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The Best and Worst Antipsychotics for Mania – Part 3

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In this 3-part series, we look at the rise and fall, and rise again of antipsychotics in mania, and sort through which ones work, which we should avoid, and whether their use in mania has gone overboard. Today, we lay out the top 3 antipsychotics for mania, and then throw out the whole idea of a rating system.

Published On: 11/1/2021

Duration: 23 mins, 25 seconds

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It’s the final episode of our 3-part series on antipsychotics, and you’re going to find out whether these drugs have a class effect in mania, and follow a trail of peanut butter cups down to Orlando, Florida, where a pharmaceutical exec runs afoul of the Justice Department by impersonating an Elvis impersonator. 

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.

When Depression is Not a Concern

KELLIE NEWSOME: In our last episode, we suggested that the best antipsychotic for mania is one that will treat, or at least prevent, depression. Only 2 or 3 that fit that bill. But what if your patient just has mania, and doesn’t tend to have much trouble with depression?

CHRIS AIKEN: Then I would use lithium. Most patients who tend toward the manic side have classic bipolar – where the manias are pure and euphoric, and they have good functioning between their episodes. Their temperament tends to be upbeat and action oriented, quite unlike the neurotic temperaments that make people vulnerable to depression. If they have depressions, they tend to come on right after the mania, as if following the law of gravity. About 1 in 3 bipolar patients have this classic kind of bipolar, and as we’ve said lithium is your best first-choice in these cases. 

Sometimes, however, I do need to use antipsychotics in these cases. I can think of a few that responded to lithium, but are unable to stay out of mania unless an antipsychotic is on board. Most of these cases had psychotic mania, by the way, and I say that hesitantly, because in the research lithium works just as well for psychotic mania as antipsychotics do. That’s a useful pearl – just because they are called “antipsychotics” doesn’t mean they treat all psychoses. They used to be called major tranquilizers, and in the 1970’s they called them neuroleptics. Now people are trying to call them “broad spectrum antipsychotics.” So you don’t need an antipsychotic for all psychotic disorders. But there are a few manic-psychotic cases that seem to need them, and in many of those cases I used aripiprazole (Abilify).

KELLIE NEWSOME: Many psychiatrists favor aripiprazole because it’s one of the better tolerated antipsychotics, and when other better-tolerated agents came out like lurasidone and cariprazine, aripiprazole was able to stay in a favorable light because it had gone generic, and to this day it remains the only generic antipsychotic with relatively good tolerability.

CHRIS AIKEN: Key word there is “relatively.” I saw a patient recently who had severe fatigue and muscle weakness. She was taking Abilify, buspirone, and lamotrigine. She stopped buspirone and lamotrigine on her own, convinced they must be causing it, but the problems didn’t go away. When I explained to her that antipsychotics like aripiprazole are among the most difficult medications to tolerate, she looked at me bewildered and said, “That doesn’t make sense. I’ve seen the Abilify ads and it sounds like a very easy med to take from what they say.” 

KELLIE NEWSOME: Jeff Lieberman is a schizophrenia expert, and he shared a revealing story in his book Shrinks: The Untold Story of Psychiatry. When he was in medical school in the 1970’s, they gave the students a small box of medications to take home and try as part of their pharmacology class. It was like one from each of the major classes – an antibiotic, a sedative, an antidepressant, and an antipsychotic. None of them did much, he recalled, except the antipsychotic, which made him feel terrible – a mix of akathisia and paralyzing sedation.

CHRIS AIKEN: It’s a good book, and they turned it into a PBS series you can stream online – The Mysteries of Mental Illness. And you know, there is one antipsychotic from Lieberman’s student days that I still keep in my back pocket.

KELLIE NEWSOME: You mean, like, there’s one you haven’t taken yet?

CHRIS AIKEN: No – when I was in medical school they didn’t give us antipsychotics to take.

KELLIE NEWSOME: Right, times had changed, you were going to sign up for that ketamine study but your professor talked you out of it.

CHRIS AIKEN: That’s a whole nother story. I’m saying there is one old school, first generation antipsychotic that I still use as a last resort in mania.

KELLIE NEWSOME: What’s that?

CHRIS AIKEN: Haloperidol.

KELLIE NEWSOME: Haloperidol? But that can cause a lot of akathisia and extrapyramidal symptoms.

CHRIS AIKEN: I know, I know. But get this – in meta-analyses, haloperidol has the largest effect size in mania – it even beat lithium in a head-to-head trial.

KELLIE NEWSOME: Then why don’t you keep it in your front pocket?

CHRIS AIKEN: Because it also has the biggest risk of causing depression after a mania, besides its considerable side effects. Here’s where I’ll use it – if a patient is on the verge of going to the hospital, and nothing else is working, haloperidol might save them from that hospitalization.

KELLIE NEWSOME: Right, and hopefully you can taper it off down the road to prevent more depression. I’ll also add that one of the old-school antipsychotics – loxapine – is FDA approved for acute agitation in mania as an inhaled version, and a few of the newer antipsychotics have this approval in intramuscular form, like olanzapine, and aripiprazole, but that use is usually reserved for the emergency room. I would prefer these newer ones for acute agitation over loxapine – but not for the reason you might think.

KELLIE NEWSOME: So, not because it’s old-school, side effect-prone, and all that.

CHRIS AIKEN: It is all that, but the new ones have a lot of side effects too. My concern with loxapine is a bit theoretical, so take it with a grain of salt. Loxapine has an active metabolite that you may recognize – Amoxapine.

KELLIE NEWSOME: Amoxapine – isn’t that a tricyclic antidepressant?

CHRIS AIKEN: Yes. And the last thing you want to give to a manic patient is a tricyclic – those are the antidepressants that have the highest risk of inducing mania.

KELLIE NEWSOME: Getting back to our review of the atypicals, there are 13 of these second generation or “atypical” antipsychotics in the US, and only 6 of them are known to work in mania: aripiprazole (Abilify), asenapine (Saphris), cariprazine (Vraylar), olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal). And if you forget that list, remember: Those are also the 6 that are FDA-approved in mania. Other than the antidepressant benefits we mentioned, we have no strong reason to recommend one over the other. 

Are Antipsychotics Overused in Bipolar?

KELLIE NEWSOME: In part 1 of this series, we detailed the rise and fall of antipsychotics in bipolar disorder. They rose in America the 1960’s when psychiatrists thought they treated everything… Hmmmm…. Sounds a bit like today? Then in the 1970’s we started to figure out that we weren’t doing a very good job in the US of separating bipolar from schizophrenia, and that if we took the effort to draw that line our bipolar patients got much better results with lithium than they did with the antipsychotics. The antipsychotics were sent to the back of the room, where they were mainly called on for their rapid action in acute cases, but never favored for long term treatment. Are we just repeating the past, or is this new generation really different?

CHRIS AIKEN: Let’s look at the issues one by one. 

  1. Antipsychotics fell out of favor because they caused tardive dyskinesia, and, yes the new agents cause this as well. Strike one against antipsychotics.
  2. Another reason for their decline was that they made patients more depressed. Here, the atypicals look a little better, but not by much. A recent analysis concluded that only one of the anti-manic atypicals was able to prevent depression– quetiapine (note, this analysis was done before the 2018 asenapine study). And two of the atypicals might still cause depression long term – at least, that is what Terrence Ketter concluded through his meta-analytic lens of the long-term data. Those are risperidone (Risperdal) and its marketable metabolite paliperidone (Invega).
  3. Then there’s the argument that lithium is more effective than the antipsychotics. Compared to the atypicals, lithium was more effective in long term, real-world studies. And in the head-to-head clinical trials, some favor lithium and some favor the atypical, but there is one finding that stands out for lithium. It comes from two different randomized controlled trials comparing lithium to our top choice, quetiapine. After 12 months, lithium had better cognitive outcomes than quetiapine, and it had more neuroprotective effects in the brain. That reminds me of Goodwins original argument – that the two types of drugs may look similar on rating scales, but that may hide bigger differences in the overall, functional outcome. 
  4. The third reason that psychiatrists were weary of antipsychotics is that before 2005 we had no evidence that these prevented mania. Many believed that they were just treating the symptoms – sedating the patient – without doing anything to modify the long-term course of the illness. And that is where the atypicals seem to have made a meaningful leap… or have they?

Atypical Antipsychotics in the Maintenance Phase

KELLIE NEWSOME: That leap came in July of 2005, when a study was published that changed everything: “Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial

CA I still remember the day I picked up the American Journal of Psychiatry and saw that study. I thought – “this should be easy – olanzapine can’t match lithium as a preventative treatment.” But I was wrong. Olanzapine was slightly better than lithium at preventing mania, and lithium was a little better at preventing depression. And lithium was the better tolerated of the two.

KELLIE NEWSOME: It was the first long-term, controlled trial of an antipsychotic for prevention in bipolar disorder, and it was followed by nearly 20 controlled trials of antipsychotics in the maintenance phase of bipolar disorder. Most, but not all, were positive, and a few earned FDA approval for the maintenance phase: Aripiprazole, olanzapine, quetiapine, risperidone, and – when as an adjunct to mood stabilizers but not on its own – ziprasidone. 

CHRIS AIKEN: But there are holes in the data. Most of the antipsychotic trials used enriched samples that favored the drug, or withdrew the drug so early – after only 3 months – that it wasn’t clear if the drug was preventing new episodes or just treating the original episode. I know of only one controlled trial that waited a more conservative 6 months before withdrawing the antipsychotic and replacing it with a placebo – and in that study the antipsychotic had no preventative effects (the study used two antipsychotics – risperidone and olanzapine – both of which are FDA approved for maintenance) (Yatham LN et al, Mol Psychiatry 2016, 21:1050-1056).

KELLIE NEWSOME: And then there’s the Kavanagh problem. Not Brett Kavanaugh, Ron Kavanagh , a reviewer at the FDA who turned into a whistleblower over the agencies handling of the antipsychotics. Ron reanalyzed the antipsychotic’s mania studies and found that the studies were only positive in patients with severe mania – those with mild to moderate mania did just as well on the placebo. Now, he only looked at data for olanzapine, paliperidone, risperidone, ziprasidone, and the FDA rejected his arguments because they were a secondary analysis, otherwise known as data fishing. His whistleblower complaints ultimately went nowhere and were never published under peer review. But another group did come to a similar conclusion in a 2017 Lancet article where they analyzed 5 randomized controlled trials of olanzapine and found that it was much more effective in severe mania than mild mania. There is also some research suggesting that they work better in manic patients with poor insight.

CHRIS AIKEN: But this is not so much a scandal as a known problem with many psychiatric meds. Remember the controversy about antidepressants – do they work or not? It was the same issue. The analyses were clear that they worked in severe cases, but they were kind of iffy in the mild cases. The issue is a bit more pressing with antipsychotics because they carry so many more risks than the antidepressants. Personally, I’ve always believed the FDA should have specified that they were only appropriate for moderate to severe cases when they approved them for depression – I don’t think their risks justify their use in mild depression – and maybe we should consider that argument in mania as well. But the jury is not out – we need more research.

Antipsychotics that Don’t Work in Mania

KELLIE NEWSOME: We’ve discussed the 6 atypical antipsychotics with FDA approval in mania, but what about the other 7? 

CHRIS AIKEN: Clozapine is the original atypical and it has some impressive open-label studies in treatment resistant mania, which gives it a role here. I mean, clozapine may lack controlled trials in mania, but when you get to the treatment resistant phase every therapy is experimental, and at least this one has some evidence there.

Illoperidone (Fanapt) and paliperidone have no FDA approvals in bipolar disorder. Illoperidone has open-label data in mania and a controlled trial is underway, so it’s a gamble. Paliperidone’s mania trials are more negative than positive, and its maintenance data in bipolar disorder is pretty week as well. 

Lurasidone (Latuda) and lumateperone (Caplyta) have good evidence in bipolar depression, but they don’t have a single trial in mania so we don’t recommend them there. Lurasidone did work for depression with mixed features, which is encouraging, but we’ve tried it in practice and haven’t seen much potential in full mania. Number 6 is pimavanserin (Nuplazid), which has no data in bipolar disorder at all, but it did augment antidepressants in a recent trial of unipolar depression.

Then there’s brexpiprazole (Rexulti). In our online edition this month we reviewed a new series of industry sponsored trials of this antipsychotic in acute mania – and they also failed. 

Class Action

CHRIS AIKEN: So it looks like we’re discovering that the antipsychotics don’t have a class effect in mania, much as we learned about the anticonvulsants 20 years ago. That was when the first negative trial of gabapentin in mania was published, and it was soon followed by disappointing results from topiramate, oxcarbazepine, and lamotrigine in mania.

The antipsychotics do have a class effect in psychosis, though even that class effect is breaking down. Traditionally what bound them together was D2 blockade, but some of the newer antipsychotics like lumateperone (Caplyta) and pimavanserin (Nuplazid) have very little D2 blockade and instead seem to treat psychosis through serotonergic (5-HT2A) antagonism. Others like aripiprazole, brexpiprazole, and cariprazine are really D2 modulators rather than blockers – they are partial agonists at the receptor. 

It has been a remarkable story, how these medications came to supplant lithium, and we began this series by saying it was a story of science and marketing. Scientifically, the atypicals did exceed expectations – compared to first generation antipsychotics, they have lower risks of depression and even a few that help bipolar depression. And if you’ve practiced in the past 20 years you’ve surely witnessed the kind of marketing made Abilify the #1 most profitable drug in the year before it lost its patent.

Let’s go back to where it started, in the Fall of 2000, 6 months after the launch of olanzapine in mania. Eli Lilly has organized a conference in Orlando Florida to launch a new initiative they call Viva Zyprexa!  The idea is to bring Zyprexa into primary care, and one of the execs has written Elvis Pressley’s Viva Las Vegas to drive the point home 

“Can`t rest now I’ve got to run

I’m gonna tell everyone

Might tell a doctor fifty times…

Remember it’s about the patients’ lives

“There’s thousands of patients waitin ‘out there

The way they’re livin’ just ain’t fair

But now you bet they can get some help from Primary Care

Viva Zyprexa! Viva Zyprexa!”

And this is where the trouble started. To teach primary care docs how to use Zyprexa, the reps are given case history of mild mood problems that blur the lines between bipolar disorder and the everyday problems of modern life. There’s Donna, a single mom who is anxious, irritable and in need of little sleep. Mark, a middle-aged man with mood swings. And Martha, a widow who has felt agitated and restless since her children left for college. These profiles are printed up in glossy brochures, which the reps leave for primary care docs along with a peanut butter cup. Nine years later, the Department of Justice would follow that trail of peanut butter cups, and fine Eli Lilly one and a half billion dollars for off-label marketing of Zyprexa. 

And now for the word of the day…. Evidence Based Medicine

As the medical literature grew in the 1970’s, doctors responded by developing practice guidelines, gathering experts at conferences to sort through the evidence and come to some consensus on the best practice. But it soon became clear that the experts did not agree, and there were no ground rules to work out their differences. So in 1976 the Deputy Health Ministers of Canada organized a committee to grade clinical evidence, starting with randomized controlled trials and working down to case series and case reports. 20 years later, David Sacket took this grading system out of the practice guidelines and into the hands of clinicians, in a landmark paper in the British Medical Journal that introduced the world to Evidence Based Medicine. 

The paper was immediately criticized in half a dozen letters to the editor for ignoring the humanistic or economic aspects of medicine. One criticism came from a psychiatrist – who pointed out that relying on randomized controlled trials would miss many bad outcomes that only show up in case reports – such as sudden death on antipsychotics. 

In his classic book Evidence-Based Medicine: How to Practice and Teach EBM, Dr. Sacket defined evidence based medicine as using our clinical skills, along with the best evidence available to us and with consideration of the patient’s wishes, to make medical decisions. Next week, our child psychiatry team will show us how evidence based medicine is reshaping the treatment of autism.

KELLIE NEWSOME: Lithium, antipsychotics, anticonvulsants, is that all there is? No, if you want to learn about a behavioral therapy that works in mania, check out our February 2019 interview with James Phelps or tune into the podcast on PsychPearls, where Dr. Aiken and I guest-hosted two recent episodes that walk you through this so-called Dark Therapy. Search for PsychPearls – one word – in your podcast store, and look for the August 2 and October 7th epsidoes on Blue Light and mood. And if 3 episodes on mood stabilizers is not enough, we cohosted the August 3rd episode “Four Myths About Lamotrigine.”


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