Lurasidone (Latuda) has gone generic. Find out where this antipsychotic fits in bipolar disorder with updates from the 2023 International Bipolar Conference.

Published On: 08/07/2023

Duration: 20 minutes, 23 seconds

Transcript:

CHRIS AIKEN: We ran into a former chief of the National Institutes of Mental Health at the Bipolar Conference last June, and asked him what his favorite treatment was for bipolar disorder. Find out why Robert Post leans on 3 medications that start with the letter L.

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.One sign that you’re at a good psych conference is a the site of a man with prowling the poster sessions with a wry smile, notebook in hand, looking like a gray-haired Robert De Niro. It’s not Robert De Niro, it’s Robert Post, a former chief of NIMH who helped identify the mood stabilizing effects of anticonvulsants and the kindling theory of bipolar disorder. For 3 decades Dr. Post has been broadcasting research updates at bipolarnews.org, and his most recent articles there summarize this year’s Society for Biological Psychiatry meeting and the Bipolar Conference where we met up with him.

We asked Dr. Post what his go-to treatment is for bipolar disorder, and he answered: “The three L’s: Lithium, lamotrigine, and lurasidone.”

CHRIS AIKEN: We covered lithium last week. We’ve covered lamotrigine a lot – and there is evidence that lithium and lamotrigine work better than either alone. But we haven’t always had the luxury of prescribing that third L, lurasidone, brand name Latuda, because everytime we prescribed it the insurers would require us to try the patient try a generic antipsychotic like quetiapine or olanzapine-fluoxetine combination, or – even worse – sometimes they’d insist on an option like risperidone that doesn’t even have any evidence to treat bipolar depression.

KELLIE NEWSOME: But this year lurasidone finally went generic, and the price has fallen fast. You can find it for $10-20 a month at GoodRx.Com. And that’s good bipolar-news for patients, because before this the only generic antipsychotics for bipolar depression were weighed down with sedation and metabolic side effects: Quetiapine (aka Seroquel) and olanzapine-fluoxetine combination (aka Symbyax). 

There are only five antipsychotics with FDA approval in bipolar depression, and they are the only five that are known to work. They are, in chronologic order of approval: 

• Olanzapine-fluoxetine combination (Symbyax)

• Quetiapine (Seroquel)

• Lurasidone (Latuda)

• Cariprazine (Vryalar)

• Lumateperone (Caplyta)

That’s it, and there’s no reason to think the others work – many have tried and failed in this prominent pole of the illness. Depression occupies some 40-60% of the lifespan in bipolar disorder. Each of these antipsychotics has about a 1 in 4 chance of working, except the weaker of the bunch, cariprazine, which has a 1 in 11 chance. If you think your odds are better than that, they probably are, because the placebo – and the natural course of the illness – just about double those chances.

CHRIS AIKEN: But the odds of antipsychotics working in depression were against them from the start. Think about it. We’re treating depression with meds that block dopamine, the source of motivation and pleasure at the D3 receptor, which is why depression is a side effect of the first generation of antipsychotics. When they block D2, they cause symptoms that mimic depression, slowing down cognition and motor function and stiffening the facial muscles so the patient has trouble connecting socially. When they block D3 in the nucleus accumbens, the block the source of pleasure and reward. This is why haloperidol has the highest risk of all anti-manic meds of causing a post-manic depression.

We don’t talk about neurotransmitters much on this podcast because it rarely informs practice, but here it does. These antipsychotics have one thing in common. They all block dopamine. But that common mechanism has nothing to do with how they treat depression. It’s that little something extra they do, and that extra mechanism is different for each of these. So even though we don’t know exactly how they treat depression, we know that each one does so in its own way, so you’re more likely to get a response by switching within this class than you are by switching from one SSRI to another.

The first large trials of antipsychotics in bipolar depression only served to illustrate how hard it is for these meds to lift these lows. Olanzapine did not work well on its own in those trials – it needed the antidepressant fluoxetine to boost it up – and it’s only with this antidepressant that it gained approval. Quetiapine invited similar skepticism – this antipsychotic is converted to an active metabolite norquetiapine that resembles an SNRI antidepressant, raising suspicions that it too needed antidepressant assistance.

KELLIE NEWSOME: That’s one reason lurasidone was such a breakthrough. It was the first antipsychotic to treat depression without any help from antidepressants or antidepressant-like molecules. How it accomplished this is not clear, here are some possibilities

• Serotonin antagonism at the 5HT-7 site

• Increases in brain-derived neurotrophic factor (BDNF)

• Normalizing circadian rhythms that are involved in the pathophysiology of bipolar. Stress and irregular sleep disrupt the CLOCK genes that regulate circadian rhythms, and lurasidone and lithium are the only medications we know of that normalize the expression of these genes.

Let’s look more at how lurasidone differs from the pack, but first a preview of the CME quiz for this episode. If you think you got this, move on to the full 2-question quiz through the link in the show notes.

1. Which antipsychotic is NOT FDA-approved in bipolar depression?

A. Quetiapine

B. Lumateperone

C. Aripiprazole

D. Cariprazine

CHRIS AIKEN: Since lurasidone, we’ve seen only two other antipsychotics make it to FDA approval in bipolar depression, emphasizing again that this is not a class effect. They are cariprazine – whose putative antidepressant mechanism is partial agonism at the dopamine D3 receptor that regulates pleasure and reward, and lumateperone, which possibly works through serotonin 5HT-2A antagonism. 

Another way the mechanism influences their use is in the dosing. Most of these antipsychotics hit their antidepressant targets in the lower dose range. As the dose goes up, dopamine blockade kicks in more, and that’s where you see a risk of causing depression. That’s why some people think aripiprazole failed in bipolar depression – in the studies it was dosed up to 30 mg/day. At the conference we met a few psychiatrists who reported success with lower doses of aripiprazole in bipolar depression, including Dr. Tammas Kelly who published a case series of 211 patients with bipolar depression on 2-5 mg of aripiprazole.

But if you go too high with aripiprazole the patient is likely to report anxiety – that is, akathisia. Or they may come in and say that people think they look depressed and are no fun to be around – that is, the EPS is stiffening their facial muscles. Or they just feel emotionally flat, like nothing inspires them. All of these are signs of too much dopamine blockade.

KELLIE NEWSOME: Lurasidone is unique here. It is the only antipsychotic we know of where the antidepressant effects get bigger as the dose goes up, from 20 mg to 120mg/day. Most patients settle in the middle. The average dose was 40-60 mg in adult trials, and 33 mg/day in children and adolescents (lurasidone is FDA approved in bipolar depression down to age 10). In our experience, some patients do get better as the dose goes up, but you still have to watch out for the opposite – lurasidone does block dopamine, and in a 2023 meta-analysis it had the strongest dose-dependent association with akathisia of any antipsychotic. The rate of akathisia rose like a straight line as the dose weng higer. 

Food and drug interactions may also explain why higher doses are necessary in some patients. Lurasidone has to be taken with a full meal – at least 350 calories – otherwise a good chunk of it – 30-70% of it – is not absorbed. Once it gets absorbed, lurasidone is metabolized by the CYP-3A4 enzyme, and only by this enzyme, so any disruption here will make the blood levels go haywire. 

Here’s what that means. If you give lurasidone with a modafinil, or carbamazepine, or St johns wort, or higher doses of topiramate or oxcarbazepine, the lurasidone levels will drop a lot, 2-4 fold, because these are all CYP3A4 inducers.

If you give lurasidone with most SSRIs (all except citalopram and escitalopram, or your patient drinks grapefruit juice with it, the levels will rise a lot, 2-4 fold, as these are all CYP3A4 inhibitors.

People who are poor or rapid metabolizers at 3A4 will have similar problems with this med.

All that brings us to a useful pear. If your patient is doing well on lurasidone and then suddenly gets depressed, ask them if they stopped taking it with food, or if they started a 3A4 inhibitor like modafinil. If they suddenly get anxious, maybe they started drinking grapefruit for breakfast and the higher levels of the medication are causing akathisia.

CHRIS AIKEN: Let’s get back to that dosing issue. We mentioned that most antipsychotics stop working in depression as they reach the anti-manic doses. Most, but not lurasidone, and lurasidone does not have an anti-manic dose. This med has never been studied in mania. It did work in unipolar depression with mixed features, so it might calm some manic symptoms, but whether it treats mania or not is anyone’s guess, and I wouldn’t get into that kind of guess work with your patient’s care. Don’t use lurasidone monotherapy for acute mania, which also means that lurasidone monotherapy is probably not a good idea for anyone with bipolar I disorder. Lurasidone also has no known benefits in the maintenance phase of bipolar disorder. Only one controlled trial tested it for episode prevention – that trial lasted 6 months and failed to find a significant difference. 

KELLIE NEWSOME: Lurasidone is not any more effective than the other options in bipolar depression, but it is better tolerated than the other generics, with very low rates of weight gain and metabolic problems. At least, that’s what the industry-sponsored studies show, must – but not all – of which are short term. A closer look shows some metabolic effects in the higher dose ranges, above 40 mg/day. But overall, we think lurasidone’s metabolic risks are about the same as its brand-only competitors in bipolar depression – cariprazine and lumateperone. Where lurasidone does cause problems is with nausea, akathisia, and sometimes sedation – and these are all side effects that can cause patients to give up on it early so you want to start low – 20 mg/day or cut that in half  – and go slow.

And here’s a shout out to our European listeners. In the EU, lurasidone is labeled based on the actual amount of medication in the tablet, while in the US they use the weight of the med and the binding agent, the hydrochloride salt. So a US 20 mg = European 18.5mg, and a US 120 mg = European 111 mg.

CHRIS AIKEN: If lurasidone does have an efficacy advantage it is in cognition. We’ve seen lots of antipsychotics make this claim, including ziprasidone which lurasidone is a structural analogue of, but so far lurasidone is the only one to prove it in bipolar disorder. That proof comes from two studies. One was a randomized placebo controlled trial where they took people who had recovered from bipolar but were still having cognitive problems. Half got lurasidone, and half got placebo, and the ones on the med did better on objective testing. The other study is from this year, and compared cognitive outcomes in teens who had been randomized to either quetiapine or lurasidone for bipolar depression. Both worked similar for depression, but those on lurasidone had greater improvements on objective tests of cognition – they used timed tests of attention, memory, and accuracy like where you have to decode symbols quickly.

KELLIE NEWSOME: The bottom line: Among the antipsychotics, lurasidone is often first line for bipolar depression. It has a low risk of metabolic side effects, possible cognitive benefits, and its cost is no longer an issue. But we’re not fully sold. No antipsychotic has it all. And if your patient needs help for mania, anxiety, or sleep, quetiapine is a better choice.

KELLIE NEWSOME: And now for the study of the day. Antipsychotic Use and Mortality in Persons with Alcohol-Related Dementia or Wernicke–Korsakoff Syndrome: A Nationwide Register Study in Finland by Anniina Palm and colleagues.

CHRIS AIKEN: When it comes to treating dementia, we are in the dark, the early industrial age at best. We have no meds that improve cognition, at best they slow the decline a little. 80% of people with dementia develop neuropsychiatric symptoms, causing problems for themselves and their families: We’re talking about agitation, anxiety, apathy, depression, and psychotic symptoms. And yet, the main pharmacologic treatment for agitation and psychosis – antipsychotics - carry a black box warning about increased risk of death and cerebrovascular events in dementia.

As if that’s not bad enough, most antipsychotics don’t even work for agitation and psychosis when put to the test in randomized controlled trials of dementia. Last May, brexpiprazole (Rexulti) broke that barrier, becoming the first antipsychotic to gain FDA approval for agitation in dementia. But that gain was based on efficacy – the studies weren’t powered to detect mortality – and so brexpiprazole retains the FDA warning about death and ischemic events.

Today’s study is thus a welcome entry into this dire landscape. The authors focused in on safety – not efficacy – of antipsychotics in alcohol related dementias. These tend to have an earlier onset than Alzheimer’s dementia, and there are two types of alcohol dementias.

1. Wernicke–Korsakoff syndrome, where people can’t form new memories due to vitamin B1 deficiency.  If you have patients who drink too much – tell them to take a multivitamin or folate and a B complex to prevent this and other alcohol-related vitamin problems.

2. Alcohol-related dementia. Besides lowering vitamins necessary for brain health, alcohol also has direct toxic effects on the brain, damaging cholinergic neurons and causing cerebral shrinkage. Some of that may be reversible if the person stops drinking.

The authors looked at 3,581 patients with alcohol related dementias over a 17 year period in Finland, about a third of whom had Wernicke–Korsakoff’s. They compared outcomes of those who took an antipsychotic with those who did not; just under half of them filled at least one antipsychotic script. And the bottom line is the opposite of what we’d expect from the FDA warning: Those who filled an antipsychotic lived longer. Clearly this is not a randomized trial, but we’d guess that most poor prognostic indicators would fall on the side of those who required antipsychotics. 

There are many types of dementia, and the risk of antipsychotics differs among them. We already know those risks are highest with Lewy Body and Parkinson’s dementia. Those with alcohol related dementias may have a safer course.

KELLIE NEWSOME: Get daily research updates by following Dr. Aiken’s DailyPsych feed on social media – you find it on LinkedIn, twitter, and the new Threads app – just search for ChrisAikenMD.

CHRIS AIKEN: Join us next time, where we ask the big questions in bipolar disorder, like when should we avoid Depakote? Who should we blame when patients don’t take their meds? And which comes first – symptom remission or functioning?

KELLIE NEWSOME: Earn CME for this episode from the link in the show notes, and get $30 off your first year’s subscription to the full journal with the promo code PODCAST. The Carlat Report is one of the few CME publications that depends entirely on subscribers. Thank you for helping us stay free of commercial support. 

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