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Schizophrenia: Catching Up to New Guidelines

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The new APA guidelines on schizophrenia go above and beyond the usual standards. Brian Miller shows us how to catch up.

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Published On: 02/14/2022

Duration: 25 minutes, 58 seconds

Related Article: Raising the Bar in Schizophrenia Treatment,” The Carlat Psychiatry Report, February 2022

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


The new schizophrenia guidelines are several steps ahead of usual care. Brian Miller shows us how to catch up.

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: We usually don’t get too excited about practice guidelines. Most of them just reiterate what we’re already doing: antidepressants and psychotherapy for depression; mood stabilizers for bipolar disorder; but not the new schizophrenia guidelines from the American Psychiatric Association. These guidelines raise the bar. Here are some examples… but first, a sneak preview of our CME quiz…

In a 2013 meta-analysis, which two antipsychotics ranked right behind clozapine for their overall effect size?

  1. Olanzapine and risperidone
  2. Olanzapine and haloperidol
  3. Aripiprazole and haloperidol
  4. Risperidone and aripiprazole

And now, back to the APA guidelines.

The new guidelines recommend a trial of clozapine when patients fail to respond to two antipsychotics, and that’s a lot of patients – about a third of the schizophrenia population. But do a third of patients with schizophrenia get clozapine? No, more like 5%. In other countries the rates of clozapine prescriptions are much more in line with where the APA would like them.

These aren’t the first guidelines to recommend the baseball approach to clozapine – two strikes and you get a trial. But take the clozapine case a little further than their forebears. For one, the APA no longer requires that one of those trials be a first-generation antipsychotic, so you can move to clozapine after two failed trials of atypical antipsychotics. And in some patients they now recommend clozapine first- or second- line, such as in people with schizophrenia who have significant aggression, suicidality, or self-harm (clozapine has an FDA indication for preventing suicide in psychotic disorders), and you can also jump into an early clozapine trial if your patient has tardive dyskinesia (little-known fact: Clozapine was originally developed in the 1970’s because drug companies were searching for an antipsychotic that did not cause tardive dyskinesia, and it still holds up to that promise). 

CHRIS AIKEN: Treatment resistance is one of the most important diagnoses you can make, because the interventions that work in treatment resistant cases are usually different from the first-line options you’d use in regular cases. And treatment resistance is urgent. The sooner you intervene, the more likely they are to recover. That’s true in depression as well as schizophrenia. Here’s a figure worth remembering: 80% of patients with treatment-resistant schizophrenia respond to clozapine if it’s started in the first 3 years of the illness, but only 30% respond if it’s started later. So when you start that first antipsychotic, you also need to start a timer – one that ticks off 6 weeks for the first trial, another 6 weeks for the second trial, and then the clozapine alarm goes off. I think there’s an iphone app for that.

KELLIE NEWSOME: If there was an app it would also need to tell us what treatment resistance is, because people toss that word around but it’s not even defined in the DSM. 

CHRIS AIKEN: If I was on a DSM committee I would definitely vote to have treatment resistance added in as a diagnostic subtype. And the definition is different for schizophrenia than it is for mood disorders. Both require two failed trials, but in mood disorders “failure” means lack of recovery, while in schizophrenia “failure” means lack of response. So a partial response to an antidepressant is a failure, but not so with an antipsychotic. For schizophrenia, failure means there was no improvement or less than 20% improvement in positive symptoms – we don’t expect to see much change with negative symptoms as those are harder to treat. If they had to stop the medication early because they could not tolerate it, that does not count as a failure.

KELLIE NEWSOME: Another big change is blood levels. These are not used routinely in schizophrenia, but the guidelines suggest we ought to rethink that. They recommend checking antipsychotic blood levels to find out if the patient is even taking the medication, particularly before you move to clozapine – you want to make sure they were taking the med before declaring it a failure. Blood levels can be ordered for most antipsychotics, and if you start checking, you’re likely to find that about 1 in 3 patients are not taking their med. But while blood levels inform us on treatment adherence, they don’t guide dosing, except for clozapine, whose therapeutic effects are greatest at levels above 350.

But perhaps the biggest change from the 2004 guidelines is the rise in psychosocial therapies for schizophrenia. The guidelines describe no fewer than 10 psychotherapies with evidence in schizophrenia, many of which have free treatment manuals that are linked in the APA’s practice guideline PDF, which is free on their website. They encourage psychosocial therapies for all patients, but particularly for first-episode cases, and here’s where we really see everyday practice – including our own – falling short. 

According to the APA, all patients in their first-episode of psychosis should be treated in a coordinated specialty care program. These teams incorporate medication treatment with education, resiliency training, family therapy, and vocational rehabilitation. That type of care is increasingly available at well-funded mental health centers, but most solo practitioners are going to have a hard time finding those resources for their patients, and some communities may not have them at all. So we turned to Brian Miller, Professor of Psychiatry at the Medical College of Augusta Georgia, to learn how to raise the bar in our care of schizophrenia when it’s just you and the patient in the room. 

What can we do to improve care in schizophrenia?

Mark Frye – who specializes in bipolar disorder at the Mayo Clinic – once shared with me that he tells all his patients “You should expect a full recovery.” I’ve found this very useful with mood disorders – because it’s try – and these patients have often lost hope because they have depression. But schizophrenia is different because negative symptoms often persist, and a full functional recovery is not as likely. How do you keep hope alive?

Are we using enough clozapine in the US?

CHRIS AIKEN: Learn more in the online edition of the interview, where Dr. Miller talks about what to do when clozapine doesn’t work, and how to treat negative symptoms of schizophrenia. Brian Miller is Professor of Psychiatry at the Medical College of Georgia in Augusta and President of the Georgia Psychiatric Physicians Association.

And now for the word of the day…. lisdexamfetamine

KELLIE NEWSOME: You know it as Vyvanse, but the generic name is lisdexamfetamine, and this year a lot of insurers are trying to reduce their costs by blocking coverage of Vyvanse. The drug is likely to go generic in 2023, but until then if you can’t get it approved your patient will have to pay out of pocket – around $370 a month – or switch to a generic alternative. But which one? To figure that out we need to break down the chemical name:

Lis-dexamfetamine is made by adding the amino acid L-lysine, aka “lis” to dextroamphetamine. Change dextro- to dex, and swap the “ph” in amphetamine for the British variant (they spell it with an f) and you get lis-dexamphetamine. Float that molecule by a red blood cell, and it will cleave off the lis- molecule, releasing the active drug dextroamphetamine.

But why go through all that trouble? Well, for one thing, it’s much harder to abuse this prodrug, locked in by the lis- amino acid, than it is to abuse the real mccoy – dextroamphetamine. So why are patients complaining that their insurance isn’t covering this? Physicians and regulators are likely to be upset that insurers are forcing a switch to a more abusable medication, but few patients are likely to be alarmed that their new formulation lacks a lysine lock.

Well, the cleaving of the lysine has another effect – it delivers the drug slowly, with levels that are steadier and longer-lasting than the alternative extended release dextroamphetamine – Dexedrine ER spansules. 

If you’re going to switch from Vyvanse to Dexedrine spansules, you need to know how to convert the dose, because that lysine molecule packs extra weight to the milligrams that never gets used. So Vyvanse 70mg is not the same as Dexedrine 70mg!  Unfortunately, we don’t have clear guidance on how to convert the dose – the makers of Vyvanse did not conduct those studies – but here’s an estimation. Multiple the Vyvanse dose by 0.3 to 0.4. So 70mg a day of Vyvanse equates to 20-30 mg a day of dextroamphetamine. One reason that conversion is not exact is the that Vyvanse is spread out more evenly for a longer period of time, while dextroamphetamine is going to have more peaks and valleys and a shorter duration, even in the extended release spansules formulation, which lasts 6-10 hours, while Vyvanse lasts 9-14.  

But whatever you do, we do not recommend converting Vyvanse to methamphetamine – a stimulant that is rarely prescribed and often abused – and the subject of next week’s podcast.

Start earning CME credits for these podcasts by following the link in the show notes. And check out our February issue where we review an old drug – gabapentin – and 3 new ones: MDMA in PTSD, Lybalvi – the new olanzapine combo pill for weight loss, and lumateperone (Caplyta) in bipolar depression.



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