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Treatment-Resistant Depression -- Part II: Augmentation Strategies

 

 

 

Michael E. Thase, MD
Professor of Psychiatry, University of Pennsylvania

 

First published in Psychiatry Weekly, March 30, 2009

This is the second installment of a three-part series covering treatment-resistant depression. Part III will be released on April 27, 2009.

 

CME Course Director

Dr. James C.-Y. Chou, MD. Associate Professor of Psychiatry at Mount Sinai School of Medicine

Accreditation Statement

Mount Sinai School of Medicine Logo

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

 

Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices.

Statement of Need

When first-line antidepressant strategies fail to bring about response or remission of an episode of depression, clinicians may re-evaluate the patient’s diagnosis, ensure that any or all comorbidities have been diagnosed properly, and assess treatment adherence. A second-line treatment strategy may then be chosen, which may entail a within-class antidepressant switch, an out-of-class switch, or augmenting the first-line antidepressant.

There is a large of body of evidence examining the tolerability and effectiveness of second-line antidepressant treatment strategies. Within-class SSRI switches have shown to be effective and may be better tolerated than an out-of-class switch, due to the prospect of serotonin syndrome.

The major rationale for augmentation is that it builds upon whatever gains have been made with the first treatment trial. An adjunctive treatment may target selected symptoms, such as a benzodiazepine or buspirone for anxiety symptoms, or modafinil for fatigue or lethargy. Lithium augmentation, now uncommon in clinical practice, is the most well-studied augmentation strategy, although there is less data on lithium augmentation with newer SSRIs and SNRIs. The addition of thyroid hormone to an antidepressant may also have a significant additive effect.

There are extensive data on switching or augmenting antidepressants for treatment-resistant episodes of depression. A careful evaluation of each patient’s history, combined with the results of controlled clinical studies, can lead to improved outcomes and safety in clinical practice.

Target Audience

This activity will benefit psychiatrists, hospital staff physicians, and office-based “attending” physicians from the community.

Learning Objectives

  • Compare the efficacy and safety of within- and out-of-class antidepressant switches to augmentation strategies
  • Assess the validity and accuracy of a patient’s current diagnosis and treatment strategy before enacting a second- or third-line switch or augmentation strategy
  • Identify less common, although well-studied, augmentation strategies and how they may be enacted according to safety and efficacy

Faculty Disclosure

Michael E. Thase, MD, has served as a consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon, Sepracor, Shire, Supernus, and Wyeth; is on the speaker’s bureau of AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, sanofi-aventis, Schering Plough, and Wyeth; and has received grant/research funding from Eli Lilly and Sepracor.
James C.-Y. Chou, MD, has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Janssen, and Pfizer.
Sanjay J. Mathew, MD, has served as an advisor/consultant to AstraZeneca and Jazz.

Activity Review Information

The activity content has been peer-reviewed by Sanjay J. Mathew, MD, Assistant Professor of Psychiatry at Mount Sinai School of Medicine. Review Date: February 19, 2009.

Acknowledgement of Commercial Support

Funding for this activity has been provided by an educational grant from Eli Lilly and Company.

To Receive Credit for this Activity

Read this poster, reflect on the information presented, and then complete the CME posttest found in the accompanying brochure or online (mbl.cmeoutreach.com). To obtain credit you should score 70% or better. The estimated time to complete this activity is 1 hour.

Release Date: March 30, 2009

Termination Date: March 31, 2011

 

 

Introduction

When patients do not respond to an initial course of antidepressant treatment, clinicians may opt for a number of alternatives. First, re-evaluating the diagnosis to make sure that no comorbidities were missed, and that the diagnosis of major depressive disorder (MDD) is accurate, particularly with respect to recognition of clinical features that might suggest previously unrecognized bipolarity or psychotic features. Secondly, clinicians should ensure that the patient has adhered to the recommended medication. When finally reaching the point of certainty or near certainty that the patient has not benefited from a truly adequate course of treatment lasting =8 weeks, the next major considerations usually are to either switch antidepressants or to augment the original choice of treatments. Lastly, selection of the most appropriate “next choice” strategy should take into account the tolerability of and degree of improvement observed with the initial antidepressant medications. Many clinicians prefer to switch patients who have poorer tolerability and minimal symptom improvement and try to augment therapy when the initial antidepressant has been well tolerated and resulted in some degree of symptom improvement.

Rationale of Augmentation and Switching Strategies

The major advantage of switching antidepressants this early on in the treatment course is that there is a sizable formulary of other extensively studied first- and second-line antidepressants to consider. There is the additional benefit of choosing medications that are either relatively similar or quite different from the medication that did not work. Since several of the selective serotonin reuptake inhibitors (SSRIs) are widely used as first-line therapies,1 some clinicians prefer two or even three trials within the class before moving on to other strategies. Yet other clinicians opt to leave the SSRI class if the patient has had little or no symptomatic benefit. Serotonin norephinephrine reuptake inhibitors (SNRIs) duloxetine, venlafaxine, and desvenlafaxine and the norepinephrine dopamine inhibitor (NRDI) bupropion, are the medications currently most likely to be used in this situation. One might also consider mirtazapine, one of the tricyclic antidepressants (TCAs), or—if the clinical scenario is right—even a monoamine oxidase inhibitor.

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There is now a fairly extensive literature on within-class SSRI switches. By and large, a within-class SSRI switch can be implemented quickly, and such switches can be surprisingly effective, with an average response rate in open-label studies of ~50%.2-5 The most compelling double-blind study compared switching SSRI non-responders to another SSRI versus switching to mirtazapine.2 There was an advantage of mirtazapine evident in the first few weeks of treatment, although the group that was switched to the SSRI actually caught up by the end of the eighth week of treatment. Tolerability somewhat favored the within-class switch over the between-class switch (Figure 1).

It is important to keep in mind that SSRIs have discontinuation symptoms associated with stopping them, even if cessation is tapered rather than abrupt. This may be one reason for the apparent tolerability advantage of the within-class switch, which is that the second SSRI covers the discontinuation symptoms of the first SSRI.

A somewhat similar result was observed in the STAR*D study, which compared three switch strategies for patients who did not remit following up to 14 weeks of citalopram therapy, including switching to a second SSRI (sertraline) or switching to 2 dissimilar antidepressants—the SNRI venlafaxine, and the NRDI bupropion. The effectiveness of switching to venlafaxine was not statistically superior to that of switching to sertraline, and the numeric difference in remission rates was small—only ~7%.3 The difference between switching to buproprion versus switching to sertraline was even smaller, in the order of ~3%.3 These results suggest that the utility of a within-class switch to an SSRI is comparable to the across class switches—particularly in a study with relatively few inclusion and exclusion criteria, and with enrolled patients who were partial responders, or intolerant, to citalopram, as well as those who were nonresponders. Of note, none of the STAR*D switching strategies were particularly effective for patients who had high levels of anxiety symptoms (Figure 2).6

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Regarding studies other than STAR*D, the best evidence for switching out of class—from an SSRI to the SNRI venlafaxine, in this case—came from one study that was limited to patients who were hospitalized or treated in a partial hospital, where patients with a history of non-response to two different antidepressants were either switched to paroxetine 40 mg/day or venlafaxine 200 mg/day (Figure 3).7 There was a large clinical and statistical advantage in favor of venlafaxine. The difference between the results of STAR*D and those of the Poirer study7 may have to do with the severity of the patients’ depression or their degree of treatment resistance. That is, switching to an SNRI may be of relatively greater advantage for patients with more severe, more highly resistant depressions.

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The major rationale for augmentation is that it builds upon whatever gains have been made with the first treatment trial, and it can enhance the pharmacologic action of the initial treatment when an adjunctive agent is chosen in order to target selected symptoms. For example, a benzodiazapine or buspirone may be added to address anxiety symptoms,8 or modafinil can be prescribed to target residual fatigue or lethargy.9,10 Lithium is the best-studied augmentation strategy, although it is used less today compared to the atypical antipsychotics.11,12 There is also a long history of augmenting TCAs with thyroid hormone, particularly T3, which, of course, should have specific benefit for a patient with subtle hypothyroidism.13 In general, the clinical interest in augmentation strategies lies in the use of these treatments for patients who have shown some partial benefit in the first treatment trial. The goal is to take a 25%–40% level of improvement and bring the patient an additional 20%–40% improvement to get them from somewhat better to, hopefully, full remission.

Lithium Augmentation

The use of lithium augmentation today is relatively infrequent, compared to other less well-studied augmentation strategies, despite its extensive efficacy and safety data. It should be noted that most of the evidence pertaining to the efficacy of lithium augmentation comes from studies done in the 1980s and the 1990s.14 This is important, because the large majority of patients participating in those studies were receiving TCAs, not SSRIs or SNRIs. Therefore, the decline of the popularity of lithium augmentation may simply reflect that the strategy does not work as well in combination with the modern SSRIs or SNRIs as it did in combination with the TCAs, or that psychiatrists have become better at differentiating between so-called unipolar depression and the depressive episodes of bipolar illness. The STAR*D results could be interpreted to support either notion, particularly with the results of patients who did not improve with Level II medications—sertraline, venlafaxine, or bupropion—following an initial Level I non-response to citalopram.15

Overall, the lithium response in STAR*D was very disappointing. Less than 25% of patients responded to lithium augmentation, with a relatively low remission rate.15 However, it is also true that lithium doses in STAR*D were relatively low,15 and plasma level monitoring in STAR*D was relatively infrequent. These observations may simply reflect that physicians today may be unfamiliar with how to use lithium augmentation. For physicians who opt to use lithium augmentation, it is important to consider the significant per individual differences in dose and plasma-level response relationships. Generally, the target dose should deliver a blood level in the order of 0.5–0.7 milliequivalents per liter.16 For the sake of tolerability, doses that lead to blood levels above 0.8 should be avoided.16

Thyroid augmentation

Another conventional augmentation strategy is thyroid augmentation. In a meta-analysis13 of controlled trials of thyroid augmentation, the addition of thyroid hormone was found to have a significant additive effect. As with the original lithium augmentation studies, these thyroid hormone studies were primarily conducted with patients taking TCAs. If thyroid augmentation works by indirectly enhancing noradrenergic neurotransmission, this could represent a potential advantage for combining thyroid hormone with TCAs, since they are potent norepinephrine reuptake inhibitors (Figure 4).

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Thyroid augmentation, like lithium augmentation, has fallen out of favor, too. It certainly would be the augmentation strategy of choice for individuals who have subtle hypothyroidism, including individuals who have a small elevation of thyroid stimulating hormone level with normal or near normal thyroid functions. Thyroid augmentation with T3 was compared with lithium augmentation in STAR*D, and it appeared to be better tolerated and easier to implement, although the difference in response rates was not statistically significant (Figure 5).15

Other Augmentation Strategies

Other augmentation strategies include specific targeting with benzodiazepines and related medications for patients with symptoms of persistent anxiety and/or insomnia.8,9,17

The non-benzodiazapine anxiolytic, buspirone, has had somewhat of a renaissance during the ascendancy of the SSRIs as the leading class of antidepressants. This is largely because buspirone is perceived as augmenting or enhancing the effects of both SSRIs and SNRIs. Controlled studies of buspirone have not convincingly demonstrated it to be a useful augmentation strategy, although buspirone augmentation of citalopram did as well on the primary outcome measure as bupropion augmentation of citalopram in STAR*D (Figure 6).18 Both strategies helped improve ~50% of patients, with remission rates of ~30% for both treatments.18

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There has not been a specific study of benzodiazapine targeting treatment of persistent anxiety in patients taking modern antidepressants, although there is a long history of using benzodiazepines in combination with TCAs. In several recent studies, however, patients who had significant insomnia associated with depression were either started on an SSRI alone, or an SSRI in combination with a benzodiazepine or GABAA selective agent,17 resulting in significantly greater improvement of insomnia or anxiety when compared to SSRI monotherapy.19,20 Given what we know from STAR*D about the poor response of the anxious-depressed patient, it may be beneficial to revisit this strategy as a possibility for future augmentation.


 

To take the free, online CME post-test, go to mbl.cmeoutreach.com


References

  1. Thase ME, Denko T. Pharmacotherapy of mood disorders. Annu Rev Clin Psychol. 2008;4:53-91.

  2. Thase ME, Schutte AJ, van der flier S, Heukels A. Remission with mirtazapine versus SSRIs: a meta-analysis on data of more than 2500 depressed patients treated in randomised controlled trials. J Affect Disord. 2004;78 (suppl 1):S136.

  3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242.

  4. Ruhe HG, Huyser J, Swinkels JA, Schene AH. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry. 2006;67(12):1836-1855.

  5. Thase ME. Therapeutic alternatives for difficult-to-treat depression: a narrative review of the state of the evidence. CNS Spectr. 2004;9(11):808-816, 818-821.

  6. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342-351.

  7. Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant depression. Double-blind, randomised comparison. Br J Psychiatry. 1999;175:12-16.

  8. Sussman N. Anxiolytic antidepressant augmentation. J Clin Psychiatry. 1998;59(suppl 5):42-48; discussion 49-50.

  9. Fava M, Thase ME, DeBattista C, Doghramji K, Arora S, Hughes RJ. Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. Ann Clin Psychiatry. 2007;19(3):153-159.

  10. Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ. Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: a 12-week, open-label, extension study. CNS Spectr. 2006;11(2):93-102.

  11. Carvalho AF, Cavalcante JL, Castelo MS, Lima MC. Augmentation strategies for treatment-resistant depression: a literature review. J Clin Pharm Ther. 2007;32(5):415-428.

  12. DeBattista C. Augmentation and combination strategies for depression. J Psychopharmacol. 2006;20(suppl 3):11-18.

  13. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996;53(9):842-848.

  14. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68(6):935-940.

  15. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530; quiz 1665.

  16. Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19(5):427-434.

  17. Thase ME. Depression and sleep: pathophysiology and treatment. Dialogues Clin Neurosci. 2006;8(2):217-226.

  18. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.

  19. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59(11):1052-1060.

  20. Smith WT, Londborg PD, Glaudin V, Painter JR. Short-term augmentation of fluoxetine with clonazepam in the treatment of depression: a double-blind study. Am J Psychiatry. 1998;155(10):1339-1345.

To take the free, online CME post-test, go to mbl.cmeoutreach.com