Side Effects and Stimulants Role in Treating Bipolar Disorder

In this podcast, Psych Congress 2021 co-chair, Julie Carbray, PhD, FPMHNP-BC, PMHCNS-BC, APRN, Clinical Professor of Psychiatry and Nursing, University of Illinois at Chicago; Administrative Director, Pediatric Mood Disorder Clinic, Pediatric Brain Research and Intervention Center, Department of Psychiatry, Chicago, Illinois, moderates an audience question and answer session with Joseph F. Goldberg, MD, clinical professor of psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, from his session, “Personalized Medicine for Bipolar Depression: Combining Evidence and Clinical Wisdom to Improve Clinical Outcomes.”

Dr Golberg tackles side effects of poor metabolizing therapies for bipolar disorder, as well as how stimulants play a role in navigating treatment options.

Read the transcript:

Dr Julie Carbray:  This question was ranked fairly high, so I thought it would be a good turf for you to cover. If Maria is a poor metabolizer, shouldn't the problem of the history of venlafaxine, paroxetine, vortioxetine be that the levels are too high so side effects are too high?

Dr Joseph Goldberg:  You'd think that's a good point. The drug doesn't know that there's a side effect and a beneficial effect. It just does its thing. Problem though is that you can sometimes get an antihistaminergic effect very quickly as soon as you hit Tmax. You're not even a steady‑state level.

Anybody ever take a cold pill at home? Within a half-hour, you're asleep. You're not at steady-state or Cmax. The intended end‑organ targets that you're going after - for me, that'd be nasal congestion and sinuses, and things like that - come later.

Some of these side effects that we see are about hitting Tmax - the maximum concentration - or Cmax, and the time frame in which that occurs, which can be quick, and then it adds up. Poor metabolizers are like when your sink is stuck and the water won't go down. Now, you've got dirty water building up.

You can't get to where you want to be in terms of the end organs of interest, but you get this Tmax side effect mush at the front end. It ends up being interpreted as either intolerable or it didn't work, and then we go back and ask, "Why didn't this work? Was it because of side effects, or lack of an adequate trial or an adequate dose?"

You could argue, if I have a known poor metabolizer, I'll give you a teeny dose and hope that that will minimize Cmax and minimize the build‑up in your sink, but then you may not get enough of a therapeutic effect at the end organs of interest. It's hard to maneuver around the poor metabolizer.

Dr Carbray:  That's a great, great metaphor. I like that. Stimulants in bipolar, how do you address that zone? You mentioned it a bit, but then made some commentary about efficacy with depressive symptoms. How do you navigate that?

Dr Goldberg:  If anybody happened to hear my virtual presentation yesterday on evidence but off-label, I talked about there is a database with desvenlafaxine and methylphenidate and amphetamine salts, both in bipolar depression and in adult bipolar disorder with ADHD, which has not shown destabilization of mood.

That's the thing we always seem to worry about. "Am I going to make the patient manic?" Roger McIntyre's and Sue McElroy's respective studies showed no movement at all with mania symptoms, but improvement in ADHD symptoms and improvement in depression symptoms. That was very encouraging from the standpoint of safety and provisional efficacy.

The problem was, again, the word provisional. They looked at 30 patients in each of their studies, and we like to see hundreds of patients in order to have confidence. It's the same way when I was showing those pharmacogenetic studies earlier. If it's a small n, we don't know if that's a Type 1 error or a Type 2 error, or if it's believable until it's replicated.

It's comforting to say there are randomized trials out there in using stimulants in bipolar disorder for the depressed phase for comorbid ADHD. If you like desvenlafaxine for comorbid binge-eating disorder, it would be an on-label and evidence-based use and things along those lines. We like more studies, but it's helpful to know what the studies are.

If you're justifying the rationale to yourself, your patient, or a third party, you can actually say in your note, "I'm following the randomized trial data, and this is why I'm using this compound," and, "I'm watching to make sure there's no exacerbation of mania or psychosis," but those studies make us not assume it's likely you'll see that happen.

Dr Carbray:  Thank you, and thank you so much for this presentation - with its scope, its step - and we look forward to hearing more from you as we move forward in helping our patients. Thanks again for being here.

Dr Goldberg:  Thank you all.