Psychiatric Annals

CME Article 

Pharmacologic Strategies for Treatment-resistant Depression: An Update on the State of the Evidence

Michael E. Thase, MD

Abstract

Approximately one-half of patients with depression do not respond to an initial trial of antidepressant therapy, and up to 30% will remain depressed despite multiple treatment trials.1 Such difficult-to-treat depressions consume a disproportionately large share of healthcare resources, cost society billions of dollars each year because of absenteeism, disability, and premature death, and result in incalculable suffering to patients and their families.2–5 Treatment-resistant depression thus continues to be an important public health problem, despite the introduction of a wide range of new therapies during the past 20 years, and should be considered a high priority for therapeutics research.6

Treatment-resistant depression is not a diagnosis. Rather, the term describes an undesirable epoch in the longitudinal course of affective illness.7 Definitions of treatment resistance abound, and some have suggested that nonresponse to two treatments be used as the most inclusive definition, reserving the term “treatment refractory” for those patients who have not responded to all major forms of therapy.

In simplest terms, resistance is best thought of using an analogy from medical microbiology;6 namely, that an episode of illness has not responded to one or more specific types or classes of medication (ie, this patient's depression is resistant to medications A, B, and C). Of course, this analogy is overly simplified and does not take into account the myriad of factors — both pharmacologic and nonpharmacologic — that determine whether a treatment will produce a favorable outcome. For example, even a highly effective medication may appear ineffective if it has been given for too short a time or at too low a dose, or if the patient has not taken the medication as prescribed. Other relevant factors include the accuracy of the diagnosis (both the primary diagnosis and recognition of relevant comorbidities) and the natural history of the disorder.6 Part of the art and skill of treating patients presumed to have treatment-resistant depression is the ability to carefully examine whether any of these factors are relevant and to act accordingly in formulating a treatment plan.

It is also important to keep in mind that the relative efficacy of proven anti-depressant therapies is surprisingly small for the “average” patient. For example, in contemporary 8-week randomized controlled trials of major depressive disorder, while 50% of participants respond to proven antidepressants, approximately 40% respond to double-blind placebo.8 These data indicate that a much larger portion of the therapeutic activity of an antidepressant is attributable to nonspecific factors (eg, placebo-expectancy, spontaneous remission) than the specific pharmacology of that compound. As the likelihood of a placebo response probably decreases across multiple trials, the absolute response rates observed in patients with more advanced cases of treatment-resistant depression can be expected to be quite low. Moreover, other factors that predict a lower probability of placebo response — chronicity, severity, undetected bipolarity, and selected psychiatric and medical comorbidities — tend to be over-represented among patients with treatment-resistant depression.6

Among the several different approaches to classifying treatment-resistant depression that have been suggested,1,9–12 a revised 5-stage classification continues to be used widely.12 In addition to simplicity, the hierarchical structure of this system directly informs choices of alternate therapies (Table 1, see page 972). At the heart of this approach is the clinical reality that different therapies will be considered for a patient who has just failed to respond to a single trial with a selective serotonin reuptake inhibitor (SSRI) than for a patient who did not respond to a course of bilateral electroconvulsive therapy (ECT).

Recommendations for Therapeutic Strategies for Treatment-resistant Depression

Discuss the application of evidence-based medicine principles for treatment-resistant depression.

List the major options for switching and augmenting antidepressants.

Describe…

Approximately one-half of patients with depression do not respond to an initial trial of antidepressant therapy, and up to 30% will remain depressed despite multiple treatment trials.1 Such difficult-to-treat depressions consume a disproportionately large share of healthcare resources, cost society billions of dollars each year because of absenteeism, disability, and premature death, and result in incalculable suffering to patients and their families.2–5 Treatment-resistant depression thus continues to be an important public health problem, despite the introduction of a wide range of new therapies during the past 20 years, and should be considered a high priority for therapeutics research.6

Defining Nonresponse and Resistance

Treatment-resistant depression is not a diagnosis. Rather, the term describes an undesirable epoch in the longitudinal course of affective illness.7 Definitions of treatment resistance abound, and some have suggested that nonresponse to two treatments be used as the most inclusive definition, reserving the term “treatment refractory” for those patients who have not responded to all major forms of therapy.

In simplest terms, resistance is best thought of using an analogy from medical microbiology;6 namely, that an episode of illness has not responded to one or more specific types or classes of medication (ie, this patient's depression is resistant to medications A, B, and C). Of course, this analogy is overly simplified and does not take into account the myriad of factors — both pharmacologic and nonpharmacologic — that determine whether a treatment will produce a favorable outcome. For example, even a highly effective medication may appear ineffective if it has been given for too short a time or at too low a dose, or if the patient has not taken the medication as prescribed. Other relevant factors include the accuracy of the diagnosis (both the primary diagnosis and recognition of relevant comorbidities) and the natural history of the disorder.6 Part of the art and skill of treating patients presumed to have treatment-resistant depression is the ability to carefully examine whether any of these factors are relevant and to act accordingly in formulating a treatment plan.

It is also important to keep in mind that the relative efficacy of proven anti-depressant therapies is surprisingly small for the “average” patient. For example, in contemporary 8-week randomized controlled trials of major depressive disorder, while 50% of participants respond to proven antidepressants, approximately 40% respond to double-blind placebo.8 These data indicate that a much larger portion of the therapeutic activity of an antidepressant is attributable to nonspecific factors (eg, placebo-expectancy, spontaneous remission) than the specific pharmacology of that compound. As the likelihood of a placebo response probably decreases across multiple trials, the absolute response rates observed in patients with more advanced cases of treatment-resistant depression can be expected to be quite low. Moreover, other factors that predict a lower probability of placebo response — chronicity, severity, undetected bipolarity, and selected psychiatric and medical comorbidities — tend to be over-represented among patients with treatment-resistant depression.6

Classification of Treatment Resistance

Among the several different approaches to classifying treatment-resistant depression that have been suggested,1,9–12 a revised 5-stage classification continues to be used widely.12 In addition to simplicity, the hierarchical structure of this system directly informs choices of alternate therapies (Table 1, see page 972). At the heart of this approach is the clinical reality that different therapies will be considered for a patient who has just failed to respond to a single trial with a selective serotonin reuptake inhibitor (SSRI) than for a patient who did not respond to a course of bilateral electroconvulsive therapy (ECT).

An Updated System for Staging Antidepressant Resistance12

Table 1:

An Updated System for Staging Antidepressant Resistance12

Stage I in this system describes non-response to one first-line therapy, which is usually an SSRI. Stage II describes nonresponse to two different first-line interventions; in current practice, this is usually an SSRI followed by either venlafaxine or bupropion. Stages III, IV, and V reflect nonresponse to a tricyclic anti-depressant (TCA), monoamine oxidase inhibitor (MAOI), and ECT, respectively.

Grading the Evidence on Treatment Efficacy

Before one can practice evidence-based medicine, there must be a sufficient number of studies to construct a sturdy empirical base. Table 2 (see page 973) describes the four-grade (A–D) rating system used in this article to evaluate the empirical support for different treatment options for treatment-resistant depression.

Recommendations for Therapeutic Strategies for Treatment-resistant Depression

Table 2:

Recommendations for Therapeutic Strategies for Treatment-resistant Depression

To give this scoring system some context, the United States Food and Drug Administration requires an A level of empirical support (ie, at least two positive, large, randomized placebo-controlled trials) to approve a novel treatment for the indication of depression.8 No therapy recommended for treatment-resistant depression — including ECT — technically meets the standard used by the FDA to approve a new antidepressant. Part of the problem is that it is much harder to conduct controlled trials of treatment-resistant depression than it is to conduct studies in uncomplicated major depressive disorder. One particular issue is selection of a valid comparison group; although double-blind placebo is widely accepted as the best control condition to evaluate the efficacy of a medication, many investigators have ethical concerns about randomizing patients with treatment-resistant depression to placebo.13

Alternate designs often are chosen for studies of resistant depression, with the two-arm randomized controlled trial using an “active” control group representing the most parsimonious choice. For Stage I (ie, SSRI nonresponders) treatment-resistant depression, switching to a second medication within the same class is a conservative yet clinically relevant standard of comparison. After all, if a novel treatment cannot be expected to deliver a better outcome, it makes the most sense to stay within this class of first-line therapies for at least one more treatment trial.

The major limitation of such a pragmatic two-group design is that statistical power is rarely adequate to reliably detect a significant difference, even if one exists. In an era in which the average difference favoring a proven antidepressant over placebo is only 10%, the difference between any pair of effective medications is likely be of the same magnitude or even smaller.8 As such, unless the study is quite large (ie, more than 300 patients per arm), it will not be possible to determine if the conclusion that “the difference between Treatment A and Treatment B is not statistically significant” represents true therapeutic equivalence or a false negative result (also known as Type II error).

If placebo alone is ethically problematic and use of an active comparator is compromised by power problems, are there any alternatives? Designs in which the ineffective first-line therapy is continued occasionally have been used, either by double-blind sham “substitution” of the same medication or by the addition of a placebo to “augment” response. The latter control group is only valid, however, when the study also includes an active augmentation agent. One other as yet untried design that warrants consideration is to provide all patients with psychotherapy and randomize only those who are not responding to therapy to “add-on” treatment with either the active intervention or its matched placebo.

Switching Options

The most widely used pharmacologic strategies for the early stages of resistant depression include switching to another antidepressant in the same class, switching to an antidepressant from a different class, augmenting the antidepressant with another (nonantidepressant) medication, and combining two antidepressants. Psychotherapy, either in combination with the ineffective antidepressant or following its discontinuation, also may be considered,14 although it is beyond the scope of this article to review these options.

Switching Within Class

The within-class switch is not only a methodologically acceptable control group but also clinically relevant. Many practitioners opt for the within-class switch strategy because of its ease of implementation, and the same factors that led to choosing one particular anti-depressant for first-line therapy usually will apply to other members of the same drug class. With the SSRI class specifically in mind, this question arises: are the pharmacokinetic and pharmacodynamic differences among the six “classmates” sufficient to expect one to work when another hasn't?6

More than a decade ago, John Rush and I questioned the utility of the within-class switch strategy for patients who had not responded to an adequate antidepressant trial with another.11 Only a few SSRI switch studies had been conducted at the time, however, and our conclusion was based largely on the older literature concerning TCAs.11 As studies of within-class switching with TCAs generally reported low (ie, lower than 30%) response rates, we reasoned that at least three alternate strategies widely used in the mid-1990s — lithium augmentation, switching to an MAOI, and ECT — could be expected to deliver better outcomes for the average patient.

Subsequent research has led to a reappraisal of the value of switching within the SSRI class. As reviewed elsewhere,6 results of a large number of case series suggest that switching from one SSRI to another can yield response rates up to 60%. Although these “open-label” case series are likely to overestimate the utility of the strategy, results of the only double blind randomized controlled trial,15 which randomly assigned SSRI nonresponders to 8 weeks of double-blind therapy with either sertraline or mirtazapine, indicated identical intent-to-treat response rates of 52%. Thus, the data support a B level of evidence for at least one switch within the SSRI class.

A second relevant randomized controlled trial, conducted as part of the Systematic Treatment Alternative for Relieving Depression (STAR*D) project,16 a large, multicenter, multistage research program sponsored by the National Institute of Mental Health, has recently been completed. For citalopram nonresponders (ie, Stage I treatment-resistant depression), one experiment contrasts a within-class switch to sertraline versus two across-class switches, to either bupropion or venlafaxine. Results will be released in 2006.

Now that there are multiple members of a second class of newer antidepressants — the serotonin norepinephrine reuptake inhibitors (SNRIs), including venlafaxine, duloxetine, and in some countries milnacipran — both case series and randomized controlled trials of switching within the SNRI class also are needed.

Switching Across Classes

When a switch from the SSRI class is indicated, psychiatrists usually opt to switch to an alternate “modern” antidepressant (ie, bupropion, venlafaxine, duloxetine) ahead of the TCAs that were the previous generation's standard of efficacy. This practice preference is entirely based on the greater safety and tolerability of the newer antidepressants, however, not on systematic studies in treatment-resistant depression.6

Among the newer antidepressants, the SNRI venlafaxine is by far the most extensively studied in treatment-resistant depression.6 Although it is true that there is controversy whether or not this “dual” reuptake inhibitor has a therapeutic advantage over the SSRIs for first-line therapy,17,18 it is also true that many psychiatrists have preferentially used venlafaxine for treatment-resistant depression since its introduction.19 There have been three randomized controlled trials of venlafaxine therapy of TRD.20–22 Results of a fourth study, the STAR*D protocol comparing switching from citalopram to extended-release venlafaxine, sertraline, or bupropion, will be available soon.

In the first trial, a double-blind study of inpatients and partial hospital patients with Stage II treatment-resistant depression, switching to the immediate-release formulation of venlafaxine (at a dose of approximately 270 mg/day) resulted in significantly higher remission rates than switching to paroxetine (at a dose of about 36 mg/day).20 The second, more recently completed randomized controlled trial21 is a massive open-label study of more than 3,000 patients with Stage I treatment-resistant depression. The investigators compared a switch to the extended-release formulation of venlafaxine (at a dose of about 150 mg/day) with the switch to doctor's choice of any other antidepressant, including the SSRIs paroxetine, fluoxetine, sertraline, and citalopram. The investigators found a modest but statistically significant advantage for switching to the SNRI compared with other antidepressants, with 6-month remission rates of 59.3% and 51.5% respectively.

In the third randomized controlled trial, patients with Stage I treatment-resistant depression were assigned randomly to 8 weeks of open label therapy with extended-release venlafaxine at either standard (150 mg/day) or higher (300 mg/day) doses.22 Higher dose therapy was found to have a significant advantage on both clinician- and patient-rated measures of response. For example, at week 8, response rates on the Clinical Global Impression scale were 57% and 82% for the lower and higher dose groups, respectively. Remission rates did not differ significantly (25% versus 29%), although there was a trend toward more rapid remission in the group receiving higher dose therapy (P = .10). Tolerability indices, particularly the overall side effect burden, favored the lower dose therapy condition, however, and the group initially treated with lower dose therapy largely “caught up” between weeks 8 and 12, when upward titration was permitted.22

Higher dose venlafaxine therapy thus warrants an A grade for Stage I treatment-resistant depression, although it would be prudent to titrate across 12 weeks to ensure that lower dose therapy has the opportunity to work. In practice, the major limitations of switching from an SSRI to venlafaxine are cost, compared with either a TCA “dual reuptake” inhibitor such as clomipramine or a generic formulation of an alternate SSRI, and the risk of treatment-emergent hypertension, which may be up to 10% when higher doses are used.23

No data are yet available for duloxetine in treatment-resistant depression. If the efficacy of duloxetine (60 mg/day) and extended-release venlafaxine are comparable, the newer drug may have two advantages: a simpler dose-titration schedule, and a lower risk of treatment-emergent hypertension.24

Two other modern antidepressants can be considered “multi-action” agents. The tetracyclic antidepressant mirtazapine enhances serotonin (5-HT) and norepinephrine neurotransmission indirectly via α2 blockade and antagonism of post-synaptic 5-HT2 and 5-HT3 receptors. A number of head-to-head studies have contrasted mirtazapine with SSRIs and venlafaxine as first-line therapies, with results suggesting that the tetracyclic may have a faster onset of therapeutic benefit.8 Tolerability concerns — especially sedation and potential for weight gain — have led most clinicians to reserve mirtazapine for patients who do not respond to reup-take inhibitors. Aside from the double-blind study comparing mirtazapine and sertraline already discussed,15 there are no other randomized controlled trials of mirtazapine in treatment-resistant depression. Mirtazapine thus warrants a B rating as a switch agent for treatment-resistant depression. In STAR*D, mirtazapine monotherapy is being contrasted versus the TCA nortriptyline in Stage II treatment-resistant depression.

Bupropion is classified as a norepinephrine-dopamine reuptake inhibitor (NDRI). Although comparably effective to the SSRIs for first-line therapy, bupropion has one major advantage in that it does not adversely effect sexual function.25 In one small study of Stage I treatment-resistant depression, patients who had not responded to citalopram were assigned randomly to a switch to bupropion monotherapy or combined treatment with bupropion and SSRI.26 Results strongly favored the combined treatment strategy, a conclusion consistent with psychiatrists' rankings of alternate strategies for SSRI nonresponders.27 Thus, unless the results of the STAR*D study lead to a higher grade, the current state of the evidence on bupropion monotherapy for treatment-resistant depression earns a C grade.

As noted, concerns about tolerability and safety in overdose generally relegate the TCAs to use with patients with more advanced stages of treatment-resistant depression.6 Indeed, for the patient who has not responded to an SSRI or venlafaxine, but for whom ECT is not yet a consideration, there may be no better option than switching to a TCA.28 The TCAs, in particular, are distinguished by a wealth of evidence on their use in combination with lithium and thyroid hormone.11 The older, reversible MAOIs likewise remain important alternatives for patients with so-called atypical depression or reverse neurovegetative features.11,29 It remains to be seen whether the newer, transdermally administered formulation of seligiline, a monoamine oxidase B inhibitor pending FDA approval, will offer a better-tolerated alternative for patients with treatment-resistant depression.

Augmentation Strategies

Augmentation strategies use medications that do not have strong primary antidepressant effects to complement or enhance the presumed mechanism of antidepressants.12 The wide use of augmentation strategies probably speaks more to ease of implementation than a track record of efficacy. In simplest terms, it is easier to augment than to switch because augmenting does not require tapering the ineffective antidepressant or cross-titration. Evidence pertaining to six augmentation strategies — lithium, thyroid hormone, buspirone, atypical antipsychotics, pindolol, and modafinil — are reviewed briefly here.

Lithium

Lithium is presumed to augment the effects of antidepressants on serotonergic (5-HT) neurotransmission via modulation of second messenger systems.30 Early placebo-controlled studies confirmed efficacy in TCA nonresponders; a meta-analysis of 10 randomized, controlled trials found about a 20% advantage over placebo, with an average response rate of 52%.31 Although lithium augmentation is supported by an A grade of evidence for TCA-resistant depression, the data on use with SSRI nonresponders are relatively weak, and most clinicians reserve it use for patients with more advanced stages of treatment-resistant depression.6

Thyroid

Thyroid hormone augmentation is thought to work by “priming” noradrenergic neurotransmission, correcting suboptimal thyroid function, or both.32 A systematic review of thyroid augmentation (most studies used 25 to 50 mcg/day of triiodothyronine) observed significant antidepressant effects in about half of the published studies.33 Like lithium, thyroid augmentation has not been well-studied in SSRI nonresponders and, despite warranting an A rating for TCA-resistant depression, it is now seldom used.

Buspirone

This generically available, FDA-approved treatment for “anxiety” is a partial agonist of serotonin (5-HTlA) receptors. Beyond the theoretic ability to potentiate the pharmacologic actions of SSRIs, the modest anxiolytic effect of buspirone can convey a welcomed benefit for patients with treatment-resistant depression and persistent anxiety. Although a number of open-label studies suggested efficacy, data from randomized, controlled trials have not confirmed the efficacy of buspirone augmentation.34,35 Post-hoc analyses of these studies did suggest some circumscribed benefits, although the weight of the evidence only justifies a C grade. In STAR*D, buspirone augmentation is contrasted against the combination of citalopram and bupropion.

Atypical Antipsychotics

Antipsychotic medications, which have played an adjunctive role in diffi-cult-to-treat depressions for decades, are thought to enhance response to antidepressants both by palliative effects (ie, relief of anxiety, insomnia, agitation, and undetected psychosis) and by directly increasing release of monoamines in prefrontal cortex.6 The small (n = 28) but well-controlled study of Shelton et al.36 provides the best evidence of potential value of the atypical antipsychotics for augmentation therapy. In this randomized, controlled trial, nonresponders to 6 weeks of fluoxetine therapy (at a dose of 60 mg/day) were significantly more likely to respond to the combination of fluoxetine and olanzapine (mean fluoxetine dose 52 mg/day; mean olanzapine dose 13.5 mg/day) than either continued fluoxetine therapy plus placebo (mean dose 52 mg/day) or olanzapine plus placebo (mean dose 12.5 mg/day).

Although there are not yet other published randomized, controlled trials of atypical antipsychotic augmentation therapy, the literature is filled with clinical case series (see, for example, Barbee et al.37 or Papakostos38), and numerous industry-sponsored randomized controlled trials are in various stages of completion. The evidence base thus justifies a B rating for olanzapine augmentation, with C ratings for the remainder. Beyond a limited level of empirical support, concerns about cost and the risks of weight gain and other metabolic complications limit the applicability of this strategy.

Pindolol

One of the less commonly used beta-blockers, pindolol (at a dose of 5 to 10 mg/day) was proposed to augment the effects of SSRIs via antagonism of inhibitory pre-synaptic 5-HT1A autoreceptors. Although there is evidence that pindolol may accelerate SSRI response, the data from randomized, controlled trials of Stage I treatment-resistant depression do not support efficacy.6

Pindolol does not readily penetrate the blood brain barrier, however, so the doses studied may not have led to sufficient 5-HT1A autoreceptor occupancy in the brain to exert the desired effect.39 The broader strategy thus will need to be re-evaluated when a more potent and selective antagonist is available.6

Modafinil

This novel “alerting” compound, which is approved for treatment of narcolepsy and idiopathic hypersomnolence, does not directly modulate the activity of central nervous system catecholamines and has a lower abuse liability than psychostimulants.40 Two randomized, placebo-controlled trials of modafinil augmentation (100 to 200 mg/day) have been completed.41,42 Although neither trial demonstrated large antidepressant effects, there was evidence of modest benefit on a number of secondary outcomes, particularly on measures of sleepiness and fatigue. Modafinil therapy thus warrants a B grade for Stage I treatment-resistant depression, with A-level support for symptomatic treatment of persistent fatigue and hypersomnolence despite SSRI therapy.

Antidepressant Combinations

Although TCA and MAOI combinations once were reserved for specialists treating patients with advanced stages of treatment-resistant depression,11 widespread use of combinations of TCAs and SSRIs was ushered in by the striking post hoc findings of Nelson et al.43 with the combination of desipramine and fluoxetine. Those patients did not have treatment-resistant depression, however, and the results of a pair of published studies of fluoxetine nonresponders have failed to confirm the utility of adding low-dose (25 to 50 mg/day) desipramine.44,45

Nevertheless, the safety and ease-of-use of the newer antidepressants has permitted a veritable explosion of use of a myriad of other antidepressant combinations. In current practice, relatively selective yet dissimilar antidepressants, such as an SSRI and bupropion or reboxetine, are combined to create a “broader spectrum” therapy.6 However, popularity does not offset a dearth of evidence from adequately powered randomized, controlled trials; the widespread use of antidepressant combinations has greatly outstripped the evidence base.

Lam et al.46 reviewed 27 peer-reviewed publications on antidepressant combinations and concluded that most of the strategies are supported by C-level evidence. Indeed, until the results of the STAR*D study are available, only the small sequential study of Lam et al.26 supports the efficacy of the most widely favored strategy — combining an SSRI with bupropion.

Among the remaining combinations, the addition of two closely related anti-depressants, mianserin and mirtazapine, to an SSRI or venlafaxine has shown particular promise.6 Significant additive effects were observed in 3 of 4 relevant randomized, controlled trials.47–49 In a fourth study,50 a large (cell number about 100) double-blind study of patients who had not responded to 6 weeks of therapy with sertraline (100 mg/day) did not document efficacy. However, as the most effective strategy in this trial was simply continuing low-dose sertraline, the study may have lacked assay sensitivity.

Alternate Somatic Therapies

Therapeutic alternatives for patients who do not respond to the more commonly used options include electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and vagus nerve stimulation (VNS).

ECT

The main contemporary indication for ECT is nonresponse to multiple trials of antidepressants.11 The system for grading empirical evidence in treatment-resistant depression breaks down in the evaluation of ECT; although it has been the standard of efficacy for decades, there are no contemporary randomized, controlled trials. Nevertheless, it can be asserted with confidence that studies conducted in the 1960s and 1970s document that ECT has an A level of evidence for treatment of more severe or advanced forms of resistant depression; even patients with Stage III or Stage IV treatment-resistant depression have at least a 50% chance of responding.6,51,52

Relapse following successful ECT is the most substantial clinical limitation.53 At this time, the only approach documented to provide significant prophylaxis following successful ECT is maintenance therapy with a potent anti-depressant and lithium.54 The use of less frequent ECT treatments as a form of continuation therapy is currently being evaluated. Further discussion of ECT therapy is provided in the article by Fink (see page 965).

rTMS

After more than a decade of research, it is still not clear if rTMS is a viable alternative to ECT for patients with treatment-resistant depression.6 Although a number of smaller randomized, controlled trials have yielded negative results, there are a sufficient number of positive studies to warrant at least a B rating for Stage I treatment-resistant depression.55,56 It may be that a longer course of treatment (ie, 4 weeks rather than 2 weeks) is necessary to ensure adequate response, especially among patients with more difficult-to-treat depression.

The major advantages of this procedure are that it does not require general anesthesia and, when compared with ECT, it has substantially better outcomes on tests of memory and other cognitive functions. The major disadvantage of rTMS is that it is still considered to be an experimental intervention and, as such, is generally not covered by third-party payers.

VNS

The antidepressant properties of VNS were observed originally in studies of anticonvulsant-resistant epilepsy. This relatively invasive intervention relies on surgical implantation of an electrode coil in the neck to send ascending intermittent stimulation to brainstem nuclei via the vagus nerve. VNS was found to have significant and sustained antidepressant effects in a large “open-label” study of patients with advanced stages of treatment-resistant depression.57 The procedure was relatively ineffective among patients who had not responded to ECT, however, and a subsequent, well-designed randomized, controlled trial contrasting VNS with a sham procedure failed to document a significant effect on the primary dependent measure.58 A substantial proportion of patients improved following a more extensive course of therapy with “open label” adjustment of dosing parameters, however, and the outcome of the VNS group was substantially better than that of a matched case-control group that received continued pharmacologic treatment across 12 months of follow-up.59

Although the pivotal trial failed to confirm efficacy, VNS received approval from the US for treatment-resistant depression earlier this year. The justification for this approval was twofold: first, FDA review of devices does not use the same standard of efficacy as for novel medications; and second, because of factors that limit the use of ECT, including stigma, cognitive side effects, and relapse risk, there is a clear-cut need for development of alternatives to ECT.

Summary

Despite the public health significance of treatment-resistant depression, the current state of the evidence is clearly not adequate to establish an evidence-based algorithm to guide sequential treatment trials. At present, only two strategies — switching to venlafaxine and augmenting with mianserin and mirtazapine — are supported by A-level evidence for SSRI nonresponders. Other strategies with A-level of empirical support, including switching to TCAs and MAOIs, lithium and thyroid augmentation, and ECT, are generally reserved for more advanced stages of treatment-resistant depression. Forthcoming results of the STAR*D study will help to place in context several of the more widely used newer strategies.

The current state of the evidence reflects the need to continue to prioritize research on treatment-resistant depression. The recently completed STAR*D project, which resulted from an unprecedented collaboration among researchers, the pharmaceutical industry, and the National Institute of Mental Health, represents only one piece of the puzzle and many important questions about the therapeutics of treatment-resistant depression remain unanswered. Building a better evidence base to guide the care of patients with treatment-resistant depression will require the ongoing collaboration of these stakeholders, enhanced by the collaboration of practitioners, professional organizations such as the American Psychiatric Association and the World Federation of Biological Psychiatry, patients and their significant others, and patient advocacy groups.

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An Updated System for Staging Antidepressant Resistance12

Stage IFailure of an adequate trial of one class of major antidepressant
Stage IIFailure of adequate trials of two distinctly different classes of antidepressants
Stage IIIStage II plus failure of a third class of antidepressant, including a tricyclic antidepressant
Stage IVStage III plus failure of an adequate trial of a monoamine oxidase inhibitor
Stage VStage IV plus failure of an adequate course of electroconvulsive therapy

Recommendations for Therapeutic Strategies for Treatment-resistant Depression

StrategyAppropriate Level of ResistanceType of TreatmentEvidence Ranking
Switching
  Within ClassStage ISelective serotonin reuptake inhibitors OthersB C/D
Across ClassesStages I – IIIVenlafaxine Other antidepressantsA B
AugmentationStages I – III
  LithiumTricyclic antidepressants Selective serotonin reuptake inhibitorA C
  T3Tricyclic antidepressants Selective serotonin reuptake inhibitorA C
  BuspironeC
  Atypical antipsychoticsOlanzapine OthersB C
  PindololC
  ModafinilB/C
Combining antidepressantsStages I–IVBupropion + selective serotonin reuptake inhibitor, mirtazapine + selective serotonin reuptake inhibitor Other combinationB C
PsychotherapyStages I - ?
  SwitchingC
  AugmentationPartial remission + selective dopamine reuptake inhibitorB/C

Educational Objectives

  1. Discuss the application of evidence-based medicine principles for treatment-resistant depression.

  2. List the major options for switching and augmenting antidepressants.

  3. Describe the current roles of electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation in the treatment of refractory depression.

Authors

Dr. Thase is professor of psychiatry, Department of Psychiatry, University of Pittsburgh Medical Center and Western Psychiatric Institute and Clinic, Pittsburgh, PA.

Address reprint requests to: Michael E. Thase, MD, 3811 O'Hara Street, Pittsburgh, PA 15213-2593; or e-mail thaseme@upmc.edu.

This work was supported in part by National Institutes of Mental Health Contract N01-MH-90003 and by MH-30915 Mental Health Intervention and Research Center.

Dr. Thase is a consultant with AstraZeneca, Bristol Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Novartis, Organon, Pfizer, and Wyeth. He serves on the Speakers' Bureau for AstraZeneca, Eli Lilly, GlaxoSmithKline, Organon, and Wyeth.

10.3928/00485713-20051201-04

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