Treatment-Resistant Depression: Strategies for Management

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.¹ In fact, even after 2 antidepressant trials, 30% to 40% of patients do not report significant improvement in their symptoms.² 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.³

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.⁴ Even if the patient is taking the medication as prescribed, the dosage may be suboptimal. Fava and colleagues⁵ studied 41 patients whose depression had failed to respond to 20 mg/d of fluoxetine(Drug information on fluoxetine). Patients were randomized to receive 40 to 60 mg/d of fluoxetine or 20 mg/d of fluoxetine augmented by desipramine or lithium(Drug information on 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).⁵

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%.⁶ It is also important to identify comorbid anxiety, personality disorders, and medical conditions that may be creating or complicating depressive symptoms.⁷ 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.

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.⁸

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.⁴ Studies have reported that between 40% and 70% of patients respond to a within-class switch.⁹

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.¹⁰ Recommendations within this option would include switching to venlafaxine or duloxetine(Drug information on duloxetine) to capture both serotonin and norepinephrine(Drug information on norepinephrine) activity, or to mirtazapine(Drug information on mirtazapine), bupropion, nefazodone(Drug information on nefazodone), a tricyclic antidepressant (TCA), or a monoamine oxidase inhibitor (MAOI). A recent study done by Rush and colleagues⁹ demonstrated that a switch to bupropion, sertraline(Drug information on 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(Drug information on buspirone), antipsychotic medication, modafinil(Drug information on modafinil), anticonvulsants, dopamine(Drug information on dopamine) agonists, inositol, pindolol(Drug information on pindolol), and others.