Understanding major depressive disorder and resistance to treatment

Sheldon Preskorn, MD, shares his knowledge of the mechanisms and delivery of drugs to better help patients with major depressive disorder.


“There appear to be at least 3 types of major depressive disorder (MDD) based on pharmacology,” Sheldon Preskorn, MD, told participants of the Annual 2021. Psychiatric schedulesTM World CME Conference. Preskorn, professor in the Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine and Psychopharmacology, Section Editor Psychiatric schedulesMT, was also named educator of the year at the conference.

The first type of MDD responds to biogenic amine antidepressants. This group represents around 60% to 65% of patients, he added. The next group does not respond to biogenic amine antidepressants, but responds to glutaminergic antidepressants (NMDA), and accounts for approximately 25% of patients. The third group does not respond to biogenic amine and glutaminergic antidepressants; this group represents about 15% of patients with MDD.

To better understand this philosophy, Preskorn turned to the STAR-D study (Sequenced Treatment Alternatives to Relieve Depression), funded by the National Institutes of Mental Health to determine the effectiveness of different treatments for MDD in cases of failure. to respond to initial treatment with an antidepressant. In the study, the initial treatment was citalopram. If MDD did not respond to treatment, patients switched to SR bupropion, sertraline, or venlafaxine XR, or treatment was increased to SR bupropion or buspirone.1 In those cases that did not respond, participants were switched to mirtazapine or nortriptyline, or had an increase with lithium of triiodothyronine. Finally, if treatment still failed, participants switched to tranylcypromine or mirtazapine in combination with venlafaxine SR.

What’s remarkable, Preskorn explained, is that the acute results worsened with the increase in the number of previous treatment failures. In the group with no prior or limited medication, 27.5% achieved remission, as measured by HAM-D 17. Those in the group with 1 prior failure saw remission rates drop to 21.1%. And those with 2 and 3 previous failures saw remission rates drop to 16.2% and 6.9%, respectively.1-4

“If you’re like me, you see these patients every day in the clinic, because we usually see patients after they’ve already been tried with an antidepressant in primary care. ”

“If you’re like me, you see these patients every day in the clinic because we usually see patients after they’ve already been tried with an antidepressant in primary care,” Preskorn said. “So we always have someone who probably hasn’t received treatment. And, not only did they not benefit, but they were also much more likely to relapse. “

Looking at current treatment strategies, Preskorn said that we know that the vast majority of people initially receive a selective serotonin reuptake inhibitor. The next most likely is either a serotonin-norepinephrine reuptake inhibitor or a dopamine norepinephrine reuptake inhibitor. If that doesn’t work, he explained that there is a likelihood of an increase with atypical antipsychotics or other types of drugs, or a newer drug like esketamine. If you still don’t see an appropriate response, you will switch to monoamine oxidase inhibitors or various types of electrical treatments such as transcranial magnetic stimulation.

“There is no requirement that a new drug be superior to antidepressants, whether it is superior in efficacy or tolerance … new does not mean improved.”

So why is there so little benefit to switching between different antidepressants, Preskorn asked the audience. “First and foremost, you need to realize that the FDA only requires superiority over placebo for approval. There is no requirement that a new drug be superior to antidepressants, either in terms of efficacy. or tolerance … New, does not mean improved. “

“The second thing is that the development of psychiatric drugs for antidepressants and antipsychotics has, for 60 years, mainly reshaped the relative receptor binding affinity of the mechanisms of action of biogenic amines,” he added. “So they all work on the same neurotransmitter system. “

To better understand the situation, Preskorn gave the example of a patient with pneumonia. Among the patients treated with penicillin 1, a certain percentage will get better. For those who do not, they are given penicillin 2, and a lower percentage is likely to improve because the infectious agent that causes pneumonia does not respond to penicillin.

While brewing identical mechanisms did not necessarily improve efficacy, Preskorn noted that it improved safety and tolerance. “This is the reason why SSRIs, SNRIs and other newer antidepressants have replaced tricyclic antidepressants, not because they are more effective, but because they are safer and better tolerated,” he said. he explained. Preskorn added that this is also the reason why there is a significant subset of patients with apparently treatment-resistant depression because they do not respond to biogenic amino antidepressants.

Find out more about the Annual 2021 Psychiatric schedulesMT CME World Conference here.

The references

1. Rush AJ, Trivedi MH, Wisniewski SR et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N English J Med. 2006; 354 ​​(12): 1231-1242.

2. Trivedi MH, Rush AJ, Wisniewski SR et al. Evaluating outcomes with citalopram for depression using measurement-based care in STAR * D: implications for clinical practice. Am J Psychiatry. 2006; 163 (1): 28-40.

3. Fava M, Rush AJ, Wisniewski SR et al. A comparison of mirtazapine and nortriptyline following two consecutive failed drug treatments in depressed outpatients: a STAR * D report. Am J Psychiatry. 2006; 163 (7): 1161-1172.

4. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following the failure of three antidepressant trials for depression: a STAR * D report. Am J Psychiatry. 2006; 163 (9): 1531-1666.

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