Tips for Clinicians Treating Patients With MDD Who Do Not Respond To Antidepressants

Psych Congress steering committee member, Rakesh Jain, MD, MPH, shares useful tips for treating patients with major depressive disorder (MDD) who are not responding to an antidepressant or who do not want to take an antidepressant due to side effects. Dr Rakesh Jain also shares insight on the usefulness of genetic testing on patients who do not respond to antidepressants.

Dr Rakesh Jain answers questions from the audience in a recent Psych Congress Regionals virtual Q&A session moderated by Saundra Jain, MA, PsyD, LPC, following the session titled “When Your Patient with MDD Fails to Respond to an Antidepressant: 5 Tips on Managing These Patients.”

Read the transcript:

Saundra:  Welcome back, everyone. Hey, Rakesh. It's nice to see you again for another Q&A. Great topic. We've got some great questions, so are you ready? I say we jump in.

First clinician, here's their question. "When a client has adult [attention deficit-hyperactivity disorder (ADHD)] plus major depression, is there evidence for the use of stimulants to manage the atypical depression?" Also asking, "Is there a particular stimulant that's evidence‑based for atypical depression and any risk of triggering a manic episode?"

Rakesh:  Goodness me, Saundra. So many wonderful questions wrapped into that one particular point that clinician made, so lots of responses. First of all, if your patient does have comorbid ADHD and major depression, both must be treated.

There's no evidence, sadly, that treating just one or the other will take care of matters. Even the very fact that there are two disorders, you're already on very solid ground that you'll be using most likely a stimulant and most likely an antidepressant.

Could you potentially get a greater bang for the buck with the stimulant? That's what our colleague is asking. The answer is yes. You asked for clarification that, do we have any formal studies looking at atypicality? We do, but they're not very convincing.

Having said so, it makes sense to me if you counteract the ADHD, which in adults, often comes with lethargy, lack of organization, low energy, etc., you're going to have some significant advantages. Go for it. It makes great sense to me.

The final sub‑question that was asked was, is there a risk of switching to mania? The answer's going to be yes and no. The answer is yes if the patient doesn't have major depression but has bipolar depression. It could happen with stimulants. Not a high risk, but it certainly could happen.

If it is major depression and ADHD, the risk is low enough that you ought to proceed without too much concern. Just stay watchful. Great question.

Saundra:  Great advice. You're right, great group of questions. A question about gene testing. We've not had this question before. They're asking, "Do you ever use gene testing on patients who simply don't respond to antidepressants?"

Rakesh:  Absolutely. It is a worthy thought to have, but I will have to comment on the following fact, that the gene testing habits of American clinicians is, at the moment, outstripping the evidence that we have for its clinical utility.

Overall, the evidence base is not very strong. It's emerging, but it's not strong. At the moment, it is not recommended as part of the protocol of taking care of patients with major depression, leave alone major depression that is resistant to treatment.

What if you did get the testing? Might there be advantages? There might be, particularly if a patient on a metabiology, on a metabolic snip is challenged. What if they are an extensive metabolizer but a ultrarapid metabolizer on a particular gene that an antidepressant is being metabolized through? Say, 1A2, for example.

There's another example. What if they are 2D6 poor metabolizers, which may explain why they get so many side effects on multitudes of medications? Those are all possibilities.

The upshot to gene testing and major depression and difficult‑to‑treat major depression, I don't think the scientific evidence is strong enough yet. I would encourage all my colleagues to continue till we have that to use our best clinical skills. Let's make sure they're adherent.

I already shared with you, adherence is a major problem. Choose the medication that has the highest chance of tolerability. In terms of efficacy, if you're not seeing it, it's so much better to consider various augmentation strategies or switch strategies, and perhaps do gene testing.

I do hope, Saundra, that when we have this conversation again next year or in the next few years, my answer will be different, that we will have gene tests that'll guide us. At the moment, we do not have it.

Saundra:  These are such great questions this afternoon. A question about atypical antipsychotics and weight gain. Here we go. Clinician says, "I have repeatedly had patients who will refuse to take an atypical antipsychotic because of fear of weight gain."

In parentheses, they say real or assumed. I'd love for you to comment on that. They're asking specifically, "What atypicals may have the least likelihood of causing weight gain?"

Rakesh:  Entirely agreed with my colleague. Yes, many patients, even before they get a chance to experience an atypical antipsychotic augmentation, for all the right reasons, and perhaps for a lot of wrong reasons, are overly concerned.

When a patient does bring up that concern, as our colleague just asked, it is so much better to fully appreciate their concern. It could be a combination of health reasons, cosmetic reasons, and they both must be appreciated.

I would then add to my patient the following information, the risk benefit ratio. I might point out to them that the suffering from depression at the moment is so intense. "Why don't you consider the risk benefit ratio, and then ultimately, you will make a decision?"

I assure them that I will monitor their metabolics closely along with body weight. If we do see adversity, we can always discontinue. I do tell them that adversity is not guaranteed. Majority of patients with many antipsychotics do not get weight gain. A substantial minority do, though. We would need to keep that in mind.

The final question you had asked, Saundra, was, is there a difference, and what may predict higher weight gain? Higher weight gain may be predicted by medications that have high histamine blockade or have high anticholinergic blockade. Some of the modern‑day antipsychotics do tend to have lower risk.

There's also one antipsychotic that recently was approved by the FDA, which is a combination of olanzapine with a particular opioid antagonist that also, quite likely, is going to be a valuable agent, because it does have lower risk than olanzapine per se, in terms of weight gain.

Some of the newer‑generation medications like cariprazine, and brexpiprazole, and some of the other ones do have lower risk. We should, of course, be considering them.

Saundra:  What do you think, Rakesh? I know we've presented before on this topic. You and I have had lots of conversations about this.

What about in the time before an atypical is prescribed and offering education around non‑pharmacological interventions around nutrition, around the exercise to get them ready to take an atypical in hopes of lessening the risk of weight gain? What are your thoughts about that?

Rakesh:  A medication's side effects are not destiny. There are things that can be done to modulate it. That is a very hopeful message we should share with our patients, but also a realistic message. They don't completely in everybody reverse the risk, but they certainly help.

For example, metformin. The database is not profoundly strong, but it's not inconsequential. We have been using that. FDA's approved five different weight loss medications and interventions in appropriate situations that could be considered.

At the end of the day, it's the two interventions you mentioned, exercise and obviously nutritional advice given to the patients, that can bend the curve of weight gain. This isn't based, as you all know, Saundra, it's not based just on hypothetical thinking or wishful thinking.

There is data that patients who are prescribed exercise and offered good nutritional tips often do have less weight gain, even on antipsychotic medications.

Saundra:  I love that. I never want to let an opportunity slip by to be able to talk about these non‑pharmacological interventions, because they, based on the data, are very powerful. We are almost at time, with a little bit less than a minute, so I'm going to challenge you on this question, Rakesh, to see if you can give us an answer in that time.

It's about scales and screeners. The clinician is saying, "In addition to the [mood disorder questionnaire] MDQ and the newer Rapid Mood Screener, what are your thoughts about BSD as the Bipolar Spectrum Diagnostic Scale?"

Rakesh:  Whoever is asking that is both an astute clinician and also a very well‑read clinician. BSDS ‑‑ colleagues, write this down ‑‑ BSDS, as Saundra said, Bipolar Spectrum Diagnostic Scale, has been ‑‑ you would agree with me, Saundra, won't you? ‑‑ has been spectacularly useful in detecting, I would have to say soft and difficult to detect bipolar disorder.

It's a narrative scale created by Ron Pies and Nassir Ghaemi. These are two gentlemen who know what they're talking about. This narrative scale does pull out the subtleties of bipolar depression and does have high sensitivity and specificity.

MDQ is great, but more so for bipolar I. Rapid Mood Screener is great, but more for bipolar I. The BSDS is great, but it is great for bipolar I, bipolar II, and what we sometimes call bipolar NOS.

Saundra:  Absolutely support everything you just said. It's very easy to get your hands on. It's in public domain. Google "BSDS PDF," you'll have it along with scoring instructions. Very simple and easy to use.

We're at time. I want to thank you, Rakesh. I know our viewers. This is such a practical presentation. Lots of clinical pearls to take and put to good use on Monday. It's hard to imagine, but we are at the end of day two of the Psych Congress regional meeting. It's been a lot of fun spending these two days with hundreds of mental healthcare practitioners. What a treat.

Rakesh, you've been part of the two days, both as a presenter as well as an attendee. I'm wondering, any last‑minute closing thoughts that you'd like to share with our Psych Congress family?

Rakesh:  Sure. Two things. I'm glad you said Psych Congress family. We are a family. We are bonded together by a common purpose of serving our patients.

You also said it was a lot of fun. It was. This is one of the largest Psych Congress regional meetings ever. There were almost 400 people today. As you said, Psych Congress family members. The breadth and depth of presentations were incredible. You are a great moderator, Saundra, so thank you very much for it.

I do want to tell people if their appetite is whetted and they want to learn about so many different topics in psychiatry at much greater depth, I would like to invite them to come to this year's Psych Congress. It's going to be live. We're going to be face to face in San Antonio, Texas.

Texas is my and Saundra's home state. San Antonio's a really amazing city. I very much look forward to welcoming all of my hundreds, thousands of colleagues to San Antonio to US Psych Congress later this year. Please check out the agenda, and I would love to see you there.

Saundra:  I feel the same way, Rakesh. If I could take a few more moments to wrap things up, I want to say to all of our colleagues, as your moderator over these two days, so much fun, so good. Thank you for letting me share in this experience with all of you now.

On behalf of the Psych Congress steering committee, a big thank you to our faculty, our supporters, and most of all, really most of all, to each of you, our attendees. As we said, truly, our Psych Congress family.

A big Texas thank you for being part of this conference. We look forward to seeing you, like Rakesh said, at our big national meeting in the fall in San Antonio. We all wish you an enjoyable weekend, but please, stay safe, healthy, be well.

From all of us, goodbye, but just for now, because I know we're going to see you down the road. Till next time.


Jain R, Jain S. When Your Patient with MDD Fails to Respond to an Antidepressant: 5 Tips on Managing These Patients Q&A. Presented at: Psych Congress Regionals; June 16–18, 2021; Virtual.