Do AntiPsychotics Work? A Look At Scientific Research

Being a Psychiatrist you may assume I am naturally going to be biased favorably. However, you may be surprised to learn that is not always the case. A Meta-Analysis published in Molecular Psychiatry took a very thorough look at this matter and here I am presenting a quick critical review of this study [1] and its findings.

The main author of this study is Stefan Leuchat who is a Professor at the Psychiatry & Psychotherapy Department, Technical University of Munich, Germany. All the other study authors are also German based except one JM Davis who is based in Chicago, IL, USA.
Conflicts of Interest

As an overview, it seems their university department is both Psychiatry and Psychotherapy oriented, which should bridge some gaps (hopefully) between the two approaches.

The authors also explicitly state that this meta-analysis did not receive any funding. However,  Stefan
Leucht has received speaker or consultancy honoraria (meaning being paid to speak or consult) from Sanofi-Aventis, BMS, Lilly, Janssen, Lundbeck and Pfizer. And that Lilly and Sanofi-Aventis sponsored some research projects done by Dr. Leucht. Another author Werner Kissling has also received speaker and consultancy honoraria from many of these ‘Big Pharma‘ corporations.

Background

Some critics and recent scientific studies have challenged the usefulness of medications used by Psychiatrists. One of the studies found that anti-dementia drugs are not significantly effective and in fact, cause side effects and result in costs to the system as well as suffering for the patients [2].

Another one challenged the usefulness of Anti-depressants finding that they only made a very small difference to the symptoms as compared to a placebo [3].

In this context the authors conducted this meta-analysis to find out if Antipsychotics were useful.

Study Design and Method

The breadth and depth of their search for relevant studies seems to be impressive and done thoroughly. The authors mainly used a large database that indexes studies from multiple other databases in English and other languages, it also catalogs an extensive amount of gray literature. This database is maintained by the Cochrane Schizophrenia Group.

They do try to stick to quality studies by having robust inclusion criteriums i.e. only Randomised Placebo Controlled studies were included which met certain quality criteria. They also did some sensitivity analyses to check for the robustness of the results.

One cannot fault the method and statistical analysis used much. Except it is unclear how they ended up with the 38 studies (that they analyzed) as it seems they had numerous citations after running the searches. But they then go on to say “Of those publications that we ordered for inspection..” yet it unclear how they decided on which ones to order for inspection, they ended up excluding 107 (for design issues) even from those they ordered for inspection.

Interestingly all the final studies were conducted by (you guessed it) pharmaceutical companies.

There are some very interesting Results:

Meta-regression of antipsychotic effect size
Figure 4. Meta-regression on the effects of publication year on the effect size for the difference between second-generation antipsychotic (SGA) drugs and placebo on the reduction of overall symptoms. Slope = 0.02, Q = 6.83, d.f. = 1, P = 0.0090. Circle size reflects the weight a study. [Used under fair use provisions]
This graph is the most interesting result for me. As you can see it appears the size of effect Antipsychotics (newer) seem to have on reducing the symptoms of psychosis as compared to a placebo (i.e. fake drug) has been constantly reducing with time. In  around1983 a small study showed an enormous difference in effect size of >-1.6 (0.8 is considered to be large), whereas in 2007 a large study is showing the difference of effect size to be merely -0.2. This is a huge difference and the trend is statistically significant as well.

So how do we account for this result?

The author’s do not appear to give any satisfactory explanation for these results. They note that the placebo response rate seems to be high and also that a large number of dropouts (around 47%) overall in the studies suggests any difference that might have been observed is reduced.

However being more cynical we need to stop and consider several other possibilities here:

  • How much of these ‘scientific’ results have been influenced by the money politics of big pharma?
  • If placebos can also substantially treat psychosis then whats the use of antipsychotics, especially when the difference between them seems to be ever decreasing?
  • How does this then reflect on all the other schizophrenia research being conducted? where dopamine overactivity is the most favorable hypothesis so far (yet anti-dopamine drugs i.e. antipsychotics seem to work less and less now)
There is also significant publication bias:

Antipsychotic publication bias
Figure 3. Funnel plot Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) total score. Egger’s regression intercept suggested statistically significant asymmetry (d.f. = 33, P < 0.001). [Used under fair use provisions]
As you can see there seem to be a few lower quality studies (i.e. with a higher standard error) with positive results. However studies which should be expected within the red circle are missing. Studies with a higher standard error should naturally have a wider variation in results so one would statistically expect there to be negative studies as well (i.e. within the red circle), yet they seem to be missing.

This is interesting because most of the studies that were published were done by pharmaceutical companies, from there we can only assume they likely did not publish the negative ones. The authors, although agree that there is a significant publication bias and agree with the above possibility, they also suggest that it could likely be due to the heterogeneous nature of the sample studies.

So do Antipsychotics work?

Having considered the above we still need to be cautious in making premature judgments. The pooled size of the effect for antipsychotics seems to be -0.51, meaning it’s a moderate effect. This is equivalent to a minimally visible difference between two things when seen by the naked eye. The caveat here is the trend of a decreasing effect. Another caveat is that the effect size for even a fake drug is substantial in comparison and in fact, the difference in effect between the two only amounts to 18%. This means 6 people will need to be treated for 1 more person to benefit on an antipsychotic as compared to a placebo drug.

Perhaps they are better in relapse prevention then? It seems so, however again the difference from placebo is only 20%.

Furthermore in 2 studies one of the antipsychotics i.e. Olanzapine appears to improve the overall quality of life for patients.

Overall the authors rightfully point out the previous studies may have overestimated the effectiveness of antipsychotics perhaps because they were not very pragmatic in terms of what type of patients they included in the study.

What about their nasty side effects?

On a more positive note, contrary to what the general perception is among the public and professionals the newer antipsychotics don’t seem to cause any significant side effects compared to a placebo medication. In fact, few of antipsychotics led to fewer people dropping out (for any reason) compared to placebos. The older antipsychotic (haloperidol) did show significantly more side effects.

In summary

It doesn’t appear that antipsychotics are immensely useful drugs especially given their apparent reducing effect size as time goes on. However, the newer ones don’t seem to be significantly harmful either. It seems even minor effects may still be worthwhile given we don’t have any better drugs for the time being.

This study, in a more general sense, also reflects on the scientific enterprise as a whole. It goes to show that having scientific evidence in favor of some position doesn’t always amount to absolute truths and that results can vary greatly from time to time. This could in part be because of further developments in methodology or because of the nature of studying human sciences. One also has to wonder about the more cynical reasons in getting widely different results i.e. political, monetary etc.

Do share your thoughts below.

References
  1. Leucht, S., Arbter, D., Engel, R. R., Kissling, W., & Davis, J. M. (2008). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trialsMolecular Psychiatry14(4), 429-447. doi:10.1038/sj.mp.4002136
  2. Bentham P, Gray R, Raftery J, Hills R, Sellwood E, Courtney C et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): Randomised double-blind trial. Lancet 2004; 363: 2105–2115.
  3. Moncrieff J, Kirsch I. Efficacy of antidepressants in adults. BMJ 2005; 331: 155–157.

Fizan

I’m a medical doctor and Psychiatrist in training. I have always had a keen interest in physics, philosophy and fundamental issues. In-fact I regularly discuss these subjects with other interested colleagues (mostly psychiatrists) and friends. I find this leads to personal/ mental growth which helps me in life as a whole.

AuthorFizan

I’m a medical doctor and Psychiatrist in training. I have always had a keen interest in physics, philosophy and fundamental issues. In-fact I regularly discuss these subjects with other interested colleagues (mostly psychiatrists) and friends. I find this leads to personal/ mental growth which helps me in life as a whole.

5 Replies to “Do AntiPsychotics Work? A Look At Scientific Research”

  1. Wow Fizan, this is really bad news. Thanks for looking at this. It almost seems on the scale of psychology’s reproducibility crisis. Why isn’t it more publicized? Are these findings still too new?

    There’s something related that I’ve been meaning to ask a professional in these fields, though hopefully without raising defenses. Your post seems to demonstrate that you can handle it.

    Of course psychiatry has traditionally been a field in which professionals would learn about their patients through discussions, and so could provide associated assessments and recommendations based upon their expertise. Sure drugs have been some part of this, though not principally so. But then maybe a decade ago I remember reading an article about how that all changed in a flash. Suddenly it was the principle job of the psychiatrist to figure out which drugs, if any, might help a given patient, not to help them understand themselves and how they might better cope with life. Of course there was no admission that psychiatrists didn’t understand people well enough to do their jobs in the traditional way, though that does seem to be a strong implication. Then with this new situation the psychiatrist’s role seems in the spirit of, “How is this medication working? Not good? Hmm… Let’s try this other one.”

    I was hoping that medications were going to help the field get by until what I think is truly needed, finally comes along, or until we have better models of our nature in general. I was wondering your thoughts on my perspective? Am I too harsh? And do you believe that better models will some day help the field help us much better?




    0
    • Hi Eric, sorry for the late response. Firstly I would like to disclaim that my views are my own personal ones and they don’t have to represent the views of any other psychiatrist or organisation including any that I work with.
      I don’t know if things suddenly changed a decade ago because drugs have been around for several decades now, although new ones keep coming. What I have heard (obviously I wasn’t a psychiatrist at the time) is that starting the early 90s there was a greater push to combat mental illness and in that momentum, drugs started to be prescribed more and more. This is likely a very complex issue but it seems to me to be based on a number of factors: defensive practice, political science and big pharma, increasing public awareness and demand and most importantly economics.

      By defensive practice, I mean the fear in doctors and health organizations for being sued against. An increasingly litigatory culture means health professionals start treating the courts rather than patients. This isn’t limited to psychiatry but all health disciplines. In psychiatric practice, it is much more defensible in court to show that you ‘treated’ the patient or at least tried rather than having done nothing. This is a very long discussion on its own so I won’t go into further details.
      It also seems plausible esp in light of these types of studies that pharmaceutical companies might be behind a push for medical prescribing of drugs which I call political science.
      Another issue is that people are becoming (or have become) more aware of mental health problems, and coupled with popular media, movies and the internet seem to have developed their own perceptions of these issues, and the nature of mental illness is such that many people feel others don’t understand their problems properly so they have their own ideas of their illness and how to treat it. This often means a greater push from patients to be given medications.
      Lastly, I think one of the main factors seems to be economics (again). It is much cheaper and time efficient to give someone a drug as compared to giving them substantial amounts of a trained professionals time. It is also cheaper to develop practitioners who have only trained for a few weeks in superficial psychotherapy techniques as compared to a medical psychotherapist. All this and a push from governments and in turn health organizations of greater efficiency in resource utilization means there isn’t enough quality time to spend with patient and more people being prescribed drugs.

      Overall you can get a rough picture of why there is increased reliance on medications.

      That is not to say medications don’t work at all. But yes I think we need much better models and medications. I also believe properly conducted psychotherapy is a great and more precise tool but which is losing favor to superficial psychotherapy or medications because of all the above. In more extreme cases admittedly medications are the only thing we can use because people need to be relatively stable in order to receive psychotherapy. I hope this helps.




      0
      • Thanks Fizan, that does help give me a better sense of things. So in the 90s there were all sorts of economic and legal dynamics which contributed to this change in approach. I believe the article that I read a decade ago must have been referencing that period, since it concerned past events to inform non professionals like me. It was probably from the science section for “The Economist”, since back then I generally went through that magazine cover to cover each week. As I recall they mentioned that during this transition doctors would often need to explain to their patients that it was no longer their job to provide general advice, though it was still possible to see a traditional psychiatrist who would. It stated that people were certainly encouraged to be open about their mental issues, whether through some kind of formal therapy or with friends and family, though drugs were generally what psychiatry was now about. Is this your perception as well?

        As you know I have my own general theory regarding our nature that I’d like others to consider. Unfortunately however I’ve noticed strong defensiveness when I’ve mentioned to professionals the need for a broad new approach. I’ve been told that everything is actually fine in these fields, so a person like me needn’t even try. To this theme I’ve even been told the preposterous notion that B. F. Skinner effectively serves as the “Sir Isaac Newton” for mental and behavioral sciences! When a professional will say such a thing in the apparent quest to protect his/her livelihood from outsiders, I must look elsewhere for productive discussions. Still my lack of diplomacy has probably been just as much to blame. I hope to do better here.

        I doubt that many of the professionals that you associate with will worry about a “guilt by association” with you from your blog, since you haven’t publicly stated who it is that you associate with. Perhaps you shouldn’t. Still I do appreciate your disclaimer. It suggests an openness to explore the issues rather than protect the status quo, even if things do get controversial.

        I’ll try not to rub salt in open wounds, though clearly things aren’t yet settled in the fields that interest us most. The situation in psychiatry presents just one example of this. Thus it may be that outside thought will be instructive, and I have plenty of that for you!




        0
        • Hi Eric,
          As I’m still in training, I don’t know much about what actually happened in the 90s and it may have been different in other parts of the world. From my own personal experience working in the field with patients as well as professionals, I think I have a reasonable picture of the current situation at least. The problem with outside opinion (as is usual in most circumstances) is that outsiders don’t generally have a good idea of the realities and intricacies. I think a lot of professionals recognize the problems within however it isn’t very simple to remedy them. Most of the problems, as I stated previously, arise because of the overarching systems within which psychiatry functions i.e. economic and political etc.
          From my perspective, the problem isn’t within psychiatry as such but the system which usually has its own separate agendas. The problem is also an increasingly litigatory and autistic society, promoting a more defensive practice. Hence I this view I don’t see such corrupting influencing being limited to psychiatry only. I think most of our fields (other medical as well as science in general) are suffering from these same diseases.

          As far as the livelihood of professionals goes, I think it would be unaffected if we were able to someday overcome these problems. The reality is that mental illness does exist and hence does and will need some form of management. This management can be in any form i.e. drugs, counseling, psychotherapy, nursing or forensic/judicial etc. But no matter what form it takes it will be delivered by professionals (including psychiatrists). So I don’t think to protect their livelihood is a strong motivating factor for all professionals. Perhaps it is a factor for psychotherapists with an increasing focus on drugs and if there were an increasing focus on psychotherapy it may be a concern for pharmacists. As for psychiatrists they are generally in the center and look at both of these aspects plus an additional aspect i.e. the interaction mental illness with physical illness. As for mental health nurses, there would be ample livelihood as well because no matter what patients depending on the severity do need some form of nursing and occupational therapy input. The real danger to livelihood is on an individual basis (as compared to the whole profession), i.e. when individual professionals try to goes against the flow of the system.

          Having said that I do have some personal qualms about forced treatment. For now, I see it as a necessary evil which may at times be overused (again because of the ‘system’).

          I don’t know the value placed on B.F Skinner has these days, he certainly has historical significance especially for psychologists. It’s my understanding that behaviorism went out of fashion a long time ago and was replaced with more cognitive approaches. Even still psychiatrists are a different bunch to psychologists and B.F. Skinner doesn’t have much significance for most of the actual practicing psychiatrists I’ve known (I say ‘practicing’ to differentiate from ‘academic’ psychiatrists who do more research or appear in the media).




          0
  2. Fizan,
    Yes I’ll go along with every bit of that. Let me try to get you a better sense of the scope of my project however. It really is quite ambitious.

    I’m not just a physicalist, as most all scientists happen to be, but an epistemic monist rather than dualist. This is to say that I don’t consider there to be a “science stuff” and a “philosophy stuff”, but rather that all aspects of reality which might be contemplated, are physically connected. As I explained over at Mike’s recently, humanity’s fourth and final basic “power innovation” seems to have occurred a few centuries back with the rise of hard science. (About 200,000 years ago there was oral language for the first, with specialization about 11,000 years ago for the second, and written language about 5,000 ago for the third.) (https://selfawarepatterns.com/2017/09/09/breakthroughs-in-imagination/#comment-17464)

    I believe that a separate kind of basic human innovation will occur as our soft mental and behavioral sciences harden up. To do so I believe that philosophy will need to become a science, which is to say, develop a respectable community with its own generally accepted understandings. Once together these sciences should teach us how to effectively use our amazing power, or instruct us about how to better lead our lives as well as structure our societies. This is my (obviously ambitious) project.

    Your status as “professional in training” is actually one of the main reasons that I was so happy to meet you back in July (along with the depth of your posts and so on.) As such you shouldn’t be quite as invested in maintaining the status quo, or to decide that there must be both “science stuff” and “philosophy stuff”. Thus it is my hope that you’ll be less hindered grasping the theory by which I mean to help our most troubled fields, become the hard sciences that we desperately need them to become.




    0

Leave a Reply

Your email address will not be published. Required fields are marked *