Tag: challenge studies

10/22/24

Risking Psychosis and Mania with ADHD

image by Gerd Altmann from Pixabay

A recent study, “Risk of Incident Psychosis and Mania with Prescription Amphetamines,” found that individuals taking high doses of amphetamines (i.e., Adderall or Vyvanse) had a fivefold increased risk of developing psychosis or mania compared to those who weren’t taking stimulants. Study participants who experienced psychosis or mania were more likely to have a family history of bipolar disorder or psychosis, to take stimulants that had not been prescribed to them, or to use cannabis daily. The researchers suggested caution should be exercised when prescribing high doses of amphetamines, and clinicians should be carefully monitored and screened for symptoms of psychosis and mania.

The lead author of the study said in The New York Times that when working as an inpatient psychiatrist, she noticed that teenagers and young adults were often being hospitalized for new psychosis or mania symptoms without a history of either. Many of these people with first-episode psychosis or mania were taking high doses of stimulants supposedly for ADHD. It was not clear why some people seemed to have a greater risk of manifesting psychosis or mania. A pediatric neurologist and ADHD expert said he had patients on 60-milligram Adderall tablets daily with no problems. He speculated the amphetamine triggered an underlying predisposition and thought more research was needed to understand the risk factors for developing psychosis or mania on stimulants.

The researchers defined a high dose as more than 40 milligrams of Adderall, 100 milligrams of Vyvanse or 30 milligrams of dextroamphetamine. The medium dosage (20 to 40 milligrams of Adderall, 50 to 100 milligrams of Vyvanse or 16 to 30 milligrams of dextroamphetamine) was associated with a 3.5 times higher risk of psychosis or mania.

Amphetamine Use and Psychiatric Disorders

Past studies have linked amphetamine use and psychiatric disorders. “Amphetamine-Related Psychiatric Disorders” noted that, “Psychosis following amphetamine use is characterized by persecutory delusions, visual hallucinations, and symptoms resembling acute psychosis most commonly observed in schizophrenia.” There was also a pattern of high dosage and daily use being associated with higher risks of substance-induced psychosis. “Amphetamines impair the cognitive thought process and subsequently precede acute psychosis. This suggests that continued impairment due to amphetamine use is a precursor to psychosis.”

Amphetamine-induced psychosis appears to have a more rapid recovery. It also seems to resolve with abstinence from stimulants. The NYT article described a 26-year-old female who fits this observation. She had her first psychotic episode while taking Vyvanse for ADHD. She had stopped taking it while pregnant and didn’t resume it until six months postpartum.

She’d often forget when she had taken her last pill and would take one when she remembered—probably leading to her taking more than her prescribed daily dose. She began felt euphoric and highly energetic. “I felt like my brain was exploding with connections.” She thought she was a “super detective,” uncovering people and organizations engaging in child sex trafficking. She also thought someone was drugging her and her baby.

She was hospitalized, taken off Vyvanse, and prescribed an antipsychotic medication. The delusions stopped, but then resurfaced a few weeks later. “Over the course of months, she began to feel like herself again.” The lead author of “Risk of Incident Psychosis and Mania with Prescription Amphetamines” said it can take time for the delusions to clear. “People have to take off a semester or even a year from college before they can go back. So it is very disruptive.”

The woman’s brother was diagnosed with schizophrenia, so at first, she wondered if she was developing a psychotic disorder. But almost a year later, the psychosis and mania have not returned. “She recently began taking a much lower dose of amphetamine: 10 milligrams of Adderall.”

However, the issue isn’t as straightforward as an association between an underlying predisposition for psychosis or mania and stimulant ADHD medication. Medical News Today reported the lead author of the “Risk of Incident Psychosis” study as saying there was limited evidence that prescription amphetamines were more effective in higher doses. “Physicians should consider other medications our study found to be less risky, especially if a patient is at high risk for psychosis or mania.” Another psychiatrist agreed, saying the study prompts an immediate reconsideration of the risk-benefit analysis of prescribing, especially for patients with a history of mental health issues. He suggested using extended-release formulations to minimize peak plasma levels, and emphasize nonpharmacologic interventions as first-line treatments whenever possible.

Additionally, with stimulant use there is a need for regular mental health evaluations and more frequent follow-ups, especially during the initiation and titration phases of amphetamine therapy. There needs to be particular care taken when considering use of amphetamines in patients with a history of psychosis, bipolar disorder, or other psychiatric vulnerabilities.

Another psychiatrist said researchers should explore whether there is a clear causal relationship between high-dose amphetamine prescriptions and the risk of psychosis and mania. The “Risk of Incident Psychosis” study did not find there was an increased risk of psychosis and mania among those who used methylphenidate drugs like Concerta or Ritalin. An article in Science Alert noted both Adderall and Ritalin raise dopamine levels. However, Adderall increases the release of dopamine, while Ritalin blocks the reabsorption of dopamine.

The Ethics of Challenge Studies for Psychosis

When you read the recent reports of the “Risk of Incident Psychosis” study, it may appear the correlation and possible causation of psychosis or mania from stimulant drugs was new information, but it’s not. And the further investigation of whether high dose amphetamine causes psychosis or mania raises some potential ethical questions.

I’ve talked to an individual working to abstain from misusing cocaine, a stimulant, who described paranoid delusions when using cocaine. When using cocaine, he’d think undercover police were hiding in the bushes across from his 2nd floor apartment, but he could never see them. So, he called in an anonymous tip for a crime happening in the next block of his street, assuming the unseen officers would have to go and investigate. He never saw anyone respond to his “tip.” When he was abstinent, he could describe and laugh about the delusion he had while under the influence of cocaine.

The association of psychosis and mania from using stimulants has also been investigated in psychiatric research for over fifty years. In 1998, Robert Whitaker and Dolores Kong wrote an article for the Boston Globe, “Testing takes human toll.” The authors described how more than 2,000 individuals had been part of a disturbing series of experiments by psychiatric researchers into the biology of psychosis with so-called challenge studies.

In their published accounts, doctors have told of injecting mentally ill patients with drugs designed to exacerbate their delusions and hallucinations. In prestigious journals, they have described studies in which they withheld effective antipsychotic medication from desperate patients who stumbled into hospital emergency rooms. In precise, clinical terms, they have reported how they deliberately stopped giving medication to stabilized schizophrenic patients to see how quickly they became sick again.

These studies were designed to gain knowledge that might lead to improved treatments for schizophrenia and related illnesses. But the experiments offered no possibility of therapeutic benefit to the subjects and exposed them to some measure of psychic pain and risk of long-term harm.

Moreover, this controversial line of experimentation has been marked by repeated instances in which researchers failed to fully disclose the risks to the mentally ill patients and obscured their true purposes.

Dr. Jeffery Lieberman, a former president of the American Psychiatric Association, was one of the researchers who conducted methylphenidate challenge tests. Remember where methylphenidate was not found to precipitate psychosis or mania in the “Risk of Incident Psychosis” study? Yet it was Lieberman’s preferred stimulant in older challenge studies to do exactly that. Dr. Lieberman acknowledged the induced symptoms could be “scary and very unpleasant.” He admitted that some patients got worse, but thought “the symptoms never exceeded the range of severity that occurred in the course of their illness previously.” See “Psychiatry, Diagnose Thyself! Part 2,” for more information on the Boston Globe article and Jeffery Lieberman.

The future research of whether high dose amphetamine use precipitates psychosis or mania essentially means those experiments will likely be some kind of challenge studies. In “Challenge Experiments,” chapter 26 of The Oxford Textbook of Clinical Research Ethics, Franklin Miller and Donald Rosenstein said challenge experiments were among the most controversial forms of clinical research. “They involve experimental interventions aimed at perturbing the biological or psychological functioning of human beings for the purpose of developing scientific knowledge about diseases and their treatment.” No precise definition of challenge experiments has been developed and there is no possible medical benefit for the enrolled participants.

What makes challenge studies morally problematic is their potential to exploit research participants for the good of society. As in the case of all clinical research, this form of experimentation stands in need of ethical justification in accordance with standard ethical requirements. To be ethical, challenge experiments must have scientific or social value; employ valid methods of investigation; select participants fairly; minimize risks and justify them by the potential knowledge to be gained from the research; be reviewed and approved by a research ethics committee; enroll participants who have given informed consent or with ethically appropriate surrogate authorization; and they must be conducted in a way that adequately protects the rights and well-being of research participants.

If there is limited evidence that prescribed amphetamines are more effective in higher doses, and other less risky medications are available to patients who are at high risk for psychosis or mania, why do an experiment to confirm what we already know? What is the risk-benefit of prescribing high doses of stimulant medications to patients with a history of mental health issues? Shouldn’t nonpharmacologic interventions be used as first-line ADHD treatments whenever possible?

05/28/19

The ADHD Fairy

© Warangkana Bunarittongchai

In case you didn’t know, there is a risk of psychosis when using ADHD stimulant medications, such as amphetamine (Adderall, Vyvanse) and methylphenidate (Ritalin, Concerta). A study published recently in The New England Medical Journal indicated the risk was low, with about 1 in 660 patients who used prescription stimulants diagnosed with new-onset psychosis. The lead author of the study, Dr. Lauren Moran, said the risk was low enough that she could not recommend not prescribing Adderall. “But from a public health perspective, there’s so many millions of people being prescribed these medications that it actually leads to thousands of people at increased risk of psychosis.” Using data from the CDC on ADHD, that meant in 2016 about 5,730 children between the ages of 2 and 17 who were taking ADHD stimulants would be diagnosed with new-onset psychosis.

Medscape reported Dr. Moran said the takeaway point was “that it’s really important to screen for potential risk factors.” These risk factors could include a history of bipolar or other psychiatric disorder, a family history of psychiatric illness, or use of cannabis (See: “Gambling with Cannabis and Psychosis”). “If patients have those risk factors, I would shy away from using the amphetamines. You don’t want to have two things that could potentially further increase the risk for psychosis.”

Moran noted that there are many college students in the area around McLean Hospital and that in her anecdotal experience as a psychiatrist working in a unit that treats patients with psychotic disorders, she’s “been seeing cases of young individuals coming in with psychosis” after stimulant use.

Moran said at the beginning of their study, a patient had a 50-50 chance of getting Adderall or Ritalin. But there has been a dramatic increase in Adderall prescriptions, to almost four times as many prescriptions for Adderall. In her experience, ADHD patients hospitalized for psychosis recovered in two weeks; some took as long as two months. But Moran is not suggesting ADHD medications are too dangerous to prescribe. Rather, she’s trying to raise awareness. “Physicians need to be aware of this when prescribing and people who are getting these medications from friends in college need to know this is a risk.”

Speaking to STAT News, Dr. Anthony Rostain said he did not think the results of the Moran et al. study was shocking. The package insert already warns of a small risk of psychosis with ADHD stimulant medication. “It will just simply be important to mention to people that the amphetamine-based compounds have a slightly higher risk… I think the take-home here should be that everyone should be informed when they are starting a medicine about risks like psychosis.” One of the risk factors he gave for psychosis was abusing the drugs—crushing and snorting them. So the implication is that the individuals at risk are those who abuse this medication, which is admittedly an issue on college campuses.

But is that the real problem, namely that the people at risk are those who are abusing ADHD stimulants? First let’s consider the industry ties of the two doctors cited here. Rostain has been a consultant to Arbor Pharmaceuticals, an amphetamine maker, and to Shire, which sells Vyvanse and developed Adderall; Dr. Moran reported only receiving a grant from the NIMH to investigate the risk of psychosis with prescription stimulants. Is Rostain contributing to some misdirection of the issue because of his industry ties?

Did you know that so-called “challenge studies,” where amphetamine and methylphenidate were used to instigate symptoms of psychosis, were done in the name of science? Robert Whitaker co-wrote a series of articles that described how beginning in 1972, psychiatric researchers used amphetamine, methylphenidate and ketamine “to deliberately provoke psychotic symptoms in more than 1,200 schizophrenic patients.” In some cases, the level of psychosis experienced by these patients was called “severe.” Some of these experiments were conducted by prominent researchers at the National Institute of Mental Health. David Janowsky’s work established the idea that psychosis-inducing drugs “could be used as ‘challenge agents’ to turn patients into models for studying psychotic illnesses.”

Symptom-exacerbation experiments were pioneered by Dr. David Janowsky of Vanderbilt University. In 1974, he reported success in developing a new tool for studying schizophrenia. He found that giving schizophrenic patients methylphenidate (Ritalin) caused ”a dramatic intensification of preexisting symptoms, such as hallucinations and delusions,” and that amphetamine also exacerbated their psychosis. Both drugs are known to release dopamine, a messenger chemical in the brain, and Janowsky’s experiments provided indirect evidence that the biological mechanism of psychosis involved an overactive dopamine system.

Dr. Jeffrey Lieberman, currently the department chair of psychiatry at Columbia, did several challenge studies with methylphenidate. In a 1987 study, 34 stable outpatients receiving antipsychotics were given methylphenidate and then withdrawn from their antipsychotics. Three weeks later, they were given another infusion of methylphenidate. They were then followed up for 52 weeks or until they relapsed—in other words until their symptoms returned.

In a 1990 study, 38 patients who met the criteria for schizophrenia or schizoaffective disorder were given methylphenidate. These were patients experiencing their first acute psychosis. The methylphenidate produced an increased psychopathology seen in the worsening of their symptoms. And in a 1987 article, Lieberman and his coauthors commented that methylphenidate appeared to have a greater “psychotogenic potency” than amphetamine. They hypothesized there was a subgroup of schizophrenic patients who exhibited psychotic activation with psychostimulants. “This biologic phenomenon may be clinically exploitable and should be investigated further.” Also see “Psychiatry, Diagnose Thyself! Part 2” for more information on challenge studies.

MacKenzie et al. found an association between the use of stimulant medication and psychotic symptoms in children and adolescents at risk of mental illness. Psychotic symptoms were found in 62.5% of the participants who had taken stimulants versus 27.4% of participants who had not taken stimulants. All participants who had used stimulants and experienced psychotic symptoms were sons or daughters of a parent with either a major depressive disorder or bipolar disorder. “The association of current use of stimulants with current psychotic symptoms and the close temporal relationship between stimulant use and psychotic symptoms in youth who started and stopped stimulants indicated a potential causal relationship.” See “Tip of the ADHD Iceberg” for more information.

ADHD stimulants are addictive. Ritalin and Adderall are Schedule II controlled substances, meaning they are considered to have a high potential for abuse, with their use “potentially leading to severe psychological or physical dependence.” Methamphetamine adverse effects can include convulsions, memory loss, severe dental problems and even death. “Cocaine and potent stimulant pharmaceuticals, such as amphetamines and methylphenidate, produce similar effects.” The effects of amphetamines are similar to cocaine but occur slower and last longer.

Chronic abuse produces a psychosis that resembles schizophrenia and is characterized by paranoia, picking at the skin, preoccupation with one’s own thoughts, and auditory and visual hallucinations. Violent and erratic behavior is frequently seen among chronic users of amphetamines and methamphetamine.

A 2015 study by Clemow and Walker reviewed the literature on ADHD medication misuse. The authors found that elevations in brain dopamine levels seemed to be necessary to both their efficacy in ADHD and in their potential for abuse. The data suggested ADHD medication misuse was a common health care problem for stimulant medications, “with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.” Conversely, nonstimulant ADHD medications did not suggest a potential for abuse. “In light of these findings, the data suggest a need for close screening and therapeutic monitoring of ADHD medication us.”

And if that is not enough to raise concerns with the use of amphetamine and methylphenidate to treat ADHD, there is evidence that challenges their long-term effectiveness. The National Institute of Mental Health (NIMH) funded a nationwide, long-term study of the effectiveness of stimulants in treating ADHD by many of the long-time advocates of stimulant medication. In 2007 the authors finally published their evaluation of long-term effectiveness. The Jensen et al. study concluded: “By 36 months, the earlier advantage of having had 14 months of the medication algorithm was no longer apparent.” The Swanson et al. study said: “All five propensity subgroups showed initial advantage of medication that disappeared by the 36-month assessment.”

So where does this leave us with regard to ADHD? Is it even a valid diagnosis? In Debunking ADHD, Michael Corrigan said ADHD diagnosis in its current form is a diagnosis of normal, using eighteen very generic, commonly observed childhood behaviors to justify giving the medications. “Coincidentally or conveniently, ordained by the all-knowing creators of ADHD as proof of ADHD’s existence, these eighteen childish behaviors … seem to drive parents and educators crazy.” ADHD is a negative label that some want you to believe is real. Like the stories of about unicorns, fairies and leprechauns, “the diagnosis of ADHD is a brilliant work of fiction.” In Our Post Human Future, Francis Fukuyama also suggested ADHD wasn’t a disease, but rather, “just the tail end of the bell curve describing the distribution of perfectly normal behavior.”

Young human beings, and particularly young boys, were not designed by evolution to sit around a desk for hours at a time paying attention to a teacher, but rather to run and play and do other physically active things. The fact that we increasingly demand that they sit still in classrooms, or that parents and teachers have less time to spend with them on interesting tasks, is what creates the impression that there is a growing disease.

For more information on ADHD, see: “ADHD: An Imbalance of Fire over Water or a Case of the Fidgets?”