Treatment-Resistant Depression in Hispanic Patients

Alan Podawiltz, DO, MS, FAPA

Texas College of Osteopathic Medicine, and the Department of Psychiatry and Behavioral Health, University of North Texas Health Science Center, Fort Worth

Larry Culpepper, MD, MPH

Department of Family Medicine, Boston University School of Medicine, Boston, Massachusetts

Hispanic or Latino refers to a person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin regardless of race. In this activity, the terms Hispanic and Latino are used interchangeably.

Treatment-resistant depression has no single definition but has been described as failure to respond to 1 or more appropriately delivered therapies or as depression that is resistant to 2 courses of monotherapy with pharmacologically different antidepressants given in an adequate dose for a sufficient length of time (AV 1).1–3 Prevalence estimates vary, but up to 21% of patients with major depression who seek treatment do not recover after 2 years, and an estimated one-third of patients do not respond to appropriately prescribed first-line antidepressant treatment.3 The STAR*D study4 found nearly 50% of patients initially treated with antidepressant monotherapy were unresponsive, while approximately 70% did not reach remission. The more severe and chronic the initial depression, the greater the risk that the patient will be resistant to initial therapies.5 Psychiatric comorbidities are also more likely to be present in patients with treatment-resistant depression.6

No specific studies on the incidence, prevalence, diagnosis, or treatment of resistant depression in Hispanic patients exist. However, the STAR*D trial7 did identify a tendency of Spanish-speaking Hispanic patients with major depression to exhibit a worse response to initial medication than English-speaking patients, although this difference was not significant after controlling for baseline differences in sociodemographic, clinical, functional, and severity variables.

Treatment for Resistant Depression

Treatment for patients with treatment-resistant depression takes a stepped approach. After patients fail to fully respond to antidepressant monotherapy, they are typically switched to another antidepressant, preferably one with a different mechanism of action (AV 2).8,9 Dual-acting antidepressants such as venlafaxine, mirtazapine, and duloxetine, as well as first-generation TCAs, show efficacy at this stage.10,11 Overall, switching antidepressants is generally effective in 40% to 60% of patients.1

If patients continue to fail to respond, primary care physicians should refer them to psychopharmacology specialists for further treatment.12 Options at this stage typically involve augmentation therapy with bupropion or other antidepressants, lithium, or other medications including thyroid hormone, dopamine agonists, modafinil, anticonvulsants, antipsychotics, testosterone, estrogen, pindolol, or stimulants.1 Combination antidepressants should be administered simultaneously as a low dose then titrated upwards gradually. Patients should be monitored carefully for signs of serotonin syndrome, and those taking a TCA should also have their plasma levels regularly monitored.3


Treatments Specific to TRD

Six treatments specific to treatment-resistant depression have been approved in the United States: ECT, TMS, VNS, the medicinal food L-methylfolate, the atypical antipsychotic aripiprazole, and the antipsychotic/antidepressant combination olanzapine-fluoxetine. Deep brain stimulation may also be effective in this patient population.13,14 The APA has published guidelines for the use of ECT, noting that "ECT has the highest rate of response of any form of antidepressant treatment and should be considered in virtually all cases of moderate or severe major depressive disorder not responsive to pharmacologic intervention."15(p51)

TMS is approved for patients with MDD who failed to respond to at least 1 antidepressant at or above the minimal effective dose and duration in the current episode.16 The noninvasive approach employs magnetic pulses from a coil placed on the head to stimulate nerve cells in the dorsolateral prefrontal cortex.17 After 6 weeks of TMS in 301 patients with MDD refractory to medication, 23.9% of those receiving the active therapy responded compared with 12.3% of those receiving sham TMS (P < .01), while 14.2% in the active therapy group reached remission compared with 5.5% in the sham group (P < .05).18

VNS is approved for the adjunctive long-term treatment of chronic or recurrent depression in patients who have had an inadequate response to at least 4 antidepressant treatments.19 Despite its approval, its efficacy in depression remains controversial and major insurers, including Medicare and Blue Cross/Blue Shield, do not cover it.

L-methylfolate is indicated for patients with MDD who also have "suboptimal L-methylfolate levels in the cerebrospinal fluid, plasma, and/or red blood cells with particular emphasis as adjunctive support for individuals who are on an antidepressant."20(p1) Aripiprazole is indicated for the adjunctive treatment of MDD in adults21 and the olanzapine-fluoxetine combination is indicated for the treatment of resistant depression.22


Treatment-resistant depression is common in patients with MDD. Treatment requires patience on the part of the clinician and the patient as different medications and medication combinations are tried (AV 3). Other options include ECT, VNS, TMS, and the medicinal food L-methylfolate.

Drug List

aripiprazole (Abilify), bupropion (Aplenzin, Wellbutrin and others), buspirone (BuSpar and others), desipramine (Norpramin and others), duloxetine (Cymbalta), lamotrigine (Lamictal and others), lithium (Eskalith, Lithobid, and others), mecamylamine (Inversine), methylphenidate (Metadate, Ritalin, and others), mirtazapine (Remeron and others), modafinil (Provigil), olanzapine-fluoxetine (Symbyax), venlafaxine (Effexor and others)


ECT = electroconvulsive therapy, MDD = major depressive disorder, MAOI = monoamine oxidase inhibitor, NDRI = norepinephrine-dopamine reuptake inhibitor, SNRA = serotonin-norepinephrine receptor antagonist, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, T3 = triiodothyronine, TCA = tricyclic antidepressant, TMS = transcranial magnetic stimulation, VNS = vagus nerve stimulation


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