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Treatment-Resistant Depression -- Part I: Introduction and Clinical Presentations

 

 

 

John P. O’Reardon, MD
Associate Professor of Psychiatry; Director, Treatment-Resistant Depression Clinic, University of Pennsylvania

 

First published in Psychiatry Weekly, March 23, 2009

This is the first installment of a three-part series covering treatment-resistant depression. Part II will be released on March 30, 2009.

 

CME Course Director

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

Accreditation Statement

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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

Treatment-resistant depression (TRD) is defined as the failure of an episode of major depression to respond fully to the adequate administration of a treatment that is known to be effective. TRD comprises many different clinical scenarios, including bipolar and unipolar depression, and known adequate treatments include psychotherapeutic and pharmacotherapeutic regimens. The severity of TRD ranges from one failed episode of treatment to multiple failed episodes. More severe cases of TRD can be treated with multiple medication augmentations, medication switches, or somatic treatments, such as electroconvulsive therapy, vagus nerve stimulation, and transcranial magnetic stimulation.

With the exception of these somatic treatments, no therapies are studied specifically for TRD; very few clinical trials recruit treatment-resistant cohorts. The clinician must, therefore, consider previously established treatment data; comorbidities on Axis I, II, and III; chronic depression, and the presence of psychotic or bipolar depression. It is also important for the clinician to distinguish between lack of response to treatment (response defined as >50% reduction in symptoms) and failed administration of an adequate treatment.

TRD that fails to respond to multiple treatment episodes is particularly troublesome. The more levels of treatment required to attain response or remission, the greater the risk of subsequent relapse, suggesting that heightened vigilance and strong treatment management are tantamount to improved chances of success in treating TRD.

Target Audience

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

Learning Objectives

  • Define treatment-resistant depression and how it relates to therapy, treatment response, and a spectrum of severity so that patients are accurately diagnosed with TRD
  • Recognize the varying presentation of TRD alone and with comorbidities to ensure appropriately managed treatment
  • Identify ongoing challenges in treating TRD of unknown cause in order to formulate strategies to proactively manage this condition

Faculty Disclosure

John P. O’Reardon, MD, is a consultant to Bristol-Myers Squibb and Eli Lilly; and receives grant/research support from CenRx BioPharma, Cyberonics, and Medtronic.
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 23, 2009

Termination Date: March 31, 2011

 

 

Definition of TRD

Treatment-resistant depression (TRD) may be defined, both pragmatically and clinically, as the failure of an episode of major depression to respond fully to the adequate administration of a treatment that is known to be effective (Table 1).1 It is important for the clinician, in terms of not inadvertently reinforcing stigma, to bear in mind, as the definition indicates, that it is the disease state or episode of depression that is treatment resistant, and not the patient, per se. The treatment that has failed must be a valid one and must also have been delivered effectively before one can conclude that this episode of major depression is resistant to any particular level of treatment.

This particular definition of TRD selected here also helps us to realize that TRD includes not just treatment resistant unipolar depressive episodes, but also bipolar depressive episodes. It also speaks of a treatment being ineffective, rather than specifying pharmacotherapy exclusively.2 Thus, a patient who has not responded to an adequate trial of a known efficacious, depression-specific psychotherapy (cognitive therapy, interpersonal therapy) or, for that matter, electroconvulsive therapy (ECT), should also be viewed as being in a treatment resistant depressive episode. This approach makes more practical sense than one that narrowly defines TRD as only those patients with unipolar major depression who have not achieved remission in response to pharmacotherapy alone.

TRD exists on a spectrum of severity in the clinic (Figure).3 It ranges from, at one end of the spectrum, a mild or early degree of documented resistance to standard treatment, to very severe levels of resistance at the other end of the spectrum. Patients who have not responded fully to a single adequate treatment trial are in the early or mild stages of TRD. More severe cases are patients who have had multiple attempts at treatment, including combinations and augmentations of medications and psychotherapy, and up to and including ECT.4,5

figure

Finally, patients may respond to a treatment (conventionally defined as >50% reduction in symptoms or “much improved” compared to baseline) but without achieving a complete response, namely remission (“very much improved” compared to baseline). Although, a response is clearly better than non-response, by our TRD definition above, responders who stop short of remission would still be viewed appropriately as being only partially rather than fully well. Non-remitting responders are thus part of the TRD spectrum of illness until such time as remission from the current depressive episode is attained.

TRD in Routine Clinical Practice

As more depression is treated on a first line basis in primary care settings, psychiatrists increasingly encounter cases of TRD in their own practice that have not responded to first line interventions, thus requiring more intensive management by the psychiatrist. At the same time, most antidepressants and psychotherapies have been studied largely in study populations not recruited as treatment resistant cohorts.6 In this regard, none of our antidepressants are specifically approved by the FDA for the treatment of TRD. The only treatments specifically studied in such populations are the somatic treatments—ECT,7 vagus nerve stimulation,8 and transcranial magnetic stimulation.9 Therefore, there is a large evidence gap between the therapeutic needs of actual patients versus what has been studied and shown to be efficacious, in randomized, placebo-controlled, clinical trials.

Clinical Scenarios

Pseudo-TRD

In the practice setting, the clinician will see TRD patients in a variety of guises, including pseudo-TRD. There are some patients who putatively appear as though they have not responded to treatment, but, upon further examination, it is apparent that adequate treatment, in terms of dose or duration of antidepressant (or number of psychotherapy sessions) has not really been delivered to date. This is often due to the treatment course being abandoned prematurely by the patient or treating physician

Poor tolerability to antidepressants is a common clinical problem.10 With selective serotonin reuptake inhibitors now as the de facto first line agents in clinical practice,3 intolerance is more often the problem with treatment delivery than an inadequate dose being prescribed for too short a period. Each of these instances of intolerance and non-adherence, as described here, are examples of failed treatment delivery, rather than true treatment resistance.

True-TRD and its Causes

In clinical practice, however, many patients appear to be true TRD cases and indeed resistant to various levels of adequately delivered treatment. Management of true TRD begins with a search of its causes and contributors in each individual case (Table 2).

Comorbidity

Severity of illness due to medical or psychiatric co-morbidity is a very common cause of treatment resistance in clinical practice. Comorbidity can, of course, exist on one or more of Axes I through III. An early task for the clinician dealing with TRD is to identify comorbidity and treat it appropriately. Accurate diagnosis is the cornerstone of treatment and rests on thorough history taking and evaluation of data.

Axis I Comorbidity

Anxiety disorders are the most common comorbidity observed on Axis I in major depression, most frequently social phobia, generalized anxiety disorder and posttraumatic stress disorder. Anxiety disorders are present in ~50% of cases of major depression and can be important predictors of negative outcomes of treatment.11 Anxiety-specific therapies, including psychotherapies, or medications such as buspirone or benzodiazepines, are often indicated and helpful.12,13

Axis II Comorbidity

Axis II disorders co-exist in up to 30% of patients with a TRD course,14 with a second personality disorder also occurring in most cases with one Axis II disorder. Such a high prevalence of Axis II disorders speaks strongly to the need for, and utility of, combined psychotherapy and pharmacotherapy in the majority of TRD cases.15 The most common dimension on which Axis II disorders occur is the C cluster—avoidant, dependant, and obsessive compulsive personality disorders. Such patients, while presenting as TRD, might be more accurately construed as a special form of TRD where the etiology has distinct characterological, as well as biological, contributions, also distinguishing it from major depression without axis II comorbidity, in terms of effective treatment approaches.

Axis III Comorbidity

Medical disorders are well known contributors to TRD.16 The commonest diagnosis we make in our TRD clinic is not, in fact, thyroid disease, but rather sleep apnea. Patients complaining of fatigue and insomnia, and who have experienced weight gain, should be questioned about symptoms consistent with sleep apnea. A polysomnogram is definitive in either ruling in or ruling out this disorder.

Chronic Depression and TRD

There are also forms of major depressive episodes that are very challenging to treat and are commonly found within the TRD patient cohort (Table 3). For example, a 10-year, long term follow-up of a population of TRD patients indicates that ~18% of those who develop a major depressive episode are still in the same episode two years later (with treatment as usual), indicating that ~1 in 5 will meet criteria for a chronic depressive episode.17 Once an episode of major depression has become chronic, the chances of responding successfully to any specific intervention declines.18 Response rates to antidepressants tend to be highest during the first year of treatment.18

Psychotic Depression and TRD

Psychotic depression responds poorly to monotherapy antidepressants, with a response rate of only about 30%.19 With the addition of a neuroleptic this response rate doubles to 70%.19 Thus, if there is a clinical failure to recognize that a depressive episode has concomitant psychotic features, then adequate treatment will be delayed.19 With a treatment response rate of ~90%, ECT, however, remains as a highly robust treatment option for pharmacotherapy-resistant cases of psychotic depression.20

Bipolar Disorder and TRD

Another common clinical scenario is the failure to recognize bipolar disorder in the context of a depressive episode not responding to antidepressants. When patients have been fully assessed with a Structured Clinical Interview for DSM-IV examination, following a referral to a specialty mood disorders clinic as TRD, as many as one-third may have already experienced either a hypomanic or manic episode in the past, thus making bipolar disorder—rather than depression—the correct diagnosis.21 Use of a screening instrument for bipolar disorder in the clinic, such as the Mood Disorders Questionnaire, combined with careful clinical assessment, has been helpful in reducing this problem, based on experience in our TRD clinic.22 It is also recognized, rightly, that there are errors of commission—as well as of omission—when it comes to diagnosing bipolar disorder correctly. A positive result on the MDQ is simply a positive screen and must be evaluated further before a firm conclusion can be drawn.

TRD of Unknown Cause

Often, clinicians will be left with the difficult scenario of having identified no clear cause that explains a particular patient’s treatment resistant course of illness. Even after looking dutifully for and treating comorbidity, and settling the question of bipolar illness, there will still be a large group of patients who have been diagnosed and treated correctly. A common, frustrating clinical situation is one where a patient responded reasonably well initially to antidepressants or mood stabilizers, but subsequently finding that the efficacy of such treatments diminish over the long term. Future studies on the genetics of TRD may cast light on polymorphisms relevant to non-response to standard treatment.

For now, the clinician managing the more severe manifestations of TRD is often dealing in the clinic with what might be called—from a therapeutic standpoint—serial tachyphylaxis. By this it is meant that an antidepressant or mood stabilizer treatment work well initially for a period of time, but then ultimately stops working for unclear reasons. This was manifest in the STAR*D trial23 where it was found that about two-thirds of subjects who had achieved remission of depression over the first year subsequently experienced a relapse or recurrence during follow-up over the next year. A major predictor of relapse/recurrence propensity was the degree of resistance exhibited before remission was achieved (as reflected in the number of trials or levels of treatment that needed to reach the point of remission of depression), or attaining response to treatment but still falling short of remission status.

In summary, clinicians must be vigilant in the recognition of TRD, and proactive in its management, to achieve the best outcomes for this patient population.


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References

  1. O’Reardon JP, Amsterdam JD. Treatment-resistant depression: progress and limitations. Psychiatric Annals. 1998;28:633-640.

  2. O’Reardon JP, Amsterdam JD. Overview of treatment-resistant depression and its management. In: Amsterdam JD, Hornig M, Nierenberg AA, eds. Treatment-resistant Mood Disorders. Cambridge; NY: Cambridge University Press; 2001:30-46.

  3. O’Reardon JP, Brunswick DJ, Amsterdam JD. Treatment-resistant depression in the age of serotonin: evolving strategies. Curr Opin Psychiatry. 2000;13(1):93-98.

  4. Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):26-31.

  5. Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):10-17.

  6. Khan A, Schwartz K. Study designs and outcomes in antidepressant clinical trials. Essential Psychopharmacol. 2005;6(4):221-226.

  7. Prudic J, Haskett RF, Mulsant B, et al. Resistance to antidepressant medications and short-term clinical response to ECT. [see comment] Am J Psychiatry. 1996;153(8):985-992.

  8. George MS, Rush AJ, Marangell LB, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005;58(5):364-373.

  9. O’Reardon JP, Solvason H, Janicak P, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multi-site randomized controlled trial. Biol Psychiatry. 2007;62(11):1208-1216.

  10. Souery D, Amsterdam J, de Montigny C, et al. Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999;9(1-2):83-91.

  11. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice.[see comment] Am J Psychiatry. 2006;163(1):28-40.

  12. Borkovec TD, Ruscio AM. Psychotherapy for generalized anxiety disorder. J Clin Psychiatry. 2001;62(suppl 11):37-42; discussion 43-45.

  13. Pollack MH. Comorbid anxiety and depression. J Clin Psychiatry. 2005;66(suppl 8):22-29.

  14. Petersen T, Hughes M, Papakostas GI, et al. Treatment-resistant depression and Axis II comorbidity. Psychother Psychosom. 2002;71(5):269-274.

  15. Thase ME, Friedman ES, Howland RH. Management of treatment-resistant depression: psychotherapeutic perspectives. J Clin Psychiatry. 2001;62(suppl 18)8:18-24.

  16. Yates WR, Mitchell J, Rush AJ, et al. Clinical features of depressed outpatients with and without co-occurring general medical conditions in STAR*D. Gen Hosp Psychiatry. 2004;26(6):421-429.

  17. Keller MB, Klerman GL, Lavori PW, et al. Long-term outcome of episodes of major depression. Clinical and public health significance. JAMA. 1984;252(6):788-792.

  18. Solomon DA, Keller MB, Leon AC, et al. Recovery from major depression. A 10-year prospective follow-up across multiple episodes. Arch Gen Psychiatry. 1997;54(11):1001-1006.

  19. Rothschild AJ. Challenges in the treatment of depression with psychotic features. Biol Psychiatry. 2003;53(8):680-690.

  20. Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE. J ECT. 2001;17(4):244-253.

  21. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry. 2000;61(10):804-808;quiz 809.

  22. Miller CJ, Klugman J, Berv DA, Rosenquist KJ, Ghaemi SN. Sensitivity and specificity of the Mood Disorder Questionnaire for detecting bipolar disorder. J Affect Disord. 2004;81(2):167-171.

  23. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.

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