When Bipolar and ADHD Overlap: Treatment 1

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. Welcome to the Carlette Psychiatry Podcast, keeping psychiatry honest since 2003. I'm Chris Akin, the Editor-in-Chief of the Carlette Psychiatry Report. And I'm Kelly Newsom, 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. Accurs 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. 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. That risk falls to negligible levels when an anti-manic mood stabilizer is on board. L'Motrogene would not count here, it's not anti-manic, but mood stabilizers do not protect against mild or worsening of symptoms. So just because the patient isn't having fulmania, that doesn't mean that 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, worsening of irritability or anxiety, on stimulants with mood stabilizers in place, based on results from 6 small clinical trials. Let me repeat that again. If you got a mood stabilizer on board, you may not have fulmania, 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 with the amphetamines, and here we're lumping all the amphetamines together at or all dexidrine and vivants. Amphetamine has been used as an animal model of mania since the 1970s, and it is twice as likely to trigger psychosis than methylphenidate. This risk of psychosis and mania goes up with the dose. So we're talking about a serious risk here for amphetamines, it's an animal model and in humans, and it's a dose dependent. Here's how we know that. In a recent study of hospitalized patients, those who took prescribed amphetamine were three times more likely to have mania or psychosis, while on it. And that risk was five times higher if the dose went above 30 milligrams a day of dextromephetamine, which is like 35 milligrams of aterol or 80 milligrams of vivants. By comparison, methylphenidate is a bit safer in bipolar disorder, but not all the way. It's still used as an animal model for mania, but not as often as amphetamines are. Methylphenidate did not flag any risk in that recent hospital study that I mentioned, and this stimulant was once thought to treat mania. Yes, you heard me right. There were psychiatrists who thought that methylphenidate treated mania by stabilizing something called mental arousal. Well, based on that theory, they even tested methylphenidate against placebo as a treatment for mania back in 2018. The study only lasted three days, and it, well, it didn't work. Methylphenidate failed to help mania, but at least the stimulant did not make mania worse in that singular controlled trial. Methylphenate also has a lower abuse potential than amphetamines, judging from its rewarding properties in pre-clinical studies and animal models. 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. Although human studies are lacking, the problem appears to be limited to the higher dose ranges, equivalent to amphetamine 140 to 700 milligrams per day. Unlike amphetamine, methylphenidate has neuroprotective effects that may mitigate any neurotoxicity from the drug. All medications have risks, but do stimulants have any benefit for ADHD with bipolar disorder? That's an important question. We can't just assume because there's stimulants that they're actually going 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 got to 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 to take it seriously, and I'm going to 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 that they do. But the studies here are not very strong at all. We only have three placebo-controlled trials, two of which were positive. These studies, which were conducted in children, are limited in size, the total number of patients is 63. Limited in duration, they only went about two weeks, and limited in design, instead of using a randomized controlled trial with two groups, they used crossover with the same patients, switch treatments. So let me just pause and say that if we had that kind of data on something like a natural supplement, psychiatrist 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 in ADHD and bipolar, and it is widely prescribed and endorsed. So stimulants don't really know that they work. What about non-stimulate 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 adamoxetine in that new one, quellabry. 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. But first let's pause for a preview of the CME quiz for this episode, or in CME for each episode through the link in the show notes. Which has evidence to treat both ADHD and mania. A) methylphenidate B) lymotrogen C) omega-3 fatty acids 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 milligrams a day of Adderol, less than 25 milligrams a day of dextramphetamine, and less than 45 milligrams a day of methylphenidate. Now let's look at some non-stimulant options. My top choices for ADHD and bipolar disorder are the non-stimulants, the alpha-agonist, clonidine, a brand name capve, and guanfacine, brand name intunif. And the medaphynils, which some might call novel stimulants, those are armadaphanil, brand name new vigil, and modaphynil, brand name. Provigil. Let's go through them one by one. The alpha agonists are FDA approved for pediatric ADHD, and they improve executive functioning in various populations, not just ADHD. They help that in schizophrenia, substance use disorders, as well as ADHD. So pretty promising there. Let's look at Medaphineal. Medaphineal actually is not approved in ADHD, but it did come close to FDA approval. So why wasn't it approved? Well, it was held back when a single child developed Steven's Johnson syndrome on the drug. That is a real but very rare risk with the Medaphineals. 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 Medaphineals and getting Steven's Johnson syndrome to treat academic problems in ADHD. So compared to the stimulants, these two classes of medications, the alpha agonists and the Medaphineals 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 Medaphineals improve 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 clonidine, 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 Medaphineals possible benefits in bipolar depression. Now another thing that I like about these non-stimulants is that neither of them are neurotoxic. And why am I harping so much about neurotoxicity? Because that is the real killer in bipolar 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 Medaphineals might have neuroprotective effects. They increased synaptic plasticity in the hippocampus in some studies. But can these meds cause mania? Well, the Medaphineals do have a few case reports of that, so it's possible, but they also treated mania in case reports. And that's true to my experience. You know, I see the Medaphineals is 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 in the other hand, if they're causing insomnia, they could be causing mania indirectly. The alpha agonist, 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 Medaphineals. And there I'm usually going to prefer our Medaphineal because it has smoother blood levels and a little bit longer duration of action. Or the alpha agonists. 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 40 milligrams a day in this head-to-head trial. Adult ADHD, who gives lithium for that? But hey, it adds 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, 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. That is pretty cool. We've got more options for ADHD and bipolar disorder, including atomoxetine and valloxazine, which we're kind of going to recommend against, and some supplements that help both conditions will pick up on that in our next episode. Let's recap. About 10 to 20 percent of patients with bipolar disorder have genuine ADHD. To treat this comorbidity, stabilize mood first. Alpha agonists and the medaphineels are good options to start with, while the stimulants carry 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 Carlates Psychiatry Report Online. Want to keep up with the latest in psychiatric research? We post new studies in the daily psych feed. Search for Chris Aiken MD on LinkedIn, Twitter, Facebook and threads. It's a first glimpse of the trials that inform this podcast. Thanks for tuning in and helping us stay free of industry support.