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A panel of ADHD specialists discuss the impact of treatment delay when dealing with an adult patient.

Patient Case #1: Dealing With Treatment Delay in Adult ADHD

Drs Stephen Faraone, Theresa Cerulli, Craig Chepke, and Andrew J. Cutler discuss how to co-manage a patient with ADHD with other specialties.

Patient Case #1: Co-Managing ADHD

Experts in psychiatry discuss tips to differentiate between ADHD and other co-morbid psychiatric disorders.

Patient Case #1: Differentiating Between ADHD and Other Psychiatric Comorbidities

Stephen Faraone, PhD; Theresa Cerulli, MD; Craig Chepke, MD, FAPA; and Andrew J. Cutler, MD, discuss factors which prompt adults for an ADHD consultation.

Patient Case #1: Prompting an ADHD Consultation

That's a good one, yes, I'd like that, it's a very creative one, thank you, thank you. OK, let's move on to the case presentation. This first patient is a 19-year-old male, who presented to his psychiatrist after being referred by his primary care provider, PCP for ADHD consultation, during the interview, he noted he was a sophomore in college and is taking 17 credits. This semester chief complaint includes a lack of ability to focus in class as well as struggling with time management. He complained that every time he's in class, he finds himself thinking about many other responsibilities he must complete at home and feels that he cannot control it. He has had this complaint for the past 6 years, but refused to seek help, because he feared being put on medication. In high school, he was assigned a counselor who taught him behavior techniques such as making a schedule, and going on walks, which he found to be very effective. However, these techniques were less effective once he started college. His symptoms tend to get worse before exams, he often feels very anxious, leading to horrible performance on exams, he claimed that he has been this anxious since he took his LSAT tests. Currently, he is on academic probation, and is not allowed to be part of the Student Work Program, which was his only source of income. The patient has no history of substance abuse, no history of taking any medications for his symptoms, and no history of suicidal thoughts.

Stephen Faraone, PhD, presents the case of a 19-year-old male with ADHD.

Patient Case #1: 19-Year-Old Male With ADHD

Let's move on and talk about what the unmet needs are given the current drugs that we have for treating adult ADHD that are approved by the FDA. What's the future for adult ADHD? What are the challenges for treating ADHD that might be solved by developments in the pharmaceutical industry? Andrew, I'll start with you this is this is one for everybody.

 I will be happy to start. OK. Steve, there are several unmet needs, even though we do have many options particularly in the stimulant world. Obviously, we need more non stimulant options, as I mentioned before there's only 2 non-stimulants currently approved for adults. I don't know about you guys, but I have a lot of about you guys, but I have a lot of patients who are on a stimulant and let's say an SSRI, because I'm trying to manage both the ADHD and the depression or the anxiety. And at least with the newest of the non-stimulants extended release viloxazine that drug that has demonstrated efficacy for depression and anxiety as well as ADHD, and perhaps I can use one medicine instead of 2. We also need medicines with better safety profiles, I'm always concerned about as people get older I'm very concerned about cardiovascular issues, and other medical conditions, drug, drug interactions because they're on multiple medications. And the 2 approved non stimulants, the norepinephrine reuptake inhibitors have warnings about blood pressure and heart rate as do stimulants. That's certainly a concern of mine. We always worry about abuse, misuse, and diversion of our medications. That's another area that we need to be thinking about as we're managing these patients and then not every patient is the same, not every patient has the same limitations, the same functional impairments, the same quality of life issues. Just having more options to be able to tailor to people's cluster of symptoms, and you had mentioned for instance, Steve earlier about executive function, this is something that I'm, I believe is a big part of ADHD especially in adults. And medications that work for that, because the rating scales that we use, at least the ADHD RS, is not specifically geared towards looking at executive function very well. I know you would agree.

That's right, it's not, and when studies have used the appropriate rating scales, like the brief, what we find is that the current medications, they help produce executive dysfunction somewhat, but not enough. The effect is much larger for the symptoms of ADHD than it is for executive functions, or emotional dysregulation as well.

: You know, well said, I completely agree with you about emotional dysregulation that is something that is underappreciated as well.

The challenge for misuse, abuse and diversion is that is a big one? There have been efforts to try to develop manipulation and resistant forms of stimulants, I hope they'll become successful, but there's it’s a difficult path, regulatory path to follow. But we may be seeing that in the next few years.

 I could add my wish list, what I would like to see is a non-stimulant or at least non controlled is probably better word, non-controlled medication for ADHD available 24/7. It's not going to be there from the time you wake up in the morning until the time you put your head on the pillow in the evening, that has the effect size. In other words, robustness of response, not just improved symptomatology, but the robustness of a stimulant, so a non-controlled substance with the 24/7 availability, and the effect size of a stimulant, that's what I would like to see.

: That's the holy grail for ADHD treatment

: Well not only that, one that works consistently. My sense is that stimulants work reliably for the vast majority of patients, and studies suggest it's up to 80%, but non stimulants are more like they're more 40 to 60% maybe patients, something that's more consistent in more patients too.

I'm going to add another one more unmet need before we move on to our case presentation, and that is the ability to do precision medicine, to be able to predict who responds to what medication. Currently, we can do it very well, I've got some data recently published showing that we can predict well who would respond to extended release viloxazine after 2 weeks of treatment. But that's still not good enough, we need to be able to have something which tells the clinician, there's a good chance that this person is going to do well on this non-stimulant, or this is formulation. We're not there yet, but I do expect we're going to get there in 5 or 10 years.

: I'll throw in one thing really quick, why not a long-acting injectable non-stimulant. Obviously, we can't do it with stimulants, but with non-stimulants it is a potential option. If Theresa can make her wish list, I can go for that one.

That's a good one, yes, I'd like that, it's a very creative one, thank you.

Experts in psychiatry discuss the future of ADHD management as well as challenges when approaching treatment of adult ADHD.

Future of Adult ADHD

Dr. Cutler. Could you give us the big picture from 50,000 feet of the efficacy and safety of each of the current classes of medications that are used for adult ADHD?

: Yes, I'd be happy to, trying to be brief here we could certainly talk for a long time about this. But let's look at big picture. First of all, we divide the treatments for ADHD into stimulants and non-stimulants, within the stimulant class as Greg said, there's very few molecules there's basically amphetamines and methylphenidates. Within the non-stimulant class, we have alpha 2 agonists, we have norepinephrine reuptake inhibitors, basically. Let's first look at the stimulants, the stimulants have great similarities as far as efficacy, the effect sizes are quite high, we're talking in the 0.9 to 1.2 range, very effective across a range of symptoms. Now, there are certain issues with safety and tolerability of course we're all aware of some of the adverse effects like insomnia, irritability, decreased appetite, certainly in kids, we worry about growth suppression. The cardiovascular risks that we know, the possibility of worsening psychiatric conditions psychosis and mania. Now, there are some differences between amphetamines and methylphenidates in how they work, they both block the re-uptake of norepinephrine and dopamine, but there are some other differences. And it is interesting that there are some patients who do better with one than the other either they have a better response, or they tolerate one better than the other. One of the points I always like to make to clinicians is if you've been using methylphenidate and methylphenidate and the patient and they're not doing well, please switch over to the amphetamine, always make sure you've tried both before you give up on them. Of course, the other issue is they are controlled substances, and there's all the issues around that, they're very liable to abuse. They all have boxed warnings about the possibility of abuse, when we talk about abuse, misuse, and diversion those 3 issues. The non-stimulants are not controlled substances, at least the ones that are currently available, they can be very effective, but they are not as universally effective, their effect sizes tend to be more in the 0.5 to 0.6 range. And they don't work for everybody obviously, but they have a lot less of some of the baggage of the stimulants. If we're talking about the norepinephrine reuptake inhibitors, we do have issues with blood pressure there, they also have bolded warnings about suicidality, there are warnings around somnolence sedation as well, and you do have to worry about activation and the possibility of mania. The alpha 2 agonists are interesting, they have sort of the opposite profile, those are medications that are also effective to treat hypertension. We worry about lowering blood pressure, not increasing blood pressure, and when used by themselves, they can be quite sedating, but and they are only FDA approved for kids. I want to be clear that 2 norepinephrine reuptake inhibitors are the only two non-stimulants approved for adults. That's one big overview, the other thing to say about this stimulant is besides being divided into amphetamine and methylphenidate, within the universe we divide them into various formulations, as Craig mentioned, that gives us different pharmacokinetic characteristics as far as how fast they start working, and the duration of how long they were.

 If I may add to that, this short acting versus long acting in terms of what I mentioned as a comorbidity and the risks with substance abuse there. These are all the stimulants that are all C2s they all carry the black box warning for abuse and dependence, but in terms of the street value on the short acting, there seems to be those are the ones we worry the most with regard to diversion, which is the most common form of abuse, and certainly in my college students. I try when I'm both practicing clinically, talking with my patients and educating my patients, but also in teaching with the residents through Beth Israel Deaconess Medical Center, that you want to consider the long acting stimulants and not be. They were afraid sometimes that what if I have an adverse effect and it's going to last me all day? True, but in terms of the risk with abuse and dependence, looking at long-acting formulations has value before we talk about the short acting formulations being standard.

 Yes, we would all agree the standard of care is the extended-release stimulant, and I the benefit clearly outweighs any downside there. It's interesting, we do need to mention - I forgot to mention there is one stimulant, at least one part of one stimulant that is a C4 the others are all C2, there is a new pro drug of methylphenidate and of D methylphenidate called., that if it was available by itself would be a C4. It showed a lower liability for abuse, but it is currently available only in combination with immediate released dexmethylphenidate, so that makes it a C2.

: One thing I'd like to throw in there about the instant versus extended-release discussion. I'm very much in favor of using extended-release formulations, but they're not all created equal, extended doesn't always mean extended. What was extended release 20 years ago, is not what we'd consider extended today. If someone did have a problem, where one extended-release formulation was too long acting for them, well we can switch them to a shorter acting, extended release formulation and vice versa. If it's too short of a short acting, don't need to necessarily add a booster of an instant release as has been common in the past, we can switch to a long-acting stimulant that is extra-long acting.

: You know Craig you mentioned this, while we have a very small number or dearth of molecules, we have a surfeit or a cornucopia of formulations which really allows you to tailor it, doesn't it to the patient?

: I've certainly seen evolve over time, is you can take the same molecule, and when you change the delivery system as we have done, and seen in the last 20 years, many times. It does feel different for the patients where they describe the exact same active ingredient in a long acting versus short acting formulation can feel quite different to the individual taking it.

: Absolutely, I've had many patients that have put on long-acting stimulants that they swear that they're not taking anything at all, they don't feel anything, but everyone around them notices a difference, their performance levels, their quality of life. It's noticeable that they're having benefit, but they don't feel anything, and some patients will want to go back to an instant release because they can tell when it's working, and what I have to tell them is that's not a good thing, that's a buzz, that's not a therapeutic effect you're feeling, you don't need that to have efficacy.

Stephen Faraone, PhD; Theresa Cerulli, MD; Craig Chepke, MD, FAPA; and Andrew J. Cutler, MD, discuss efficacy and safety of treatment options in adults with ADHD.

Efficacy and Safety of Treatment Options Utilized in Adult ADHD

: Let's move on, Doctor Chepke, what are current unmet needs in adults with ADHD?

 There's quite a few of them, the first one that I would mention would be the under diagnosis or misdiagnosis of ADHD, but we've covered that very well already, so far here. But then, even once the ADHD is diagnosed in adults, then having it under treatment of it what I think is a significant problem, I mean, I practice in the southern part of the United States and sometimes I say that ADHD around here isn't treated with stimulants, it's treated with a hickory switch. And that tends to persist until adulthood too, that there's this stigma, is the biggest unmet need is combatting the stigma, because there's the belief that the person is just lazy, that they just need to work harder, they just need to pick themselves up by their bootstraps and do it, similar to what we hear in many different diagnosis in psychiatry, and having the acceptance of this diagnosis and the treatments for it is a significant unmet need. But then also, just the treatments that we have themselves. Although we have dozens, literally, of stimulants, and we have some non-stimulants as well, we still don't have enough treatment. One aspect is the small range of molecules that we have, we only have a few molecules despite the dozens of stimulants, and then of the non-stimulants as well, and each one of those has certain pharmacokinetic limitations, and we could get, we could have a very long discussion about that but, really, when it comes to the stimulants, you have to match the pharmacokinetics to the person, and I find that I need all the dozens of stimulants for each individual person, because everyone's day is a little bit different, and they have different needs.

 Yes, I would add, one of the unmet needs is, more effective non-stimulants, we only have 2, as of now, that are FDA approved, non-stimulants, that is, and there's a lot of adults that I'm concerned about abuse or diversion, or I don't want to use a stimulant because, as we talked about earlier, maybe they have hypertension or cardiovascular issues, and medications that help us address the comorbidities, because those comorbidities are so common, depression, anxiety, substance abuse, as we talked about, bipolar disorder as well.

Craig Chepke, MD, FAPA, and Andrew J. Cutler, MD, discuss unmet needs in adults with ADHD.

Unmet Needs in the Treatment of Adult ADHD

When used as clinically indicated at the appropriate doses, stimulants are safe and effective for the treatment of 

 (ADHD); however, misuse may lead to serious adverse effects, including medication-induced persistent psychotic disorder. A case report published in 

found that the long-acting injectable haloperidol decanoate may be able to improve compliance and prognosis in patients with ADHD.

As described by Desai et al, long-acting injectable haloperidol decanoate—although not FDA approved for the treatment of stimulant-induced psychosis—was successfully used to treat a patient with stimulant-induced psychosis and a history of noncompliance with antipsychotic treatment.

In the case example, Desai et al describe “Mr X,” a 29-year-old Caucasian male who was brought to the emergency department (ED) for altered mental status. Mr X was found to be agitated, incoherent, and responding to internal stimuli when evaluated by emergency medical services. Mr X has a past psychiatric history of ADHD, anxiety disorder, and stimulant-induced psychosis, though there is no known psychiatric history in Mr X’s family. Mr X was diagnosed with ADHD as an adult, and was prescribed Adderall at the age of 19, taking a dosage of up to 90 mg per day. Mr X had been hospitalized before in an inpatient psychiatric unit for a similar symptomatic presentation that was attributed to Adderall use above the approved dosage. Previously, he was prescribed olanzapine and risperidone for 

, but was noncompliant with treatment. Following his last discharge from an inpatient unit, Mr X continued to obtain Adderall.

Following this inpatient admission, Mr X was started on oral risperidone 1 mg BID; however, he continued to refuse medications. Eventually, Mr X agreed to take oral Haldol 5 mg BID that was later up titrated to 7.5 mg BID. Throughout his inpatient stay, he continued to remain insistent on getting Adderall or Vyvanse for his ADHD without specifying dosage. Due to his 2 inpatient psychiatric hospitalizations in the past 6 months, his continuation of Adderall abuse, and noncompliance with prescribed antipsychotic treatment, clinicians offered Mr X long-acting Haldol. He was given 2 injections of Haldol Decanoate 50 mg and 100 mg intramuscularly. Additionally, Mr X was prescribed clonidine 0.1 mg daily for the management of his ADHD. Mr X tolerated the prescribed treatment without any adverse effects. His behaviors were reduced significantly, and he was safely discharged, where he remained compliant with the treatment plan for a follow-up period of 6 months.

“Long-acting Haldol provided a great response; however, further research is required to assess long-acting injectables as a definitive treatment for stimulant-induced psychotic disorders, especially in patients with a history of noncompliance and recurrent hospitalizations,” wrote the authors.

 might increase the risk of developing subsequent psychotic disorders during adulthood.

 Prolonged stimulant misuse might contribute to the development of a subsequent psychotic disorder in genetically susceptible individuals; more research is needed to determine. Overdiagnosis and treatment of ADHD, plus a rise in prescription stimulant misuse, might further complicate this relationship.

Amphetamines can mimic psychosis, especially when taken recreationally above approved doses. Acute amphetamine intoxication can present as a substance-induced psychotic disorder, although some individuals may go on to develop a psychotic disorder with onset during intoxication that continues. This poses an especially unique challenge in young adults, when separating first onset psychosis from a stimulant-induced psychotic disorder and subsequent transition to schizophrenia-like illness, can be difficult but is crucial for determining appropriate care.

Distinguishing First Onset Psychosis From Stimulant-Induced Psychosis

Some studies indicated there may be different symptom presentations in the case of amphetamine-induced persistent psychosis. Yang et al suggested that methamphetamine-induced psychosis presents with less 

 and negative symptoms compared with patients with primary schizophrenic psychosis.

Obvious predictors of amphetamine-induced psychosis include the dosage and duration of amphetamine use, but research has highlighted the additional role of gamma-aminobutyric acid (GABA) dysfunction resulting in a heightened risk of stimulant-induced psychosis. A study by Ahn et al suggested that preexisting GABA deficits increased vulnerability to stimulant-induced psychosis in healthy subjects.

Treatment of stimulant-induced psychosis may be similar to treatment of psychotic disorders and schizophrenia. For example, a recent systematic review by Fluyau et al found that aripiprazole (Abilify), haloperidol (Haldol), quetiapine (Seroquel), olanzapine (Zyprexa), and risperidone (Risperdal) were able to reduce or control stimulant-induced psychosis with similar efficacy.

 Additionally, a systematic review by Coles et al found long-acting injectable antipsychotics to be an effective treatment for dual diagnosis schizophrenia and substance use disorder.

Desai et al noted further research is needed to identify individuals that are at increased risk of developing persistent psychosis from stimulant abuse. They suggested that α2-adrenergic agonists may be a safer alternative for the management of ADHD in such cases.

Adderall-induced persistent psychotic disorder managed with long-acting injectable haloperidol decanoate.

2. Nourredine M, Gering A, Fourneret P, et al. 

Association of attention-deficit/hyperactivity disorder in childhood and adolescence with the risk of subsequent psychotic disorder: a systematic review and meta-analysis.

Methamphetamine-associated psychosis: links to drug use characteristics and similarity to primary psychosis.

Role of GABA deficit in sensitivity to the psychotomimetic effects of amphetamine.

Antipsychotics for amphetamine psychosis. A systematic review.

6. Coles AS, Knezevic D, George TP, et al. 

Long-acting injectable antipsychotic treatment in schizophrenia and co-occurring substance use disorders: a systematic review.

Long-acting injectable haloperidol decanoate may work as a treatment for Adderall-induced persistent psychosis. 

Stimulant-Induced Persistent Psychotic Disorder: New Treatment Potential  

A study found that methylphenidate use is associated with an increased risk of suicide attempt in adults up to 40 years old.

The study, a population-based matched cohort design, investigated potential associations between methylphenidate and depression, suicide attempt, and overall mortality. The researchers stated that they wanted to explore effects of methylphenidate because it is one of the most commonly prescribed medications for both children and adults for attention-deficit/hyperactivity disorder (ADHD); it has been connected to serious psychiatric and cardiovascular adverse events; some clinicians also believe the properties of methylphenidate mean the drug has the potential to induce psychotic symptoms and disorders.

In the study, the researchers pulled from a pool of 97,198 participants within the Integrated Primary Care Information system database in The Netherlands, identifying 8905 adults who started methylphenidate and matching each set of 1 individual prescribed the medication to 10 individuals who were not taking the medication based on factors including age, sex, and prescription date. Participants were 54% male and 64% within the age group of 18 to 40 years. The methylphenidate group showed a significantly higher prevalence of substance use and history of psychiatric comorbidity compared to those who were not taking the medication. The researchers analyzed the participant pools for risk of development of each psychiatric event (expressed as HR) with 95% CI, which they adjusted for relevant confounders using methylphenidate as a time-dependent determinant. They also adjusted for intervention, or “intention to treat.”

They found during follow-up that depression, psychosis, and psychiatric disease in the patient’s medical history were no longer significant after adjustments for alcohol abuse, substance abuse, and psychiatric disease in the medical history. The risk of suicide attempt, however, still showed a significant increase after full adjustment (HR 2.0; 95% CI 1.1 to 3.6) and was the highest in women and the age group of 18 to 40 years. They identified 168 cases with a notification of suicide within the patients’ medical records and noted that 117 of these cases were suicide attempts, 16 of which were successful, and 51 cases involved suicidal ideation, fantasies, or tendencies.

For risk of overall mortality, the researchers identified 1027 cases of death and validated them within the patient history to distinguish dates and causes. Of these 1027 cases, they verified that 19 were suicides and that 30% of all deaths occurred within 80 days after the start of methylphenidate use. The unadjusted risk of overall mortality showed a strong increase (HR 7.5; 95% CI 6.3 to 8.9) but, after full adjustment, dropped to a significant 30% risk increase (HR 1.3; 95% CI 1.1 to 1.6).

“Especially the strong association with death in our study is striking,” the researchers wrote. “The risk increase of death was genuine but mainly explained by confounding by the indication palliative care because from validation of the medical records, it became clear that this risk increase was largely explained by starting methylphenidate in depressed or extremely tired patients in their latest phase of life. Because regular antidepressants take 6 to 8 weeks before they exert their therapeutic effects, they may be too late for treating depression in the last weeks of life, and then psychostimulants may help.”

The researchers concluded that, “there is an increased risk of suicide attempts in adults up to 40 years of age after starting methylphenidate, and this risk should be carefully considered before prescribing to this group.”

General practice database on mortality in adults on methylphenidate: cohort study

Risk of suicide attempt is higher among adults, women.

ADHD