Understanding Major Depressive Disorder and Treatment Resistance


Sheldon Preskorn, MD, shares insights into drug mechanisms and delivery to better help patients with major depressive disorder.

Sheldon Preskorn, MD, discusses psychopharmacological issues of MDD.

Sheldon Preskorn, MD


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

The first type of MDD responds to biogenic amine antidepressants. This group represents about 60% to 65% of patients, he added. The next group is nonresponsive to biogenic amine antidepressants, but responsive to glutaminergic (NMDA) antidepressants, and represents about 25% of patients. The third group is nonresponsive to both biogenic amine and glutaminergic antidepressants; this group represents about 15% of patients with MDD.

To get a clearer understanding of this philosophy, Preskorn turned to the Sequenced Treatment Alternatives to Relieve Depression (STAR-D) study, which was funded by the National Institutes of Mental Health to determine the effectiveness of different treatments for MDD in cases in that failed to respond to initial treatment with an antidepressant. In the study, the initial treatment was citalopram. If MDD was not responsive to treatment, patients were switched to bupropion SR, sertraline, or venlafaxine XR, or treatment was augmented with bupropion SR or buspirone.1 In cases that remained unresponsive, participants were switched to mirtazapine or nortriptyline, or had augmentation with lithium of triiodothyronine. Finally, if treatment still failed, participants were switched to tranylcypromine or mirtazapine combined with venlafaxine SR.

What was noteworthy, Preskorn explained, was that acute outcomes worsened with increasing number of prior treatment failures. In the group with no or limited prior medications, 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 prior 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 get patients after they have already been tried on an antidepressant in primary care.”

“If you're like me, you see these patients every day in the clinic, because we usually get patients after they have already been tried on an antidepressant in primary care,” Preskorn said. “So we always are getting someone who has probably not benefited from treatment. And, not only did they not benefit, they also were much more likely to relapse.”

In looking at current treatment strategies, Preskorn said we know the vast majority of people initially receive a selective serotonin reuptake inhibitor. Next, most likely is either a serotonin-norepinephrine reuptake inhibitor or a norepinephrine dopamine reuptake inhibitor. If that does not work, he explained there is the likelihood of augmentation with atypical antipsychotics or other kinds of medications, or a new drug like esketamine. If you still are not seeing a proper response, you would move into monoamine oxidase inhibitors or various kinds of electrical treatments such as transcranial magnetic stimulation.

"There is no requirement that a new drug is superior to antidepressants, be it superior either in efficacy or tolerability… new, does not mean improved."

So, why is there so little benefit from switching among them the various antidepressants, Preskorn asked the audience. “First and foremost, you have to realize that the FDA only requires superiority over placebo for approval. There is no requirement that a new drug is superior to antidepressants, be it superior either in efficacy or tolerability… new, does not mean improved.”

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

To better help understand the situation, Preskorn gave the example of a patient with pneumonia. Out of the patients treated with penicillin 1, a certain percentage will get better. For those who do not, they receive penicillin 2, and a smaller percentage is likely to get better because you have the infectious agent causing the pneumonia does not respond to penicillin.

Although shuffling identical mechanisms has not necessarily improved efficacy, Preskorn noted it has improved safety and tolerability. “That's the reason why SSRIs, SNRIs, and other newer antidepressants have replaced tricyclic antidepressants—not because they are more efficacious, but because they are safer and better tolerated,” he explained. Preskorn added it is also why there is a meaningful subset of patients with seemingly treatment resistant depression, because they are not responding to biogenic amine antidepressants.

Learn more about the 2021 Annual Psychiatric TimesTM World CME Conference here.


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

2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of 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 medication treatments for 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 three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531-1666.

Related Videos
brain depression
nicotine use
brain schizophrenia
eating disorder brain
© 2024 MJH Life Sciences

All rights reserved.