Innovations Psychother Psychosom 2006;75:139–153 DOI: 10.1159/000091771 Current Status of Augmentation and Combination Treatments for Major Depressive Disorder: A Literature Review and a Proposal for a Novel Approach to Improve Practice a b Maurizio Fava A. John Rush a Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, b Boston, Mass. , and UT Southwestern Medical School, Dallas, Tex. , USA Key Words rates since the lack of response with antidepressant Augmentation therapy Combination therapy monotherapy may lead many depressed patients with Antidepressant-resistant depression Remission little or no benefi t to drop out of treatment, precluding the subsequent use of augmentation or combination strategies altogether. In addition, the emergence of cer- Abstract tain side-effects (e.g., agitation, insomnia) or the persis- Most patients with major depressive disorder (MDD) do tence of some initial baseline symptoms (e.g., anxiety, not reach symptom remission. These patients with re- insomnia) may lead to premature discontinuation from sidual symptoms have worse function and worse prog- monotherapy in the absence of concomitant use of aug- nosis than those who remit. Several augmentation and menting pharmacological options targeting these symp- combination treatments are used to either increase the toms. chances of achieving remission or to eliminate/minimize Copyright © 2006 S. Karger AG, Basel residual depressive symptoms. Evidence for these phar- macological approaches rests primarily on open, uncon- trolled studies, and there are clearly not enough con- Treatment-resistant depression typically refers to the trolled studies. Clinicians should carefully weigh these presence of an inadequate clinical response following ad- different treatment options to increase their patients’ equate antidepressant therapy among patients suffering chances of achieving and sustaining remission from de- from major depressive disorder (MDD). While the more pression. This paper will review the pertinent studies and traditional view of treatment resistance has focused on will propose a novel approach to improve practice in- nonresponse (i.e., patients with minimal or no improve- volving the use of augmentation or combination strate- ment), ‘inadequate response’ is now viewed as the lack of gies at the outset of initial treatment to primarily enhance symptom remission. Achieving remission is a signifi cant the chances of remission through synergy and/or a clinical challenge [1] , as a signifi cant proportion of pa- broader spectrum of action. This novel approach could tients with MDD do not achieve full remission despite potentially enhance retention and/or increase remission adequate treatment and (for some) signifi cant symptom © 2006 S. Karger AG, Basel Maurizio Fava, MD Depression Clinical and Research Program, Massachusetts General Hospital Fax +41 61 306 12 34 Bulfi nch 351-55 Fruit Street E-Mail [email protected] Accessible online at: Boston, MA 02114 (USA) www.karger.com www.karger.com/pps Tel. +1 617 724 0838, Fax +1 617 726 7541, E-Mail [email protected] Downloaded by: Llumc.CP 11105 Loma Linda Univ. 151.112.124.130 - 3/13/2014 10:04:42 PM improvement [2]. In fact, pooled analyses of double-blind Psychoeducational materials and an emphasis on the im- antidepressant effi cacy trials in typically uncomplicated portance of communication and collaboration may help (i.e., minimal general medical and psychiatric comorbid- set the stage for meaningful dialogue. Psychoeducation ity), nonchronic depressions treated under research clin- may therefore increase the degree of collaboration be- ic conditions reveal that remission rates range between tween the patient and the treating clinician and may en- 30 and 45%, so that the majority of MDD patients are hance the acceptability of any subsequently proposed expected to fail to achieve remission with a single trial of treatment approach. monotherapy with antidepressants [3] . Patients who do (2) Enhancing treatment adherence. Adequate follow- not achieve remission, including those who respond (e.g., up with patients (offi ce visits or phone contacts) is known experience a 650% reduction of symptoms) but do not to lead to better adherence to treatment [9] . In certain remit, continue to be affected by psychological, behav- settings (e.g., primary care), improved care management ioral, and somatic residual symptoms [4] , including de- can greatly improve treatment adherence [10] . Antide- pressed mood, reduced levels of interest, excessive guilt, pressants with relatively greater tolerability, fewer side- fatigue, sleep disturbances, appetite changes, and pain. effects, or that require only once-a-day dosing, also can Even among 108 patients who had reached ‘remission’ enhance adherence. It is important to discuss possible based on the convention of a 17-item Hamilton Rating side-effects that may occur during antidepressant treat- Scale for Depression (HAM-D) score !8, 25.9% had 1 ment and possible approaches to their management, residual symptom, and 56.5% had 2 or more symptoms should they occur, even before prescribing a treatment. [4] . Engaging the patient in the choice of the medication and Relapse and recurrence after successful treatment of in discussing the relative risk of potential side-effects is MDD is both common and debilitating [5] . Patients with thought to also enhance patient engagement in the treat- MDD who do not achieve complete symptom remission ment process [11] . are particularly vulnerable to relapse [6–8] . For example, (3) Ensuring adequacy of antidepressant dose. Al- in a 15-month study of long-term outcome of treatment though antidepressant medications are typically admin- of depression, Paykel et al. [6] followed 60 patients with istered at doses within recommended therapeutic ranges, major depression in remission. Relapses occurred within some patients may require doses well above the therapeu- the fi rst 10 months of follow-up in 76% (13/17) of patients tic range in order to remit. Monitoring antidepressant with residual symptoms but in only 25% (10/40) of pa- blood levels may be useful for patients who are not re- tients without residual symptoms. Taken together, these sponding and do not report side-effects, even with the data strongly support the need to improve the treatment newer antidepressants for which there is no clear blood of depression to achieve higher rates of remission and to level-response relationship. eliminate residual symptoms. (4) Ensuring adequacy of antidepressant treatment du- ration. Most patients require 6–12 weeks of treatment to achieve adequate response [12] . On the other hand, stud- Treatment Tactics to Increase Remission ies have shown that minimal improvement by week 4 or Rates with Antidepressant Monotherapy 5 leads to a very small chance of response [12, 13] . In fact, a study from our group has demonstrated that nonre- Clinicians can employ several treatment tactics to in- sponse as early as week 4 or 6 predicted poor outcome at crease the chances of achieving full remission with anti- week 8 [13] . These fi ndings suggest that, in general, clini- depressant monotherapy. These include (1) psycho-edu- cians must consider taking action, if at least minimal cation, (2) enhancing treatment adherence, (3) ensuring symptom improvement has not occurred by weeks 5 or 6 adequacy of antidepressant dose, (4) ensuring adequacy with an adequate dose. Improved longer-term outcomes of antidepressant treatment duration, (5) choosing anti- may be achieved with longer courses of treatment, per- depressant medications with relatively greater effi cacy in haps especially for the chronic or comorbidly ill pa- specifi c subtypes or populations, and (6) adding psycho- tients. therapy. (5) Choosing antidepressant treatments with relatively (1) Psychoeducation. It is considered quite helpful to greater effi cacy in specifi c subtypes or populations. Re- explain to patients that depression is a medical illness that mission rates tend to be comparable across the different is associated with changes in brain functioning and that antidepressant medications and classes. The chances of antidepressants are used to help improve brain function. remission, however, may be enhanced by choosing agents Psychother Psychosom 2006;75:139–153 140 Fava/Rush Downloaded by: Llumc.CP 11105 Loma Linda Univ. 151.112.124.130 - 3/13/2014 10:04:42 PM with relatively greater effi cacy in a specifi c depressive treatment, precluding the use of augmentation or combi- subtype. For example, dual-action antidepressants, act- nation altogether, and (4) the emergence of certain side- ing to inhibit the reuptake of both serotonin and norepi- effects (e.g., agitation, insomnia) or persistence of some nephrine, have been associated with higher remission initial baseline symptoms (e.g., anxiety, insomnia) may rates than certain single-action selective serotonin reup- lead to premature discontinuation from monotherapy take inhibitors (SSRIs) among patients with melancholic/ without pharmacological options to deal with these symp- endogenous depression [3, 14] . toms. In addition, such initial combinations may create (6) Adding psychotherapy. Recent evidence indicates a broader spectrum of action (i.e., a larger proportion of that for those who respond but do not remit to a medica- patients initially treated may at least respond if not re- tion, cognitive therapy not only removes the residual mit). Finally, the pharmacological synergism achieved symptoms but