Options for Treatment-Resistant Depression

Options for Treatment-Resistant Depression

Sponsored by CME LLC for 1.5 Category 1 credits.

Original release date 07/02. Approved for CME credit through 07/03.

Educational Objectives:

After reading this article, you will be familiar with:

  • Definitions of treatment response and remission.
  • Strategies for augmenting and combining medication for patients with treatment-resistant depression (TRD).
  • Strategies for switching treatment.
  • Nonpharmacological options for treating TRD.

Who will benefit from reading this article?

Psychiatrists, neurologists, primary care physicians, physician assistants, psychologists, psychiatric nurses, social workers and other mental health care professionals. Continuing education credit is available for most specialties. To determine if this article meets the requirements of your specialty, please contact your state licensing board.

Dr. Stimmel is professor of clinical pharmacy and psychiatry for the Schools of Pharmacy and Medicine at University of Southern California (USC). Dr. Stimmel has indicated that he has received speaking honoraria from Organon Inc., Wyeth Pharmaceuticals and Pfizer Inc., and he has served as consultant for Janssen Pharmaceutica Products L.P., Eli Lilly and Company, AstraZeneca Pharmaceuticals LP and Pfizer Inc.

Dr. Myong is a lecturer and resident in psychiatric pharmacy practice for the School of Pharmacy at USC. Dr. Myong has indicated that she has no financial relationships to disclose relating to the subject matter of this article.

Treatment-resistant depression (TRD) is primarily a phenomenon of labeling. Patients are treatment-refractory only because they have been labeled as such by their clinician, even though most patients have the potential to respond to treatment (Guscott and Grof, 1991). The current standard in treating major depression is defined as full remission of symptoms and restoration of functioning (Nierenberg and Wright, 1999). Thus, it could be argued that most patients treated for an acute depressive episode are treatment-resistant since most do not achieve full remission of symptoms with the first somatic or psychosocial treatment they receive (Sackeim, 2001).

True TRD is usually defined, however, as a much smaller percentage of patients in whom contributory factors to treatment failure have been ruled out. When a patient presents with presumed TRD, the diagnosis requires re-evaluation to identify comorbid medical or psychiatric conditions that may be interfering with expected clinical response. The next step is to identify "pseudo-resistance," in which the patient, for whatever reason, did not have an adequate antidepressant trial.

Given an accurate diagnosis and an adequate antidepressant trial, patients can then be categorized as nonresponders to a single antidepressant drug or as patients with true TRD who fail at least two separate and adequate trials of antidepressants from two different pharmacological classes (O'Reardon and Amsterdam, 2001; Thase, 2002). The following discussion of augmentation and switching strategies is appropriate only for patients with true TRD.

Adequate Trial

Adequate antidepressant drug therapy for a major depressive episode has been well-defined in the clinical literature and in several national treatment guidelines. At least eight weeks at a full therapeutic dose is necessary to evaluate the efficacy of an antidepressant (O'Reardon and Amsterdam, 2001), and treatment must continue for an additional four to five months (American Psychiatric Association, 2000). Unfortunately, many patients with major depression do not receive an adequate course of therapy. It is estimated that 30% to 60% of patients referred for evaluation of treatment resistance have received inadequate treatment (Dawson et al., 1999; Keller et al., 1986; Keller et al., 1982; Souery et al., 2001; Souery et al., 1999). A large proportion of patients referred to university settings were found to never have received even one adequate antidepressant trial.

Remission Versus Response

Antidepressant response traditionally has been defined as a 50% reduction from baseline in depression rating scales. Clinical efficacy trials of most antidepressant drugs show a response rate of approximately 50% to 70%. For many patients, however, a 50% reduction in symptoms means they will continue to have significant residual symptoms. The new standard of practice in the treatment of major depression is to treat to full remission of symptoms (Nierenberg and Wright, 1999). Remission is usually defined as a 17-item Hamilton Rating Scale for Depression (HAM-D) score of either <7 or <10. Given these criteria, only 25% to 50% of patients in clinical trials achieve remission of symptoms (Nierenberg and DeCecco, 2001).

Treatment Options

Treatment options for the nonresponding patient with an accurate diagnosis of major depression uncomplicated by other psychiatric and medical conditions include optimizing the existing antidepressant therapy, augmenting therapy or switching therapy.

For the many patients who receive an inadequate dose or duration of therapy, all attempts should be directed to optimizing their ongoing therapy. Adverse effects, partial response, noncompliance and unrealistic patient expectations may all contribute to the lack of treatment success and must be addressed.

For the remaining patients with true TRD, treatment options include a number of possible augmentation strategies or switching therapy. Table 1 describes representative studies of the more viable treatment options.


The two older, established augmentation strategies are lithium and thyroid. Lithium is the only augmentation strategy that has adequate controlled clinical trials as an augmenting agent. More recently, strategies have been investigated that add a different mechanism of action to yield additional clinical efficacy and that lack the negative adverse effects possible from lithium. Newer augmentation strategies discussed are generally only supported by case reports and open trial data. They are based primarily upon theoretical advantages of multiple mechanism approaches to achieve remission of depressive symptoms.

Lithium. Lithium carbonate is the most extensively studied augmentation strategy, although not the most widely used (Joffe et al., 1993; Rybakowski et al., 1999). Fava (2001) reported that 11 double-blind, controlled trials of lithium augmentation in depression have been published; of those, 10 reported the observed response rate, which averaged 52% for a total of 135 lithium-treated patients. Lithium's proposed mechanism of action is reduction of postsynaptic serotonergic activity, which reduces the negative feedback to presynaptic serotonergic neurons and thus increases serotonin levels in the synapse. Lithium also may have effects on other neurotransmitter systems and neuromodulators. Lithium blood levels >0.4 mEq/L are most effective. This usually translates into doses ranging from 600 mg/day to 1500 mg/day.

A significant proportion of lithium-treated patients may report bothersome side effects (Fava, 2001). Adverse effects that may be experienced with lithium augmentation are hand tremor, gastrointestinal upset, polyuria and polydipsia, weight gain, hypothyroidism, dermatological problems, and diabetes insipidus-like syndrome.

Thyroid. The addition of liothyronine (Cytomel), a synthetic form of the natural thyroid hormone triiodothyronine (T3), to an existing regimen also has been studied as an augmentation strategy (Joffe et al., 1993). The mechanism of action of thyroid augmentation is unclear, but may be related to the correction of a subclinical hypothyroid state imperceptible through usual thyroid function testing (e.g., thyroid-stimulating hormone [TSH] suppression test or free thyroxine [FT4] levels).

Adverse effects are uncommon, but may include nervousness and insomnia (Fava, 2001), irritability, sweating, and possible cardiac arrhythmias. Use of T3 may interfere with thyroid metabolism if taken chronically, so its use should generally be limited to two or three weeks. Doses of T3 between 25 mcg/day to 50 mcg/day are more effective than T4 (Joffe and Singer, 1990).

Buspirone. Buspirone (BuSpar) augmentation has not been as frequently or as thoroughly studied as lithium or thyroid. Although it is an anxiolytic, buspirone may have augmentative antidepressant effects. Buspirone is believed to aid in the alleviation of depressive symptomatology by enhancing net 5-HT1A-mediated synaptic activity via desensitization of presynaptic 5-HT1A receptors and down-regulation of postsynaptic 5-HT2 receptors.

Doses range from 20 mg/day to 50 mg/day with a response usually being observed within a three-week period. One study found that buspirone augmentation to a selective serotonin reuptake inhibitor antidepressant regimen (fluoxetine [Prozac], paroxetine [Paxil] or citalopram [Celexa]) resulted in 59% of patients showing complete or partial remission of their depressive symptomatology (Dimitriou and Dimitriou, 1998). Similarly, among patients with buspirone augmentation of clomipramine (Anafranil) treatment, 63% showed complete or partial remission.

Landen et al. (1998) conducted the only randomized, double-blind, placebo-controlled trial of buspirone augmentation of an SSRI. The study failed to show any statistically significant difference between the buspirone- and placebo-augmented groups. However, the study investigators noted that the study results may be inconclusive due to the unusually high placebo response and that 69.4% of patients responded in a follow-up of open SSRI plus buspirone treatment.

Buspirone is fairly well tolerated; side effects such as lightheadedness and nausea usually occur early in treatment and are usually transient. The development of serotonin syndrome when buspirone is added to a current regimen containing monoamine oxidase inhibitors or other serotonergic agents is a possible yet very rare occurrence.


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