Choosing Among Long-Acting Injectable Antipsychotics: Practical Aspects

David N. Osser, MD

Associate Professor of Psychiatry
Harvard Medical School
Brockton Division of the VA Boston Healthcare System

Last updated: June 4, 2018


First-generation LAIs (haloperidol, fluphenazine) have higher rates of acute extrapyramidal symptoms, tardive dyskinesia and hyperprolactinemia symptoms compared to most second-generation antipsychotics. However, they have lower costs.

Most second-generation antipsychotics cost more than $1000 a month, sometimes considerably more.

Risperidone microspheres (Risperdal Consta) has a lower risk of movement disorders than FGAs. It requires oral supplementation for 2 weeks.

Paliperidone palmitate (Invega Sustenna, Invega Trinza) does not require oral supplementation.

Aripiprazole long-acting injectable requires two weeks of oral supplementation. Aripiprazole comes in different forms: aripiprazole monohydrate (Abilify Maintena) and aripiprazole lauroxil (Aristada).

Olanzapine pamoate (Zyprexa Relprevv) requires special observation for three hours, making use impractical.

The next slide shows some specific aspects of the long-acting injectable armamentarium that we have now. So these are the ones that you could presumably try, a long-acting injectable instead of the oral, for giving those adequate trials. And as you can see, in the United States, among the first generation antipsychotics, we’ve got fluphenazine and haloperidol. Although outside the US, there are some other first generation long-acting injectables such as flupenthixol, perphenazine decanoate, pipotiazine and zuclopentixol that are available outside the United States.

Now, among the second generation antipsychotics which we do prefer generally for at least one, if not both of the two trials prior to clozapine, the ones that have long-acting injectables are risperidone, olanzapine, paliperidone and aripiprazole.

The first generation LAIs might be expected to cause more acute extrapyramidal symptoms, tardive dyskinesia and hyperprolactinemia symptoms compared to most second generation antipsychotics. It seems that the rate of movement disorders like tardive dyskinesia is similar with the long-acting injectables compared to the oral. So these are reasons to not particularly prefer them. Fluphenazine decanoate and haloperidol decanoate also have a higher rate of movement disorders than the other LAIs although they do have possibly lower risk of weight gain and lower cost in most places.

As far as risperidone, the first of the long-acting injectable second generation LAIs, they have lower risk of movement disorder. They do have increased risk of prolactin elevation compared to the other second generation antipsychotics. They do have a problem though with delayed release. It takes about three to six weeks. Some studies suggest it can be as long as six, although the package insert says that you should continue the oral for three weeks after starting the injections and you should be able to then remove it.  But some of the studies suggest that six weeks really would be better. That’s of course rather impractical for someone who’s an outpatient and who’s not adherent. How are they going to comply with the oral results continuing for those whole six weeks? And this may have something to do with the poor performance of risperidone Consta in the 2007 California Medicaid study.   You can and should supplement with oral risperidone and that may improve your results.

Paliperidone palmitate was the second one that became available. It does not require much oral supplementation. You only have to give it for a two-day period of either risperidone or paliperidone ER tablet just prior to starting the IM to demonstrate tolerability.

And the real advantage to paliperidone palmitate in being able to get it going right away, the usual process is to start with a 234 mg IM injection and then a week later, you can give the 156 mg dose and then continue, for the average patient, 156 every four weeks. So this gets them up to therapeutic concentration rapidly without the need for the oral supplementation.  Subsequent injections as I said would be every four weeks for the Sustenna version. But there’s also now a three-month formulation Invega Trinza which may be started after four months on the monthly paliperidone palmitate. And the usual dose of that is 546 mg every three months.

The next option is olanzapine pamoate.  It’s similar to oral olanzapine in both effectiveness and side effects. It does have a new side effect though that developed called post-injection delirium or sedation syndrome. This was seen in about 1.4% of patients treated. It’s due to occasional inadvertent injection going into a blood vessel and that is what can result in this experience of delirium or extreme sedation.  And because of this possible side effect, there’s a requirement that patients have to be observed in your office for three hours after each injection.  And you must have facilities for immediate transfer to hospital care if they should develop symptoms of the syndrome.  And the drug company in the United States only licenses certain clinics that can demonstrate that they have those abilities before they will allow the drug to be prescribed.  And these precautions certainly make olanzapine pamoate rather impractical.

Other clinical features can include sedation, confusion, dizziness, dysarthria, somnolence and as I said, there are even some cases of unconsciousness from the injections.

And finally, among the newer antipsychotics, we have aripiprazole which has now several forms. We have aripiprazole monohydrate. It goes by the brand name Abilify Maintena. And there’s another company making it, a very similar product called aripiprazole lauroxil which goes by the brand named Aristada. These long-acting injectables require two weeks of initial oral treatment. And then they also require oral supplementation like risperidone Consta does for three weeks. So it has those disadvantages.

It comes in the monthly version which is the Abilify Maintena 400 mg once a month. And the lauroxil version comes in three different dosaging. There’s a 441 to 882 mg once monthly version. There’s an 882 mg version that is every six weeks. And just recently, they marketed a 1064 mg injection which is good for two months.

And some barriers that are important to mention on the use of LAIs in general which is stigma and also cost. Most of these new ones cost more than $1000 a month, sometimes considerably more than that US dollars.

So again, to repeat the key points about the long-acting injectables, the LAIs, fluphenazine decanoate and haloperidol decanoate have higher rates of movement problems, lower risk of weight gain and lower costs. Olanzapine pamoate requires patients to get the special observation for three hours making use impractical.  And aripiprazole and risperidone LAIs require oral supplementation but paliperidone does not. And overall, we think perhaps the most critical and important use is to enable really good adequate trials early in the course of schizophrenia so you can be firm in your conclusion that the patient is suboptimally responsive to these kinds of agent and should be a candidate for clozapine.


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