How to treat ADHD in bipolar disorder without destabilizing mood part 1: stimulants and non-stimulants.

Publication Date: 11/18/2024 

Duration: 17 minutes, 24 seconds 

KELLIE NEWSOME: Is it safe to give a stimulant in bipolar as long as they are on a mood stabilizer? Or is there a better way to treat ADHD in these cases? Today, we show you how to treat the vexing overlap of ADHD and bipolar.

CHRIS AIKEN: Welcome to The Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor-in-chief of the Carlat Report. 

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. Cognitive problems are a common chief complaint in bipolar disorder, and last week, we laid out a diagnostic plan for these symptoms, which may be caused by:

1. Untreated mood symptoms
2. A distractible temperament such as cyclothymic disorder
3. Cognitive deficits that build up with repeated mood episodes
4. Or, a genuine ADHD comorbidity

Genuine ADHD begins before age 12, occurs independent of mood episodes, and sometimes improves in adulthood. The research on how to treat ADHD in bipolar disorder is scant, so we’re going to borrow from clinical experience in sketching out a treatment approach today, starting with a look at stimulants in bipolar.

CHRIS AIKEN: Stimulants are first line for pure ADHD, but they carry several risks that we worry about in bipolar disorder: mania, psychosis, insomnia, substance abuse, and neurotoxicity. Stimulants raise the risk of mania 7-fold when taken without a mood stabilizer (Viktorin A et al., Am J Psychiatry 2017, 174:341-348). That risk falls to a negligible level when an anti-manic mood stabilizer is used (lamotrigine would not count here), but mood stabilizers do not protect against milder symptomatic worsening, so just because a patient is not having full mania does not mean things are going quite well; they could be having irritability, anxiety, agitation, because of the stimulant. Around 1 in 7 patients with bipolar disorder and ADHD experienced worsening of mood, irritability, or anxiety on stimulants with mood stabilizers in place, based on results from 6 small clinical trials. Let me repeat that again, you have a mood stabilizer on board you may not have full mania, but about 1 in 7 patients are going to have some worsening of mood.

These risks may be a little less pronounced with methylphenidate than the amphetamines (e.g., Adderall, Dexedrine, Vyvanse). Amphetamine has been used as an animal model of mania since the 1970s, and it is twice as likely to trigger psychosis than methylphenidate (Moran LV et al., N Engl J Med 2019, 380:1128-1138). This risk goes up with the dose, so we are talking about a serious risk here for amphetamines in the animal model and in humans, and its dose dependent. Here is how we know that in a recent study of hospitalized patients, those who took prescribed amphetamine were 3 times more likely to have mania or psychosis, and the risk was 5 times higher if the dose went above 30 mg a day dextroamphetamine, which is like 35 mg of Adderall or 80 mg of Vyvanse. By comparison, methylphenidate is a bit safer in bipolar disorder, but not all the way. Its still used as an animal model for mania, but not as often as amphetamines are. Methylphenidate didn’t flag any risk in that recent hospital study, and this stimulant was once thought to treat mania by stabilizing mental arousal. Based on that theory, they even tested methylphenidate against placebo as a treatment for mania back in 2018. The study only lasted 3 days, and it failed to help mania, but at least the stimulant didn’t make maniaworse. (Hegerl U et al, Eur Neuropsychopharmacol 2018;28(1):185-194). Methylphenidate also has a lower abuse potential, judging from its rewarding properties in preclinical studies and animal models.

KELLIE NEWSOME: With stimulants, we don’t just worry about addiction, psychosis, and mania. We also worry about neurotoxicity, particularly with high doses and particularly with amphetamines. As you might imagine, neurotoxicity causes cognitive problems, and it is well documented in animal studies with stimulants, especially amphetamines, which can deplete vesicular storage pools of dopamine (methylphenidate does not have this effect) (Moratalla R et al., Prog Neurobiol 2017;155:149-170). Although human studies are lacking, the problem appears to be limited to the higher dose ranges (equivalent to amphetamine 140-700 mg/day). Unlike amphetamine, methylphenidate has neuroprotective effects that may mitigate any neurotoxicity from the drug (Wiguna T et al., Clin Neuropharmacol 2012;35(2):81-85). 

All medications have risks, but do stimulants have any benefit for ADHD with bipolar disorder? 

CHRIS AIKEN: That's an important question. We can't just assume, because they're stimulants, that they're actuallygoing to improve cognition. I mean, stimulants have been studied for cognition in schizophrenia, and they did not improve it. They made psychosis worse as part of the side effect, and here we're talking about risks like mania, psychosis, neurotoxicity. So we better have some serious benefits to justify using this. I mean, I gotta pause a minute and say that this podcast is just a little crazy. I mean, if we were oncologists, would we be talking about using a pro-cancer agent to treat cancer? Absolutely not. Here, we're talking about whether we should be using a drug that is the animal model for mania to treat bipolar disorder. I just don't know how we're getting into this conversation, but it is so commonly done I'm going totake it seriously. And keep pressing forward with it. So, do stimulants help, symptomatically at least, when they're given to people with bipolar disorder and ADHD symptoms? Intuitively, we’d think they do, but the studies are not very strong at all. We have only three placebo-controlled trials, two of which were positive. These studies, which were conducted in children, are limited in size (total n=63), duration (2 weeks), and design (cross-over instead of the parallel group). Instead of using a randomized controlled trial with two groups, they used crossover, where the same patients switched treatments. So, let me just pause and say that if we had that kind of data on something like a natural supplement, psychiatrists would be laughing. They would not even be considering it as a possible treatment. But here, that's the kind of data we have for stimulants and ADHD and bipolar, and it is widely prescribed and endorsed. So, stimulants, hmm, don't really know that they work. What about nonstimulant options? Well, these are largely unstudied for bipolar with ADHD, and some of them might even pose greater risks because they have antidepressant-like structures, like atomoxetine and that new one, qelbree, but some of them actually have fewer risks in bipolar disorder, and we might feel safer using them. Let's get into some of those.

KELLIE NEWSOME: Let’s pause for a preview of the CME quiz for this episode. Earn CME for each episode through the link in the show notes. 

1. Which has evidence to treat both ADHD and mania?

A. Methylphenidate

B. Lamotrigine

C. Viloxazine

D. Clonidine

Stimulants are a bit risky. I mean, if something is used as the animal model for the disease, we probably shouldn’t use it to treat that disease. If you do go the stimulant route, try to stick with methylphenidate and keep them in the low dose range, like less than 30 mg a day of Adderall, less than 25 mg a day of dextroamphetamine, and less than 45 mg a day of methylphenidate. Now, let’s look at some non-stimulant options.

CHRIS AIKEN: My top choices for ADHD in bipolar disorder are the non-stimulants: the alpha-agonists (clonidine (Kapvay) and guanfacine (Intuniv)) and the modafinils (armodafinil (Nuvigil) and modafinil (Provigil)). Let's go through them one by one. The alpha-agonists are FDA-approved in pediatric ADHD and improve executive functioning in various populations, not just ADHD, including schizophrenia, substance use disorders, and ADHD (Arnsten AFT, Neurobiol Learn Mem 2020;176:107327). So, pretty promising there. Let's look at modafinil. Modafinil actually is not approved inADHD, but it did come close to FDA approval. So, why wasn't it approved? Well, it was held back when a single child developed Stevens-Johnson syndrome on the drug. That is a real but very rare risk with the modafinils. And actually, Congress got involved in this approval. And the thinking was that we just can't have mass numbers of American children exposed to modafinils and getting Stevens-Johnson syndrome to treat academic problems and ADHD. So, compared to the stimulants, these two classes of medications, the alpha agonists and the modafinils, are not quite as effective. They have smaller effect sizes for ADHD, but each of them do have benefits in bipolar disorder, so you're getting a kind of double benefit here. Let's go over that. The modafinils improve bipolar depression. The modafinils improved bipolar depression in some, but not all, trials. So why don't they work all the way? To my mind, it's because they only improve a few symptoms, like energy, alertness, and attention, rather than the full episode of depression. The alpha agonists, particularly Tlonidine, do improve relevant symptoms to bipolar, like sleep, irritability, anxiety, in many populations. And they have improved bipolar mania in a few small controlled trials. So, clonidine has particular benefits in bipolar mania. The modafinil's possible benefits in bipolar depression. Now, another thing that I like about these nonstimulants is that neither of them are neurotoxic. And why am I harping so much about neurotoxicity? Because that is the real killer inbipolar disorder. I mean, it's these cognitive problems that build up over time, and they're related to neurotoxic changes in the brain with chronicity of illness. That is what I want to avoid in people with bipolar, and amphetamines are not a way to avoid that. So, none of these are neurotoxic, and in fact, the modafinils might have neuroprotective effect, theyincreased synaptic plasticity in the hippocampus in some studies (Yan YD et al., Transl Psychiatry 2021;11(1):116). But can these meds cause mania? Well, the modafinils do have a few case reports of that, so it's possible. They also treated mania in case reports, and that's true to my experience (Hardy-Bayle MC, Encephale 1989;15(6):523-526; Schoenknecht P et al., Biol Psychiatry 2010;67(11):e55-e57). You know, I see the modafinils as really regulating the circadian rhythm. They help patients to get up and be alert, get up at regular times each day, and regulate their sleep-wake cycle. And that helps bipolar disorder, but on the other hand, if they're causing insomnia, they could be causing mania indirectly. The alpha agonists, on the other hand, like clonidine and guanfacine, are not known to cause or worsen mania. Even in clinical trials of bipolar disorder, they didn't do that at all. And like I said, clonidine recently augmented mood stabilizers in a placebo-controlled trial of hospitalized patients with mania. So, to sum up, my go-to treatments, first line for bipolar and ADHD, are the modafinils, and there I'm usually gonna prefer R modafinil because it has smoother blood levels and a little bit longer duration of action or the alpha agonist. And there, I'm going to prefer clonidine because of its studies in mania, as well as some studies in anxiety. And now, for one of the most surprising trials I have ever seen in psychiatry. Strange fact, lithium actually has a controlled study in adult ADHD where it worked as well as methylphenidate. Which was given 40mg/day in this head-to-head trial. Adult ADHD. Who gives lithium for that? But hey, it had some benefits. In this trial, the two meds equaled each other on measures of ADHD symptoms, mood symptoms, and irritability. And the lithium levels were kept at 0. 5 to 0. 7. I don't know why that study went nowhere. It was done about 20 or 30 years ago. But hey. Lithium has broad effects, and it might help ADHD symptoms, and particularly good to know for a person with bipolar, and here's something else you want to know about lithium because I've kind of gotten stirred up about neurotoxicity on amphetamines here and I haven't given you an easy way out other than avoid them. Well, here's what you need to know. Lithium reverses some of the neurotoxicity that we see in animal models of amphetamines (Dorrego MF et al., J Neuropsychiatry Clin Neurosci2002, 14:289-295). That is pretty cool. We've got more options for ADHD and bipolar disorder, including atomoxetine and viloxazine, which we're kind of going to recommend against, and some supplements that help both conditions.  

KELLIE NEWSOME: Let’s recap. About 10-20% of patients with bipolar disorder have genuine ADHD. To treat this comorbidity, stabilize mood first. Alpha-agonists and the modafinils are good options to start with, while the stimulantscarry risks in bipolar disorder, particularly the amphetamines. If you’d like a table with all the treatments we’ve discussed and dosing tips, check out the November 2021 issue of the Carlat Psychiatry Report online.

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