Most of the literature on Treatment Resistant Depression (TRD) has based its definition of resistance on the failure to respond to antidepressant drug treatment of adequate dose and duration. The prevalence of TRD is lowest in primary care settings and progressively increases in outpatient psychiatry settings, inpatient psychiatric settings, and academic/tertiary care settings. Strategies available for the treatment of TRD include optimization, substitution or switching, combination, and augmentation therapies. Currently there are no clear guidelines on when to substitute, combine, or augment therapies in the treatment of patients with TRD. Some new and novel therapies that show promise for the future include addition of an atypical antipsychotic to the initial antidepressant; newer pharmacologic interventions; and non-pharmacologic therapies such as vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS). The newer models of interpersonal, cognitive, and behavioral therapies offer structured, pragmatic methods to work with such difficult patients. Guidelines for psychotherapeutic intervention for TRD suggested that the therapy should be collaborative and centered on the goal of teaching new skills to improve coping with a chronic illness. A better understanding of the many facets of the etiology of TRD as well as the availability of new and effective therapies hopefully will decrease the morbidity and mortality associated with this condition.
Trivedi, M.H., Fava, M., Wisniewski, S.R. et al. (2006). STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med, 354, 1243-1252.
Rush, A.J., Kraemer, H.C., Sackeim, H.A., et al. (2006). Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology, 31(9), 1841–53.
Kessler, R.C., Chiu, W.T., Demler, O., et al. (2005). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry, 62, 617–27.
Berlim, M.T. and Turecki, G. (2007) Definition, Assessment, and Staging of Treatment–Resistant Refractory Major Depression: A Review of Current Concepts and Methods. Can J Psychiatry 2007; 52: 46–54
Souery D, Lipp O, Massat I, Mendlewicz J. (2001). The characterization and definition of treatment-resistant mood disorders. In: Amsterdam JD, Hornig M, Nierenberg AA, editors. Treatment-Resistant mood disorders. New York (NY): Cambridge University Press; p 3–29.
Krishnan V. and Nestler E.J. (2008) The molecular neurobiology of depression. NATURE, 455:16
Thase & Rush, 1997
Petersan et al. (2005). Empirical testing of two models for staging antidepressant treatment resistant resistance. J Clin Psychopharmachol, 25(4), 336-341.
Nierenberg et al (1995),
Petersen, T., Papakostas, G.I., Bottonari, K., Iacoviello, B., Alpert, J.E., Fava, M. et al. (2002a). NEO-FFI factor scores as predictors of clinical response to fluoxetine in depressed outpatients. Psychiatry Res, 109, 9–16.
Bellivier, F., Roy, I., Leboyer, M. (2002). Serotonin transporter gene polymorphisms and affective disorder-related phenotypes. Curr Opin Psychiatry, 15, 49–58.
Pollock, B.G., Ferrell, R.E., Mulsant, B.H., Mazumdar, S., Miller, M., Sweet, R.A. et al. (2000). Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology, 23, 587–590.
Zanardi, R., Benedetti, F., Di Bella, D., Catalano, M., Smeraldi, E. (2000). Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol, 20, 105–107.
Serretti, A., Zanardi, R., Rossini, D., Cusin, C., Lilli, R., Smeraldi, E. (2001). Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity. Mol Psychiatry 6: 586-592.
Kim, D.K., Lim, S.W., Lee, S., Sohn, S.E., Kim, S., Hahn, C.G., Carroll, B.J. (2000). Serotonin transporter gene polymorphism and antidepressant response. Neuroreport, 11, 215–219.
Southam-Gerow MA, Kendall PC, Weersing VR. Examining outcome variability: correlates of treatment response in a child and adolescent anxiety clinic. J Clin Child Psychol 2001;30:422–36.
Geller, B. Zimmerman, M., Williams, R., et al. (2001) Bipolar disorder at prospective follow-ups of adults who had prepubertal pubertal major depressive disorder. Am J psychiatry. 158(1) pp. 125-127.
Nemeroff, C.B. et al (2003) Improving antidepressant adherence. J. Clin. Psych. 64 (suppl) 25-30.
Kaminski, K.M., and Garber, J. (2002) Depressive spectrum disorders in high-risk adolescents: episode duration and predictors of time to recovery. J Am Acad Child Adolesc Psychiatry;41: 410–8.
Goodyer, I.M. (2006). Arandomised controlled trial of SSRIs with and without cognitive behaviour therapy in adolescents with major depression. Cambridge, England: NHS Technology Assessment Programme.
Alexopoulos, G.S., Meyers, B.S., Young, R.C., Campbell, S., Silbersweig, D., Charlson, M. (1997). ‘Vascular depression’ hypothesis. Arch Gen Psychiatry, 54, 915–922.
Dew et al.,(2007) outcome of antidepressant therapy in old age group. Am J Psychiatry. 163: 864-866.
Scott, M. et al. (2005). evidence based psychotherapeutic interventions for geriatric depression. PCNA, 805-820.
de Montigny, C. (1994). Lithium addition in treatment-resistant depression. Int Clin Psychopharmacol, 9(Suppl 2), 31-5.
Trivedi, M.H., Rush, A.J., Wisniewski, S.R., et al. (2006). STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement based care in STAR*D: implications for clinical practice. Am J Psychiatry, 163, 28–40.
Du, F., Li, R., Huang, Y., et al. (2005). Dopamine D3 receptorpreferring agonists induce neurotrophic effects on mesencephalic dopamine neurons. Eur. J. Neurosci, 22(10), 2422–30.
Duman, R.S., Role (2004) of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med, 5(1), 11–25.
Patkar, A.A., Masand, P.S., Pae, C.U., et al. (2006). A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J. Clin. Psychopharmacol, 26(6), 653–6.
Davis, L.L., Frazier, E., Husain, M.M., et al. (2006). Substance use disorder comorbidity in major depressive disorder: a confirmatory analysis of the STAR*D cohort. Am. J. Addict, 15(4), 278–85.
Fava, M., Thase, M.E., DeBattista, C. (2005). A multicenter, placebo-controlled study of modafinil augmentation in partialresponders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J. Clin. Psychiatry, 66(1), 85–93.
McGrath, P.J., Stewart, J.W., Fava, M., et al. (2006). Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am. J. Psychiatry, 163(9), 1531–41.
Thase, M.E., Feighner, J.P., Lydiard, R.B. (2001). Citalopram treatment of fluoxetine nonresponders. J. Clin. Psychiatry, 62, 683–7.
Dunner, D.A., Amsterdam, J.D., Shelton, R.C., Hassman, H., Rosenthal, M., Romano, S. (2003). Adjunctive ziprasidone in treatment resistant depression: a pilot study. Poster presented at: annual meeting of the American Psychiatric Association. San Francisco, Calif.
Papakostas, G.I., Peterson, T., Worthington, J. (2003). Ziprasidone augmentation for major depressive disorder rfractory to SSRIs. Poster presented at: annu-al meeting of the American Psychiatric Association, San Francisco, Calif.
Kessler, R.C., Berglund, P., Demler, O., et al. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry, 62(6), 593–602.
Devous, M.D., Husain, M., Harris, T.S., Rush, A.J. (2002). Effects of VNS on regional cerebral blood flow in depressed subjects. Poster presented at the 42nd Annual New Clinical Drug Evaluation Unit
Nahas, Z., Marangell, L.B., Husain, M.M. et al. (2005). Twoyear outcome of vagus nerve stimulation (VNS) for major depressive episodes. J Clin Psychiatry, 66, 1097–1104.
Fitzerald, B.P., Benitez, J., DeCastella, A., et al. (2006). A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression. Am j Psychiatry, 163, 88–94.
Lisanby, S.H., Schlaepfer, T.E., Fisch, H.U., Sackeim, H.A. (2001b). Magnetic seizure induction for the treatment of major depression [letter]. Arch Gen Psychiatry, 58, 303–305.
Lisanby, S.H., Luber, B., Barroilhet, L., Neufeld, E., Schlaepfer, T., Sackeim, H.A. (2001c). Magnetic seizure therapy (MST): Acute cognitive effects of MST compared with ECT. JECT, 17, 77. Abstract 4.
Mayberg, H.S., Lozano, A.M., Voon, V. et al (2005). Deep brain stimulation for treatment-resistant depression. Neuron, 45, 651–660.
Greenberg, B.D., Malone, D.A., Friehs, G.M., et al. (2006). Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology, 31, 2384–93.
Puri, B.K., Counsell, J.K., Hamilton, G. et al. (2001) Ecosapentanoic acid in treatment-resistant depression associated with symptom remission, structural brain change andreduces neuronal phospholipid turnover. Int J Clin Pract. 55:560-563.
Khan et al. (2003) Placebo response and antidepressant trial outcome. J Nerv Ment Dis 19: 211-218.