Options for Treatment-Resistant Depression

Psychiatric TimesPsychiatric Times Vol 19 No 7
Volume 19
Issue 7

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.

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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 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.


The addition of liothyronine (Cytomel), a synthetic form of the natural thyroid hormone triiodothyronine (T


), 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 [FT


] 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 (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-HT


-mediated synaptic activity via desensitization of presynaptic 5-HT


receptors and down-regulation of postsynaptic 5-HT



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.


Most of the literature on pindolol (Visken) is anecdotal and is primarily focused on its use as an agent to speed the onset of action of SSRIs, rather than as an augmentation strategy (Bordet et al., 1998; Maes et al., 1999; Perez et al., 1997). Pindolol is a ß-blocker and 5-HT


-receptor antagonist (Fava, 2001). It is believed to increase extracellular release of serotonin by SSRIs at synaptic terminals through disinhibition of the neuronal firing rate by blockade of somatodendritic 5-HT


receptors. Doses for pindolol usually range from 2.5 mg/day to 7.5 mg/day, given for up to six weeks.

Adverse effects may include nausea, diarrhea and mild bradycardia. One study found that when patients with TRD were given pindolol to potentiate their antidepressants, they exhibited increased irritability (Blier and Bergeron, 1998).


Bodkin et al. (1997) evaluated the efficacy of combining bupropion (Wellbutrin) and SSRIs by retrospective analysis in a group of 27 subjects who were only partially responsive to adequate doses and duration of either an SSRI or bupropion as monotherapy.

With combination therapy, 70% (n=19) showed significant clinical response compared to either agent alone. Mean daily doses were bupropion 243 mg (range=100 mg to 450 mg) and 31 mg of an SSRI (range=7 mg to 60 mg of fluoxetine or its equivalent).

Notable adverse effects of combined treatment were sexual dysfunction, insomnia, reduced energy level and tremor. The incidence of these adverse effects was generally similar to that seen with monotherapy of either treatment. Panic attacks have also been reported with the combination of bupropion and SSRIs (Bodkin et al., 1997; Young, 1996).


Theoretically, augmentation with venlafaxine (Effexor) in a patient who had previously been taking an SSRI or a tricyclic antidepressant would be beneficial due to its additional mechanism of action. Venlafaxine acts as a reuptake inhibitor of both serotonin and norepinephrine, thus adding adrenergic activity to an SSRI's serotonergic effect.

Gmez Gmez and Teixid Perramn (2000) added venlafaxine to either clomipramine (Anafranil) or imipramine (Tofranil) in depressed patients who had shown only partial response to maximal doses of one of those TCAs. They found a sustained positive response to venlafaxine augmentation in nine patients (82% of the sample), with seven patients (64% of the sample) reaching full remission and sustaining it over a two-year period. No significant changes in blood pressure, heart rate, electrocardiogram or blood tricyclic levels were found.

Currently there are only anecdotal reports of venlafaxine 75 mg/day to 300 mg/day as a successful augmentation strategy for SSRI nonresponders (Fava, 2001). The possibility of hypertension (more likely at doses >225 mg/day) necessitates blood pressure monitoring.


Carpenter et al. (1999) reported positive results with mirtazapine (Remeron) 15 mg/day to 30 mg/day augmentation of various SSRIs, venlafaxine or desipramine (Norpramin). At the end of four weeks of open-label augmentation, 55% (n=11) of previously refractory patients became responders to treatment. In a double-blind, controlled study, researchers found a significantly higher response rate to the combination of paroxetine and mirtazapine than monotherapy with either drug (Debonnel et al., 2000, as cited in Fava, 2001).

Like venlafaxine, mirtazapine has a dual mechanism of increasing serotonergic and noradrenergic activity. Mirtazapine also blocks postsynaptic 5-HT2 and 5-HT3 receptors, further contributing to selective 5-HT1A receptor activity (Stimmel et al., 1997).

Possible adverse effects of mirtazapine include weight gain and sedation (could have deleterious effects on patient compliance), agitation, and gastrointestinal distress.

Atypical antipsychotics.

Ostroff and Nelson (1999) reported a case series of eight patients with major depression unresponsive to fluoxetine or paroxetine. Risperidone (Risperdal) 0.5 mg/day to 1.0 mg/day was added to the SSRI therapy. Based upon HAM-D scores, all eight patients had remission of depressive symptoms within the first week of risperidone therapy. One concern regarding adding risperidone to paroxetine therapy is the cytochrome P450 2D6 isoenzyme-inhibition effect of paroxetine on risperidone that results in increased likelihood of adverse effects, including extrapyramidal side effects. No controlled trials have yet been reported with risperidone. In a case report, the addition of risperidone to the MAOI tranylcypromine (Parnate) also resulted in improvement (Stoll and Haura, 2000).

Shelton et al. (2001) conducted a randomized, double-blinded, placebo-controlled trial in 28 patients with fluoxetine and olanzapine (Zyprexa). Concomitant use of olanzapine 5 mg/day to 20 mg/day in addition to fluoxetine doses of up to 60 mg/day resulted in 60% response rates in patients previously unresponsive to treatment with fluoxetine alone. Clinical response to the combination therapy was observed within the first week of the eight-week study. Possible side effects include somnolence, increased appetite, weight gain, asthenia, headache, dry mouth and nervousness.

It is hypothesized that the coadministration of olanzapine with fluoxetine results in a pharmacodynamic synergy, in which norepinephrine and serotonin levels increase to much higher levels in the prefrontal cortex than when either is administered alone.

Other pharmacological approaches.

Many other augmentation and combination strategies involving antidepressants and other agents are being studied. Such strategies include anticonvulsants such as carbamazepine (Tegretol) and divalproex sodium (Depakote); dopaminergic drugs such as pergolide (Permax) and amantadine (Symmetrel); psychostimulants such as methylphenidate (Ritalin, Concerta, Methylin, Metadate), dextroamphetamine (Dexedrine, Adderall) or pemoline (Cylert); a2-antagonists such as yohimbine (Yocon, Yohimex) and nefazodone (Serzone) (Charney et al., 1986; Fava, 2001; Nelson, 2000; Nierenberg et al., 1998; Rybakowski et al., 1999).

The studies and anecdotal reports regarding these agents show inconclusive or contradictory results. Additionally, augmentation with some of these options proved to predispose to adverse effects and the potential for serotonin syndrome when serotonergic agents were used to augment SSRIs (Fava, 2001).

Options for Switching

Switch to an MAOI.

Monoamine oxidase inhibitors remain a very effective strategy for refractory depression. McGrath et al. (1993) found a statistically significant difference in the response rates between groups in a double-blind, crossover trial of imipramine and phenelzine (Nardil), where phenelzine proved to be more effective for patients who had been unresponsive to imipramine.

Despite very good efficacy, MAOIs are rarely used (Fava, 2000) because of strict dietary restrictions, serious drug-drug interactions (e.g., fluoxetine or imipramine switch to tranylcypromine) and the risk of hypertensive crisis.

Switch to bupropion.

Until the more recent data regarding venlafaxine and mirtazapine became available, a common switching strategy was to move from an SSRI to bupropion in refractory depression, despite a paucity of published data. Fava (2000) noted that clinicians switched patients to bupropion in search for a drug with an improved adverse-effect profile rather than to enhance efficacy. Switching from an SSRI to bupropion is often chosen when the patient has experienced sexual dysfunction and a less than optimal response (Marangell, 2001).

Switch to venlafaxine.

De Montigny et al. (1999) reported a 58% response rate (e50% improvement from baseline on the 21-item HAM-D) and a 28% remission rate (e75% improvement) in 152 patients with TRD. Patients had been switched to venlafaxine therapy after failure to reach an adequate response in at least an eight-week trial on another antidepressant. It was suggested that because venlafaxine has more serotonergic than noradrenergic activity, venlafaxine might be expected to be more beneficial in nonresponders to TCAs and MAOIs than SSRI nonresponders. The most common adverse events reported with venlafaxine were headache, insomnia, nausea, constipation, diaphoresis and xerostomia.

Switch to mirtazapine.

A study by Fava et al. (2001) showed that SSRI nonresponders exhibited a 48% response rate and SSRI-intolerant patients exhibited a 53% response rate to mirtazapine. Response rates did not differ significantly between patients who were switched immediately from the SSRI to mirtazapine and those who were first given a four-day SSRI-washout period. In this study, mirtazapine also improved sexual functioning in several patients who had had SSRI-induced dysfunction. The adverse events most commonly reported by the mirtazapine-treated patients were somnolence, increased appetite, headache, weight gain, dizziness and nervousness.

To Augment or Switch?

The decision to augment or switch drug therapy should be based primarily on the patient's degree of clinical response as well as the presence and severity of adverse effects. Augmentation may be considered for the patient who has been on an adequate dose and duration of an antidepressant and has had good tolerability, but has shown only partial response. Augmenting allows patients to continue to reap whatever benefits they have from their original drugs but with the additive or synergistic benefits of the augmentor (Nelson, 2000).

In contrast, switching therapy should be considered for patients who have shown inadequate response to their current therapy or for those who experience intolerable adverse effects (Fava, 2000). Switching also offers simplicity of drug therapy compared to use of multiple drugs with augmentation strategies.

Posternak and Zimmerman (2001) compared the strategies of switching and augmentation in patients with TRD. They concluded that switching antidepressants was somewhat less effective than augmentation, although the difference was not statistically significant.

Given the very limited number of treatment option studies, the choice of augmentor or switch agent must be based upon several considerations. These include history of past drug response, adverse-effect profile differences, concomitant medical disorders and concurrent drug therapy.

Nonpharmacological Options

Electroconvulsive therapy (ECT) is a highly effective treatment for psychotic depression and severe refractory depression. Unfortunately, there continues to be a stigma associated with ECT despite its safety under medically monitored conditions, its efficacy and its more rapid onset of effect (Olfson et al., 1998). The Texas Medication Algorithm Project consensus panel recommends ECT after three ineffective treatments for major depressive disorder without psychotic features (Crismon et al., 1999). Generally, ECT is a very safe treatment. The chief side effects are transient confusion and memory impairment (APA, 2000).

Psychotherapy is a treatment option that may be used either alone or in combination with pharmacotherapy for enhanced patient response. Types of psychotherapy include cognitive-behavioral therapy, interpersonal therapy and behavior therapy.

Light therapy with a 10,000 lux intensity light box for 30 minutes per day directly upon the patient's face has been studied for first-line therapy in subsyndromal winter "blues," as well as for adjunctive therapy in chronic major depressive disorder or dysthymia with seasonal exacerbations (APA, 2000). Side effects can include headache, eye strain, irritability, insomnia and occasionally hypomania.

Vagus nerve stimulation (VNS), a treatment option for treatment-resistant seizure disorder, was recently evaluated in TRD (Rush et al., 2000). Escalating amounts of output current were administered to patients' left vagus nerves via an implantable and multiprogrammable pulse generator for 10 weeks. Approximately 40% of patients experienced a positive response, and 17% had a full remission of symptoms. An open, naturalistic follow-up study (Marangell et al., 2002) was conducted to determine whether the initial promising results of the acute-phase study would be sustained for an additional nine months. Longer-term VNS treatment was associated with sustained symptomatic benefit and sustained or enhanced functional status.

In an open pilot study of VNS in 60 patients with TRD, Sackeim et al. (2001) found the response rate ranged from 30.5% to 37.3%, depending on the rating scale used. The most common side effect was voice alteration or hoarseness. This is an interesting alternative strategy for TRD that requires further study.


For major depression, the new standard of practice requires treatment that leads to remission of symptoms and a return of occupational and social functioning. Most nonresponse is explained by inadequate treatment, treatment nonadherence, comorbid medical or psychiatric disorders, or failure of an individual drug or treatment method. Strategies for these patients involve identification of the causative factor and correction of it whenever possible.

For the remaining patients with TRD, there are many options including multiple pharmacological mechanisms, VNS, psychotherapy and ECT. Most patients with major depression have the potential to achieve full remission of symptoms.

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