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June 28, 2019 by Sandra Steingard, MD

A Guide to Long-Acting Neuroleptics: Education or Promotion?

Several weeks ago, I received a number of emails notifying me of a new pamphlet released by the National Council for Behavioral Health titled “Guide to Long-Acting Medications for Providers and Organizations.”

The pamphlet begins:

“This Guide to Long-acting Medications (LAMs) is a Call to Action for psychiatrists, other clinicians and behavioral health organizations to increase the use of LAMs.” It goes on to suggest that psychiatrists and their organizations (which comprise the membership of the National Council) rally resources to make these drugs more readily available as “first-line treatment.”

The authors opine upon “What Science Tells Us,” namely, that “there is enough science to demonstrate the degradational effects on brain tissue of each psychotic episode.” Moreover, we are informed that — when started early — the neuroleptic drugs will “avert progressive neurodegeneration and subsequent disability.”

The pamphlet is designed as a public health promotion with this message: If we can stop the progression of schizophrenia, we will improve long-term outcomes. This is purported to be based on science.

I would argue that if one follows the science, one might support instances in which long-acting drugs are useful but not necessarily to the extent suggested in this pamphlet. In addition, one would not promote the newer drugs as first-line treatments.

By downplaying some aspects of the available science, the pamphlet implicitly is acting as a promotional tool for the pharmaceutical industry. Furthermore, this pamphlet serves as an example of why simple disclosures of conflict do not adequately address deeper issues of bias and influence in our field.

While the authors correctly state that this was not funded by pharmaceutical companies, it is nevertheless influenced by their interests via the incursion of commercial interests into academia over the past few decades.

Some history

Long-acting neuroleptics are drugs, in this case given by injection, that remain in one’s system for up to 4 weeks. This allows a person to avoid taking a pill daily. This type of drug is not new. Fluphenazine decanoate (a form of the drug initially branded as Prolixin) was approved in 1966. It was developed as a response to the observation that while many people seemed to improve when given the drug in the hospital, their problems returned after discharge.

This was thought to be due to poor adherence; long-acting injections were hypothesized to improve adherence and, therefore, outcome. It was thought this would be especially helpful in the outpatient clinics where those discharged from hospitals were to be treated. Haloperidol decanaote — which has an advantage over fluphenazine in that it can be given every 4 rather than every 2 weeks — was approved around 1990.

When the newer drugs — risperidone, olanzapine, aripiprazole, among others — were introduced, many clinicians waited eagerly for these drugs to be available in long-acting forms. CONSTA — long-acting risperidone — was not introduced to the market until 2009, about fifteen years after the release of Risperdal (risperidone). We now have long-acting forms of several “newer” neuroleptics.

The long-acting formulations were approved as the short-acting versions were going off patent. Although there are still some new short-acting neuroleptics on patent, long-acting neuroleptics comprise a significant share of the patented neuroleptic drugs marketed today. This is obvious when you look at any journal or online site that accepts pharmaceutical advertising; this group of drugs is highly promoted.

But we know what happened after fluphenazine decanoate was marketed. We continued to observe the “revolving door” where people discharged from the hospital frequently returned. While there are deep disagreements over how to fix the community mental health system, it seems clear that long-acting neuroleptic drugs did not offer the kind of benefits that were anticipated in the 1960s.

Contrary to popular belief, there is a lack of evidence in support of the core hypothesis that these drugs improve adherence (Leucht 2011).  Since improved adherence is presumed to be the mechanism by which they improve outcome, this raises a serious challenge to the advantages of these drugs. In 2015, Castillo and Stroup published a paper in Evidence Based Mental Health reviewing this topic. They admit “the evidence [in favor of long-acting formulations] is conflicted and weaker than expected.”

Of note, they point out that there does not seem to be any advantage for the newer rather than the older drugs. So while the National Council pamphlet promotes “What the Science Tells Us,” the authors appear selective in what they seem to hear.

However, there is a broader implication of this kind of pamphlet that goes beyond my arriving at different conclusions regarding the role of long-acting neuroleptics in clinical treatment.

In Psychiatry Under the Influence, Cosgrove and Whitaker offered a model, called economies of influence, for understanding the complex forces that might lead academic and guild institutions of psychiatry to act in ways that are not consistent with their stated missions. I believe those influences are at play here.

To make this point, I will stipulate that improved adherence is an advantage for at least some people. I suggest, however, that the science would lead us to conclude that the advantage rests with haloperidol decanoate rather than the newer drugs.

While the pamphlet does not discourage the use of haloperidol and appears to be neutral on this topic, there is a failure to address the underlying structural reasons why far more people will be prescribed the newer long-acting drugs rather than haloperidol. This constitutes an implicit promotion of the newer, patented drugs.

While this position may seem inconsequential to those who do not like the use of neuroleptics in any setting regardless of formulation, for me, this is important. It addresses deep structural problems in psychiatry (and medicine) and the influences that have distorted clinical practice.

Moreover, the pamphlet promotes shared decision making (SDM) which encourages a process in which a person is “empowered to make decisions about their care and experience the clinician as a recovery partner.” I do not believe SDM can occur when the biases of the clinicians are unacknowledged.

More history

In the 1990s and early 2000s, a number of new antipsychotic drugs were introduced and highly promoted. They quickly became first-line treatments based on the belief that they had fewer side effects. The marketing of this era is what led me down the path towards critical psychiatry.

It was clear to me that the promotion did not match the data. For instance, the main finding of the premarketing studies that led to their approval was that the new drugs caused fewer parkinsonism symptoms than the older ones. However, in these early studies, the drugs were compared to haloperidol prescribed in very high doses.

There were other claims that the newer drugs had benefits for cognitive problems and motivation but these claims were both generally lacking substantial evidentiary support and, to the extent there was support, likely secondary to the very high doses of haloperidol used in the studies (high doses of haloperidol would be expected to cause cognitive problems and apathy so the newer drugs would appear to be better by comparison).

The effects the newer drugs had on weight gain were obvious to me after a few years and are now widely recognized but these effects were downplayed in academic and marketing circles for many years. In fact, what was disconcerting is that the separation between marketing and academia became so small as to be undetectable.

This was a general phenomenon in that era. New drugs were presented as “breakthrough” medications with claims of greater efficacy than older ones. Over time, there were expanded indications — either by identifying new disorders for which they are effective or by expanding the boundaries of the initial target condition.

In later years — often coincident with the drugs no longer having patent protection — there is a retrenchment; the drugs are found to be not as effective as initially thought. Problems with the drugs gain wider attention. By that point, however, the drugs are entrenched in clinical practice. Despite emerging evidence questioning their efficacy and highlighting worrisome side effects, they continue to be widely prescribed.

All of this happened with the neuroleptics. In 2005, a study funded by National Institute for Mental Health was published. Called the CATIE study, it compared most of the newer neuroleptics to perphenazine, an older drug. It found no advantage for the newer drugs. However, clinical practice changes slowly or promotion is hard to ignore; by the time CATIE was published, the older drugs were rarely used as first-line treatment. This has not changed.

Before it was approved, when risperidone was tested against haloperidol, various doses of risperidone were compared to 20 mg of haloperidol. Risperidone is now considered to be dose equivalent to haloperidol. In the initial studies, researchers concluded that 6 mg of risperidone was optimal but over time, average doses of risperidone used in clinical practice more commonly range from 2-4 mg.

In the late 1980s, I participated in a study examining optimal doses of haloperidol. The study found that on average 3.5 mg was as effective as higher doses; the higher doses only produced more neurologic symptoms but conferred no clinical advantage. Many of the worst problems associated with haloperidol are moderated by dose — parkinsonism, tardive dyskinesia. If used in low doses, a strong argument could be made that it has less toxicity — particularly with regard to obesity and metabolic problems — than the newer drugs.

Aside from cost, there is another technical advantage to haloperidol decanoate. One of the recommendations of the pamphlet is to “start low and go slow.” This is possible with haloperidol but not with the newer drugs. Haloperidol can be dosed with infinite flexibility. The newer drugs come in fixed doses and reducing to very low doses is impossible. In addition, the manufacturers of the new drugs suggest starting with loading doses. There are essentially no guidelines available for starting low and going slow with these drugs.

By not directly addressing the pros and cons of the various long-acting drugs available, the pamphlet implicitly endorses the newer drugs. This is why: since one needs to first try the short-acting version before taking the long-acting one and since many more people are treated initially with either risperidone or aripiprazole than with haloperidol, it stands to reason that the newer forms of the long-acting drugs will be prescribed far more often than haloperidol. In fact, the pamphlet implicitly acknowledges this.

There is the suggestion that doctors tell patients that “this form of medication ‘is more expensive for Medicaid/Medicare/insurer but you deserve the best treatment available and we will work hard to get it for you.’”

Economies of  influence seem to manifest in this pamphlet. While not being funded directly by the pharmaceutical companies, the pamphlet quotes psychiatrists who have major ties to them. National Council receives at least indirect support from the pharmaceutical companies; their ads adorned the halls at the recent national meeting.

The pamphlet suggests that educational material created by the companies that make the drugs are offered to patients to enhance the decision making process. The pamphlet also suggests a specific name change for this group of drugs.

The authors suggest that one “Use language that is less frightening and stigmatizing such as long-acting medications rather than ‘the IM,’ long-acting injectables or ‘the needle.’”  I wonder to what extent this is done for the comfort of the patient and to what extent this is done for the comfort of the clinician. I find it hard to believe that this language switch did not originate with a marketing executive.

Finally, there is the promotion of these drugs as a first-line treatment for individuals who have experienced a first episode of psychosis. This constitutes a major expansion for the use of these drugs. The pamphlet cites the science but again it appears there is, at least to some degree, a conflation with improved adherence and improved outcome.

The Castillo and Stroup article, which is overall restrained in its discussion of the advantages of these drugs, does suggest their use in those with recent onset schizophrenia. However, in their conclusion, they point out the disadvantages of the newer drugs for reasons I mentioned above: “we caution that this [new onset psychosis] is also a time to use medications judiciously . . . as dosages of LAI antipsychotics are not immediately changeable, they are less convenient.”

Oddly, despite this article making it clear that there is little evidence suggesting the newer drugs have any advantages over the older ones, the authors fail to point out that haloperidol does allow for flexible dosing.

How could my colleagues do a better job of addressing these problems?

An immediate answer would be that my colleagues would need to share my concerns about the nature of the problem. I suspect there will be some disagreement.

But while the National Council might contend that their pamphlet does not promote any particular drug or group of drugs, I would argue that by not acknowledging some of the biases present in the field — particularly the bias to use the newer drugs as first-line treatments — they are indirectly aligning themselves with the interests of the drug companies.

To be clear, while I am addressing these issues with one particular pamphlet, I am using this as an example. I receive emails frequently from various sources that contain this kind of information. It is a low-level drum beat of marketing dressed as education that has an insidious effect on clinical practice. As with this pamphlet, this kind of promotion is no longer just addressed to clinicians — it goes to organizations that have influences as well as various advocacy groups.

My profession has an obligation to address this directly. Ignoring the problem implicitly favors practice as usual which is a practice that favors the financial interests of the pharmaceutical companies over the interests of our patients. Those interests will hopefully align at times but, given their vast influence, we need to be proactive, cautious, and vigilant.

It seems that is the only way we can we have any credibility as being true partners in the sort of shared decision making process that the National Council and many other well-intentioned organizations profess to support.

Source: MadInAmerica.com/2019/06/guide-long-acting-neuroleptics/

2 thoughts on “A Guide to Long-Acting Neuroleptics: Education or Promotion?

  1. Pablo Sadler says:

    Thanks Sandy for your detailed analysis of this piece of advertisement masked as science. Given that the “new” LAIs cost around 100 times more than haloperidol or fluphenazine IM you would expect some evidence that justifies the expense. I couldn’t find any head-to-head comparison study between “old” and “new” LAI, would you direct me to any study addressing the issue?
    Thanks again,
    Pablo

  2. Sandra Steingard says:

    Thanks, Pablo. I do not believe there are head to head studies of the new vs old LAIs. It is rarely even addressed and much of what is circulating is written by authors heavily engaged in pharma-sponsored research. After I wrote this blog, someone forwarded me an announcement of a pharma on line training that includes as a discussing the recently retired NatCon CEO.

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