Researchers Debate Benefits of Long-Acting Injectable Antipsychotics

Researchers critique an analysis in Lancet Psychiatry that included poorly designed studies and was written by pharma-employed authors.

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An ongoing correspondence between researchers explores the benefits and harms of long-acting injectable antipsychotics (LAIs) for schizophrenia. A recent systematic review in Lancet Psychiatry, led by researcher Taishiro Kishimoto of Keio University, concluded that compared to oral antipsychotics, LAIs were superior in avoiding hospitalization or relapse. Other researchers, led by Lisa Cosgrove of the University of Massachusetts, Boston, have challenged these claims, citing concerns about poorly designed studies and industry influence.

LAIs are drugs that are administered through injections and can stay into one’s system for up to four weeks. Advocates for their use often note that they help with drug adherence among patients, especially since patients on antipsychotics tend to discontinue. This is unsurprising, since the largest survey of antipsychotics users to date found that the majority of patients reported negative experiences. These patients are often called forgetful, non-adherent, or treatment resistant.

Photo of medicine vials and syringe

Stigmatizing laws, such as the RESPONSE act, that equate mass violence with mental health issues also condone the forced use of LAIs. This is despite past research repeatedly finding that LAIs such as risperidone and aripiprazole were no more effective than oral antipsychotics in reducing discontinuation. Patients cited adverse effects and non-efficacy as reasons of discontinuation. Another study similarly found that LAIs increased the cost significantly but did not provide additional benefits. One LAI was initially implicated in patient deaths but the FDA found evidence to be inconclusive.

In the original article, Kishimoto and colleagues reviewed 137 studies, which included randomized controlled trials, cohort studies, and pre-post studies. They concluded:

“LAIs were associated with a lower risk of hospitalisation or relapse than oral antipsychotics in each of the three study designs… In all other outcomes related to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, LAIs were more beneficial than oral antipsychotics in 60 (18.3%) of 328 comparisons, not different in 252 (76.8%) comparisons, and less beneficial in 16 (4.9%) comparisons.”

Cosgrove and her colleagues have challenged these findings in a response in Lancet Psychiatry, noting that the benefits of LAIs have been overestimated. They cite industry influence as playing a major role in this.

Their first concern is that Kishimoto and others have several commercial ties with pharmaceutical companies, especially those that make LAIs—one author on the analysis was an employee, while two others were stakeholders. These conflicts of interest can work in numerous and subtle ways to influence interpretations and conclusions. They can also influence how these drugs are promoted.

Their second criticism is about the quality of studies which were included. While randomized controlled trials (RCTs) are often touted as the gold standard, in this review, only 6 of the 32 included RCTs were adequately randomized. Allocation of concealment was assured for only 5 out of the 32 RCTs. (Allocation of concealment prevents researchers from unconsciously or consciously influencing who is assigned to treatment versus control groups.)

The authors write:

“Many rules of evidence synthesis to identify and minimise bias were not observed, studies with too weak of a design to accurately assess comparative efficacy were included, and treatment harms were not adequately considered.”

It was the weakest type of study, the pre-post method, that produced the best results in favor of LAIs. Additionally, while the appendix reported that in RCTs, LAIs had a worse adverse effect profile than oral antipsychotics, this fact did not feature in the authors’ conclusion and interpretation.

The next set of problems comes from the numbers needed to treat (NNT) statistic. For any treatment, NNT is the number of patients who need to be treated in order for one patient to benefit. For example, when it comes to psychiatric drugs like antidepressants, the NNT according to one review is seven (seven patients need to be given antidepressants for one to show any benefit). Cosgrove and colleagues note that in the RCTs for LAIs, the upper limit of the confidence interval for NNTs was 540, which means up to 539 people might experience no benefits from LAIs (when compared to oral antipsychotics) for every one person who does benefit from LAIs.

They conclude that given these formidable criticisms, the benefits of LAIs over oral antipsychotics might be modest, if any at all. Most importantly, they note that no patient-centered outcome measures were a part of this review. In other words, what patients felt helped or harmed them was ignored.

Kishimoto and colleagues responded to these criticisms by agreeing that poor masking of patients made many included RCTs poor in quality. But they noted that LAIs were better than oral antipsychotics in cohort studies. According to them, in these studies, patients with more severe conditions (non-adherent, chronically unwell) were given LAIs rather than oral antipsychotics. Thus, they assert that while cohort studies might be of lower quality, the fact that LAIs performed much better than oral antipsychotics, despite being given to patients who were severely unwell, points to their superiority.

They further write that when it comes to adverse effects of LAIs versus oral drugs, another bias that needs to be sorted is that the drugs given in different forms are often themselves different. In other words, the difference found could be based on the differences in the type of antipsychotic rather than the way it was administered. This can confound comparisons.

They further write that of the 112 comparisons only 10 indicated larger risks for LAIs when compared to oral administration. However, Cosgrove and her colleagues had specifically pointed to worse adverse reaction profiles seen in RCTs, which is important because they are considered higher quality than the other research designs. Kishimoto and colleagues did not respond to the specific adverse reactions seen in RCTs.

They end by agreeing that patient-centered outcomes are an essential part of measuring whether a treatment is effective. Given that other meta-analyses and reviews have found antipsychotics to be minimally effective in reducing symptoms for chronic patients, the fact that patient voice is missing from these reviews is of grave consequence. These criticisms must be seen in light of earlier research which finds that LAIs are twice as likely to be used for patients of color than white patients.

 

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Kishimoto T, Hagi K, Kurokawa S, Kane JM, Correll CU. Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies. Lancet Psychiatry 2021; 8: 387–404. (Link)

Cosgrove L, Mintzes B, Bursztajn HJ, Shaughnessy AF. Long-acting antipsychotics: is what we know really so? Lancet Psychiatry 2021; 8: 651. (Link)

Kishimoto T, Hagi K, Kurokawa S, Kane JM, Correll CU. Long-acting antipsychotics: is what we know really so? – Authors’ reply. Lancet Psychiatry 2021; 8: 651. (Link)

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Ayurdhi Dhar, PhD
MIA Research News Team: Ayurdhi Dhar is assistant professor of psychology at Mount Mary University. She is the author of Madness and Subjectivity: A Cross-Cultural Examination of Psychosis in the West and India (to be released in September 2019). Her research interests include the relation between schizophrenia and immigration, discursive practices sustaining the concept of mental illness, and critiques of acontextual and ahistorical forms of knowledge.

26 COMMENTS

  1. The title of this article leads off with “Researchers Debate Benefits of Long-Acting Injectable Antipsychotics” in this business of knowledge production for the benefit of whom? One in reading this title could imagine that the field of medicine has miniaturized the debate of law to be injected into the human. And left to the movement of scales and the war within, that somehow through sheer perseverance the human finds a way forward to pursue happiness.

    But in the language of business of this one life, what were, are and will the language of costs be understood from the customer’s perspective. Opportunity costs lost due to confinement, experiences created in response to the outside world meeting the interior of thinking that is akin more to a circus?

    To try to realize the space of healing/calming where the customer gains insights into the uniqueness of his/her self, that if honest, is open to life long learning, that in itself, might be a better path forward. To understand the war for monetization of “health care” now in the crisis field of public health, seemingly will require the emergence of thinkers who understand the importance of calling out, to bare witness to the conditions that are destroying lives rather than fostering the space to learn who I/We are.

    There seems to be in the short term an absence of how to even frame experiments whose answers being sought after may well emerge through the Arts from the long term perspective. And the engineering of the technologies, to capture/generate the data is a step behind and below the joy of creating one’s way forward into the aura and comprehension for a universal truths.

    • Yes, I’m quite certain the debate is about the wrong thing. The debate should be about whether it should be legal to prescribe any form of antipsychotics at all.

      Especially given the fact that the patients already know the antipsychotics can create psychosis and hallucinations – positive symptoms of “schizophrenia” – via ‘anticholinergic toxidrome.’ Plus we know the antipsychotics / neuroleptics can create the negative symptoms of “schizophrenia,” via ‘neuroleptic induced deficit syndrome.’ Plus we know that withdrawal from the antipsychotics can create a drug withdrawal induced ‘super sensitivity manic psychosis.’

      Information which points to the fact that it should be made illegal to prescribe the antipsychotics all together.

  2. The point is this: anti-psychotics like all other classes of psychiatric drugs cause brain damage just as much as the psychadelics like LSD. They are also addictive like the opiates and nicotine; in fact the benzos may be the most addictive drug on the planet. The question, yes, should be how to we make these illegal without causing any more pain than they already have? The other question is why are we trying not to just decriminilize marijuana, but legalize it, when it has many of the same effects as the still legal psychiatric drugs. If a drug is prescribed for an alleged mental class as loosely, falsely and unscientifically defined by the DSM, I would say the goal of all governmental entities is to make it illegal. This would save so many lives, increase our productivity, makes us more economically prosperous and on the whole makes a healthier, happier population. But, that could be too much for some….Huh?….Thank you.

    • I’m not sure that psychedelics actually do cause brain damage; stories about people going on a bad acid trip and never “coming back” from what I’ve read turned out to be largely myths created by the media, similar to things like “reefer madness” and the putative crack baby epidemic (which never actually occurred).

      P.S. I don’t use any mood-altering drugs myself, so I’m not trying to defend their recreational use for personal reasons.

        • Perhaps (although if we believe in neuroplasticity it’s important to clarify whether we’re talking about permanent non-reversible changes or not) I was just addressing the perception that things like LSD (which I thought the OP was implying) are so dangerous that often lead to psychotic breaks in their users (they don’t, like probably all illegal drugs their image has been crafted deliberately with heavy doses [no pun intended] of fear-based hysteria).

      • My friend who tried to walk through walls after taking a psychadelic drug was no myth. “Reefer Madness” became a cult classic, but we are finding that marijuana is not kind to the brain either and can be addictive. And babies have been unfortunately born addicted to both “crack” and the “opiates” among other drugs that the media probably denies or keeps secret. These drugs along with the psychiatric drugs so popularly prescribed are very dangerous to the brain. Drugs like adderall and ritalin are related to diet drugs which are related to drugs like “crack.” If there is one thing the media has done is to under-report the damage these drugs—-all these drugs have done to individuals and to society. Of all the scourges foisted on humanity, drugs that impact the brain, have caused the most damage individually and society-wise than almost any other thing. Until we rid humanity of these drugs, both the psychiatrically prescibed drugs, the “psychadelic” drugs and all other drugs discussed here and even drugs not mentioned, humanity will only suffer needlessly and risk extinction unlike the dinosaurs of the past. These drugs—all these drugs— can be said to be humanity’s true deadly asteroid. Thank you.

        • Your friend hurting himself is not a myth but it is anecdote (meaning not generalizable).

          And addiction is not even the paradigm that should be discussed as it is not the physical properties of the drugs themselves that matters most contrary to popular belief (e.g., the many thousands of American soldiers who returned from Vietnam hooked on opiates who simply stopped when they returned; the issue is dependence which is slightly different). Another example is that the studies on crack babies did not disaggregate other factors which had greater explanatory power, for example the fact that pregnant women who smoked also had poor nutrition, didn’t go to prenatal counseling, etc.

          Marijuana may indeed be damaging but it’s *how* someone uses drugs that determines their harmfulness, same as eating white bread or overexercising.

          (I agree that the media has downplayed the dangerousness of certain drugs but those tend to be the legal ones, not the criminalized ones such as psychedelics [whose danger is usually exaggerated]. Plus when you talk about “ridding the world of drugs” in practice that can mean getting rid of the people who use or sell them, in which the cure can be worse than the disease [in the Phillipines nowadays for example people sometimes kill people they don’t like and then claim they were a drug dealer]. For the record I don’t even drink caffeinated coffee.)

          • Yes, the story of my friend can be described as an anecdote? Does that make it invaluble information? Hardly! The stories we read on this site from psychiatric survivors are just that anecdotes! Anecdotal information is, in my opinion, and probably the opinions of others, far better than scientific statistical information. As far as “dependence” versus “addiction” the only difference that could be applied is that in “addiction” you need increasing quantities of the item, while in “dependence” you usually do not. However, in modern society, we do throw these words around like candy and popcorn and thus they can meaningless. But the suffering is not. As far as other factors as causal in any issue that is also questionable, because when you deal with any “human subject” the ability to screen out any and all variables is an impossibility, which does, don’t you think may anecdotal information far superior to experimental information. The other problem with experiments is the effect of the experimenter upon the outcome of the experiment which is rarely ever discussed, but the effect is always there. Finally, as far as the men and women returning from Vietnam and their opiate use and how they were able to get off the opiates upon their return, I can not state. Sadly, the one person whom I could verify this with is no longer here; that would be my Father, a decorated Vietnam Veteran who passed away in Veteran’s Hospital several years ago partly from being subjected to Agent Orange. Yes, I am for the idea that all these drugs should be illegal. These drugs all deal with the human brain and seek to create different effects through rearrangement of the chemicals, wiring, etc. in the brain. This is beyond dangerous. It is very damaging and it can be deadly. Much suffering has been caused by these drugs. And they affect society in dangerous and damaging ways, also. I appreciate what you say in your comment, but, I can not morally agree with you. Thank you.

  3. The reason for injectable neuroleptics is to force/coerce people to take them. That was their stated purpose, to make people comply. Someone given oral drugs can choose to not take the drugs themselves. Someone being injected can’t without having to beg their drug dealer to let them.

    Everyone knows psych drug dealers can forcibly jail and drug people with no accountability. There is no consent when force and punishment are used and the person is injected by those make the threats and dishing out the punishments. Abusers use this tactic a lot “well the person I’ve been abusing didn’t tell me to go to hell while I was threatening them with overwhelming power so they consented.”

    • As I’ve stated before, the whole idea of “shared decision making” suggests that the CURRENT model is “non-shared decision making,” which equates to THE DOCTOR GETS TO DECIDE! In other words, “Shared decision making” means the DOCTOR deigns to “allow” the patient to “have a voice” in deciding what will happen to his/her OWN BODY! Something is VERY wrong with this whole idea!

  4. (Responding to rebel above, no reply box for some reason):

    I’m not saying that anecdotes have no values, but they’re not the best way to understand issues collectively. Yes if thousands of people come out of the woodwork with personal stories that challenge the conventional narrative then it needs to be reexamined but by and large the epidemic of people deranged by psychedelics never took place (and it’s not done by experiments, no one gave LSD to participants and then calculated how many of them went crazy; it’s done by analyzing data on emergency room admissions correlated with the drug that caused the crisis; yes it’s imperfect like all statistics are but that’s how it’s done to get the bigger picture and not just listen to personal stories–people can have just as strong biases on their own, for example after completed suicides where the physical evidence is incontrovertible those around the deceased will insist they had not been suicidal, generally to assuage their own potential guilt).

    (The story about returning Vietnam vets is well-known; any modern textbook on drug abuse will describe how branches of the American government were terrified of armies of heroin-addicted vets roaming the streets of American cities but it never happened, something that the disease model of addiction cannot explain.)

    And *everything* affects the brain, including all positive (and negative) life experiences. Caffeine is the most widely-used drug in the world (half of all adults on the planet use it daily iirc) and is addictive, do you propose banning that as well because it changes the brain? (The brain is much more “plastic” than previously thought in any case).

    The damage done by the so-called war on drugs is just as real, probably more so (especially for communities of color which have been systematically targeted by law enforcement despite having lower rates of drug use than the white majority) than the problems wrought by addiction/dependence (many of which are the by-product of criminalization and/or social/economic factors, not the substances themselves).

    • The biggest problem, unfortunately, with your response is the word, “collectively.” This word connotes images of communism and robotism. It is a very tragic word, very unAmerican and unFreedom. It is also a word of elite academia that disregards the common man and woman. Anecdotal information works because it is concerned with each unique person on an individual level. The problem with our healthcare system, our educational system, our governmental system and most other systems is their emphasis not on the individual but on some aggregate, or statistical average or some sort of easily made deceptive statistic. Drugs are dangerous. And, it is my contention that drugs are probably the root cause of much what ails us both individually and as a society and culture. The drugs strip away who we are individually and as a society and culture. Perhaps, that is their job to confuse, confound, damage, and strip away who we are to make us docile little creatures and take our humanity and our God-given talents, skills, and character, etc. As long as we have these drugs available either legally or illegally, we will suffer. Our first goal in this society is to make taking drugs so aborrent that no would want to take them. Right now, we have a drug culture; pop a pill and all of life’s problem will simply go away. It’s that simple. DRUGS ARE KILLING US! And, it is not climate change or anything else that jeopardizes our survival as a species, and risks our possible extinction, but drugs! As soon as we awaken to this real truth and fact, life on this planet will visibly improve. Thank you.

      • Just use the word “sociologically” or something else than, it’s really not that important.

        And why do you still think the drugs themselves are still the problem? It’s people’s relationship to them, and what drives them to use in the first place, that counts no matter how much you demonize the external object.

        • Sociology is just another pitiful subject like psychiatry/psychology. As long as we continue to blame the individual in regards to drugs, we lose; because we will be unable to place the blame where it truly exists, the makers and the pushers of these drugs, whether in psychiatrist’s offices and other doctor’s offices or whether from “drug pushers” on the streets of America and the world. These “drug pushers” of both legal and illegal drugs only take advantage of the vulnerablities of the individual and use various brainwashing techniques to convince the person that the answer to their problems lies within a “pill” and if you take this “little pill” all will be wonderful. These lies endanger humanity. The first step to get rid of these lies is to end psychiatry and stop the drug flow from all sources. This is so patently obvious that although I do honor disagreement and questioning can not see how anyone can not see this. We have known this for many millenia. Many great authors and thinkers have seen this too. Perhaps, we are too afraid to implement measures to stop this. The very first thing we must do is to de-emphasize the drug culture in which we live. We must assist others in realizing that pills are not the answer and help people learn to value their unique God-given gifts and talents, etc. So many people feel their unique God-given gifts and talents are useless and then they are prey to this drug world. There is no other way. We must stop this drug culture now. Thank you.

  5. Again it’s just a word (“sociologically”) and doesn’t need to be read into too much (the very basis of sociology as a discipline, by the way, is *not* looking at issues through an individualized lens).

    I agree that Western society is over-medicated but saying that the flow of all drugs needs to be stopped absolutely to me sounds like when people say that religion is the scourge of humanity and needs to be eliminated which in practice means imprisoning, torturing and/or killing believers (so that the cure becomes worse than the disease).

    • The issue, in drugs, is that the “cure is worse than the disease.” Yes, it would benefit humanity to eradicate many of the drugs, if not, eventually, all. There are much better, more natural ways to treat our illnesses than drugs. And much of the time, we are treating non-existent illnesses that we, humans created mainly just to create a market for these drugs. Psychiatric drugs are the prime example. The main thing is when we need to work first to eradicating this drug culture. We, humans, can not continue thinking a little pill can cure all. Probably all drugs do have a tendency for either dependency or addiction and the difference between difference and addcition could very well be jsut splitting hairs. Like I said, the main thing we have in the US and in the world, now is a DRUG CULTURE and it is dangerous to our very survival. It fuels violence and unnecessary illnesses and suffering. We need to re-educate ourselves and our children that drugs are not the cure, but are worse than the disease. We need to step up our law enforcement in many areas and there are many drugs that need to be banned and/or made illegal. We need to not decriminalize or legalize drugs such as marijuana. We need stricter controls on medical doctors so that they just don’t write a prescription like they’re making a candy recipe. Drugs are killing us. Ending psychiatry would help too. Yes, the cure is worse than the disease and right now we consider drugs the cure. We need to stop the cure and the drug flow now! Thank you.

      • Well the cure I was referring to in this case was getting rid of all drugs (presumably apart from those with a clear medical purpose), not using psychotropic drugs to “treat” human misery.

        I am no fan of the expansive long-term use of psychotropics but the decades-long radical failure of the so-called war on (recreational) drugs has created far more problems than it has solved in my opinion. Perhaps prescribing of legalized drugs needs to be made much more restrictive, but (for now) trying to simply ban them runs the risk of creating resistance and kickback (not to mention accusations of Scientology).

        If you feel that the culture is the problem, as you indicate, I think you need to offer something more nuanced than simply an outright ban–such approaches throughout history have generally failed and/or created problems of their own (e.g., the rise of organized crime during Prohibition).

  6. My son was given a long-acting intramuscular shot of Invega Sustenna several years ago. Within days he was desperate to find an antidote (which of course is impossible).

    He was bedridden for months, and applied for disability, which was eventually approved. He kept asking me to go on line and find out if anyone ever recovers from the shot. What I found on line was depressing and surprisingly common.

    I found a website called bluelight . org, a web forum which focuses on harm reduction of drug use. One of the longest running, most active discussions was about Invega Sustenna. The misery and despondency of the posters was depressing to read.

    I am mystified how such a dangerous medication could ever be approved.

  7. I attempted Suicide several times on Long Acting Injections but I had never attempted Suicide when off Long Acting Injections (either before going on them or after coming off them).

    I also made Full Recovery in 1984 as a result of responsibly coming permanently off LAI s – and eventually ALL medications suitable for “Schizophrenia”( – with the help of practical ‘psychotherapy’).

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