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 around 1983 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.

Do we even need our brains ? – Some Scientists aren’t so sure

Once during a discussion, a respectable someone (who I won’t name) suggested to me:

“I believe the seat of the self is the heart. Not the brain!. I laugh at these scientific notions stating consciousness is in the brain. I believe in the future scientists will also accept the true seat of the self is in the heart..”

He went as far as suggesting we ‘think’ with the heart as well. Out of respect, I refrained from saying anything in person, but inside I was thinking “that’s ridiculous!” This person is very invested in eastern Yogic, Sufi, and Buddhist ideas. Which gave me some perspective on his views, but all the same (being a man of science myself), I rejected them entirely. Though I have high respect for such (Buddhist) ideas myself when they lead to rejecting empirical evidence they fail for me greatly.

This person then suggested that there was evidence to support his claim. He referenced to stories of normal people who on brain scans were found to have no brain in the skull, only water! Again I was thinking that’s preposterous. Probably some anecdotal stories which get exaggerated as Chinese whispers.

I was greatly surprised and humbled when I found out that those stories were actually with some merit!

In Dec 1980, Roger Lewin published an article in the Journal ‘Science’, titled: “Is Your Brain Really Necessary?” [1]

This article was based on case studies (hundreds of them) done by British Neurologist, Professor John Lorber on patients with hydrocephalus. Particularly focusing on one case. The case of a university student who had an IQ of 126 and had gained a first-class honors degree in mathematics, and was socially completely normal. But on doing a brain scan they found he for all practical purposes did not have a Brain!

The anatomy of the brain - containing its mechanism and physiology, together with some new discoveries and corrections of ancient and modern authors upon that subject - to which is annex’d a (14784527925)
Inside the skull, with no brain tissue

Instead of the normal 4.5 cm cortical thickness, he only had about a 1mm thin layer. The rest was just CSF (Cerebro Spinal Fluid) which is practically water. This had likely happened due to a slow displacement of the cortex outwards (and against the skull) because of increasing pressure and quantity of the CSF fluid. This meant that the deeper, more primitive, structures were relatively more intact (although still under pressure to shrink and likely not normal either).

This case was well documented and has been greatly debated, including in the original article. The leading explanation seems to be of neuro-adaptation (which has also been called a cop-out). Nevertheless, it still remains difficult to explain away such observations. As Emeritus Professor William Reville states [2]:

“I certainly cannot explain Lorber’s observations, except to note that in some cases the brain shows itself to be amazingly adaptable and capable of servicing the body in a manner equivalent to the familiar “normal” brain, even though its volume and structure is remarkably compressed and distorted.”

Lorber’s other interesting observation was that this isn’t a unique finding either. In fact, in his studies, 50% of people with more the 95% of the cranium filled with CSF still have an IQ greater than 100![1]

Now I don’t know why this hasn’t shaken the field of neurology as it should have. I, on the other hand, find it earth shattering.

Perhaps neuroadaptation can explain some take over of functions. But surely having a 50 to 150 grams brain (and only a millimeter thick cortex) compared to the normal 1.5 Kg brain should have huge impacts on cognition. Our neurological theories usually associate the cortex with specialized areas of processing e.g. sensory cortex, motor cortex, auditory cortex, visual cortex etc. Some other functions include abstractions, calculation, sequencing, memory etc.

Blausen 0102 Brain Motor&SensoryApparently, it seems all these specialized areas get compressed and mushed into a millimeter thick layer and still function properly. Although there is no mention of the morphological changes in this article. Other and more recent research suggests there is extensive axonal, cytoskeletal and synaptic damage with hydrocephalus. There is relatively less neuronal death. However secondary changes are observed in neurons as well. [3][4][5]

There is such great damage to the communication apparatus yet still normal levels of intelligence and cognition! Does this not beg some reflection on our current direction of understanding? Most of our theories center around communication and signaling having a central role.

The reduced space would also reduce the ability to form new interconnections between neurons, as the shape of the cortex changes to a flatter one. These new interconnections are a fundamental basis for how we generally understand brain activity and how we explain learning and memory.

Take for example Grid Neurones which have been experimentally shown to be located in the entorhinal cortex and which along with Place Neurons (the discovery of which earned the 2014 Nobel prize in Medicine and Physiology) constitute the navigation system within animals and humans [6][7]. The mechanics of Grid neurons are complex but an essential component is their ‘Modular Organization’ (a good article describing this can be found here). This is an example of the ‘spatial’ organization of neurons having a specific and integral purpose. Now I wonder what happens when these also get compressed and distorted in shape, how should it still be possible to have a working navigation system?

If we consider that the 1 mm thick brain is still fully responsible for all the cognitive, conscious and subconscious processes then at-least we have to concede that all these processes (including consciousness) are much simpler and should be easier to explain. The brain then shouldn’t be immensely complicated. This view would also lend support to the idea (which is my personal intuitive inclination as well) that consciousness has more to do with the specific configuration into which a human brains develop rather than being dependant on any specific structural parts and/ or complexities of specialized areas.

Overall this article made me much more malleable in my views. And it goes to show how sometimes especially in social sciences we are biased towards deriving conclusions based on population or summated data. By finding the best fit or a generalizing principle from a collection of individual data, where as overlooking the significance of the individual data itself.

Does that mean we Think with our Hearts?

This still sounds like a ridiculous conclusion, after all the heart as we know is mostly made up of cardiac muscle tissue.

However humbled away from my previous staunch opinions I tried to dig a little into such murky waters and found some very interesting things.

An article published in 2003 in The Guardian suggested, based on anecdotal evidence, a concept of transplanted memories. Apparently, such memories occur in some heart transplant patients. Who develop new tastes or have a change of personality, which are similar to the original heart donor.

A few other concepts of interest are also suggested in the same article. Firstly of the ‘Auerbach Plexus’ functioning as a second brain in the gut. Which may govern emotional responses or ‘gut feelings’. Secondly of the idea that neuropeptides, which are found in the whole body, give a sense of ‘self’ and are carriers of our emotions and memories.

NeuropeptideY 1RON
Neuropeptides may carry a sense of self, memory, and emotions

Now, in general, these do not come across as very plausible to me. At least not the extent of explaining the full picture of what we observe. However, it does seem that scientists and not eastern mystics are the ones who have suggested these ideas and/or are working on them.

I found a good article in Namah Journal (the credentials of which I’m not sure of). It goes into some detail covering much of these alternate ideas and many others [8].  It also does provide a list of references at the end to back-up the claims and hypothesizes.

To sum up, personally, I don’t know whether to accept alternate explanations or whether to look at ways in which neuroplasticity in itself might be sufficient. Either way, it does make a dent in my preconceived ideas and I am humbled by that.

So what do you think?


References
  1. Roger Lewin (12 December 1980). “Is Your Brain Really Necessary?“. Science210 (4475): 1232–1234.
  2. https://www.irishtimes.com/news/remarkable-story-of-maths-genius-who-had-almost-no-brain-1.1026845
  3. https://onlinelibrary.wiley.com/doi/10.1002/ddrr.94/abstract
  4. https://www.ncbi.nlm.nih.gov/pubmed/16848091
  5. https://www.sciencedirect.com/science/article/pii/S030645220100166X
  6. https://www.nature.com/nature/journal/v436/n7052/abs/nature03721.html
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042558/
  8. https://www.namahjournal.com/doc/Actual/Memory-transference-in-organ-transplant-recipients-vol-19-iss-1.html

Operant Learning Shows Bacteria can Imagine! – True or False

Is imagination necessary for operant learning? And if so are bacteria imagining!

Bacteria imagine

This question came from an interesting discussion I was recently having on selfawarepattern’s blog post regarding Consciousness and Panpsychism. The author says:

“..Imagination is the fourth layer.  It includes simulations of various sensory and action scenarios, including past or future ones.  Imagination seems necessary for operant learning.. “

After several replies, I thought it would be a good idea to present this as a separate post here. To be fair the author only extends imagination to all vertebrates having the ability to sense at a distance. But can we take it a few steps further than that?

Operant Learning:

When talking about classical examples of Operant conditioning, we usually refer to the Skinner Box experiments:
In this experiment, the rats bar pressing behavior is the ‘operant’. The consequence of which is a food pellet (positive reward) and this acts as a ‘reinforcer’ for the preceding behavior. If the reward is given every time the bar is pressed (called continuous reinforcement) then learning is taking place based solely on the behavior (operant) and its consequences (reinforcer). This is not based on imagination but only on actions (behavior) and reactions (consequences).

Skinner box scheme 01
A good explanation can be found here: https://www.scholarpedia.org/article/Operant_conditioning

One of the commentators (Paultorek) argues:

“…research has analyzed the brain activity of rodents trained in such tasks, and finds that when they are (by the above hypothesis) anticipating future results, memories of the past experiences are being activated… “

Evolution du cortex prefrontal
However I argue such behavior is not limited to humans and vertebrates, but almost all organisms including protozoan and bacteria. The only conditions are the ability to change the environment and having a goal, which for the bacteria can be only brute survival.

Referring to brain activity analyzed in rodents during such behaviors, the biggest issue is that their brains are not the same as ours, so how do we know they are imaging like we are?

In the general sense processing of such learned behavior happens in the bacteria, the rodent and in humans. The processing in bacteria is simpler than the rodent. The rodents processing is simpler than the humans. But they all occur using chemical processes.

So if we can extend the courtesy of imagination to rodents why not extend it to bacteria as well? My opinion is that we cannot extend this courtesy at all!

Take Gambling for example:

Pompeii - Osteria della Via di Mercurio - Dice Players
Gambling machines are a good example of exploiting operant conditioning in humans. When the gambler’s gambling activity leads to the occasional reward, the gambling activity is reinforced. Yes, one could say that the gambler can imagine getting a reward but that’s not what’s driving his behavior. It is the reinforcement that drives the behavior and imagination is entirely separate from this contingency.

This is because the gambler can also imagine NOT getting the reward which is in truth the most likely outcome that he is suffering. Such imagination however usually does not reduce his gambling behavior.

The pull of gambling (using operant conditioning) is opposite and it is an uphill battle to resist this. This can go to the extent of becoming a disease, now formally recognized in the DSM 5 as ‘Gambling disorder’.
So as far as operant conditioning goes there is no role of imagined outcomes, only of outcomes. Any imagination that happens is separate from this contingency.


References:
  1. https://www.scholarpedia.org/article/Operant_conditioning
  2. Huitt, W., & Hummel, J. (1997). An introduction to operant (instrumental) conditioning. Educational Psychology Interactive. Valdosta, GA: Valdosta State University. Retrieved from, https://www.edpsycinteractive.org/topics/behsys/operant.html
  3. C.F. Lowe (1985). Behaviour Analysis and Contemporary Psychology. Retrieved from https://books.google.co.uk
  4. https://www.sciencedirect.com/science/article/pii/S0091677372801809
  5. https://journals.sagepub.com/doi/abs/10.2466/pr0.98.3.705-711