Artigas F: A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch Gen Psychiatry 1999;56:375–379.
61.
Perry EB, Berman RM, Sanacora G, Anand A, Lynch-Colonese K, Charney DS: Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial. J Clin Psychiatry 2004;65:238–243.
62.
Fava M, Kendler KS: Major depressive disorder. Neuron 2000;28:335–341.
63.
Bouckoms A, Mangini LP: An antidepressant adjuvant for mood disorders? Psychopharmacol Bull 1993;29:207–211.
64.
Stryjer R, Strous RD, Shaked G, Bar F, Feldman B, Kotler M, Polak L, Rosenzcwaig S, Weizman A: Amantadine as augmentation therapy in the management of treatment-resistant depression. Int Clin Psychopharmacol 2003;18:93–96.
65.
Rogoz Z, Dziedzicka-Wasylewska M, Daniel WA, Wojcikowski J, Dudek D, Wrobel A, Zieba A: Effects of joint administration of imipramine and amantadine in patients with drug-resistant unipolar depression. Pol J Pharmacol 2004;6:735–742.
66.
Sporn J, Ghaemi SN, Sambur MR, Rankin MA, Recht J, Sachs GS, Rosenbaum JF, Fava M: Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review. Ann Clin Psychiatry 2000;12:137–140.
67.
Lattanzi L, Dell’Osso L, Cassano P, Pini S, Rucci P, Houck PR, Gemignani A, Battistini G, Bassi A, Abelli M, Cassano GB: Pramipexole in treatment-resistant depression: a 16-week naturalistic study. Bipolar Disord 2002;4:307–314.
68.
Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, Cassano GB: Pramipexole in treatment-resistant depression: an extended follow-up. Depress Anxiety 2004;20:131–138.
69.
Perugi G, Toni C, Ruffolo G, Frare F, Akiskal H: Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry 2001;34:137–141.
70.
Zarate CA, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK: Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 2004;56:54–60.
71.
Fawcett J, Kravitz HM, Zajecka JM, Schaff MR: CNS stimulant potentiation of monoamine oxidase inhibitors in treatment-refractory depression. J Clin Psychopharmacol 1991;11:127–132.
72.
Feighner JP, Herbstein J, Damlouji N: Combined MAOI, TCA, and direct stimulant therapy of treatment-resistant depression. J Clin Psychiatry 1985;46:206–209.
73.
Linet LS: Treatment of a refractory depression with a combination of fluoxetine and d-amphetamine. Am J Psychiatry 1989;146:803–804.
74.
Masand PS, Anand VS, Tanquary JF: Psychostimulant augmentation of second generation antidepressants: a case series. Depress Anxiety 1998;7:89–91.
75.
Metz A, Shader RI: Combination of fluoxetine with pemoline in the treatment of major depressive disorder. Int Clin Psychopharmacol 1991;6:93–96.
76.
Stoll AL, Pillay SS, Diamond L, Workum SB, Cole JO: Methylphenidate augmentation of serotonin selective reuptake inhibitors: a case series. J Clin Psychiatry 1996;57:72–76.
77.
Wharton RN, Perel JM, Dayton PG, Malitz S: A potential clinical use for methylphenidate with tricyclic antidepressants. Am J Psychiatry 1971;127:1619–1625.
78.
Lavretsky H, Kim MD, Kumar A, Reynolds CF: Combined treatment with methylphenidate and citalopram for accelerated response in the elderly: an open trial. J Clin Psychiatry 2003;64:1410–1414.
79.
Menza MA, Kaufman KR, Castellanos AM: Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000;61:378–381.
80.
DeBattista C, Solvason HB, Flores BH, et al: Modafinil as an adjunctive agent in the treatment of fatigue and hypersomnia associated with depression. 39th Annu Meet Am Coll Neuropsychopharmacol, San Juan, P.R., USA, 2000.
81.
DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR: Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 2003;64:1057–1064.
82.
Fava M, Thase ME, DeBattista C: A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 2000;66:85–93.
83.
Ninan PT, Hassman HA, Glass SJ, McManus FC: Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue. J Clin Psychiatry 2004;65:414–420.
84.
Ostroff RB, Nelson JC: Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 1999;60:256–259.
85.
Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman PD, Meltzer HY: A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158:131–134.
86.
Adson DE, Kushner MG, Eiben KM, Schulz SC: Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors. Depress Anxiety 2004;19:121–126.
87.
Worthington JJ 3rd, Kinrys G, Wygant LE, Pollack MH: Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients. Int Clin Psychopharmacol 2005;20:9–11.
88.
Papakostas GI, Petersen TJ, Kinrys G, Burns AM, Worthington JJ, Alpert JE, Fava M, Nierenberg AA: Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 2005;66:1326–1330.
89.
Papakostas GI, Petersen TJ, Nierenberg AA, Murakami JL, Alpert JE, Rosenbaum JF, Fava M: Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry 2004;65:217–221.
90.
Dunner DL, Amsterdam JD, Shelton RC, Romano SJ, Loebel A: Adjunctive ziprasidone in treatment-resistant depression: randomized, double-blind, 8-week pilot study. 44th Annu Meet Am Coll Neuropsychopharmacol, San Juan, P.R., USA, 2004.
91.
Nemeroff CB, Gharabawi GM, Canuso CM, Mahmoud R, Loescher A, Turkoz I, Rapaport MH, Gharabawi GM: Augmentation with risperidone in chronic resistant depression: A double-blind placebo-controlled maintenance trial. 44th Annu Meet Am Coll Neuropsychopharmacol, San Juan, P.R., USA, 2004.
92.
Dube S, Andersen S, Paul S: Meta-analysis of olanzapine-fluoxetine use in treatment-resistant depression (abstract P.1.021). J Eur Coll Neuropsychopharmacol 2002;12(suppl 3):S182.
93.
Casey DE: Dyslipidemia and atypical antipsychotic drugs. J Clin Psychiatry. 2004;6(suppl 18):27–35.
94.
Newcomer JW: Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J Clin Psychiatry 2004;65(suppl 18):36–46.
95.
Cheng-Shannon J, McGough JJ, Pataki C, McCracken JT: Second-generation antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol 2004;14:372–394.
96.
Nemets B, Mishory A, Levine J, Belmaker RH: Inositol addition does not improve depression in SSRI treatment failures. J Neural Transm 1999;106:795–798.
97.
Levine J, Mishori A, Susnosky M, Martin M, Belmaker RH: Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry 1999;45:270–273.
98.
Stoll AL, Rueter S: Treatment augmentation with opiates in severe and refractory major depression. Am J Psychiatry 1999;156:2017.
99.
Bodkin JA, Zornberg GL, Lukas SE, Cole JO: Buprenorphine treatment of refractory depression. J Clin Psychopharmacol 1995;15:49–57.
100.
Stahl SM: Basic psychopharmacology of antidepressants. Part 2: estrogen as an adjunct to antidepressant treatment. J Clin Psychiatry 1998;59(suppl 4):15–24.
101.
Shapira B, Oppenheim G, Zohar J, Segal M, Malach D, Belmaker RH: Lack of efficacy of estrogen supplementation to imipramine in resistant female depressives. Biol Psychiatry 1985;20:576–579.
102.
Zohar J, Shapira B, Oppenheim G, Ayd FJ, Belmaker RH: Addition of estrogen to imipramine in female-resistant depressives. Psychopharmacol Bull 1985;21:705–706.
103.
Amsterdam J, Garcia-Espana F, Fawcett J, Quitkin F, Reimherr F, Rosenbaum J, Beasley C: Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affect Disord 1999;55:11–17.
104.
Rasgon NL, Altshuler LL, Fairbanks LA, Dunkin JJ, Davtyan C, Elman S, Rapkin AJ: Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. J Clin Psychiatry 2002;63(suppl 7):45–48.
105.
Schneider LS, Small GW, Hamilton SH, Bystritsky A, Nemeroff CB, Meyers BS: Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Am J Geriatr Psychiatry 1997;5:97–106.
106.
Schneider LS, Small GW, Clary CM: Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry 2001;9:393–399.
107.
Stahl SM: Augmentation of antidepressants by estrogen. Psychopharmacol Bull 1998b;34:319–321.
108.
Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, Roberts E: Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 1999;156:646–649.
109.
Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI: Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:105–111.
110.
Orengo CA, Fullerton L, Kunik ME: Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antidepressant therapy. J Geriatr Psychiatry Neurol 2005;18:20–24.
111.
Alpert JE, Mischoulon D, Nierenberg AA, et al: Nutrition and depression: focus on folate. Nutrition 2000;16:544–546.
112.
Spillmann M, Fava M: S-adenosylmethionine (Ademetionine) in psychiatric disorders: historical perspective and current status. CNS Drugs 1996;6:416–425.
113.
Alpert JE, Mischoulon D, Rubenstein GE, Bottonari K, Nierenberg AA, Fava M: Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry 2002;14:33–38.
114.
Coppen A, Bailey J: Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo-controlled trial. J Affect Disord 2000;60:121–130.
115.
Alpert JE, Papakostas G, Mischoulon D, Worthington JJ 3rd, Petersen T, Mahal Y, Burns A, Bottiglieri T, Nierenberg AA, Fava M: S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol 2004;24:661–664.
116.
Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H: Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res 1992;44:257–262.
117.
Yasmin S, Carpenter LL, Leon Z, Siniscalchi JM, Price LH: Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review. J Affect Disord 2001;63:243–247.
118.
Schmidt do Prado-Lima PA, Bacaltchuck J: Topiramate in treatment-resistant depression and binge-eating disorder. Bipolar Disord 2002;4:271–273.
119.
Otani K, Yasui N, Kaneko S, Ohkubo T, Osanai T, Sugawara K: Carbamazepine augmentation therapy in three patients with trazodone-resistant unipolar depression. Int Clin Psychopharmacol 1996;11:55–57.
120.
Varney NR, Garvey MJ, Cook BL, Campbell DA, Roberts RJ: Identification of treatment-resistant depressives who respond favorably to carbamazepine. Ann Clin Psychiatry 1993;5:117–122.
121.
De la Fuente JM, Mendlewicz J: Carbamazepine addition in tricyclic antidepressant-resistant unipolar depression. Biol Psychiatry 1992;32:369–374.
122.
Hantouche EG, Akiskal HS, Lancrenon S, Chatenet-Duchene L: Mood stabilizer augmentation in apparently ‘unipolar’ MDD: predictors of response in the naturalistic French national EPIDEP study. J Affect Disord 2005;84:243–249.
123.
Rybakowski JK, Suwalska A, Chlopocka-Wozniak M: Potentiation of antidepressants with lithium or carbamazepine in treatment-resistant depression. Neuropsychobiology 1999;40:134–139.
124.
Normann C, Hummel B, Scharer LO, Horn M, Grunze H, Walden J: Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study. J Clin Psychiatry 2002;63:337–344.
125.
Barbosa L, Berk M, Vorster M: A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry 2003;64:403–407.
126.
Wong IC, Lhatoo SD: Adverse reactions to new anticonvulsant drugs. Drug Saf 2000;23:35–56.
127.
Cates M, Powers R: Concomitant rash and blood dyscrasias in geriatric psychiatry patients treated with carbamazepine. Ann Pharmacother 1998;32:884–887.
128.
Nolen WA, Haffmans PM, Bouvy PF, Duivenvoorden HJ: Hypnotics as concurrent medication in depression. A placebo-controlled, double-blind comparison of flunitrazepam and lormetazepam in patients with major depression, treated with a (tri)cyclic antidepressant. J Affect Disord 1993;28:179–188.
129.
Smith WT, Londborg PD, Glaudin V, Painter JR: Is extended clonazepam cotherapy of fluoxetine effective for outpatients with major depression? J Affect Disord 2002;70:251–259.
130.
Asnis GM, Chakraburtty A, DuBoff EA, Krystal A, Londborg PD, Rosenberg R, Roth-Schechter B, Scharf MB, Walsh JK: Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry 1999;60:668–676.
131.
Fava M, Buysse DJ, Rubens R, Wessel T, Caron J, Roth T: Eszopiclone coadministered with fluoxetine for insomnia-associated with major depressive disorder (MDD): Effects on sleep and depression. 45th Annu NCDEU Meet, Boca Raton, Fla., USA, 2005.
132.
Terzano MG, Rossi M, Palomba V, Smerieri A, Parrino L: New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf 2003;26:261–282.
133.
Roehrs T, Roth T: Hypnotics: an update. Curr Neurol Neurosci Rep 2003;3:181–184.
134.
Moller HJ: Effectiveness and safety of benzodiazepines. J Clin Psychopharmacol 1999;19(suppl 2):S2–S11.
135.
Fredman SJ, Fava M, Kienke AS, White CN, Nierenberg AA, Rosenbaum JF: Partial response, non-response, and relapse on SSRIs in major depression: a survey of current ‘next-step’ practices. J Clin Psychiatry 2000;61:403–407.
136.
Bodkin JA, Lasser RA, Wines JD Jr, Gardner DM, Baldessarini RJ: Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. J Clin Psychiatry 1997;58:137–145.
137.
Ramasubbu R: Treatment of resistant depression by adding noradrenergic agents to lithium augmentation of SSRIs. Ann Pharmacother 2002;36:634–640.
138.
Kennedy SH, McCann SM, Masellis M, McIntyre RS, Raskin J, McKay G, Baker GB: Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry 2002;63:181–186.
139.
DeBattista C, Solvason HB, Poirier J, Kendrick E, Schatzberg AF: A prospective trial of bupropion SR augmentation of partial and non-responders to serotonergic antidepressants. J Clin Psychopharmacol 2003;23:27–30.
140.
Lam RW, Hossie H, Solomons K, Yatham LN: Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression. J Clin Psychiatry 2004;65:337–340.
141.
Carpenter LL, Jocic Z, Hall JM, Rasmussen SA, Price LH: Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry 1999;60:45–49.
142.
Carpenter LL, Yasmin S, Price LH: A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry 2002;51:183–188.
143.
Debonnel G, Gobbi G, Turcotte J, DeMontigny C, Blier P: The alpha-2 antagonist mirtazapine combined with the SSRI paroxetine induces a greater antidepressant response: a double-blind controlled study. 39th Annu Meet Am Coll Neuropsychopharmacol, San Juan, P.R., USA, 2000.
144.
Lauritzen L, Clemmesen L, Klysner R, Loldrup D, Lunde M, Schaumburg E, Waarst S, Bech P: Combined treatment with imipramine and mianserin. A controlled pilot study. Pharmacopsychiatry 1992;25:182–186.
145.
Medhus A, Heskestad S, Thue JF: Mianserin added to tricyclic antidepressants in depressed patients not responding to a tricyclic antidepressant alone. A randomized, placebo-controlled, double blind study. Nord J Psychiatry 1994;48:355–358.
146.
Ferreri M, Lavergne F, Berlin I, Payan C, Puech AJ: Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatr Scand 2001;103:66–72.
147.
Licht RW, Qvitzau S: Treatment strategies in patients with major depression not responding to first-line sertraline treatment. A randomised study of extended duration of treatment, dose increase or mianserin augmentation. Psychopharmacology (Berl) 2002;161:143–151.
148.
Nelson JC, Mazure CM, Bowers MB, Jatlow P: A preliminary open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry 1991;48:303–307.
149.
Nelson JC, Mazure CM, Jatlow PI, Bowers MB Jr, Price LH: Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study. Biol Psychiatry 2004;55:296–300.
150.
Weilburg JB, Rosenbaum JF, Meltzer-Brody S, Shushtari J: Tricyclic augmentation of fluoxetine. Ann Clin Psychiatry 1991;3:209–214.
151.
Zajecka JM, Jeffries H, Fawcett J: The efficacy of fluoxetine combined with heterocyclic antidepressant in treatment-resistant depression: a retrospective analysis. J Clin Psychiatry 1995;56:338–343.
152.
Hawley CJ, Sivakumaran T, Ochocki M, Bevan J: Co-administration of reboxetine and serotonin selective reuptake inhibitors in treatment-resistant patients with major depression. 39th Annu Meet Am Coll Neuropsychopharmacol, San Juan, P.R., USA, 2000.
153.
Dursun SM, Devarajan S: The efficacy and safety of reboxetine plus citalopram in treatment-resistant depression – An open, naturalistic case series. 39th Annu Meet Am Coll Neuropsychopharmacol, San Juan, P.R., USA, 2000.
154.
Lucca A, Serretti A, Smeraldi E: Effect of reboxetine augmentation in SSRI resistant patients. Hum Psychopharmacol 2000;15:143–145.
155.
Milosavljevic N, Schecter JM, Price LH, Carpenter LL: Antidepressant augmentation with open-label atomoxetine. APA Annu Meet, New York, N.Y., USA, 2004.
156.
Taylor FB, Prather MR: The efficacy of nefazodone augmentation for treatment-resistant depression with anxiety symptoms or anxiety disorder. Depress Anxiety 2003;18:83–88.
157.
Nierenberg AA, Cole JO, Glass L: Possible trazodone potentiation of fluoxetine: a case series. J Clin Psychiatry 1992;53:83–85.
158.
Maes M, Vandoolaeghe E, Desnyder R: Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord 1996;41:201–210.
159.
Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M: Trazodone for antidepressant-associated insomnia. Am J Psychiatry 1994;151:1069–1072.
160.
Smith DL, Wenegrat BG: A case report of serotonin syndrome associated with combined nefazodone and fluoxetine. J Clin Psychiatry 2000;61:146.
161.
Stewart DE: Hepatic adverse reactions associated with nefazodone. Can J Psychiatry 2002;47:375–377.
162.
Cassano P, Fava M: Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004;16:15–25.
163.
Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, Quitkin FM, Wisniewski S, Lavori PW, Rosenbaum JF, Kupfer DJ; for the STAR*D Investigators Group: Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Psych Clin North Am 2003;26:1–38.
164.
Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G; STAR*D Investigators Group: Sequenced Treatment Alternatives to Relieve Depression (STAR*D): rationale and design. Control Clin Trials 2004;25:119–142.
165.
Thase ME, Rush AJ, Howland RH, Kornstein SG, Kocsis JH, Gelenberg AJ, Schatzberg AF, Koran LM, Keller MB, Russell JM, Hirschfeld RM, La Vange LM, Klein DN, Fawcett J, Harrison W: Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry 2002;59:233–239.
166.
McGrath PJ, Stewart JW, Nunes EV, Ocepek-Welikson K, Rabkin JG, Quitkin FM, Klein DF: A double-blind crossover trial of imipramine and phenelizine for outpatients with treatment-refractory depression. Am J Psychiatry 1993;150:118–123.
167.
Fava GA, Ruini C: What is the optimal treatment of mood and anxiety disorders? Clin Psychol Sci Pract 2005;12:92–96.
168.
Moncrieff J, Cohen D: Rethinking models of psychotropic drug action. Psychother Psychosom 2005;74:145–153.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.