Treating ADHD in Patients With Bipolar Disorder and Substance Use

Lenard Adler, MD, explains how clinicians can safely and effectively treat ADHD when bipolar disorder and addiction are also in the picture. He addresses how to distinguish chronic ADHD symptoms from episodic mood disorders, why bipolar disorder is often missed in adults referred for depression or attention problems, and how substance use complicates both diagnosis and medication selection.

Dr. Adler also shares guidance on identifying red flags for diversion or misuse, setting appropriate expectations for medication trials, and navigating the limits of current treatment guidelines. The episode closes with a look toward emerging directions in ADHD treatment, including research on emotional dysregulation, executive function deficits, and next-generation neurofeedback approaches.

Lenard Adler, MD, is Pottash Professor of Psychiatry and Director of the Adult ADHD Program at NYU Langone Health

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00:00 Why ADHD, Bipolar Disorder, and Addiction Must Be Treated Together
01:02 What Makes These ADHD Cases So Difficult
02:05 ADHD vs. Bipolar Disorder: Key Diagnostic Distinctions
04:43 The Link Between ADHD and Addiction
05:53 Using Stimulants Safely When Substance Use Is a Concern
07:57 Choosing Stimulants vs. Non-Stimulants
10:07 How Severity and Comorbidity Shape Treatment Decisions
12:06 The Limits of Guidelines and Biomarkers in ADHD Care
15:34 Executive Function and Emotional Dysregulation
16:13 Where ADHD Treatment Is Headed Next

This episode is intended for psychiatrists, mental health clinicians, and others interested in complex adult ADHD presentations.

This discussion is for educational purposes and does not substitute for individual clinical judgment or patient care.

Senior Producer: Jon Earle

Transcript

[00:00:00] LENARD ADLER, MD: Substance use disorders are a very common comorbidity in ADHD, and when the substance use disorder is active, it's really critical to realize that you can't treat the ADHD through the substance use disorder, and you can't treat the substance use disorder through the ADHD. They have to treat them both concurrently.

[00:00:26] CHARLES MARMAR, MD: Welcome to Insights on Psychiatry. I am Dr. Charlie Marmar, Chair of the Department of Psychiatry at NYU, where I direct a center in precision psychiatry in PTSD and alcohol use. And it's my pleasure to welcome our distinguished guest today, Dr. Lenard Adler, who is the Pottash Professor of Psychiatry and Director of our ADHD Clinical Education and Research Program at NYU.

[00:01:00] LENARD ADLER, MD: It's a pleasure to be with you today, Charlie.

[00:01:02] CHARLES MARMAR, MD: While protecting patient privacy, can you tell me about a kind of composite case of someone who presents to you with ADHD, which is very difficult to care for. The patient may be referred from an internist or from another psychiatrist, and they present challenges that require a high level of expertise.

[00:01:26] LENARD ADLER, MD: So the type of patient that is one of the most difficult types of patients to treat is one who comes in with a mood disorder that may have been treated for depression, and there is concern there may be ADHD. And in the process of doing the evaluation, it comes out actually that one of the reasons that the depression has been difficult to treat is actually that there is a form of bipolar disorder that's been missed and that has been contributing to some of the mood instability and potentially to some of the attention problems.

[00:02:05] CHARLES MARMAR, MD: Bipolar disorder and ADHD share some common features. They share problems in emotional regulation, problems in attentional mechanisms, impulsivity, and risk for addictive behavior. How do you think about the differential diagnosis? And I know that there's been a major controversy, especially in children and adolescents, about what is ADHD and what is bipolar disorder.

[00:02:37] LENARD ADLER, MD: So in general, bipolar disorder tends to be more episodic. And the disorders can co-occur and co-occur anywhere from 10 to 20 percent of the time actually. And when they do co-occur, bipolar disorder tends to be more severe. Data from Andy Nierenberg show that the course when ADHD is present, the bipolar disorder tends to have an earlier onset. It's more severe. But when we look at trying to make the differential, in general, ADHD is a developmental disorder, tends to be more persistent through the lifespan, and we look for more of the cognitive-based issues in terms of trouble paying attention, distraction, some of the trouble with organization and planning along with the hyperactivity, difficulty with restlessness, maybe impulsivity. But with bipolar disorder, those impulse-driven behaviors tend to be more episodic, whereas for ADHD, the threads run through the individual's life.

[00:03:53] CHARLES MARMAR, MD: So it's very interesting. So cross-sectionally, they may look more similar. Longitudinally, they have a different pattern. So if someone has a pattern of being ill and having some of these attentional and impulsivity problems, and they have interludes in which they function very highly with excellent attention, concentration, memory, and emotion regulation, they're more likely to be in a euthymic period of a bipolar disorder than part of a chronic ADHD problem. Would that be fair?

[00:04:29] LENARD ADLER, MD: In general, I think that's a fair estimation, and it does highlight what I do talk with our trainees about, and that all of our adult patients were children once, and taking this developmental history is really critical.

[00:04:43] CHARLES MARMAR, MD: I think that it is also very, in my experience in caring for both bipolar patients and ADHD problems, there are significant risks of addiction. How do you think about addiction in the context of ADHD?

[00:05:01] LENARD ADLER, MD: So substance use disorders are a very common comorbidity in ADHD, and they're important to identify. They must be brought under the treatment umbrella if they're present, and they influence the course of medication selection that you may choose. Obviously, because stimulant medicines are C-II compounds, and they therefore have to be used with some thought and caution if there is a substance use disorder, thinking about whether the substance use disorder is active at this point in time or whether it's remote. But when the substance use disorder is active, it's really critical to realize that you can't treat the ADHD through the substance use disorder, and you can't treat the substance use disorder through the ADHD. They have to treat them both concurrently.

[00:05:53] CHARLES MARMAR, MD: How do you think about the use of stimulant medications, which are a first-line treatment for many people with ADHD, but are also drugs of abuse or can be—Adderall, other drugs, of course, major use on campuses for cognitive enhancement, but also misuse to some extent. How do you think about safely managing the risks of dependency or misuse in patients who really require a stimulant to function well?

[00:06:27] LENARD ADLER, MD: I think it depends whether the patient has a history of substance use disorder or whether the substance use disorder is active or remote, and those will influence the selection potentially of a stimulant or a non-stimulant. And the first order of business, if you're going to choose to think about using a stimulant, is to take that careful history. But also, if you have a young adult coming in that's asking for immediate-release mixed amphetamine salts, that should be a warning sign to clinicians. The data that's coming out from studies from [Sean Esteban] McCabe and also from Tim Wilens out of Mass General really indicate that most of the diversion, meaning that individuals who are taking—and misuse—individuals who are taking stimulants and don't have ADHD, really come from the use of immediate-release mixed amphetamine salts. And we have many long-acting preparations of stimulants that can treat the adult throughout the day. And if you have an individual coming in really demanding short-acting, immediate-release mixed amphetamine salts, bells and whistles should really go off for the clinician to think about whether this is someone who might be, not necessarily, but might be trying to misuse or divert, because why would you want to take a medication or insist on taking a medicine three to four times a day when we have a longer-acting preparation that would cover them?

[00:07:57] CHARLES MARMAR, MD: When you're referred a patient who has been either unrecognized or undertreated for ADHD, and you're considering from a patient-specific perspective, rather than a general guidelines perspective, whether to start with a stimulant medication, maybe Adderall, or a non-stimulant, maybe Strattera or one of those drugs, how do you think about that? Are there guidelines for our listeners?

[00:08:28] LENARD ADLER, MD: So in terms of actual guidelines, we don't have US adult guidelines for the treatment of adults with ADHD. We have child guidelines actually, and there are guidelines from Canada and Britain and Australia, actually. And we're in the process, actually, of designing those guidelines for treatment, and the American Professional Society of ADHD and Related Disorders will have guidelines coming out at some point in the near future. And I'm actively involved in the development of those guidelines. But in speaking of that decision in terms of whether to use a stimulant or a non-stimulant, there are some things that can be helpful for the clinician. The literature isn't that supportive here, but there are some things that can help. First thing is, what have they taken before? Many adults have had a treatment course as a child, may not have been all that long, but if they've taken a stimulant as a child and they've responded to something, that's fairly indicative they have a good chance of responding to that as an adult. Do they have any particular family members that have responded to a particular agent? The pharmacogenomics of ADHD haven't been fully worked out. We have over 10 candidate genes with odds ratios greater than one, but it's a highly familial disorder with familiality greater than 0.8, tends to have high rates of concordance in first-degree relatives. So if you have a family member that's responded to one type of agent, then that's likely that you may also. Then the severity of the symptoms also comes into the equation. Stimulants have an effect size. The magnitude of the effect on the symptoms is about twice as large as the non-stimulants. So if an individual's presenting, if everything else is equal, with very severe symptoms, since the effect size of stimulants is greater, their chance of responding is going to be greater to a stimulant as compared to a non-stimulant. Another factor might be, let's say, tics. Stimulants are known to occasionally induce tics or worsen tics, not all that commonly, but the non-stimulants, the selective norepinephrine reuptake inhibitors, tend not to do that. So if you have a patient with really severe tics, you might select a non-stimulant first. Other potential side effects or comorbidities might influence the decision. If the substance use disorder is particularly active, that might push you to a non-stimulant, let's say. And there is some inkling in the literature, and there's some studies that have been coming around to this, that if you've ever taken a stimulant and had a response to it, the chance that you're going to respond to the non-stimulant course may be somewhat less because stimulants have such a robust effect. And if I have someone that's coming in for a first trial of medication and everything else being equal between stimulants and non-stimulants and their symptom severity isn't severe, I may be more likely to try the non-stimulant first because it will give them the opportunity to take a non-controlled substance potentially and respond. Once you give them the stimulant, it may be harder to get a response to the non-stimulant.

[00:12:06] CHARLES MARMAR, MD: Great guidelines. Somewhat reminiscent of how we select antidepressants, also, the personal history of response, the family history of response, the comorbidities, the side effects, and so on. We are in the unfortunate situation in psychiatry compared to internal medicine or oncology where we don't have yet reliable objective biomarkers to help us make a decision. If a patient presents with a blood infection, we culture their blood and we know which antibiotics they're sensitive to or not. In psychiatry, there's still a lot of trial and error, and that's difficult because patients experience delays in recovery and side effects till we get the right treatments to help them. Is there any progress in moving towards objective ways to know which treatment for ADHD should be offered to which patient?

[00:13:06] LENARD ADLER, MD: So I think there is some progress, but I think it's not ready for prime time yet. It's in development. One thing that I think is important though is setting expectations with our patients that, what is an adequate trial of medication? What to expect? Stimulants will have effects more rapidly, but they'll notice some effects within days of starting the stimulant, but that doesn't mean that the full effects will be present within a day or two. They really, an adequate trial will be weeks or longer, and the doses have to be adjusted. And for our non-stimulants, because they're reuptake inhibitors, we're looking at two weeks for monitoring effects every time we adjust the dose. And I think it's really important to set those expectations so that our patients know what we're really looking for.

[00:13:57] CHARLES MARMAR, MD: It's very interesting about the uptake inhibitors. I've had a deep interest in those in stress disorders, and in the early studies we did of Zoloft for PTSD, in the early FDA registration trials, it was very interesting that although patients continued to improve over the eight to 12 weeks of the trial, which was expected, when we followed those patients for an additional, as was done in Sweden, for an additional 24 weeks after that, so there was a 36-week follow-up, many patients continued to improve between 12 weeks and 36 weeks. So it's not even crystal clear in the case of reuptake inhibitors at what point do we actually asymptote out to maximal benefit?

[00:14:51] LENARD ADLER, MD: And for ADHD, it's a complicating factor in that we're dealing with a disorder that has a cognitive component. So as patients get better, they become more aware of their symptoms, and it influences their reporting of symptoms. And that sometimes, and this is a discussion I have with patients, what sometimes is reported as tolerance really isn't tolerance to the medicine. It's that the individual is more aware of what's left as they've gotten better. 

[00:15:22] CHARLES MARMAR, MD: Understood. That's fantastic. So that conversation with the patient and the education of that patient is critical for them to understand their sense of their own recovery. 

[00:15:34] LENARD ADLER, MD: Right. 

[00:15:34] CHARLES MARMAR, MD: One of the things we're excited about at NYU and is exciting about your work is you're one of the people moving the ball down the field for next-generation treatments for ADHD, not just translating what we know into what we do, which is very important, but adding to the body of literature on what we're learning and how that will perhaps radically change how we treat psychiatric illness, including ADHD, in the future. In your own research, what are you most excited about for next-generation treatments that are in development for ADHD?

[00:16:13] We've been spending a lot of time focusing on some co-occurring symptoms that tend to travel with ADHD: executive function deficits, which are higher-level cognitive problems, trouble with organization, planning, task initiation, task execution, working memory, keeping things in mind, and also emotional regulation issues, emotional dysregulation, which is a moodiness, a changeability of mood, not a formal mood disorder, but it's very context-based, reacting to the environment and over-reactivity. Those two sets of symptoms are actually quite common in ADHD, almost as common as the symptoms of inattention and hyperactivity and impulsivity. They're not in our diagnostic criteria, but they're quite impairing, and they tend to not be as responsive to our standard treatments. So we've been spending some time in our recent studies trying to understand them further and trying to develop new treatments. One new treatment that we're really excited about is a new form of neurofeedback called PRISM EFP neurofeedback, which targets the emotional dysregulation through the amygdala, trying to down-regulate amygdala function. It's been shown and is FDA-regulated. It's actually FDA—not approved, but it's a device, so it can be marketed. It's cleared for PTSD, another condition, obviously well-known to you, that has problems with emotional dysregulation. And we did a pilot study that found it was highly effective in improving emotional dysregulation, but also improving ADHD symptoms very early in this pilot study, and we're hoping to follow it up in future investigations.

[00:18:05] So my understanding is, since I work on this with you, that PRISM EFP neurofeedback actually has a way to target the amygdala, but we don't do the work in a magnet, we do it in an office. How can you target the amygdala activity, which is deep in the brain, using an office EEG approach?

[00:18:26] LENARD ADLER, MD: The way it's done is by developing an electronic fingerprint through the EEG that's been matched up through the fMRI so that they can actually target the amygdala and look at amygdala regulation and therefore look at the EEG changes. And then actually, through a computational method, actually look at the ability to look at activation. And there's actually a capacity to look at a score that will actually computationally show the ability to correlate with amygdala down-regulation.

[00:19:07] CHARLES MARMAR, MD: The brilliance of this approach was the conception by Talma Hendler and her colleagues at Tel Aviv University to simultaneously acquire the fMRI BOLD signal in the MRI with the person wearing an EEG, 32-channel EEG cap in the fMRI at the same time, compare the two signals and use machine learning to find an EEG signal that tracked the fMRI BOLD signal, and then you can export the treatment to a clinic.

[00:19:45] LENARD ADLER, MD: That's correct. So there's no need to have the fMRI, which is critical for doing this in the clinic. The other important thing in ADHD is that traditional forms of neurofeedback that target areas in the brain that are involved specifically in attention have not been shown to be effective when we use a control group. So our hope is to go ahead and do that next study with a larger sample and with a control group with PRISM EFP neurofeedback.

[00:20:14] CHARLES MARMAR, MD: Great luck with that research. It's been my pleasure speaking with Dr. Lenard Adler, the Pottash Professor of Psychiatry and the Director of the ADHD Program at NYU on current state-of-the-art treatment, and perhaps more importantly, envisioning the future of ADHD treatment, since we know that for many of our patients, ADHD is a lifelong vulnerability, which can have enormous effects on their relationships and their intellectual development, education, and work ability, and safely and effectively managing their ADHD can give them a much richer life.

[00:20:58] LENARD ADLER, MD: Thanks, Charlie. It's been a pleasure speaking with you today.