TRD is a medical condition that will likely require behavioral therapy to improve the signs and symptoms. A therapist identifies unhealthy behavior and helps implement new behaviors designed to treat TRD. Once a patient has successfully been treated and the signs and symptoms of TRD have abated, he or she should be kept on maintenance therapy for approximately two years to prevent relapse of depressive symptoms.

Pharmacotherapy options for the treatment of depression include SSRIs, serotonin and norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, atypical antidepressants, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors. An SSRI is typically considered the first-line therapy. SSRIs have fewer side effects than do other medications. Given the number of medications available to treat depression, patients need to be evaluated individually to ensure the maximal pharmacotherapeutic effect.6

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Q: What is the prognosis for people with TRD?

A: Once deemed effective, the treatment plan should be continued and reassessed periodically for patient compliance and improvement. Expect a poorer clinical outcome if the signs and symptoms of depression can only be controlled with the use of multiple antidepressants. Absence of early improvement is highly predictive of overall response failure.8 One study noted that longer unsuccessful treatment leads to a worse long-term prognosis.9 Other research, found disappointing long-term therapeutic results in patients with depression and raised the possibility that impaired sleep — especially insomnia — is at least partly responsible.10 Impaired sleep has led to increased morbidity and mortality in TRD. 

These studies illustrate the need for more research on the topic of TRD. The general prognosis is not good once a depressed person becomes resistant to treatment. Patients must be constantly reassessed in long-term treatment for the recurrence of symptoms or the onset of new symptoms. To assure compliance and maximize treatment, reassess the medication side-effect profile in patients with TRD.10

Q: What preventive measures can be used to stop the incidence of TRD?

A: A study compared the effects of treatment with fluoxetine (Prozac) plus cognitive behavior therapy (CBT) with those of fluoxetine alone. Estimated probabilities of relapse at 36 weeks were 37% in the fluoxetine group and 15% in the fluoxetine-plus-CBT group.11 Although more studies must be done to confirm the results, this suggests that CBT is effective in preventing relapse in patients being treated for depression. In other words, psychotherapy might be a way to achieve greater efficacy of antidepressants and might be a promising strategy to prevent relapse and the development of TRD.11

Q: What are the barriers to achieving successful remission of TRD? 

A: Part of the difficulty of treating TRD is that the cause of this condition is not fully understood. An individual’s misunderstanding of how his or her treatment plan works is one of the main reasons for failure. Most patients do not realize that medication must continue even if symptoms improve. Once the medications are out of the person’s system, a relapse can occur. The person then returns to the clinic for more medications, more treatments plans have failed, and the likelihood of TRD increases. 

Sometimes a full remission of symptoms is not possible even with the best therapy, which can be frustrating for the patient and provider alike. Additional research will lead to a better understanding of the etiology of TRD, and patients will see much improved therapies in the future.

Chase B. Spell, PA-C, is a physician assistant at Georgia Sports Medicine and Orthopedic Clinic in Tifton.

Laura M. Gunder, DHSc, MHE, PA-C, is assistant professor and director of research and faculty development at Georgia Health Sciences University in Augusta.


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  8. Fekadu A, Wooderson SC, Markopoulo K, et al. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord. 2009;116:4-11.

  9. Papakostas GI, Petersen T, Pava J, et al. Hopelessness and suicidal ideation in outpatients with treatment-resistant depression: prevalence and impact on treatment outcome. J Nerv Ment Dis. 2003;191:444-449.

  10. Mendlewicz J. Sleep disturbances: core symptoms of major depressive disorder rather than associated or comorbid disorders. World J Biol Psychiatry. 2009;10:269-275.

  11. Kennard BD, Emslie GJ, Mayes TL, et al. Cognitive-behavioral therapy to prevent relapse in pediatric responders to pharmacotherapy for major depressive disorder. J Am Acad Child Adolesc Psychiatry. 2008;47:1395-1404.

All electronic documents accessed December 5, 2011