FDA strengthens warning on clozapine induced constipation. What do we do when it happens? And what does this mean for the rest of our psych meds? Dr. Jonathan Meyer explains.

Published on: 5/18/20

Duration: 14 minutes, 2 seconds

Article Referenced: "A Potentially Lethal Side Effect You Probably Never Heard Of," The Carlat Psychiatry Report, May 2020

Transcript:

Opening

You probably didn’t go into psychiatry because you’re interested in constipation. But it’s here, it’s potentially fatal, and our medications are causing it.

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.

Introduction

In this month’s report we covered a new FDA warning about constipation on clozapine. With a fatality rate of 1 in 1000, this is not just a nuisance side effect. What’s going on is that clozapine slows down the bowels, called hypomotility, and when it gets severe the bowels literally grind to a hault ─ that’s called paralytic ileus.  Paralytic ileus is one step away from intestinal obstruction, which can quickly progress to bowel ischemia, perforation, sepsis, and death.

And it’s not just clozapine that causes this. Hypomotility and paralytic ileus can happen on other antipsychotics  ─ particularly the high potency first generation antipsychotics like haloperidol and fluphenazine, and other anticholinergic medications like the tricyclic antidepressants. The fatality rate is far lower with these other medications than it is with clozapine, but the risk of hypomotility and paralytic ileus is still high.

In our online edition we have a basic 3-step guide to managing this hypo-motile constipation that begins with preventative measures and moves on to first-line therapy with docusate (that’s Colace) and senna (aka Ex-Lax or Senokot).

We recommend you read that guide to get the most out of this podcast, because here we’re going to delve into the 2^nd line therapies to turn to when those basic interventions don’t work.

I spoke with Jonathan Meyer about when to use clozapine and how to manage constipation on it. These steps will be useful for patients who have constipation on other psych meds as well, but keep in mind they are advanced steps for patients who haven’t responded to the first interventions.

Clozapine itself is an advanced step  ─ we are supposed to start it after failure of two antipsychotics in schizophrenia. But what does that mean? Schizophrenia is not an illness where we expect to see full recovery ─ only about 1 in 10 return to a decent level of functioning. So should we be using clozapine in the other 90%?  Not at all.

I’m about to tell you one of the most important definitions in psychiatry that IS NOT in the DSM.

Treatment resistance in mood disorders means failure to RECOVER on 2 antidepressants. In schizophrenia, treatment resistance means failure to RESPOND to 2 antipsychotics.  That’s a world of difference.  In my practice, I use “Treatment Resistance” as a specifier. The DSM guides us to say “Schizophrenia Paranoid type” or “Schizophrenia Disorganized type” ─ but what is most important is treatment resistance ─ as that tells us what to do with the medication.

KN:  Dr Aiken  ─ I think you’re talking about DSM-4 there.  In DSM-5 they actually dropped those specifiers in schizophrenia because ─ as you did correctly state ─ they don’t tell us much about treatment or prognosis. They kept in catatonia, and they kept and even added to all the specifiers for mood disorders. So anyway, what does this made-up specifier “Treatment Resistance” tell us about medication?

CA: In depression, it means we need to stop changing antidepressants and move on to augmentation strategies, ECT, TMS, or intensive psychotherapies that focus on behavioral change. Antidepressant switches don’t help in treatment resistant depression, but augmentation strategies can. In schizophrenia, it means we need to move to clozapine.

Again, treatment resistance in schizophrenia means failure to respond to 2 antipsychotics, where response is a 30% or more improvement.  Dr. Meyers ─ is that 30% improvement in positive or negative symptoms?

[JM]

Treatment resistance is based on “non-response”, but how long do you have to wait to see a response?

[JM]

So you wait 2 weeks and then raise the dose, as long as you’re within the therapeutic dose range?

[JM]

What about long-acting injectables, is it the same 2-week wait?

[JM]

So in theory you could move a patient across two antipsychotic trials and onto clozapine within 2-3 months, and you can expect to do that in 30% of patients. This is not too hard to remember, but we’re not doing it right in America.  Only 5% of people with schizophrenia take clozapine in the US, while in other countries its 25% - much more in line with the 30% who have treatment resistance.

KN:  That’s why we’re featuring clozapine in so many of these podcasts ─ start using it ─ let’s change those numbers!

CA: But the hard part is not knowing when to use it, it’s knowing how to manage its side effects. And this year the FDA added a new one to the list – paralytic ileus. So Dr. Meyer how common is this?

[JM]

CA:  What can we do if we have to stop clozapine ─ I mean what else works in treatment resistant schizophrenia?

[JM]

CA: You’ve been recommending that we talk about constipation from the day we start clozapine, and now the FDA is agreeing with you. What to you tell the patient?

[JM]

CA:  And what are your first steps for constipation?

[JM]

CA:  For our subscribers you can read that protocol online.  Dr. Meyer I noticed you left fiber supplements like Metamucil/Psyllium out of the picture.

[JM]

CA: What do you do when the first-line protocol  from New Zealand doesn’t work?

[JM]

CA: Thank you Dr. Meyer

KN: Jonathan Meyer is a Clinical Professor of Psychiatry at University of California, San Diego, and the coauthor of The Clozapine Handbook.

Word of the Day

And now for the word of the day…. Noesis  N-o-e-s-i-s

Noesis is a the belief that one has a divine calling.  It can occur in manic, psychotic or dissociative states.  people with noesis have an intense experience of revelation where they were chosen to lead or command.  Noesis can also be part of normal mystical experiences. Psychiatrist Peter Buckley compared noesis in mystical writings from that seen in schizophrenia, and concluded that the two differed in an important way: mystics lacked the disruption of thought so often seen in acute psychosis.

KN: Join us every Wed and Sat for 60-second psych, and next Monday for a full-length edition of Research Theme Park, where we take a ride through the food-mood connection, including a new clinical trial of blueberries in depression.

Get the full constipation protocol online at thecarlatreport.com, where our podcast listeners will receive $30 off your first year’s subscription 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.

Got feedback? Take the podcast survey.