Learning Objectives
After taking this webinar, clinicians should be able to:

1. Providers will understand the key findings of the phase II clinical trial evaluating the combination of cyproheptadine and prazosin for severe alcohol use disorder, including the observed improvements in total alcohol consumption and the need for further replication in larger populations.
2. Providers will understand the reasoning behind the FDA's recent approval of the NeuroStar Advanced Therapy TMS device for the treatment of major depressive disorder in adolescents aged 15-21, the first TMS device approved for this age group.

[Transcript edited for clarity]

Chris Aiken, MD: I'm Dr. Chris Akin

Greg Malzberg, MD: I'm Dr. Greg Malzburg

Kellie Newsome, PMNHP: and I'm Kelly Newsome, a psychiatric MP. Welcome to Carlet Psychiatry News from May 2024.

Greg Malzberg, MD: This month features Dr. Jonathan Meyer and goes over TMS and medications for insomnia and alcohol use disorder. The FDA has given Neurostar Advanced Therapy the green light to treat major depressive disorder in teens aged 15 to 21.

making it the first TMS device approved for this age group. It's also NeuroStar's fourth FDA cleared indication, joining adult depression, adult OCD, and anxiety that occurs as a part of depression. This opens up a promising new option for adolescents, who have far fewer treatments available compared to adults.

Real world data from over 1100 teens treated with NeuroStar showed a 78 percent response rate, on par with the device's performance in adults. The FDA's decision was based on this dataset, along with published research showing Neurostar is equivalent to antidepressants alone. Systematic review and meta analysis published in the Journal of Affective Disorders in September 2023 looked at repetitive TMS combined with antidepressants for kids and adolescents with depression.

The paper included 18 randomized control trials involving over 1, 300 patients aged 8 to 24 years. They found that RTMS successfully augmented antidepressants and accelerated the response to medications in this age group. RTMS was generally safe in teens, with common side effects including headache, nausea, constipation, dizziness, loss of appetite, sweating, and insomnia.

There are two types of TMS machines on the market, and they differ in their coil design. Neurostar uses a figure 8 coil, while Brainsway uses an H coil for a patented deep TMS. Brainsway coil is not approved in teens, although studies suggest it's safe and effective there. Neurostar, which earned this new approval, is no longer on patent, but there are generic versions of this coil available.

TMS gives teens and families an important new alternative to consider, especially given the global burden of youth depression.

Chris Aiken, MD: This next study is a game changer for Olanzapine and Schizophrenia. It was a meta analysis that gathered individual data from 7 trials to test whether the improvements in psychotic symptoms correlated with either the dose of Olanzapine, Or the serum levels of olanzapine.

In clinical practice, it's the dose that we think about. But in this study, the improvements did not correlate with the dose at all. And instead, there was a strong correlation with the serum level. So Dr. Myers, what do these results mean for clinical practice?

Jonathan Meyer, MD: So this article, I think, really reinforces a lot of what we understand about antipsychotics, is that there probably is a response threshold based on plasma level below which the likelihood of response is lower.

And how clinicians put that into practice is that if you have somebody who's a non responder, The first thing you want to do is check the level and see what's going on. Maybe they're not taking it, maybe they're a rapid metabolizer, but if you're below that response threshold, you optimize your chances of making this person a responder by at least getting beyond that minimum number.

It's no guarantee, but it just increases your odds significantly compared to people below that. And then lastly, this paper talks about, as you're getting to levels in the higher end of the range, you have diminishing chances of response. And we know that. Um, where you finally stop, I think will depend upon your context.

They note in the one paper, we'll talk about a level of around 56. 47, where you start to see diminishing returns. And I think we appreciate that, but certainly for molecules like olanzapine in particular, or clozapine, where you start to see diminishing returns. We may continue to push it up to a point where we'd say the chances of response are less than 5%, which I might in my book, I've called the point of futility.

So that's kind of the general sense, but the nice thing is that their threat response threshold is almost exactly what I have in my book. because they looked at a somewhat broader number of studies, some of which have been published since I wrote that book. I think I cited a number of 23 as the response threshold.

They came up with 22. 07. So it's nice to see that there's consistency. The data is fairly clear that when you have a non responder, your best chances of getting in responders, at least getting above 22.

Chris Aiken, MD: If I hear you right, you wouldn't check an olanzapine level on everyone with schizophrenia who takes the drug.

But you would check it if they weren't responding well to it.

Jonathan Meyer, MD: I think that's the primary use when you're starting the medication, is why is this person not getting better, especially when you're on a dose where you think you should see some response, and particularly when you're not seeing adverse effects.

Because occasionally, as we'll talk about, there are people who don't take their oral medications, and not my patients, of course, but you know. other people's patients. And then secondly, there's just variances in drug clearance. So you want to see where this person is and you want to get a sense if you can optimize this.

I rarely get consults at the state hospital or elsewhere for somebody saying, Hey, this person's level is low, but they're doing really well. So there's no interest in getting the level at that point, but often it's non responders trying to figure out how can we get this molecule to work.

Chris Aiken, MD: I notice you have old Camel Cigarette ads in your office there, and I know you're doing that to remind us all that smoking lowers antipsychotic levels, particularly Olanzapine.

And another factor that might lower lansipine level is genetics. So where does genetic testing fit into all this?

Jonathan Meyer, MD: I'm not a big fan of genetic testing because genetic testing, for one thing, doesn't always give you the answers you want. People Assume that if they get a P450 panel from a genetic company, testing company, that it's complete, but many of those panels were fixed a number of years ago, and a number of polymorphisms since then have been discovered, which may affect drug metabolism.

So it says, you're an extensive metabolizer. You might be, you might not. In the end, if better to get the number that you want, which is the plasma level, as opposed to the indirect information. And it would be like in the world of lithium, rather than getting a lithium level, you gave me the person's GFR.

Like, okay, it gives me a sense of how they're going to clear lithium, but in the end, I want to know the level. And that's why I tell people, um, You know, go for the result that you really want, which is what's going on in their body. Plus, also, genetic testing doesn't tell you if the patient's non adherent.

And that's a big issue as well. When you see these low levels, you're like, well, I don't know what's going on. Well, often it's non adherence. Not always. But the level will give you that answer. I'd say that the one time I would get genetic testing is occasionally I see somebody who has really unusual levels, and I know they're adherent.

I'm trying to figure out what's going on. Are they a poor metabolizer or an ultra rapid metabolizer? It becomes more of an academic question at this point, but it may be useful for the future if I know, for example, someone's a really poor metabolizer at 1A2 or 2D6.

Chris Aiken, MD: Olanzapine is one of our more potent antipsychotics.

And some guidelines recommend a trial of olanzapine before moving on to consider clozapine. And that is where the serum levels come in. You'd want to make sure that your patient is taking the olanzapine and that their serum level is in a decent range before considering clozapine.

Kellie Newsome, PMNHP: Psychotherapy is the main treatment for alcohol use disorder, but medications can aid recovery and they are underutilized here.

We have three that are FDA approved, and here's a summary of how they work from a new review. Naltrexone blocks the rewarding properties of alcohol through the opioid system, reducing cravings and relapse rates. Patients often say that they feel satisfied even after one drink, or they don't even have to drink at all.

Acamprosate modulates glutamate through antagonism of NMDA and other glutaminergic receptors in the trials. It increased abstinence rates, but it wasn't effective for heavy drinkers. Then there's disulfiram, which blocks the enzyme that gets rid of the toxic metabolite of alcohol that causes severe hangovers.

The fear of experiencing the unpleasant reaction from the metabolite acts as a deterrent to alcohol consumption. But disulfiram does not directly reduce alcohol cravings, so many patients struggle with adherence. In terms of label options, there's also topiramate, ondansetron, gabapentin, and possibly baclofen, although that muscle relaxant has a misuse potential all on its own.

It sounds like a lot of options, but it's so easy to run through them in this difficult to treat disorder. So we were pleased to see this next trial, which is the first to test two older medications from the 1960s. Cyproheptadine and Prazosin in a Phase II trial of alcohol use disorder.

Chris Aiken, MD: Cyproheptadine is an antihistamine that was originally developed to treat allergies.

It also blocks the serotonin 5 HT2A receptor, and in that way, it's a little bit like mirtazapine. It has about the same side effects as mirtazapine, with weight gain and sedation the main issues, and in my experience with it, it's about as well tolerated as mirtazapine. Now before this large trial in alcohol use disorder, it was studied in small trials of depression, anorexia, sexual dysfunction, and nightmares.

Prazosin is a noradrenergic blocking blood pressure medicine that is often used in psychiatry to treat PTSD nightmares. The idea behind combining them in this study is that addictions cause imbalance of the two systems they work on, the noradrenergic alpha 1b and the serotonergic 5 HT2A, and that by blocking them at the same time, it can restore the balance and reduce addictive behaviors.

Animal studies support that idea for stimulants, opioids, and alcohol use disorder. And this new study tested it in 154 patients with severe alcohol use disorder. The researchers divided the patients into three groups. They either got a low dose of the combo, a high dose of the combo, or a placebo. They used an extended release version of prazosin to reduce side effects like orthostatic hypotension.

Now that's not commercially available, but you can replicate it by giving the medication three times a day. All of the patients also got a bare bone psychotherapy using an empathic advice giving model that was developed for primary care. After three months, both treatment groups saw significant reductions in their total alcohol use compared to placebo.

And the effect size was in the medium range, suggesting that this is a meaningful difference for patients. Those who drank the most benefited the most from this combo. We find few flaws with this study, other than that it is a single study and needs to be replicated in larger populations, which we expect to see as this industry sponsored trial is a Phase II trial from Kinov Therapeutics approaching FDA approval.

For now, I'll add this combo to my own therapeutic list for alcohol use disorders and consider it particularly if the patient also has PTSD. See? As prazosin and cyproheptadine both improve PTSD nightmares. If you do decide to use it, best to use them both together. Remember, the theory here is that you're balancing two pharmacodynamic systems, and if you just use one, well, that would be off balance.

That was tested in animal studies, and using one did not reduce addictive behaviors.

Greg Malzberg, MD: As mental health providers, we're always on the lookout for an effective strategy to manage insomnia in our patients. Orexin receptor antagonists are a newer class of sleep medications that have gained popularity in recent years due to their favorable side effect profile.

They are Darodorexin, which is Quivevic, Lemborexin, which is Davigo, and Suvorexin, which is Belsamra. They work by blocking the orexin receptors in the hypothalamus that keep us awake and alert. Unlike other hypnotics, these orexin antagonists are approved in elderly by the Beer's criteria, which also give a green light to ramelteon and doxepin.

In some studies, they improve sleep quality and next day functioning, something not found in the benzodiazepines or the z hypnotics. The orexin antagonists are also less rewarding than older hypnotics, a quality that adds to their safety and but can also make it difficult for patients to switch to them.

These next two industry sponsored studies offer some guidance. Both are small and open labeled, so they don't prove any grand points, but they do lay out a path for switching hypnotics. The first study, published in Advances in Therapy, looked at what happens when patients change to lemborexant from other hypnotics, including Z drugs, suvorexant, and remelfion, both as monotherapy and in combination with benzodiazepines.

An impressive 95. 6 percent of the 90 participants successfully transitioned to Lemborexin by the end of the two week titration phase, with 82 percent continuing on Lemborexin during the 12 week maintenance phase. Here's how they did it. When changing from a Z drug like Zolpidem, the Z drug was stopped and switched directly to Lemborexin.

When changing from a benzodiazepine, they first used them both together for two weeks, and then gradually tapered off the benzo over several weeks. After the transition, patients reported improvements in sleep onset, maintenance, and sleep quality, and there were no serious adverse events. The second study also involved Lemborexin, but focused specifically on transitioning patients from Zolpidem to Lemborexin.

The study was randomized, but it was small and open label. Of the 53 adults with insomnia who were enrolled, 81 percent successfully transitioned from Zolpidem to Lemborexin. More participants reported that Lemborexin helped them return to sleep after waking compared to Zolpidem. 71 percent versus 49%.

Subjective experiences while falling asleep were generally similar between the two medications. There were a few notable differences though. More patients described their experiences as peaceful with Lemborexin. Fewer reported difficulties, remembering details of the night before falling asleep compared to Zolpidem, as in the first study, most adverse events were mild and consistent with lumbar recant's known safety profile.

Most hypnotics have withdrawal effects, which makes it difficult to switch from one to another. These studies give us some reassurance that a gradual transition is safe and effective, even if it means using two hypnotics simultaneously for a few weeks.

Chris Aiken, MD: Our next two papers bring some clarity to some controversial issues in preventative psychiatry.

One, does lithium prevent suicide? And two, do omega 3 fatty acids prevent psychosis? Now there's good reason for this controversy, because when we're talking about preventative psychiatry, we're talking about long term trials. And those are expensive and hard to do, particularly when we're talking about generic options like these.

That's a bummer, because in psychiatry, we're playing for the long game. These are chronic disorders. But, unfortunately, most of our best scientific studies are with short term trials.

Kellie Newsome, PMNHP: Lithium and clozapine are the only psychiatric medications that can prevent suicide. But lithium's anti suicide effects were recently challenged in a controlled trial where it failed to prevent suicide attempts in 519 veterans who had recently made an attempt.

Researchers have tried to explain this surprising result. Was the dose too low? The comorbidities too many? One possibility is a lot of the patients weren't even taking the lithium. However, the investigators did find an anti suicide benefit when they removed non adherent patients from the data. But that was just a secondary outcome, not the proof they'd been looking for.

Chris Aiken, MD: So lithium's anti suicide effects hang in the balance. Promising, but not proven. That's where this new paper comes in. Leonardo Tondo and Ross Vadosarini gathered 13 randomized controlled trials that looked at suicide as an outcome using lithium. Most of the papers involved bipolar depression, but some involved unipolar as well.

The bottom line, lithium cut the risk of suicide in half. That's encouraging, but it's still not a closed case. First, none of these 13 trials were positive on their own. The statistical significance only emerged when the results were combined together. Second, suicide is difficult to measure, and most of these studies did not look at suicide as a primary outcome, which raises some questions about how accurate their data is.

The authors did find more support when they brought in their search to include uncontrolled trials. from which they estimated that lithium lowers the suicide risk by a factor of five. So, where does that leave us? Despite all this mounting evidence, the proof that lithium prevents suicide is still shy of the gold standard of replicated randomized controlled trials in psychiatry.

And it's likely to stay that way, given how hard this is to measure and the lack of funding for these kinds of studies. On the other hand, no other mood medication has anywhere near the evidence that lithium does for preventing suicide. And when it comes to treating patients, we need to rely on the best evidence we have, not just wait for better evidence to come.

Kellie Newsome, PMNHP: What about esketamine? That one is FDA approved for depression with acute suicidality.

Chris Aiken, MD: Esketamine's bravado reduces suicidal ideation quickly, but only temporarily. With lithium, we're talking about long term prevention. For

Kellie Newsome, PMNHP: So would you give lithium to an actively suicidal patient, say one who has a history of overdosing on pills?

Chris Aiken, MD: I would, because those are just the kinds of patients that were included in these trials. I know it can feel like you're giving a patient who's overdosed a means to overdose. But you got to remember that the means to overdose is as close by as a bottle of Tylenol. And when I do give lithium to patients who've had overdose attempts or ideation of that, I do warn them that an overdose of lithium is not likely to kill them, but can leave them wheelchair bound.

In 2010, a study came out that seemed too good to be true. They took 81 teens and young adults who had early warning signs of psychosis And they gave half of them omega 3 fatty acids, fish oil, and the other half got a placebo. Six years later, only 10 percent of those who got omega 3s went on to develop a full psychotic disorder, compared to 40 percent of those who got the placebo.

That's a huge difference, especially considering that they only took the omega 3s for three months. The problem was with replication of this finding. Studies that followed were a mix of positive and negative results. But this month, two papers came out that moved the proof a little forward. The first paper is a meta analysis that gathered 21 trials in over 2, 000 patients with early warning signs of psychosis.

One weakness is that this was a network meta analysis, which means that they gathered the treatment arms and placebos from different studies and combined them together as though it was all from the same study. It's a bit like creating a collage and claiming it's a single photo. Here's what they found.

Omega 3s did reduce the transition to psychosis. and the effect was greater the longer the trials went on, lowering it from 7 percent at 6 months, 14 percent at 12 months, and 16 percent after 2 years or more. Omega 3s even prevented psychosis better than antipsychotics did, which might seem surprising, but think for a minute.

We're talking here about prevention. And, turning to medicine, you know, we don't use insulin to prevent diabetes, we use it to treat it, and we shouldn't expect that treatments that work for an acute phase are also going to prevent.

Kellie Newsome, PMNHP: No sooner than this analysis came out, another trial looked at omega 3s in people at risk for active psychosis.

With 290 children aged 11 to 12 years old, it is the largest test of this kind, but we have to hedge our enthusiasm because this wasn't a direct test. It's a secondary analysis of an earlier trial that looked at whether omega 3s reduced aggression in children with active conduct disorder. The authors had a sense that some of those children had soft psychiatric symptoms.

So they ran the schizotypal personality questionnaire in this randomized placebo controlled trial.

Chris Aiken, MD: The children in this trial were only treated for three of those twelve months. So, like that earlier trial, we're looking here at whether omega 3s can reduce a risk by intervening at a key time of development.

The study tested two treatments against a placebo arm. They were CBT, omega 3, or the two in combination. The results favored all the omega 3 groups. Only those groups separated from placebo, and they did so throughout the 12 month study. Surprisingly, CBT alone did not make a difference. despite having positive results from other trials of prodromal psychosis.

Kellie Newsome, PMNHP: The study differs from the earlier trials that we discussed because the main outcome was a reduction in the schizotypal scores, not transition to full psychosis. But it does add support to the idea omega 3s are helpful for children with mild psychotic symptoms. Both for reducing those symptoms and for developing schizophrenia.

Chris Aiken, MD: This is a problem that comes up a lot in practice, particularly as I treat adults with schizophrenia or bipolar disorder, who tell me that their 13-year-old daughter is starting to act the way they did when they were 13. These illnesses tend to start in the later teens, but they usually have milder prodromal symptoms that crop up before them.

What that suggests is that there might be a crucial, vulnerable time of development and that if we can intervene there with stress reduction, exercise, omega 3 fatty acids, we can help that child get across the dangerous river of bipolar psychosis and into adulthood where they have a much lower risk of these illnesses coming on.

Kellie Newsome, PMNHP: Most of these studies use doses of omega 3 that were similar to the ones that we use to treat depression. Around 1, 400 milligrams daily, with at least 60 percent of the omega 3 in the form of EPA.

Greg Malzberg, MD: Most of us rely on our daily dose of coffee to get going in the morning, but a new meta analysis raises some red flags about our beloved beverage's impact on anxiety.

Published in Frontiers in Psychology, this study pulled data from 8 studies with a total of over 500 healthy participants, to examine the link between caffeine intake and anxiety risk. Overall, consuming caffeine significantly increased the odds of experiencing anxiety compared to placebo. Higher doses cause more anxiety, especially at doses containing over 400 milligrams of caffeine.

So how much is that? That's five shots of espresso or four standard cups of coffee. But we'll caution that people with anxiety disorders might have a lower threshold for the caffeine jitters. Lowering caffeine is one of the top lifestyle tips you can share with patients who suffer from anxiety. or have them switch to tea.

While tea still contains caffeine, the levels are generally lower. And tea is rich in L theanine, which is a unique amino acid known for its anxiolytic properties. L theanine works synergistically with caffeine, promoting a state of relaxed alertness, without the jitters or crash often associated with coffee.

References: 

Admad, Maha et al. “Transitioning insomnia patients from zolpidem to lemborexant: A multicenter, open-label study evaluating a next-dose transition approach to insomnia pharmacotherapy.” Sleep Medicine: X,vol. 7, (2024). https://doi.org/10.1016/j.sleepx.2023.100098

Aubin, Henri-Jean et al. “Prazosin and cyproheptadine in combination in the treatment of alcohol use disorder: A randomized, double-blind, placebo-controlled trial.” Addiction (Abingdon, England), 10.1111/add.16484. 10 Apr. 2024, doi:10.1111/add.16484

Chen, Chengfeng et al. “Network Meta-Analysis Indicates Superior Effects of Omega-3 Polyunsaturated Fatty Acids in Preventing the Transition to Psychosis in Individuals at Clinical High-Risk.” The international journal of neuropsychopharmacology vol. 27,3 (2024): pyae014. doi:10.1093/ijnp/pyae014

Katz, Ira R et al. “Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial.” JAMA psychiatry vol. 79,1 (2022): 24-32. doi:10.1001/jamapsychiatry.2021.3170

Liu, Chen et al. “Caffeine intake and anxiety: a meta-analysis.” Frontiers in psychology vol. 15 1270246. 1 Feb. 2024, doi:10.3389/fpsyg.2024.1270246

Ozone, Motohiro et al. “Efficacy and Safety of Transitioning to Lemborexant from Z-drug, Suvorexant, and Ramelteon in Japanese Insomnia Patients: An Open-label, Multicenter Study.” Advances in therapy vol. 41,4 (2024): 1728-1745. doi:10.1007/s12325-024-02811-2

Raine, Adrian et al. “Nutritional supplementation to reduce child aggression: a randomized, stratified, single-blind, factorial trial.” Journal of child psychology and psychiatry, and allied disciplines vol. 57,9 (2016): 1038-46. doi:10.1111/jcpp.12565

Tondo, Leonardo, and Ross J Baldessarini. “Prevention of suicidal behavior with lithium treatment in patients with recurrent mood disorders.” International journal of bipolar disorders vol. 12,1 6. 9 Mar. 2024, doi:10.1186/s40345-024-00326-x

Wesner, Katja et al. “Therapeutic Reference Range for Olanzapine in Schizophrenia: Systematic Review on Blood Concentrations, Clinical Effects, and Dopamine Receptor Occupancy.” The Journal of clinical psychiatry vol. 84,5 22r14626. 19 Jul. 2023, doi:10.4088/JCP.22r14626

__________

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 half (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.