Treatment Resistant Depression

Hasnain Afzal, MDSindh Medical College, Pakistan.

Clinical Observer at Griffin Memorial Psychiatry Hospital

•Major depression is one of the most common mental disorders in the United States.•In 2014, an estimated 15.7 million adults aged 18 or older in the United States. had at least one major depressive episode in the past year. This number represented 6.7% of all U.S. adults.•Up to 50% treated with single antidepressant don’t reach full remission.• Approximately one-third of patients with major depressive disorder (MDD) are treatment resistant.•Depression is the second-leading cause of disability-adjusted life years in those 15 to 44 years old.

Treatment resistant depression – The term “treatment resistant depression” often refers to major depressive episodes that do not respond satisfactorily to at least two trials of antidepressant monotherapy. However, the definition has not been standardized.

Treatment refractory depression – The term “treatment refractory depression” typically refers to unipolar major depressive episodes that do not respond satisfactorily to numerous sequential treatment regimens. However, the definition has not been standardized, and there is no clear demarcation between treatment resistant and treatment refractory depression.

Strategies — For patients with unipolar major depression who do not respond to initial treatment with an antidepressant medication, treatment strategies include

●Switching treatment•Different antidepressant•Psychotherapy (eg, cognitive-behavioral therapy)•Electroconvulsive therapy (ECT)•Repetitive transcranial magnetic stimulation

●Augmentation (adding a treatment)•Medication (eg, second-generation antipsychotic, lithium, or triiodothyronine)•Psychotherapy

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study evaluated feasible treatment strategies to improve clinical outcomes for real-world patients with treatment-resistant depression. Although the study found no clear-cut “winner,” it does provide guidance on how to start therapy and how to proceed if initial treatment fails.STAR*D involved a national consortium of 14 university-based regional centers, which oversaw a total of 23 participating psychiatric and 18 primary care clinics. Enrollment began in 2000, with follow-up completed in 2004.

Dosing recommendations were flexible but vigorousMedications often were increased to maximally tolerated doses. For example, citalopram (Celexa) was started at 20 mg/day and increased by 20 mg every 2 to 4 weeks if the patient was tolerating it but had not achieved remission, to a maximum dose of 60 mg/day. Treatment could be given for up to 14 weeks, during which side effects and clinical ratings were assessed by both patients and study coordinators.

Depression ScalesThe severity of depression was assessed by the clinician-rated, 16-item Quick Inventory of Depressive Symptomatology QIDS-CS16 or QIDS-SR16(the self report version) and Hamilton Depression Scale HAM-D17 score.

Entry criteria were broad and inclusive Patients had to:• Be between 18 and 75 years of age• Have a nonpsychotic major depressive disorder, identified by a clinician and confirmed with a symptom checklist based on the Diagnostic and Statistical Manual, fourth edition revised, and for which antidepressant treatment is recommended• Score at least 14 on the 17-item Hamilton Rating Scale for Depression (HAMD17)• Not have a primary diagnosis of bipolar disorder, obsessive-compulsive disorder, oran eating disorder, which would require a different treatment strategy, or a seizuredisorder (which would preclude bupropion as a second-step treatment).

STAR*D was a multisite, multistep, prospective randomized controlled trial comparing treatments and treatment strategies in outpatients with major depressive disorder. The study provided data on treatment effectiveness, or “real world” outcomes in typical patients, making the results generalizable to standard practice. The study was organized into four levels. In level 1, 2,876 outpatients received citalopram for up to 14 weeks. In level 2, nonresponders (N=1,493) were offered three alternatives, which were selected based on patient choice: change to another medication (N=727), augment citalopram with another medication (N=565), or start psychotherapy (N=147). If the patient changed to another medication, he or she wasrandomly assigned to receive sertraline, bupropion SR, or venlafaxine XR. Patients who chose medication augmentation were randomly assigned to augment citalopramwith bupropion SR or buspirone. Patients who agreed to start psychotherapy were randomly assigned to change to cognitive therapy (discontinuing citalopram) or to augment with cognitive therapy (continuing citalopram)

For patients who did not respond to level 2, level 3 offered two alternatives: changing or augmenting with another medication. Patients in the change group were randomly assigned to receive mirtazapine (N=114) or nortriptyline (N=121) for up to 14 weeks. Patients in the augmentation group were randomly assigned to receive lithium (N=69) or triiodothyronine (N=73) for up to 14 weeks. Finally, level 4 randomly assigned nonresponders from level 3 to receive tranylcypromine (N=58) or the combination of venlafaxine XR and mirtazapine (N=51). STAR*D therefore provides data for several randomized controlled trials of change or augmentation of medications at various stages. Two such studies based on STAR*D data provide evidence for continued efficacy of medication augmentation and medication change for treatment-resistant depression. Remission rates were equivalent and approximately 25% upon changing from citalopram to either an SSRI or SNRI or bupropion at the second step; there was no difference in remission between changing to either mirtazapine or nortriptyline at the third step.

Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G: Sequenced treatment alternatives to relieve depression (STAR*D): rationaleand design. Control Clin Trials 2004; 25:119–142 [G]

Outcomes measured

Remission (complete recovery from the depressive episode), the primary study outcome, was defined as a Hamilton Depression Scale HAM-D17 score of 7 or less, as assessed by treatment-blinded raters.A secondary remission outcome was a QUICK INVENTORY OF DEPRESSIVE SYMPTOMATOLOGY QIDSSR16 score of 5 or less. Of note, the HAMD17remission rates were slightly lower than the rates based on the QIDS-SR16, sincepatients who did not have a HAM-D17 score measured at exit were defined as not being in remission a priori. Thus, the QIDS-SR16 rates might have been a slightly better reflection of actual remission rates.

Response, a secondary outcome, was defined as a reduction of at least 50% in the QIDS-SR16 score from baseline at the last assessment.

Overall, what was the cumulative rate?The theoretical cumulative remission rate after four acute treatment steps was 67%. Remission was more likely to occur during the first two levels of treatment than during the last two. The cumulative remission rates for the first four steps were:• Level 1—33%• Level 2—57%• Level 3—63%• Level 4—67%.

Warden et al. Curr Psychiatry Rep. 2007;9:449-459.BUP-SR, bupropion sustained-release; BUS, buspirone; CIT, citalopram; Li, lithium; MIRT, mirtazapine; NTP, nortriptyline; SERT, sertraline; T3, triiodothyronine; TCP, tranylcypromine; VEN-XR, venlafaxine extended-release.

Key Points

Remission (ie, complete relief from a depressive episode) rather than response (merely substantial improvement) should be the goal of treatment, as it is associated with a better prognosis and better function.

Should the first treatment fail, either switching treatment or augmenting the current treatment is reasonable.

For most patients, remission will require repeated trials of sufficiently sustained, vigorously dosed antidepressant medication. Physicians should give maximal but tolerable doses for at least 8 weeks before deciding that an intervention has failed.

After two well-delivered medication trials, the likelihood of remission substantially decreases. Such patients likely require more complicated regimens. Given the thinexisting database, these patients are best referred to a psychiatrist for more complex treatments.

For patients who present with major depressive disorder, STAR*D suggests thatwith persistence and aggressive yet feasible care, there is hope: after one round, approximately 30% will have a remission; after two rounds, 50%; after three rounds, 60%; and after four rounds, 70%.

While STAR*D excluded depressed patients with bipolar disorder, a depressiveepisode in a patient with bipolar disorder can be difficult to distinguish from a depressive episode in a patient with major depressive disorder. Primary care physicians need to consider bipolar disorder both in patients presenting with a depressive episode and in those who fail an adequate trial.

New medications for treatment of depression continue to be developed and studied. STAR*D was designed prior to publication of data on the efficacy of antidepressant treatment augmentation using atypical antipsychotic agents. Future studies on treatment strategies and effectiveness in treatment-resistant MDD should include atypical antipsychotic options, as well as examination of how these drugs fit into the treatment paradigms described in STAR*D. Another important finding of STAR*D was that CBT, both alone and in combination with CIT, was as effective as the various second-step pharmacologic strategies, although medication augmentation produced remission more rapidly. Future studies that incorporate comparisons of psychotherapy would be useful. STAR*D has provided important insights into the management of treatment-resistant MDD, and its results will continue to be utilized to formulate future studies in this difficult-to-treat patient population.

Gaynes BN, Rush AJ, Trivedi MH, et al. The STAR*D study: treating depression in the real world. Clev Clin J Med. 2008;75:57–66

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