Alicia R. Ruelaz, MD

Despite advances in our understanding of depression therapy, many patients with depression remain unresponsive to treatment. As many as 50% of patients who begin treatment with an antidepressant do not respond.

 In fact, even after 2 antidepressant trials, 30% to 40% of patients do not report significant improvement in their symptoms.

 There is no universally accepted definition of treatment-resistant depression; however, a working definition is depression that fails to respond to an adequate trial of antidepressant treatment. In this case, nonresponse is defined as the failure to obtain at least a 50% reduction in symptom severity on a standard rating scale score. A growing consensus in the field suggests that an adequate trial of an antidepressant is the highest dosage tolerated by a patient within the approved therapeutic range for 6 weeks.

There may be many reasons for treatment failure. Before deciding that a patient's depression is treatment resistant, it is important to verify that the patient is taking the medication, since the most common cause of apparent treatment failure is nonadherence.

 Even if the patient is taking the medication as prescribed, the dosage may be suboptimal. Fava and colleagues

 studied 41 patients whose depression had failed to respond to 20 mg/d of fluoxetine. Patients were randomized to receive 40 to 60 mg/d of fluoxetine or 20 mg/d of fluoxetine augmented by desipramine or lithium. The patients who received the higher doses of fluoxetine were more responsive than either of the other 2 groups (53% vs 25% and 29%, respectively).

A complete and comprehensive diagnosis is essential as the basis for appropriate treatment. For example, if the presence of psychotic features is ignored and an antipsychotic medication is not used, the response rate can be as low as 20%.

 It is also important to identify comorbid anxiety, personality disorders, and medical conditions that may be creating or complicating depressive symptoms.

 Substance abuse should be screened for, since it can significantly affect a patient's ability to respond to treatment. Equally important is to make sure that bipolar disorder is not being missed.

Treatment options Medication substitution

There are many treatment options available once an antidepressant trial has been determined to be a failure. Clinically, it has been postulated that those patients who do not respond at all to the original antidepressant may benefit from switching to another agent and that those patients who have partially responded may be more appropriate for augmentation.

If one chooses to switch from one antidepressant to another, the easiest and safest first choice is a within-class switch (SSRI to SSRI). The structural diversity among the SSRI antidepressants is assumed to be great enough to mediate different effects on second neurotransmitter systems or to result in different side-effect profiles that may enhance response.

 Studies have reported that between 40% and 70% of patients respond to a within-class switch.

The next option would be to switch from an SSRI to an antidepressant with a different mechanism of action. This would allow for the recruitment of additional or different neurotransmitters that might be required for that particular patient. Studies have shown this to be a valid mechanism for improving response rate.

 Recommendations within this option would include switching to venlafaxine or duloxetine to capture both serotonin and norepinephrine activity, or to mirtazapine, bupropion, nefazodone, a tricyclic antidepressant (TCA), or a monoamine oxidase inhibitor (MAOI). A recent study done by Rush and colleagues

 demonstrated that a switch to bupropion, sertraline, or venlafaxine actually led to remission in 1 in 4 treatment-resistant patients.

Pharmacologic augmentation options include lithium, thyroid hormone, a second antidepressant, stimulants, buspirone, antipsychotic medication, modafinil, anticonvulsants, dopamine agonists, inositol, pindolol, and others.

Lithium augmentation is the best- known and best-studied. The rationale for using lithium in treatment-resistant depression is that it potentiates the action of serotonin by reducing negative feedback through the serotonin (5-HT)-1A receptor. It may also modulate second-messenger systems that may not only enhance the actions of antidepressants but also confer intrinsic antidepressant effects. Lithium can be added to TCAs, MAOIs, and SSRIs; however, the majority of studies report the use of lithium augmentation of TCAs. The usual dosage of lithium is 600 to 1200 mg/d, with the goal of achieving a blood level of 0.4 to 0.8 mEq/L.

Response rates to lithium augmentation have been reported between 30% and 50%, and a review of 22 clinical reports listed response rates as high as 71%. A response may be seen as soon as 48 hours after the initial dose, but it usually takes about 2 weeks. Disad- vantages in using lithium include the need for monitoring blood levels and the risk of toxicity.

Augmentation using thyroid hormone is another commonly employed strategy. The use of triiodothyronine (T

) to augment antidepressants has a response rate of 60% in patients with treatment-resistant depression.

 In contradistinction to lithium, thyroid hormone is thought to potentiate norepinephrine. It may also correct subclinical hypothyroidism that can contribute to depressive symptoms, or it may down-regulate thyroxine (T

, the form of thyroid that enters the brain. Depressed patients may display relative hyperthyroidism because they have elevated T

 and most antidepressant treatments lower T

 levels. Level A evidence supports the use of thyroid augmentation but most controlled trials augmented TCAs. In most of the studies, patients who responded to thyroid augmentation were maintained on it for 2 to 3 weeks.

Adding another antidepressant with a different mechanism can also enhance the response to the original treatment. Two agents commonly used for their addition of noradrenergic effects to SSRI treatment are bupropion and nortriptyline.

 Nortriptyline is the best- studied noradrenergic agent, and open-label response rates have been reported as 87% and higher when it is used as an augmentation agent.

 Bupropion augmentation in patients in whom citalopram monotherapy had failed led to 30% to 40% remission rates.

 Another antidepressant used in augmentation is mirtazapine. It acts by blocking postsynaptic a-2 heteroceptors. This blockade prevents the normal feedback of serotonin inhibition by norepinephrine. It also blocks 5-HT2 and 5-HT3 receptors, which may decrease the side effects of increased serotonin, including nausea, anxiety, and sexual dysfunction. In at least 1 double-blind study, significant additive effects were observed.

Another class of medication to use in augmentation is the stimulants. They are commonly used in the consultation-liaison service where depression may be interfering with the patient's ability to receive medical care and a rapid antidepressant response is needed while waiting for the SSRIs to take effect. Stimulants target somatic symptoms seen in medically ill patients with de- pression, such as fatigue, decreased appetite, decreased cognitive function, and pain.

 Unfortunately, most of the data are from case series or case reports, which points to the need for further studies. The dosages prescribed are usually 5 to 10 mg of methylphenidate 3 times a day and 5 mg of dextroamphetamine 3 times a day. Modafinil is similar to the stimulants and can also be used to augment antidepressants. In 1 study, SSRI-refractory depression had a response rate of 63% when 200 mg/d of modafinil was added versus a 45% response rate with placebo.

An entirely different agent that is commonly used in clinical practice is buspirone. The rationale behind using buspirone to augment antidepressants is that it is a partial agonist at the 5-HT-1A autoreceptor. It not only blocks feedback inhibition of serotonin release but has some agonist activity in the setting of low serotonin. There are several open series studies with positive results. However, 2 large, double-blind placebo-controlled trials found buspirone augmentation to be equivalent to placebo.

 More recently, however, when buspirone was used for augmentation in patients in whom citalopram therapy had failed, about 30% of patients achieved remission, which was similar to the response achieved by patients receiving bupropion augmentation.

Recently emerging data on the use of antipsychotic medication as augmentation agents for treatment-resistant depression afford clinicians another option. The rationale for using atypical antipsychotics is that they enhance antidepressant effects by blocking postsynaptic serotonin receptors and by increasing the release of monoamines in the prefrontal cortex. A study of the rat prefrontal cortex showed that when fluoxetine and olanzapine are used together, the synergy produced a much greater increase in dopamine and norepinephrine levels than when either agent was used alone.

Initial results from clinical studies investigating atypical antipsychotic augmentation were positive. In one study, 28 patients with treatment-resistant depression in whom not only an SSRI but also a serotonin-norepinephrine reuptake inhibitor (SNRI) had failed, were given fluoxetine for 6 weeks. When this also failed to treat their depression, they were randomly assigned to treatment with fluoxetine and placebo, olanzapine and placebo, or the combination of olanzapine and fluoxetine for 8 weeks.

 continuation of fluoxetine alone caused no additional benefit as measured by Montgomery-Asberg Depression Rating Scale (MADRS) scores. Olanzapine alone produced only a transient benefit. The combination of olanzapine and fluoxetine, however, was robustly effective by the end of the first week and this was not only sustained through the 8-week trial but also continued through an 8-week extension period.

More recent research has produced similar findings on a much larger scale. A study at 57 sites in the United States, Canada, France, and the United Kingdom looked at augmentation with risperidone. This was a 3-phase study. The first phase consisted of screening patients to find those with a Hamilton Rating Scale for Depression (HAM-D) score of greater than 20 and failure of at least one adequate antidepressant trial during the current episode. Qualifying patients were given citalopram monotherapy of 20 to 60 mg/d for 4 to 6 weeks. Patients who did not respond were eligible for open-label augmentation with risperidone for 4 weeks. Patients who achieved symptom resolution with this combination were eligible to enter the double-blind continuation phase, which lasted 24 weeks and involved patients either continuing with risperidone and citalopram or with placebo and citalopram.

A small number of patients with de- pression achieved a significant reduction in symptoms with an SSRI alone. However, of the patients with treatment-resistant depression who went on to receive risperidone augmentation, more than 60% achieved greater than a 50% reduction and about 90% achieved at least a 20% reduction in symptoms.

In this first large-scale continuation trial, the longer-term benefit of continued augmentation with risperidone could only be demonstrated for the most severely ill patients who had treatment-resistant depression.

Looking more closely at another SSRI-atypical antipsychotic combination in patients who have treatment-resistant depression suggests that the matching of augmenting agents to specific patient groups needs to be explored. Dunner and colleagues

 found that patients in whom sertraline monotherapy as well as non-SSRI treatment had failed had much larger decreases in depressive symptoms with the combination of ziprasidone and sertraline than those whose depression was only SSRI-resistant.

It is important to consider other treatment modalities besides pharmaco-therapy. Psychotherapy should be considered as an augmentation strategy when medication alone does not provide complete remission of symptoms. There are particular symptoms of depression that are targeted by psychotherapy, including hopelessness, anhedonia, low energy, anxiety, negative thoughts and beliefs, interpersonal problems, and medication adherence.

 Cognitive-behavioral therapy (CBT) is one of the best-known, most studied, and most structured formats of psychotherapy. A randomized trial of 156 subjects found that those treated with 8 months of CBT had lower relapse rates at the end of 2 years.

 Another study showed that adding 20 weeks of CBT for patients with incomplete response to antidepressants increased the rate of remission and decreased relapse from 47% with medication alone to 29% with the addition of CBT.

A type of psychotherapy especially designed to treat chronic, resistant depression is the Cognitive Behavioral Analysis System of Psychotherapy (CBASP). This therapy builds on CBT by including training in interpersonal skills and stress management; these may be significant for persons with longer-term struggles with depression and can hinder recovery if not addressed. A study of 681 patients with chronic depression showed significant response, at least acutely. Of the 519 patients who completed the study, 55% of those treated with nefazodone alone and 52% of those treated with CBASP therapy alone achieved a response. However, 85% of those who received a combination of CBT and CBASP achieved a response.

Finally, somatic therapies such as electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), and light therapy can be used in this population. It has been demonstrated that ECT plus medication is superior to medication alone in preventing relapse and recurrence in chronically depressed patients and improving patient survival.

 A complete discussion of VNS is outside the scope of this article, but it is important to include it as an augmentation strategy. VNS is currently approved for the most severely treatment-resistant patients, who would receive it in addition to antidepressant medication. In fact, patients must have failed at least 4 adequate treatment trials for depression. Another option that can be considered is rTMS; however, more research is needed to establish its efficacy in this population.

 Bright-light therapy may also be an effective addition to medication in those patients in whom antidepressant therapy alone fails. A small study found this to be true in 7 of 10 patients.

Our treatment paradigms for treatment-resistant depression are in evolution. We currently have a wide array of options with a limited amount of empiric data to support these strategies. The most compelling data historically are for pharmacologic augmentation with lithium and thyroid hormone. However, there is an increasing body of data supporting the use of atypical antipsychotic medications and synergistic antidepressant medications. Psychotherapy has proved to be beneficial in treatment-resistant depression and somatic therapies may also prove effective.

[Note: Medications used for treatment-resistant depression may not be FDA-approved for that purpose.]

Dr Ruelaz is a faculty psychiatrist of the consultation-liaison division in the department of psychiatry and behavioral neurosciences at Cedars Sinai Medical Center in Los Angeles. She reports that she has no conflicts of interest concerning the subject matter of this article.

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Author | Alicia R. Ruelaz, MD

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