We're supposed to move to clozapine after two failed antipsychotics in schizophrenia, but how many of us are really doing that?  Not enough. Clozapine may be difficult to use, but it is life changing for many patients. Here we bring you 7 tips, from serum plasma levels to little-known side effects like OCD.

Published on: 4/6/2020

Duration: 20 minutes, 17 seconds

Related Article: "How to Choose an Antipsychotic in Schizophrenia," The Carlat Psychiatry Report, April 2020

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Full Transcript

Kellie: If you’ve been suffering from a case of “Cloza-phobia”, tune in. Because practice guidelines recommend you try clozapine after only two failed antipsychotics.

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Kellie: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003.

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Dr. Aiken: I’m Chris Aiken, the editor-in-chief of The Carlat Psychiatry Report.

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Kellie: And I’m Kellie Newsome, a psychiatric nurse-practitioner and a dedicated reader of every issue.

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In this month’s Carlat Report, we condense a lot of recent clinical trials into a three-step algorithm for treating schizophrenia. In Steps One and Two, we highlighted antipsychotics that had the best balance of efficacy and tolerability. For Step Three, after a patient fails to respond at Steps One and Two, we list only one option – clozapine. And by our estimates, about one in three patients with schizophrenia are going to make it to this clozapine step, because that’s how many have treatment resistance and all it takes is two antipsychotic failures to be placed into that classification.

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Kellie: So, one in three ought to be taking clozapine. But here’s what’s shocking. In America, only one in twenty are on it. Why is that, Dr. Aiken?

Dr. Aiken: This is definitely an American phenomenon. In other countries, about 20 to 30 percent of people with schizophrenia take clozapine, which is much closer to the rate we’d expect based on how many have treatment resistance. I don’t think anybody knows the reason, but my guess is that it has to do with stigma and the way that we value physical health over mental health.

American psychiatrists might be a little timid to use a medication that has so many physical health problems associated with it when they’re using it to treat something that’s a mental health problem.

Kellie: Today, we are all going to get more comfortable with clozapine. Dr. Aiken has seven tips on managing clozapine, and I’m also going to read some passages from the book, Return From Madness, a psychotherapy textbook from the 1990’s by psychiatrist and psychotherapist, Drs. Kathleen Degen and Ellen Nasper. They witnessed some of the first responses to clozapine after the drug came out in 1989. Their responses were so dramatic that they developed a group psychotherapy to help these patients adjust to the new normal of recovery. And that’s one of the main reasons to consider clozapine, as it can bring your patients to full recovery and even improve their negative symptoms.

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Dr. Aiken: Another reason to consider clozapine is that it’s the only antipsychotic that doesn’t seem to have a risk of tardive dyskinesia, and that’s actually what first generated excitement about clozapine in the 1970’s. Clozapine was discovered in 1959, so it’s a very old antipsychotic, and in the 1970’s, pharmaceutical companies started to develop it because they were looking for an antipsychotic that wouldn’t cause tardive dyskinesia.

Along the way, they discovered that it worked in treatment-resistant cases. They also discovered that it has a one percent chance of lowering white blood count, which almost kept it from coming to market. But the FDA recognized that there was an urgent need for help for people with treatment-resistant schizophrenia, and allowed clozapine on the market with the unusual requirement that patients have their blood checked once a week. Now that’s been relaxed where they can go every two weeks after six months, and then every month after 12 months on the medication.

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Kellie: From Return to Madness: Zach struggled with tardive dyskinesia and tardive dystonia that were progressive. Within two weeks of taking Clozaril, animation came back into Zach’s face and light came back into his eyes. His ability to make eye contact also returned. There was somebody home. He spoke of the ability to read street signs and to finish a short story he had been reading a long time. He wondered if he would be able to complete a course at a local college and have his driver’s license reinstated. 

Dr. Aiken: Tip Number One: Patients who take clozapine actually live longer than those who take other antipsychotics. According to a metanalysis of 24 studies from 2019 that encompassed 220,000 life years. Now, on the downside, that’s not controlled data; but on the upside, we would kind of expect the clozapine group to not live as long because these are generally sicker patients. However, they do get their blood checked more often and probably see their physician more often which could extend their lifespan.

In this paper, clozapine was actually cutting the mortality rate in half with a mortality rate ratio of 0.56. But how do we trust that that kind number is solid? The way to do that is to look at the P value, which we want to be really low. In this case, it was - .007 and to look not just at the bottom line number but at the confidence interval around that number. So, while the bottom line was a reduction of .5 or 50%, the confidence interval was from .4 to .8 which is a pretty tight group of numbers around that .5.

Nobody knows why people are living longer on clozapine, but I have a guess. What’s good for the brain is good for the body, and when your brain is in full recovery, everything in the body works better from the heart to the immune system and you just live longer. So, it’s remarkable that even though clozapine has more black box warnings than just about any medicine we use, it actually extends the lifespan.

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Kellie: From Return From Madness: After three months of Clozaril treatment, Nando was able to contain aggressive feelings. His agitation was focused, and he was easily consoled and talked down. After six months on the medicine, Nando’s appearance had improved remarkably. He dressed in clean and very well-coordinated clothes that were fashionable. His personal cleanliness improved, and he expressed how much he would like to work. After eight months, he got a job in the maintenance department of the agency.

Dr. Aiken: Number Two – The Ideal Plasma Level: People on the same dose of clozapine can have a lot of variability in their plasma level based on their genetics and their metabolism, other drug interactions, and whether they’re smoking or not. So, it’s a good idea to check the level and aim for a therapeutic one. The ideal level is between 350 and 700 for people with treatment-resistant schizophrenia. Going beyond 1000 is generally futile. Those ranges are in nanograms per milliliter, but for our listeners outside the U.S., you might be using a different unit – nanomoles per liter. And if you are, the equivalent range would be 1,070 to 2,140. As with most antipsychotics, you should wait about two to three weeks after they achieve a therapeutic level to see a response.

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Dr. Aiken: Another thing you might see in clozapine labs is the clozapine and norclozapine levels. It’s generally thought that it’s the clozapine that contributes to the drug benefits, while norclozapine might actually be responsible for more of the side effects like sedation and weight gain. The ratio of clozapine to norclozapine is what you want to look for here. And that ratio should be around 1.3. If it’s not, that might be telling you something – that your patient may be a slow or rapid metabolizer at the enzymes clozapine goes through, or they might be a smoker, or they might be taking medications that interact with it, changing the ratio of these metabolites. The most potent drug interactions with clozapine occur at CYP1A2, like fluvoxamine, which can significantly raise clozapine levels and reduce the norclozapine levels.

Here’s some guidance on how to interpret that ratio. If this ideal of 1.3 in the ratio falls low, below 1.0, then it’s like that an inducer like carbamazepine or nicotine is onboard. Or the person is just a rapid metabolizer at those enzymes, so something is making the clozapine speed away into norclozapine, lowering the clozapine levels. If, on the other hand, the ratio goes high, rising above 2.0 then there’s probably an inhibitor like fluvoxamine on board slowing down the metabolism into norclozapine or the patient may genetically be a slow metabolizer there.

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Dr. Aiken: Smoking also changes the metabolism of clozapine. People who smoke will have lower levels of clozapine and higher levels of the metabolite, norclozapine. But if they stop smoking – and this applies to you who are working in the inpatient units where they’re not allowed to smoke, you might expect the clozapine level to suddenly go up by about 50%. This is true for anyone smoking more than six cigarettes a day, and it’s the burn that matters, not the nicotine. The burn of the cigarette produces hydrocarbons that create this interaction, so you might see a similar interaction with people who smoke marijuana, but you’re not going to get this with vaping, because there’s no burn.

Here’s what you do then, when your patient on clozapine is admitted to the hospital and has to stop smoking. Lower the dose by 10% every two days toward a maximum dose reduction of 50%. This has to be done gradually because the drug interaction doesn’t stop right away. It takes about eight days for it to settle down.

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Kellie: From Return From Madness:  Mary had the best change of all. Within a year of beginning Clozaril, Mary’s emotional ability had diminished appreciably, and her cognitive capacity improved to the extent that she was now able to engage in relationship-mediated expressive psychotherapy.

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Dr. Aiken: Three. Once daily dosing is just fine with clozapine. Most physicians give clozapine all at night, even in doses up to 500 mg. True, its half life is 12 hours, but the half life relates to its side effects. The pharmacodynamic effects in the brain, the ones we’re looking for, those build up over time and aren’t going to fall out within a daily dip of serum level. In a study of nearly 1,000 patients who were treated with clozapine at academic medical centers, 75% were given the entire dose at night. Much like quetiapine (Seroquel), which actually resembles clozapine and is related to it on a molecular level, clozapine is a heavy sedative and much better tolerated when given all at night.

But, as with quetiapine, there may be one reason to divide up the dose and that is orthostatic hypotension, which is also by the way, that we tend to raise the clozapine dose slowly upon first starting it. Orthostatic hypotension is a side effect that tends to happen when the blood level of a medication peaks, so giving it in divided doses or in the case of quetiapine in the XR form that’s going to flatten out those peak levels, will reduce orthostasis and that might be a good thing for your elderly patients.

Clozapine, unlike quetiapine, does not have an extended release form. Clozapine does come as tablets, liquid, orally disintegrating tabs and injection.

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Dr. Aiken: Four: Take constipation seriously on clozapine. We’re going to cover this more in next month’s issue, but everyone should know that the FDA recently amped up its warning about constipation on clozapine. The problem is not just uncomfortable. It can be fatal when it progresses to ileus and small bowel obstruction, and this actually leads to more fatalities than neutropenia from the drug. The first-line intervention for this constipation is senna and Colace, which are available over the counter and come as a combo pill. For example, on Amazon, your patient can order Wellness Basics Stool Softener with Docusate and Sennosides. Check out next month’s issue for more tips on that.

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Kellie: From Return From Madness: People who are initially irritable, delusional, thought-disordered and paranoid came alive. They became articulate and more self-assured.

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Dr. Aiken: Five. Sialorrhea, or drooling is very distressing to patients because it’s socially embarrassing. Drooling is a common side effect on clozapine, happening in up to 90% of patients who take it and although it’s usually at night, about half of the patients have it during the daytime where it’s socially embarrassing. Paradoxically, by the way, clozapine can cause both dry mouth and drooling, sometimes in the same patient.

A good first step is to waterproof the pillowcases. A pillowcase cover made out of vinyl, such as Everlasting Comfort Waterproof Pillow Protectors are available on Amazon. After that, anticholinergics are usually helpful, but you have to be careful here to give them topically in the mouth, rather than have the patient swallow them systemically because that can cause more constipation. Atropine 1% drops, sublingually, or ipratropium (that’s i p r a t r o p i u m) 0.06% spray are first-line options given twice a day or all at night.

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Kellie: From Return From Madness: All of life’s issues, of course, were not solved by Clozaril. For some, the improvements presented new challenges that were met with mixtures of avoidance, anxiety, and delight. For a few, the challenges of such radical improvement have as yet been intolerable, and they have chosen to discontinue Clozaril.

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Dr. Aiken: Six. Clozapine has the highest risk of metabolic problems of any antipsychotic. Here’s how to manage it.

Nearly everyone who takes clozapine will develop at least one component of metabolic syndrome – weight gain, diabetes, dyslipidemia, especially high triglycerides and hypertension. Dose reduction does not work in these cases. The first-line intervention is metformin. Start at 500 milligrams a day. The main side effect is nausea and diarrhea, which improves by raising it gradually and taking it with food or through an extended-release formulation. After a week of 500 milligrams, try raising it toward a target dose of 1,000 to 2,000 milligrams per day. You can divide that twice a day, or if it’s an extend-release, give it all at once.

What about diet and exercise? We recommend those along with metformin. If you follow this podcast, you know we often recommend lifestyle modifications as first-line interventions, but here I have to admit that metformin has outperformed lifestyle change in at least one head-to-head trial of patients on atypical antipsychotics. And metformin is a low-risk drug. It has anti-aging properties and in animal models, it improves depression and anxiety, although so far, that benefit has only showed up in human studies of people with diabetes.

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Dr. Aiken: And Seven, [yay] [music] watch for OCD on clozapine. Obsessive-compulsive disorder or OCD is not just about serotonin. That might be a myth that was propagated by the fact that serotonin medications became FDA approved for it. Dopamine dysregulation has long been thought to underly OCD as well. And I use the word dysregulation here, because this is a situation where dopamine can swing both ways. There are reports of OCD worsening and improving on dopamine agonists like the stimulants. Likewise, there are reports of it worsening and improving on dopamine blockers, like the antipsychotics. So, even though antipsychotics have controlled studies, as do stimulants now with methylphenidate to treat OCD as augmentation agents, all of these medications can also cause OCD.

Clozapine is the antipsychotic with the highest risk of causing OCD. It’s not clear why clozapine stands out in this way. It actually has low dopamine binding, but it might be due to clozapine’s affinity for the 5HT2A serotonin receptors. We’re seeing that receptor show up in a lot of new medications and we plan to cover it in a podcast soon. When you see OCD as a side effect, dose reduction might help as can exposure therapy and if they don’t have a history of mania, maybe an SSRI. Just make sure to use one that doesn’t interact with clozapine, particularly to stay away from fluvoxamine, Luvox.

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Dr. Aiken: For more clozapine tips, try the Clozapine Handbook by Jonathan Meyer and Steven Stall. The book is new this year. It clocks in at 305 pages. Each one of those is practical, diligently researched, and evidence-based.

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Kellie: Join us next week for an interview with Dr. David Osser, A Practical Guide to Psychopharmacology, but first an update on coronavirus.

As the nation has moved state by state to a stay-at-home order, Dr. Aiken and I have recorded this episode from separate houses. Many of us have moved all of our appointments to telepsychiatry, as well, and we are going to bring you a practical guide to setting up telepsych in the next issue of The Carlat Report. The issue will include an interview with Peter Yellowlees, who wrote the APA’s 2018 textbook on telepsychiatry.

As we rush that off to press, here are two tips that you can use today in your practice. [Music] The first one is that during the crisis, you’re allowed to use any digital platform, including Facetime and Skype to connect with your patients. But remember as things get back to normal, you want to make sure you are on a HIPPA-compliant platform. And for people on a low budget, Dr. Yellowlees recommends, Zoom, VDC and video.

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Kellie: Secondly, during the crisis, physicians, nurse practitioners and PA’s are allowed to prescribe controlled substances and treat people across state lines through telepsychiatry.

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Kellie: Read more at thecarlatreport.com, where we have a special discount for our podcast listeners. You can get $30.00 off your first year’s subscription with the promo code podcast.

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Dr. Aiken: Your subscription will help us to keep operating free from industry influence.

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