KELLIE NEWSOME: We close our top 10 research updates with a new med combo for alcohol use disorder, a surprise result for antipsychotics in schizophrenia, and guidance on stimulants in ADHD.

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.

Dose Reduction in Schizophrenia

KELLIE NEWSOME: Our first study answers a long-standing debate in schizophrenia. While antipsychotics treat acute psychotic episodes, they don’t relieve negative symptoms, and some believe they even worsen cognition in this illness. So over the past decade, a few trials have tested whether functioning improves when the dose is lowered or even stopped when they aren’t in a psychotic episode. Some trials say yes, and some say no, but it’s hard to conduct the long-term investigations needed to answer this vexing question. 

CHRIS AIKEN: So enter this large, 2-year study from 19 centers in England. The patients had stable schizophrenia, and they were randomized to either have their dose reduced gradually or to stay on the same antipsychotic. The dose reduction was very gradual – it was cut by 67% in the first year and then lowered by another 33% after the 2^nd year. 

The results were not as expected. There was no difference on the main outcome - social functioning - in either group, so dose reduction did not help. Instead, it came with a major risk. There were more hospitalizations with dose reduction, a lot more, 39% vs 16%.

But before we write off the dose reduction strategy, I’ll mention a few limitations of this study. First, it only went 2 years, which seems like a lot, but the earlier study that found functional improvements with dose reduction went much longer – 7 years. A longer follow-up of this study is underway. Second, part of the trial took place during COVID lockdown, and it’s kind of hard to assess social functioning when people are required to keep a wide social distance.

The study was sponsored by the UK National Institute for Health Research, led by Joanna Moncrieff and colleagues, and published in Lancet Psychiatry.

The bottom line: Lowering the antipsychotic in schizophrenia is a risky proposition, and unless further updates of this study tell us otherwise, we don’t recommend it.

KELLIE NEWSOME: We are in the final stretch of our top 10 findings, with 3 more to go. We’ve covered some of these in the podcast, but stay tuned if you’ve heard them before as we have new updates to weave in.

CHRIS AIKEN: What do you do when a patient comes in on 80 mg of Adderall or 100 mg of methylphenidate? This next study tells us how high is too high with stimulant dosing.

KELLIE NEWSOME: This was a systematic review and meta-analysis from an international group led by Luis C Farhat, and published in JAMA Psych. They included 47 randomized controlled trials of adult ADHD, most of which dosed the stimulant flexibly. 29 of the studies involved methylphenidate, dosed from 15-82.5mg, and 18 involved amphetamines dosed from 12.5-75mg per day – that’s in Adderall equivalents; if you’re using dextroamphetamine the equivalent dose is 10-60 mg, and for Vyvanse, it’s 30-170 mg. They then graphed the dose-response curves, as well as the adverse effects curves – where adverse effects were only counted if they led to treatment discontinuation.

Here’s what they found. For methylphenidate, the benefits began to plateau at 35-40 mg, but there was still a small benefit – and not much risk – to going higher, at least up to the FDA-approved max of 60 mg. Going beyond 60 mg led to very small and diminishing gains but there was also a 2-fold higher rate of problematic side effects as the dose went beyond that 60 mg threshold. So for methylphenidate, it’s unwise to go beyond 60 mg a day, and the gains are marginal between 40 and 60. If you’re converting to dexmethylphenidate, like Focalin, just cut those doses in half, so 20 to 30 mg is the maximal range.

For amphetamines, we saw a different pattern. The improvements also came to a more abrupt halt at a moderate daily dose of 30-35 mg Adderall equivalents. Unlike methylphenidate, there was no additional benefit when going higher than 30-35 mg Adderall equivalents. However, side effects increased steadily on amphetamines as the dose went higher, and unlike methylphenidate where the side effects peaked after 60 mg, we saw a steady increase in amphetamine side effects throughout the entire dose range. 

That 30-35 range if for mixed amphetamine salts, aka Adderall. If you’re using dextroamphetamine (Dexedrine), the equivalent dose is 25-30 mg. And if you’re using lisdexamfetamine (Vyvanse), the equivalent is 70-80 mg.

KELLIE NEWSOME: But wait a minute. The FDA-approved max of Vyvanse is 70 mg, which is the same max they arrived at in this study. But the approved max of Adderall is 40-60mg, which is much higher than the max they arrived at.

CHRIS AIKEN: Yes here’s what’s going on. Vyvanse releases the amphetamine at a very steady rate, so there’s not much peaking. Other amphetamine products like Adderall have peaks – they basically dump too much of the dose at once. Now, most meds do that to some degree, but with stimulants, it’s a bigger deal because those peaks and valleys cause uncomfortable feelings for some patients and enhances the addictive qualities for others. Anyway, because Vyvanse isn’t wasting much of its dose with these unnecessary peaks it is able to get the In this month’s Carlat’s report we feature a full review of the now generic Vyvanse – and conclude that its unique release mechanism makes it a top choice among the amphetamines.

KELLIE NEWSOME: Now, this study tells us that – on average – it’s not worth marching beyond, say, 35-60 mg methylphenidate or 30-35 mg Adderall, but it doesn’t tell us about outliers. What if there are rare cases where higher doses are safe and effective?

CHRIS AIKEN: I’ll speak for that, and against that. In favor of that is a secondary analysis from one of the trials included in this analysis. This was a 2006 study by Richard Weisler and colleagues that randomized 255 adults with ADHD to Adderall 20 mg, 40 mg, 60 mg, and placebo. Amazingly, there was no difference between the three doses – all had nearly the same outcome on ADHD scales. But the authors reanalyzed the data, comparing patients with severe vs mild-moderate ADHD. And indeed the higher dose did work better in severe ADHD, so if you do go up to 40-60 mg it might be justifiable in severe cases.

Now I’m going to speak against it. What I see happening more and more in adults is not severe ADHD but ADHD with a lot of comorbidities – PTSD, autism, head injury, substance use disorders, bipolar disorder, etc, etc. Now, when there are a lot of comorbidities around, it doesn’t mean the ADHD is not real – although if the patient has schizophrenia I would not diagnose ADHD and would not use stimulants. But ADHD can exist with bipolar disorder – 10-20% of bipolars have ADHD – so the ADHD may be real, but with other comorbidities present you’re less confident of your diagnosis, and you’re not as likely to get a full recovery. So what I see happening in practice is the patients with multiple comorbidities are the ones who march up to the higher dose range, and that’s where we start to see a lot of problems, particularly with the amphetamines. Amphetamines are the animal model for mania and psychosis, and they tend to cause a lot more psychiatric problems than methylphenidate. In a study from the New England Journal of Medicine, they were associated with double the risk of psychosis, and this next study from the American Journal of Psychiatry tells us more about that risk. The study is from September 2024, so it’s a little too late to make it into my annual review, but I’m going to quickly stuff it in because it is so relevant.

This was a case-control study from of electronic health records at McLean Hospital that looked at the odds of developing mania or psychosis after starting a stimulant. Around 4,000 patients were included. The found a 5-fold increased risk of psychosis or mania with prescribed amphetamines, and that risk shot up above a dose of 30 mg a day of dextroamphetamine, which is equal to about 35 mg a day of Adderall – the same dose where problems got worse in the earlier study. In contrast, they saw no risk of mania or psychosis with methylphenidate.

I could go on and on and on about this, and in fact, I do – if you want to hear all about the risks with amphetamines vs methylphenidate, from neurotoxicity to suicidality, check out my Carlat Webinar on methylphenidate vs. amphetamines.

KELLIE NEWSOME: Our next study looked at what happens when you give stimulants – in this case amphetamine – to adults with ADHD and cannabis use disorder. The authors used high-dose amphetamines – Adderall 80 mg a day – and compared it to a placebo in this randomized trial. All subjects received substance counseling. The study was small and the drop out rates were high, so we can’t draw any meaningful conclusions, but still we were surprised by the results – even at this high-dose, amphetamines made no difference – no difference in ADHD symptoms and no difference in cannabis cessation. 

So we did a deep dive into this subject. And there is another study of cannabis and ADHD, and it was a large study of methylphenidate in teens – where the stimulant also made no difference compared to placebo in drug use or ADHD. And there are two randomized trials of atomoxetine which also made no difference in cannabis use or ADHD.

CHRIS AIKEN: That’s just a few studies, so not enough to say anything definitive, but it suggests we at least need to warn patients that if they are using marijuana it’s likely to cancel out any benefit from the stimulant, and patients are likely not aware of this. In opinion surveys, patients tend to think that marijuana helps ADHD, when in fact, all the studies show it worsens ADHD symptoms, particularly when used before age 25. 

One thing that is missing in all this is the dose of marijuana. Some people just use it on the weekend, and we don’t know that the threshold is to block the stimulant’s benefits. Beyond warning patients, we don’t have clear guidance here on what to do. Some use urine drug screens and avoid stimulants if there is any sign of drug use. Others stick to non-stimulants, while others give the patients the benefit of the doubt, and try to treat the ADHD, believing that keeping people in treatment is going to do them better than pushing them away.

Prazosin Cypropheptadine for Alcohol Use Disorder

CHRIS AIKEN: In substance use disorders, the importance of therapy vs meds depends on the substance. For opioids, the medical approach – MAT – is essential, and therapy is optional. For alcohol use disorders, the meds are optional and therapy is essential. That guidance is based on evidence – outcomes – and I understand some might disagree with it if they have a different philosophical position about, say, replacement therapy for opioid use. But disagreements aside, we can all agree that our medications for alcohol use disorder are not strong enough, so if you’re not getting recoveries with acamprosate or naltrexone, and you’re patients aren’t staying on disulfiram, this next study has something new to offer. 

It’s an industry-funded trial but they tested two drugs that have long been generic: prazosin and cypropheptadine. Cypropheptadine an antihistamine from the 1960s used for allergies, and prazosin is an antihypertensive that’s also used in PTSD. 

The theory behind this combination is that an imbalance of serotonergic and noradrenergic transmission perpetuates addictions. The combo hopes to correct that imbalance, cyproheptadine through the serotonin 5HT2A receptor, and prazosin through noradrenergic alpha 1 B blockade. Animal studies support this theory for opioids, stimulants, and alcohol, and this new study is the first to test it in humans, in 154 patients with severe alcohol use disorder.

They divided the patients into three groups: a low-dose combo, a high-dose, and placebo. The meds they use are available in the US, except that they used an extended-release version of prazosin to minimize the risk of orthostatic hypotension, but we can mimic that by dosing it 2-3 times a day. All patients received a bare-bones psychotherapy using an empathic advice-giving model designed for primary care.

After 3 months, both the high- and low-dose combo groups saw significant improvement in the primary outcome – total alcohol consumption – over placebo – and the effect size was in the medium range, suggesting a meaningful difference. Those who drank the most benefited the most.

The study was from Henri-Jean Aubin and colleagues and published in the journal Addiction last July.

We find few flaws with this study, other than its need for replication in larger populations, which we expect to come as this was a phase II trial sponsored by Kinnov Therapeutics. I’ll add this combo to my list of off-label options, particularly for patients with PTSD – as both prazosin and cyproheptadine improve nightmares. If you do use them, best to use them both together. Remember the theory here is that they are rebalancing the serotonergic and noradrenergic systems – using one would be off balance, and in the animal trials they did not work in isolation.

KELLIE NEWSOME: At least, that’s what the authors wrote, but we’re not so sure it’s true. There are a few studies of cyproheptadine in alcohol use dating back to 1964. And prazosin has an even richer history here. Although the prazosin trials are a mix of positive and negative, there is a signal that it may work well on its own in patients who have bad alcohol withdrawal symptoms. Although it doesn’t treat alcohol withdrawal directly, it helps people cope with those symptoms better – and sober. Prazosin also lowers alcohol use in PTSD, and it recently augmented naltrexone in a very small randomized trial of veterans with alcohol use disorder. The doses in that trial were 50 mg for naltrexone and 4 mg twice a day for prazosin.

CHRIS AIKEN: The bottom line. If you’re an early adopter, the prazosin-cyproheptadine combo is going to broaden your list of options for alcohol use disorder, particularly in patients with PTSD. If you’re not an early adopter, wait for the 2^nd trial or for FDA approval. Here’s how to use these drugs. For prazosin, the most important thing is to start low because that greatest risk of hypotension and falls is with that first dose. I’d start with 1 mg at night and raise gradually, and raise by 1–2 mg every four to seven days, to a target of 5-10 mg per day. At 5 mg a day you can start to give some of the dose in the morning, around 25% of it. 5-10 mg is the range used for alcohol in today’s study, and you can go higher - up to 25 mg/day for men and 12 mg/day for women – for PTSD. The main side effect is orthostatic hypotension, so check that at visits. For cypropheptadine, the main side effects are weight gain and fatigue, so I’d give it all at night – and it does help insomnia. Cypropheptadine has a similar pharmacodynamics profile as mirtazapine – in fact it even improved depression in a small trial – so if you’re comfortable with mirtazapine you should be comfortable with this. Start with 4 mg at night and raise to the target of 8-12 mg. You can start it with prazosin or space them out. The half-life of cyproheptadine is 8 hours, and in this study they gave it twice a day, but if fatigue is a problem you can move most or all of it to evening. 

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

1. What is the main limitation of a new trial of prazosin-cyproheptadine in alcohol use disorder?

A. Lack of a pathophysiologic basis for the results

B. Results were only positive on secondary outcomes

C. Lack of replication in a second trial

D. High drop out rates

Psychosis in Magicians

We have one bonus study. A fun one about psychosis in magicians. Now and then, psychiatric researchers poke into the creative professions, and inevitably they find that this or that mental illness is more common among artistic souls. It’s an age-old observation that dates back to Aristotle, and not worth the top ten list, but in this study from the British Journal of Psychiatry they came back empty-handed, and that caught our attention. 

Gil Greengross and colleagues screened for autistic and psychotic traits in a sample of 196 professional magicians, matched with a comparison group that was similar in most respects except the magic. To their surprise, the magicians had no more autistic traits, and even less psychotic traits, than the control group.

Had they been to a magic show, they might have known this all along. The magician is the rational one. It’s the audience who has a thin grasp on reality.

Find more and newer research updates in the October episode of Carlat Psychiatry News – search for it on Youtube. We cover new guidelines on benzo tapering and new studies of brexpiprazole in PTSD, antidepressants in bipolar, oral ketamine, CBD oil, e-Cigs, and fraudulent stimulant scripts.

The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one quarter (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.