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The Best and Worst Antipsychotics for Mania – Part 1

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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, how an anesthetic agent turned into an antipsychotic, and how Bing Crosby lit a spark that would eventually lead psychiatrists to revise their entire diagnostic system.

Published On: 10/17/2021

Duration: 17 minutes, 3 seconds

Today, the rise and fall of the antipsychotics in bipolar disorder, and how Bing Crosby lit a spark that would lead psychiatrists to revise their entire diagnostic system.
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.

The Myth of the Class Effect
KELLIE NEWSOME: Last week we took on one of the great myths in psychopharmacology – the idea that you can diagnose a patient based on how they respond to medication, sometimes called “pharmacologic dissection.” Today, we’ll delve into another myth – the class effect – the idea that you can predict how a medication works based on the class it’s in.
There are many ways to classify drugs, but usually they are grouped by their mechanism of action, chemical structure, or therapeutic effects. The antipsychotics are usually lumped together by that last one. All of them are FDA approved in schizophrenia, which earns them all the antipsychotic title. But some have branched off from that root – gaining FDA approval in depression, bipolar depression, and mania. One of them – quetiapine – even auditioned for a role in generalized anxiety disorder, and though its anxiolytic effects were very potent the FDA turned it down because its side effects were considered too much for anxious minds to bear.

All this branching has lead to some confusion about how these second generation, or atypical, antipsychotics work as a class. Yes they are antipsychotics, but do they all treat depression? No – that has become clear with, for example, the failure of aripiprazole in bipolar depression, and we never should assume that these meds have broad antidepressant effects because dopamine blockade isn’t good for depression, and the original antipsychotics were notorious for making people depressed.

But do they all treat mania? Once upon a time we thought they did, but a new study reviewed in this month’s Carlat Report has changed our minds, and today we’re going to re-examine each of these agents in bipolar mania.

DR. AIKEN: I thought this was going to be a 5 minute podcast. And if you just want the bottom line, well, here’s how it was going to go. If you’re going to use an antipsychotic in bipolar mania, quetiapine (Seroquel) is first-line. Cariprazine (Vraylar) comes next. Both of those cover the manic and depressive poles. And keep haloperidol (Haldol) deep in the back of your pocket. It is stronger than any other med in acute mania – even lithium – but it is also the most likely to swing your patient from mania into depression, among other problems, so you should only use it if your patient is on the verge of going to the hospital and nothing else is working.

That was it, end of story. And if that’s all you need, you can stop here. But as we did our diligent background research we found more pages in this story that are worth telling. There is new data on asenapine (Saphris) that puts this generic option in a favorable light. There are times when quetiapine might actually make mania worse, and there are several antipsychotics that probably don’t work in mania at all. If you want to learn about that and more, come along.

A Brief History of Antipsychotics in Mania
KELLIE NEWSOME: Although we’re going to disrupt the idea that antipsychotics have a class effect in mania, this isn’t the first time that ground has been shaken. The antipsychotics were first used for mania in the 1950’s, ironically, even before they were tested in schizophrenia. That use exploded in the 1960’s, but several things happened in the early 1970’s that sent the antipsychotics to the back of the row. Then like a phoenix they rose again in the early 2000’s, and today the antipsychotics are top the list of popular prescriptions in bipolar disorder. One out of 2 bipolar patients take them. That’s a wild ride, and to understand it better let’s go back to the beginning.

The year is 1952. Queen Elizabeth has just ascended the throne in England, Bing Crosby was shifting his act from radio to television, and a French pharmaceutical company has sent a shipment of their new drug chlorpromazine to a Navy surgeon, Henri Laborit, for testing as an anesthetic. The goal is to prevent surgical shock by inducing an artificial state of hibernation, and chlorpromazine, which lowers body temperature, is a promising candidate. The treatment seemed to work, and the surgeon noticed an unusual effect that he thought might interest in psychiatric colleagues. After taking chlorpromazine, patients became slightly sedated and less interested in the world around them. They were not exactly depressed, but their mood was definitely dampened.
The psychiatrists listened to Dr. Laborit’s story with ripe attention. The drug had cooling effects, and they were already using cold baths to treat mania in their ward. Further, it made patients disinterested, and manic patients were too interested in everything around them. They moved quickly, and at 10 am on January 19th, 1952, they gave an IV infusion of chlorpromazine to Jacques L, a 24 year old man with mania. They published their findings two months later, and after reading the report two psychiatrists at a nearby hospital, Pierre Deniker and Jean Delay, started using chlorpromazine in schizophrenia. Deniker and Delay quickly published a series of influential papers on the drug, setting up a long rivalry between the two groups of physicians over who was the first to discover chlorpromazine. But we’ll put that debate aside and move across the Atlantic to the United States, where chlorpromazine was introduced as Thorazine in 1954.

DR. AIKEN: Psychiatric diagnosis was a pretty loose business back then, particularly for the psycho-analytically governed United States. Doctors were more interested in treating symptoms, and the list of symptoms that chlorpromazine promised to treat was a long one: Anxiety, tension, agitation, confusion, delirium, hostility, obsessions, neurosis, drug withdrawal, and a variety of psychosomatic disorders, according to the American Journal of Psychiatry and the company’s promotional brochures.

In the 1960’s, antipsychotics were the mainstay treatment for mania in the US, but things were different in Europe. Stepped in the Kraepelin tradition, European psychiatrists made sharper distinctions between manic-depression and schizophrenia, while American physicians increasingly blurred those two disorders. And that diagnostic work paid off as the Europeans came to appreciate that schizophrenia responded better to the antipsychotics, while manic-depression responded better to lithium.

But something was about to happen that would disrupt this cross-Atlantic disparity. It would change not just the fate of antipsychotics but the entire diagnostic system of psychiatry. And if you grew up in the 1980’s and 90’s it would turn your living room into a small movie theater and preserve your childhood memories into frames of continuous replay. The videotape. And to get there, we have to go through Bing Crosby.

From Bing Crosby to DSM-III
KELLIE NEWSOME: Bing Crosby was one of the most successful recording artists of all time, and technology was the secret to his success. He was the first singer to figure out the potential of microphones. While other singers belted, Bing held the mike close, allowing him to sing in an intimate, conversational tone and bring out the lyrics with nuanced phrasing. He was also the first to pre-record his radio shows with magnetic tape, allowing him to banter freely and then edit the tape so that only the best jokes made it on the air. In the early 50’s – actually the same year that chlorpromazine was introduced, Bing was transitioning his show to television, but he ran into a problem. TV was recorded live on Kinescope, and Bing couldn’t edit the tapes as freely as he did with his radio broadcasts. So he hired an engineer to develop a videotape recorder, financing the project with his own money, and by the end of 1951 they had a blurry prototype that they demonstrated to a small audience in Los Angelos.

Fast-forward to 1967 and the first portable videorecorder is released. These players were still big and bulky, more like the reel-to-reel machines in the Bat Cave than the sleek VCRs of the 1980s, but their portability gave a small group of psychiatrists and biostatisticians in New York and London an idea. They suspected that American psychiatry had gone astray, diagnosing every foible under the sun as “schizophrenia” based on an expansive psychoanalytic definition of the word. So with funding from the NIMH they videotaped 8 patients with different disorders, and played the 40-minute videos to an audience of American and British psychiatrists. The results were shocking.

The Americans, in large part, diagnosed every patient with schizophrenia, whether their videotaped interview revealed symptoms of psychosis, depression, mania, anxiety, or a personality disorder. The Brits were more precise. The publication, which appeared in 1971, was an embarrassment to American psychiatry, and inspired the APA to rework their diagnostic system into the more exacting language of DSM-III.

DR. AIKEN: But perhaps we overdramatize how earth-shattering this finding was. In an accompanying editorial, Jerome Frank wondered if clarifying the diagnosis would really do much to improve the treatment, since depressed patients seemed to respond to antipsychotics as well as antidepressants. Jerome Frank has put forth some great ideas in psychiatry, but this was not one of them.

But one US psychiatrist was waiting in the wings with a better answer. Fred Goodwin had just published the first controlled trial of lithium in bipolar disorder, and he was about to publish another showing that lithium worked much better in bipolar depression than it did in unipolar depression. Taking a nod from his European colleagues, Goodwin believed that diagnosis made a difference, and that lithium lead to more meaningful and lasting recoveries in bipolar disorder than the antipsychotics, which were better suited for for schizophrenia. Antidepressants, he thought, could trigger mania, and were better reserved for patients whose moods only traveled in a downward direction.

Goodwin didn’t just believe these things, he had proof. And in 1979 he laid it out in a paper analyzing all the trials of antipsychotics and lithium in mania. Here’s what he concluded. Antipsychotics worked faster than lithium, so they were useful in emergencies, but they mainly treated the agitated, hyperactive symptoms, and their benefits might just be a byproduct of their sedative effects. Lithium, in contrast, didn’t just treat the symptoms but seemed to address something closer to the core of the illness. Patients who recovered on lithium got out of the hospital faster, had better functioning, and stayed well longer compared to those on antipsychotics. Besides, antipsychotics caused major problems in bipolar disorder, including depression, tardive dyskinesia, and weight gain.

I’m struck by something else in Goodwin’s paper. He makes the point that medications can have broader effects on judgment and functioning that aren’t captured in symptomatic rating scales. That’s something to consider in today’s world, where medications are approved based on symptomatic measures that rarely look at the patient’s functioning. I mean, getting back to work and repairing your marriage are much more important than normalizing appetite and psychomotor retardation. Maybe we should pay more attention to the CGI – the global impression scale – which captures a broader picture of how the patient is doing than a symptom list. It was in the CGI that Dr. Goodwin detected a difference with lithium.
Goodwin’s views on treatment fit well with the new diagnostic directions in the DSM, and they soon came to dominate American psychiatry. In the early 1990’s Dr. Goodwin released an influential textbook, Manic-Depressive Illness, and was selected to lead the NIMH. A few years later, the APA released their guidelines on the treatment of bipolar, recommending that antipsychotics should be limited to short-term use and acute agitation. Journal articles from this era adopted an apologetic tone when discussing antipsychotics in mania, and expressed alarm that 30-50% of bipolar patients were still taking them in spite of the better judgment of the APA.

But things were about to change once more. A new generation of antipsychotics was on the march. They were safer versions of clozapine, and they claimed to be free of tardive dyskinesia and other problems that held back the chlorpromazine generation. It was March of 2000, and the FDA had just tossed out one drug and raised up another. In a landmark defeat, the Supreme Court ruled that month that the FDA could not regulate tobacco as it did every other drug, putting to rest Bill Clinton’s plans to hold big tobacco to the same standards that big pharma was accountable to. And beneath that headline was a notice that didn’t make as much of a splash in the media but soon would launch a revolution in psychiatry. Olanzapine joined chlorpromazine as the second antipsychotic to gain approval in bipolar mania.

KELLIE NEWSOME: And today we have 20 years of data on all those atypical antipsychotics that have tried to calm those manic highs. Next week, we’ll dig through it all to help you choose the best antipsychotic for your patient.
And now for the word of the day…. Active metabolite

DR. AIKEN: Drug interactions are complicated business, because the warnings that you read about usually don’t play out in practice. One reason is active metabolites. Take venlafaxine (Effexor). It is metabolized by CYP 2D6, so in theory if your patient is taking this antidepressant and you give them a strong 2D6 inducer, or genetically they are a rapid metabolizer at that enzyme, the venlafaxine will get flushed out of their system so fast that the drug won’t work. But that would only be true if the metabolites created by 2D6 are inactive. Venlafaxine has an active metabolite, and you know it very well. In fact you’ve probably prescribed it: Desvenlafaxine (Pristiq). So the inducer will simply turn venlafaxine into desvenlafazine, probably with no loss of antidepressant effect. Lots of drugs have active metabolites, usually with the same effect as the parent drug, but sometimes with the opposite or different effect. Quetiapine has an active metabolite that acts like an antidepressant – but can that flip patients into mania? Tune in next week to find out.

KELLIE NEWSOME: And if you can’t wait that long to hear from us, check out the podcast Let’s Get Psyched. This month they are featuring a few interviews with Dr. Aiken. On September 25, they discuss UnderPrescribed Medications in Psychiatry, and on October 3rd it’s Behavioral Therapy for Bipolar Disorder. Let’s Get Psyched is hosted by psychiatrists Toshia Yamaguchi (Yama-gushi) and Alan Atkins and psychologist Eyrn Parks. Search for “Let’s Get Psyched” in your podcast store, and make sure to include the apostrophe in Let’s.

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