Optimizing Management of Schizophrenia with LAIs - Episode 16

Second-Generation LAIs for Schizophrenia

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Segment Description: Experts react to the advantages noted with the use of second-generation long-acting injectables to treat schizophrenia and consider for whom they may be appropriate for when compared with first-generation options.

John M. Kane, MD: There are post hoc analyses and studies that were designed in early phase patients. One study looked at the effect of the 3-month paliperidone in adults with early diagnosis of schizophrenia, and showed advantages. We’ve seen studies with risperidone, out of UCLA in first episode patients. There are studies in Europe and other countries showing advantages in early phase patients. We have a study that we presented at the ACMP [Association of Change Management Professionals] last year suggesting that we can show an advantage in time before hospitalization, in early phase patients. We are accumulating significant data to support the use of long-acting formulations earlier in the illness and demonstrating advantages in terms of relapse and prehospitalization.

Henry A. Nasrallah, MD: The study from UCLA [the University of California, Los Angeles] is mind-boggling in its implications. Hardly any clinicians read it, because if they did, they would be using long-acting at the very beginning. That study at UCLA, published in JAMA Psychiatry, took 100 patients with first episode, treated them with oral in the hospital, discharged half of them on oral and half on injectable for the same antipsychotic. I think it was risperidone at that time.After a year they followed up and reported in their paper that the relapse rate was 650% higher relapse rate in the oral group compared with the injectable, with the same antipsychotic. It is maddening and mind-boggling. We have an opportunity to save so many patients—a 600% difference between 2 treatments is rare in medicine. We’d be lucky if a new medication comes to the market that’s 30%, 40% better than the existing drug. Everybody rejoices at 30 or 40% better. We’re talking 650% better, and it’s available right now. And nobody is using it in the first episode.

John M. Kane, MD: Hopefully our remarks will help persuade physicians to utilize LAIs [long-acting injectables].

Sanjai Rao, MD: From my perspective as an acute care psychiatrist, I agree with everything that’s been said about the desirability of using the second-generation injections, as much as possible, and for everyone for whom they’re going to be effective. I see a small subset of the population that has more chronic illness, for whom even the maximum doses of the second-generation antipsychotics are insufficient. For those patients I do 1 test to continue to consider first-generations, especially haloperidol, because it is possible to titrate that up to higher levels of beta-2 antagonism.

Henry A. Nasrallah, MD: I beg to differ, Sanjai. And it’s OK to have a conflict with opinion here. There are patients who tend to relapse in the fourth week on oral paliperidone monthly or in the 11th to 12th week on the 3-monthly. And we see that with their aripiprazole. These are chronic patients. And we’ve done research and published it, showing that the more episodes the patient had, the more likely they are to fail to respond completely to a second-generation injectable. Those are patients who are treatment resistant now because of multiple relapses. They need to go to clozapine. I never go back to haloperidol. I use clozapine for those patients. There are 2 kinds of patients who deserve clozapine. The first is naturally treatment refracting. It’s a subset of schizophrenia that you identify in the first episode. If you give them long-acting injectables, 30% of them will not respond. Those are direct clozapine candidates because they’re among dopaminergic psychosis. Another subtype of clozapine candidates, which you’re referring to react after multiple episodes and they stop responding, even to high dose, injectable or oral. These are patients who clozapine should be given to as well. It’s 2 types of treatment resistance.

Sanjai Rao, MD: There is a subset of patients, for example, if you look at the top-end dose of Invega Sustenna, the paliperidone injectable. The top-end dose is theoretically 234 mg every 4 weeks, and some people maybe even dose a little quicker than that.

That dose gives you a plasma level that’s roughly equivalent to 5 or 6 mg of oral risperidone a day. And we all know from our clinical experience that there are some people who need more than 6 mg of oral risperidone a day. They might need 8 or 10 mg to stabilize on those higher doses. What do you do with them? Do you give them Sustenna more often? Or do you try to approximate their higher levels of [dopamine receptor] D2 antagonism with something that can do that? Or do you do a little of both? I’m not disputing anything you’re saying, Henry. There are a subset of people who require more medication. Not that they are nonresponsive or treatment resistant at that point. They’re just not going to get better on the maximum doses that we currently have for our current second-generation long-actings, and so you either need to consider dosing those long-actings more often, supplementing orally, supplementing with something else, or using a drug that can generate higher levels of D2 blocking. But I have no fundamental disagreement with what you’re saying.

Henry A. Nasrallah, MD: The 234 mg of Invega Sustenna is 150 mg of the drug. I did the clinical trials, and we had round numbers—25, 50, 75, 100, 150 mg. And the FDA forced them to add the weight. So the 234 mg is really 150 mg, and its the blood-level equivalent to 12 mg a day of oral paliperidone, not the 6 mg.

Sanjai Rao, MD: I meant oral risperidone. It’s about equal to about 6 mg of oral.

Henry A. Nasrallah, MD: Oral risperidone, yes. We have patients in the clinic like that. What do the residents do, with my supervision? They give them some oral pills or paliperidone to take in the fourth week because we recognize that they tend to fall off. Or they give it to them off-label every 3 weeks. If it is fluphenazine, the 3 monthly, they give it every 10 weeks instead of every third week. We tend to give them more frequent injection or supplementation with oral and give the patient the power to determine, “I’m getting psychosis again; I’d better take an extra pill every day.”

Transcript Edited for Clarity