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Lybalvi: The Diet Olanzapine

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Lybalvi combines olanzapine with the opioid blocker samidorphan in hopes of curbing the weight gain on that antipsychotic. Here, we look at how well it works.

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Published On: 02/28/2022

Duration: 25 minutes, 03 seconds

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Chris Aiken, MD, and Kellie Newsome, PMHNP, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.


Lybalvi is a new combo pill that aims to reduce the notorious weight gain on olanzapine, but does it offer anything more than the antidotes we already have?

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

KELLIE NEWSOME: Before the antidepressants, before the benzodiazepines, the first marvel of modern psychopharmacology was the antipsychotic. These drugs offered the first glimpse of a cure for schizophrenia, and after their release in the early 1950’s policy makers started to wonder if we would even need psychiatric hospitals in the future. John F Kennedy signed that dream into law on October 31st, 1963 in the Community Mental Health Act. This bill shifted funding from inpatient facilities to community clinics, or in the words of President Kennedy, so that the “cold mercy of custodial care would be replaced by the open warmth of community.”

It was the last bill the president signed. Three weeks later, he was assassinated in Dallas Texas.

In the decades that followed, antipsychotics continued to bring high hopes and big problems, and today we’re going to take you down that bumpy road because by the end of it you’ll understand where the newest antipsychotic Lybalvi fits. But first, a preview of the CME quiz for this episode.

Lybalvi reduced olanzapine-associated weight gain in which population?

A. Patients who responded to olanzapine but developed obesity on it

B. Schizophrenia, bipolar disorder, or alcohol use disorders

C. First episode schizophrenia

D. Non-obese patients with schizophrenia

CHRIS AIKEN: By the 1970’s, it looked like John Kennedy’s dream of deinstitutionalization would have to be deferred. Many patients did not respond to antipsychotics, or they responded but were not able to function because the drugs didn’t do much for their negative symptoms. Others missed their doses, or simply stopped them altogether. Psychiatrists responded by prescribing higher and higher doses of high potency antipsychotics, pushing haloperidol over 100 and then over 200 mg a day. But this didn’t bring more recoveries. It simply overstepped the sweet spot on the dopamine receptor and caused another problem: Extrapyramidal symptoms and Tardive dyskinesia. 

Tardive dyskinesia tarnished the reputation of the drugs, and brought expensive lawsuits to the companies that made them, so the pharmaceutical firms searched for a drug that would treat psychosis without causing this disfiguring side effect. The solution they arrived at was clozapine, the first atypical antipsychotic, but most countries pulled clozapine from the market soon after its release when 9 patients died from agranulocytosis on it in 1975. This sent pharmacologists on another search: for a clozapine-like molecule that would not cause agranulocytosis. 15 years later, the first crop of these atypical antipsychotics were released: Risperidone, olanzapine, and quetiapine, bound together by their preferential affinity for the 5HT2 over the D2 receptors, a pharmacodynamic profile that was thought to underlie clozapine’s unique success.

KELLIE NEWSOME: But as the new atypicals replaced the older drugs, a new problem emerged: Weight gain. At first, the reports centered around clozapine, which returned to the market in 1990 after a paper by John Kane and colleagues showed that clozapine worked in treatment resistant schizophrenia – 1 in 3 patients responded to it after failing 4 antipsychotic trials. At the time, weight gain was not on the radar, and the company behind clozapine claimed that only 1% of patients gained weight on the drug. But soon after its release papers came out suggesting the rates were as high as 85%. 

Olanzapine followed a few years later, released in 1996. Olanzapine is structurally similar to clozapine, and awareness of its weight-gaining risk followed a similar route of misinformation. Eli Lilly tried to convince the FDA that weight gain was not a side effect but a benefit of the drug, suggesting that olanzapine simply normalized weight in patients who were underweight. The FDA didn’t buy it, but they still launched the drug with little warning of its metabolic risks. 

CHRIS AIKEN: Two years after its release, the first article on olanzapine-associated weight gain came out, followed by articles suggesting the drug may also increase triglycerides, glucose, and diabetes. The manufacturer, Eli Lilly, tried to unlink these associations from their drug, claiming it was a class effect for all antipsychotics, or shifting the blame to patients with schizophrenia, suggesting that the metabolic problems were due to disease itself. But as hundreds of reports of diabetes on olanzapine found their way to the FDA’s post-marketing surveillance system, Eli Lilly had to cave, and the FDA placed warnings about the metabolic effects of the drug, first in 2000 with wording that was buried in the label, and then in 2003 with a prominent black box. Today, we know that about 3 out of 4 patients who take olanzapine gain weight on it, and a little over half of patients who take the drug gain significant weight. Unfortunately, olanzapine usually ranks right behind clozapine for its efficacy in schizophrenia, along with other highly effective antipsychotics like risperidone and the European amisulpride. These 4 antipsychotics are also the ones with the highest risk of weight gain.

In response, the industry set on a third race, to find antipsychotics that did not cause weight gain or diabetes. That search brought us another generation, so-called dopamine stabilizers’ or ‘partial dopamine agonists’ like aripiprazole, brexpiprazole, and more recently a group with little to no dopamine blockade, lumateperone (Caplyta) and pimavanserin (Nuplazid). Unfortunately, none of these match the efficacy of olanzapine and clozapine, and there may be some pharmacologic inevitability to that. The serotonin 5Ht2A receptor that gives these their “atypical” antipsychotic qualities is also the center that moderates appetite and eating. We see the same dilemma with traditional antipsychotics, which treat psychosis through the same receptor that moderates movement: D2.

On the other hand, many patients respond well to the partial dopamine agonists, but for those that don’t Alkermes pharmaceuticals has a new solution: Lybalvi.

KELLIE NEWSOME: You may not have heard of this antipsychotic, because it’s started with a soft launch, but you will surely recognize its main ingredient: olanzapine. Lybalvi is a combo pill that pairs olanzapine with samidorphan. Samidorphan works much like naltrexone. It lowers the rewarding effects of rich foods by blocking the opioid receptor. 

CHRIS AIKEN: On the surface, Lybalvi looks pretty good. Compared to olanzapine alone, or actually, olanzapine with a placebo, patients on Lybalvi gained 5 lbs less after half a year, on average, based on the 3 controlled trials that compared the two. That benefit has a slow build. After 1 month, there was no difference between the two, and after 3 months there was a 3 pound difference (Srisurapanont M et al, Sci Rep 2021;11(1):7583).

The problem is that these were surface benefits. Despite this weight reduction, Lybalvi had no effect on metabolic parameters, including insulin and glucose levels, hemoglobin A1c, and triglycerides and other lipids. Without those changes, we don’t know if this weight loss is purely cosmetic, or if it is actually lowering the risk of metabolic syndrome.

KELLIE NEWSOME: That’s why we’re not ready to recommend Lybalvi just yet. We’ll stick with our top two meds for antipsychotic weight gain – metformin and topiramate. Metformin improves insulin sensitivity, hemoglobin A1C, dyslipidemia, and prolactinemia on antipsychotics. Some of those results are not surprising – as metformin is FDA approved in diabetes – but we were surprised to learn it improves levels of lipids and prolactin. But what about topiramate? This one may have metabolic benefits as well. 

In our May 17th 2021 podcast “13 ways to use topiramate”, we looked into topiramate’s origin story. The drug was originally developed as a synthetic sugar for use in diabetes. When it was eventually released as an anticonvulsant, doctors noticed that people with diabetes had better glycemic control when they took it. People lose weight on topiramate even when their caloric intake is unchanged, suggesting it may have metabolic benefits, and indeed it does lower glucose and lipid levels and improves insulin sensitivity. 

CHRIS AIKEN: Both these drugs also have psychiatric benefits that are meaningful to patients who take antipsychotics. In schizophrenia, topiramate improves negative symptoms, and in mood disorders it improves common comorbidities like bulimia, borderline personality disorder, OCD, alcohol, meth, or cocaine abuse. There is even a controlled trial where topiramate improved depression, although we’ve also seen that as a side effect on topiramate. Lybalvi, on the other hand, tried to get approval in schizophrenia with alcohol use disorders, but it did not work in that trial.

Metformin also has cognitive and mood benefits. That’s been shown in several trials of diabetes, but recently we’re seeing promising data in non-diabetes. This year, metformin improved treatment resistant bipolar depression in a randomized controlled trial. The patients did not have diabetes, but they did have insulin resistance. And last year, they tested metformin in patients with major depression who had no diabetes. Surprisingly, metformin worked, even though the patients weren’t selected for metabolic problems like they were in the bipolar study. Improving insulin resistance and glycemic controls has known effects on the brain that might explain how metformin treats depression, but how it lifts mood in people with normal metabolism is a mystery. Metformin does have anti-inflammatory, antioxidant, and neuroprotective effects, as well as anti-aging properties.

KELLIE NEWSOME: But how do topiramate and metformin compare to Lybalvi in terms of weight loss? They’ve never gone head to head, and we can’t really answer that question because the studies that tested them used very different designs. On the surface, metformin and topiramate look better. They led to weight loss of approximately 7 lbs for metformin and 8 lbs for topiramate. That’s based on meta-analyses of 14 trials – most of which lasted about 3 months. Now, recall that Lybalvi only had 3 pounds of weight loss at that point, but we can’t quite conclude that topiramate and metformin are any better on the weight loss front. Here’s why.

The Lybalvi studies looked at whether the medication could prevent weight gain when started with the antipsychotic. The metformin and topiramate studies looked at the odds after the fact – adding the antidote in patients who had already gained weight on their antipsychotic. The Lybalvi patients enrolled people with a BMI under 30 – the average was a slip of 25 – while most of the other studies looked at patients with a BMI over 30. On the one hand, that difference favors Lybalvi, because these different levels of weight loss balance out a bit more when seen as a percentage of body weight.

But on the other hand, it favors topiramate and metformin, because it’s harder to lose weight once you’ve gained it, so these two had more working against them. Obesity causes changes in the body that perpetuate weight gain. The microbiome shifts. Fat cells grow. And both of these secrete messengers that make us want to eat more rich and sugary foods.

CHRIS AIKEN: It might seem odd that the Lybalvi studies excluded patients with obesity, but we like how that changes the focus – toward early intervention – because whether you use Lybalvi, metformin, or diet and exercise, patients are going to have much better luck with a preventive approach. In my practice, I often start metformin 1 month after starting a button-bursting antipsychotic like clozapine, olanzapine, or quetiapine. I don’t start it in all patients, but I will in those who gain at least 7% of their body weight after starting it, or in those who are just really concerned with weight. I also add melatonin, which is relatively benign and does reduce antipsychotic weight gain at 3-5mg/night. Metformin is also relatively safe by the way.

Then I tell patients that this drug – the antipsychotic – is going to make them allergic to junk food. These antipsychotics light up the brain’s reward center when you eat comfort foods – fatty, processed, sugary stuff. It’s a powerful drive, and it easily overwhelms a person’s will. So they just can’t have it in the house. They have to clear out the pantry and the fridge – it’s a big commitment.  It’s not easy advice, but I feel like sometimes we have to tell patients a hard truth. When an immunocompromised patient is in the hospital, they don’t allow flowers in the room – the risk of infection is too high. I’d take the same precautions for a person on olanzapine – they need to steer clear of that bag of potato chips.

KELLIE NEWSOME: We’ve tried to present a balanced picture of Lybalvi here, and to write it we drew from the original Lybalvi trials, as well as two two independent meta-analyses and an industry sponsored review. Among the independent meta-analyses, one gave it thumbs up, and the other gave it thumbs down, and you can guess which side the industry sponsored paper landed on. The positive analysis was a little more inclusive – allowing non randomized controlled trials into the mix. And, in fairness to Lybalvi, the study that brought the negative meta-analysis down only lasted 4 weeks, and we reported earlier that Lybalvi didn’t make any difference at the 4 week point. The industry sponsored paper briefly mentioned this negative study, but didn’t report the disappointing weight outcomes – only the psychosis outcomes.

And here’s where the industry sponsored paper stands on metformin. They say that metformin didn’t work so well when started along with an antipsychotic, while their drug, Lybalvi, did. And they have a point. Metformin only worked in 3 out of 4 trials that started it alongside an antipsychotic, suggesting that the drug is more useful in patients who already have metabolic problems. But on the other hand, Lybalvi has never been tested in obese patients, and we have reason to suspect it might not work so well there. And this gets into a question that is probably on many listeners minds – can’t you just substitute naltrexone?

CHRIS AIKEN: The opioid antagonist in Lybalvi, samidorphan, has very similar pharmacodynamic effects as naltrexone, which is available at a much lower price. And naltrexone has robust data in weight loss, at least when combined with bupropion in the FDA approved Contrave pill. So can you just use this generic option? Maybe. We found 2 trials that tested naltrexone in antipsychotic associated weight gain – one was positive, and one was negative. But these trials looked at patients who were already obese, with a BMI > 30 kg/m2, remember the Lybalvi studies excluded patients with a BMI over 30, which makes us wonder how well Lybalvi would perform if it was tested in this population. 

So, yes you might be able to substitute naltrexone, but what we’re finding here is a pattern. This isn’t definitive, but suggestive. Maybe Lybalvi or naltrexone are ideal when you’re first starting olanzapine – as a preventative measure. These are opioid blockers, and they might keep that appetite from rising to an addictive level. But once a person gains weight, or if they already have crossed that line in their BMI, their weight gain might be driven by metabolic changes beyond appetite alone. That’s where metformin, or perhaps topiramate, seems to have a role.

KELLIE NEWSOME: We’ll leave that as a tentative conclusion – awaiting further data. For now, all we can really say is that metformin improves not only weight but the metabolic changes that make antipsychotics damaging, while Lybalvi just prevents some – and by no means all – of the weight gain. And while all these measures entail adding another drug, metformin and topiramate have additional psychiatric benefits, which Lybalvi does not, unless your patient takes opioid medicine or suffers from opioid abuse – in which case there’s a risk: You can’t start Lybalvi until they are sober, and perhaps this opioid blocker will help them stay sober.

CHRIS AIKEN: And now for the word of the day…. ALKS-5461

KELLIE NEWSOME: This antidepressant was never christened with a brand name, but we’d sure like to know what Alkermes would have named it. ALKS-5461 was the research code name for a controversial antidepressant that combined samidorphan – the opioid blocker we just reviewed in Lybalvi – with buprenorphine, an opioid partial agonist better known as Sublocade, Butrans, or Subutex. The medication made it to the final stages of FDA review, but the agency denied it, and you’re not likely to replicate it by mixing the two meds as samidorphan is only available as an olanzapine combo.

The initial studies of this combo pill looked promising. Much like ketamine, it quickly reduced depression and suicidal ideation. But the phase III trials failed on their primary outcome measure. Alkermes made a bold Hail Mary, attempting to switch the primary measures after the fact, but the FDA did not buy it. Much as in professional sports, moving the goalposts is not allowed in clinical research. 

Alkermes also paired samidorphan with baclofen in hopes of treating alcohol use disorders. Not a bad idea, as the gabaergic baclofen has a few randomized controlled trials by itself for alcohol use disorders, some positive, some negative, and samidorphan’s cousin naltrexone is FDA approved in alcohol use disorders. But that hope didn’t make it to the finishing line of FDA approval either.

Join us next week, where we explore a metabolically friendly approach to psychiatric disorders: Omega-3 fatty acids.

Earn CME credits for this podcast by following the link in the episode notes. Carlat Publishing is a family of CME journals led by psychiatrist Danny Carlat. We cover all things psychiatric, but you won’t find advertising in our pages, and we operate free of industry support.


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