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A New Option for Bipolar Depression

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Lumateperone (Caplyta) just got FDA approved for bipolar depression. Find out how it compares to other atypical antipsychotics.

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Published On: 01/24/2022

Duration: 24 minutes, 09 seconds

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


We interrupt our regularly scheduled broadcast this morning to bring you breaking news: The FDA has approved lumateperone, Caplyta, for bipolar depression

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: The winter holiday season is always one of great anticipation for us at the Carlat Report. With our winter double issue safely in the mail, we have time to sit beneath the twinkling lights and festivus pole and wonder what coming week will bring. Who will come to visit – or at least zoom – what presents will they bring? And what medications will the FDA approve as their final quarter closes.

That’s right, most psychiatric medications are approved in the last week of December, and on December 20 2021 the FDA delivered lumateperone (Caplyta) for bipolar I & II depression.

CHRIS AIKEN: That right there is a first, because no other medication specifically lists bipolar II in its indication. Lumateperone made a bold move of enrolling a lot of bipolar II patients in its FDA registration trials. Only one other atypical antipsychotic has a lot of data in bipolar II, and that’s quetiapine (Seroquel). Quetiapine doesn’t have the bipolar II word in their official indication for bipolar depression, but it is mentioned in the prescribing information that the approval was based on studies in bipolar I and II.

OK, so it’s unique, but does it really matter? I mean wouldn’t you think that anything that works for bipolar I depression would work for bipolar II and vice versa? Sometimes that’s true, but it wasn’t true for the last atypical that got approved in bipolar depression – cariprazine (Vraylar) – failed in its bipolar II studies, so the company stopped enrolling bipolar II patients and stuck with the traditional bipolar I depression.

KELLIE NEWSOME: Bipolar I and II use the same criteria for their depressive phases in DSM-5, so what’s the difference between them?

CHRIS AIKEN: To me, bipolar II is closer to recurrent major depression than it is to bipolar I disorder. Just look at the symptoms. On average, people with bipolar II spend 50% of their lives in some form of depression, and only 4% of their lives with hypomania or mixed states, so the numbers already give hint that this is a depressive illness. For bipolar I, it’s 30% in depression and 15% in mania or mixed states. The nature of the symptoms are also different. Bipolar II is more likely to have atypical features like overeating, oversleeping, and leaden paralysis, while some studies show a greater tendency for the opposite – melancholic features – in bipolar I. In bipolar II, the depressions are more mixed with psychiatric comorbidities, which occur at alarmingly high rates in both kinds of bipolar but particularly in bipolar II patients – things like anxiety disorders, OCD, ADHD post-traumatic stress disorder, bulimia, addictions, personality disorders, and temperamental problems like cyclothymia and dysthymia. 

KELLIE NEWSOME: OK so I’m just speculating now but it’s starting to make sense to me why quetiapine would be favorable in bipolar II, because it treats a lot of those comorbidities. Quetiapine treats anxiety disorders, OCD, and borderline personality disorder. And – arguably –  quetiapine contains something that other atypicals do not – an antidepressant. One of its metabolites, norquetiapine, acts like an SNRI. 

CHRIS AIKEN: That’s intriguing, and I’m not saying that bipolar II patients do better with antidepressants. I mean, we have lots of evidence that antidepressants cause rapid cycling in bipolar I and II, and we don’t have much evidence that antidepressants help bipolar II – it just hasn’t been adequately studied. But the expert consensus is that a small minority of bipolar patients respond to antidepressants – maybe 10-20%. The responses are not great, and the meds might be doing some harm, like increasing the frequency of episodes, even while they do some good, like treating the anxiety or depression. And the expert consensus is that if a patient with bipolar disorder is going to respond to an antidepressant, they are more likely to have bipolar II than I.

KELLIE NEWSOME: But lumateperone is not an antidepressant to be clear, right?

CHRIS AIKEN: Yes, back to lumateperone. Lumateperone’s mechanism of action does not resemble that of an antidepressant. This is a unique antipsychotic in that it treats psychosis without significant dopamine (D2) blockade. Its receptor occupancy at D2 is 39%, while most antipsychotics occupy D2 at 60% and above. So how does it do it? Some think lumateperone might treat psychosis through serotonergic (5-HT2A) antagonism, and in these ways its mechanism overlaps a bit with quetiapine – which is also low on dopamine blockade and high on serotonergic (5-HT2A) antagonism.

KELLIE NEWSOME: That’s interesting because psilocybin is a psychedelic that is trying to gain FDA approval for depression, and it is a serotonergic (5-HT2A) agonist, as are other psychedelics like LSD. Someday I hope to find out how two drugs with opposite mechanisms of action can both treat depression.

CHRIS AIKEN: Yes and some antidepressants also block 5HT2A, like trazodone, nefazodone, and mirtazapine. Another antipsychotic that shares a similar profile with lumateperone is pimavanserin (Nuplazid), which has low dopamine blockade – that’s why it’s FDA approved for parkinsonian psychosis – and also blocks serotonin 5-HT2A. And like lumateperone, pimavanserin is showing promise in depression – in this case in the randomized controlled CLARITY trial where it worked as antidepressant augmentation in unipolar major depression.

KELLIE NEWSOME: So quetiapine, lumateperone, and pimavanserin might but loosely lumped together as 5HT2A blockers with low dopamine blockade. All of these drugs also improve sleep, which many patients appreciate, although on the other hand fatigue is the main side effect for lumateperone and it can be a problem with the other two as well. Outside of that, the three really differ in their side effects. Quetiapine has more weight gain and metabolic issues, and although it was rumored to have low rates of tardive dyskinesia, a 2018 meta-analysis concluded that quetiapine had the highest risk of tardive dyskinesia among the atypical antipsychotics. And pimavanserin is a wild card – it was approved through an expedited pathway so the studies on it are pretty small, and post-marketing surveillance data suggests possible trouble with long term morbidity and mortality on it, including a recent analysis from late 2021. But we can at least say that these 3 antipsychotics have low rates of extrapyramidal symptoms like muscle stiffness, cogwheeling, and akathisia, along with clozapine which could be added to this group. And that makes these a good choice for psychosis in parkinson’s disease.

CHRIS AIKEN: Let’s get into side effects, because that’s where lumateperone stands out. In the schizophrenia and bipolar studies, the drug had similar rates as placebo for akathisia, extrapyramidal symptoms, prolactinemia, and the dreaded metabolic symptoms of weight gain and lipid or glucose abnormalities. Its main side effects are fatigue, dry mouth, nausea, and dizziness. 

KELLIE NEWSOME: That sounds pretty tolerable, but this is a new drug so I’m guessing those are just short term studies.

CHRIS AIKEN: In bipolar disorder they are short term – 6 weeks – but in schizophrenia they did an uncontrolled extension study for 1 year that confirmed this favorable profile. I put more trust in the low rate of akathisia and extrapyramidal symptoms, as those tend to show up early in the trials. 

KELLIE NEWSOME: So lumateperone might be used for bipolar II depression, and you might consider it when a patient is unable to tolerate other atypical antipsychotics. Anything else we should know about this drug?

CHRIS AIKEN: It’s approval was based on 3 randomized controlled trials, only one of which has been published – we reviewed it in February’s report – but we were able to get abstracts of the unpublished studies.  Here’s what we found. The first trial was negative, but lumateperone worked in the next 2 with a small to medium effect size (0.27-0.56), and the benefits showed up as early as week 1, which is common with this type of medication. One of those trials was as an adjunct to other mood stabilizers – it was positive – and the other two were as monotherapy – of which one was positive one was negative.

KELLIE NEWSOME: How do you explain the negative finding?

CHRIS AIKEN: We can only speculate. It was a large multicenter trial, and the more centers there are in a trial the more likely you are to get a negative result. In this case, there were 58 study centers.

KELLIE NEWSOME: Why do more centers reduce the chance of a positive result?

CHRIS AIKEN: It’s not really the number of centers, but the ratio of investigators to subjects, and when you have more centers you have a lot more investigators dosing their attention on a small group of subjects. The more attention those subjects get, the higher the placebo response, and the more likely a negative result. In lumateperone’s case, the placebo response was 1.7 times greater in the negative trial than in the positive ones.

KELLIE NEWSOME: But, on the other hand, maybe the drug is not just that effective. I mean, one of the positive studies you quoted had an effect size of 0.27, which is about the same as the effect size of omega 3 fatty acids in bipolar depression.

CHRIS AIKEN: Good point. And omega 3’s are generally good for physical health, which is more than I can say for antipsychotics. We have an article on how to use omega-3’s coming up in our March issue, which is exciting because we found new data on how to refine the dosing of these agents.

KELLIE NEWSOME: Now that the approval is in place, what does the future hold for lumateperone?

CHRIS AIKEN: A fourth trial is underway that will test the drug in a third group: unipolar depression with mixed features. This is a new concept in DSM-5 that recognizes patients with unipolar depression who have at least 3 manic symptoms during the depression – previously these patients were said to have “bipolar spectrum” depression or “agitated” depression. Only one medication –  lurasidone (Latuda) has robust data in unipolar depression with mixed features so this will be interesting to see if lumateperone is positive there as well.

KN: But that also reminds me of a drawback of lumateperone. It has no data in mania, and neither does lurasidone for that matter. Would you use these meds for mania?

CHRIS AIKEN: Only as a last resort. Just because something is an antipsychotic does not mean that it treats mania – we covered the negative trials of brexpiprazole and iloperidone last October.

KELLIE NEWSOME: Lumateperone is approved as monotherapy for bipolar I and II depression because it was studied that way, but this is more reflective of the clunky, binary thinking of the FDA than a thoughtful recommendation. We don’t recommend lumateperone as monotherapy in bipolar I, because mania destroys lives, and lumateperone has no evidence to prevent mania. But what about in bipolar II, Dr. Aiken?

CHRIS AIKEN: You’ve just touched on two misconceptions in bipolar disorder. The first is that all bipolar patients need long-term mood stabilizers. That recommendation was created for bipolar I to prevent those life-destroying manias, but bipolar II patients don’t have manias, and rarely have hypomanias, so they need something to treat and prevent depression. And for that, you’ll usually get the best balance of tolerability and efficacy with lamotrigine, and possibly lithium. The second misconception is that the DSM way of separating bipolar – into types I and II – is the most useful way of slicing the pie. It is useful, because it points to the need for an antimanic agent in bipolar I, but I get just as much utility out of another concept that was crystalized by Fred Goodwin in his book Atypical Bipolar. He speaks of the difference between atypical bipolarity – where there are a lot of mixed states, rapid cycling, and complex comorbidities like anxiety, addiction, and personality disorders. The other form is classic bipolar – where the manias or hypomanias are pure, euphoric types, and the depressions and manic states are cleanly separated, with good functioning between the two and not a lot of comorbidities, except maybe panic disorder.

KELLIE NEWSOME: Sounds like these distinctions – atypical and classical bipolar – can apply to both bipolar I and II patients.

CHRIS AIKEN: Yes, either can have it, although you do tend to see the atypical form more often in the bipolar II patients. The atypical form also has an earlier onset – in childhood or at puberty – and these patients rarely reach full recovery. Often they have milder mood, anxiety, or temperamental problems that continue after their major episode is resolved. 

KELLIE NEWSOME: Why is the atypical vs. classical distinction important?

CHRIS AIKEN: Because it informs treatment. Classical bipolar is more likely to respond to lithium, whether they have bipolar I or II, while atypical bipolar is more likely to respond to anticonvulsants and antipsychotics. 

KELLIE NEWSOME: So you might use lithium in bipolar II?

CHRIS AIKEN: Definitely. If it’s the classic type. About 1 in 3 patients have classic bipolar, and these patients are great lithium responders. Lithium can also be tried in atypical bipolar – sure it’s less likely to work there – but then again most treatments are less likely to work in that population.

KELLIE NEWSOME: Let’s end with a run down of the atypical antipsychotics in bipolar depression. At this point, the only ones that have positive controlled data are the ones that are FDA approved, so you don’t have to search too hard to find them. Starting with generics, they are:

Olanzapine-fluoxetine combination. Dosed as 6mg olanzapine with 25mg fluoxetine, or up to double those amounts of each. Some insurers will require you to write for the two as separate scripts, even though the combo pill is generic. 

CHRIS AIKEN: A lot of people think that insurers have an unfair bias against branded drugs. But this is not true. Their mission to impede care is universal – generic drugs, brand name drugs. If you think you can escape their scrutiny by sticking with generic drugs for FDA indications, like olanzapine-fluoxetine combination, clomipramine, and some of the older MAOIs, think again. 

KELLIE NEWSOME: The other generic is quetiapine: For bipolar depression, the optimal dose is 300mg/night, and either the XR or instant release will work. Higher doses treat mania and mixed states, like 400-800 mg/night.

And now for the brands…

Cariprazine (Vyralar): Works in bipolar depression and mania, but has a possible lower efficacy in bipolar depression with a number needed to treat of 11, about half the efficacy of the others in this class. The dose for bipolar depression is 1.5mg/day, and for mania is 3-6 mg/day.

Lurasidone (Latuda): Approved for bipolar depression in adults and children over age 12. This one needs to be taken with mood, and it has some evidence of a dose response relationship between 20mg and 120mg/day. That’s unusual because most of these drugs work for depression in low doses and mania in high doses, but lurasidone also stands out because it does not have evidence in mania.

And finally lumateperone.

If you’re going to use lumateperone in bipolar depression, the dosing is the same as it is for schizophrenia: 42 mg once at night – the starting dose is the same as the ending dose. Taking it with food may improve tolerability by dampening and delaying the peak blood level, but is not necessary for absorption. It is metabolized through CYP3A4 and isn’t known to have active metabolites. 

CHRIS AIKEN: And now for the word of the day…. Mu-opioid receptors

It’s through the Mu-opioid receptors that opioid medications treat pain, as these receptors are densely concentrated in brain regions that regulate perception of pain perception. The Mu receptor also shows up in the amygdala, where it influences the emotional response to pain. These pain receptors can develop tolerance to the analgesic effects of opioids, which explains why long-term opioid therapy doesn’t work so well for chronic pain, but it does not explain why opioids are additive. Addiction, abuse, and a “use disorder” are different from tolerance. To explain the addictive qualities of opioids we have to turn to the ventral tegmental area and nucleus accumbens, which register the rewarding and euphoric properties of opioids. 

CHRIS AIKEN: But none of this fully explains the opioid crisis. The opioid crisis is not just about tolerance and addiction to these drugs, it’s also about accidental overdose. We’re not talking about suicide. We’re talking about accidentally taking more opioids than prescribed, or taking the prescribed amount with alcohol, a benzo, or another respiratory depressant. Opioids cause death through respiratory depression, and the Mu receptor in the brainstem is the one that’s responsible for that effect. Join us next week, where we detail the history of the opioid epidemic. It’s a story of medical misconceptions, industry corruption, and the loss of life for over a million Americans.

KELLIE NEWSOME: With the release of the first FDA-approved medication for bipolar II, we can expect to see a lot more industry-sponsored education on this disorder. But you can get ahead of the tide with Dr. Aiken’s unsponsored bipolar II textbook, Bipolar, Not So Much, available in print and audio editions from WW Norton. David Dunner, who developed the concept of bipolar II almost 50 years ago, had this to say about it “This informative book is easy to read and provides practical information.” It includes information on diagnosis, medications, and psychosocial and lifestyle approaches to bipolar II. 

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