Magic bullet?

Some weeks ago now, I had an excursion into the world of depression. A complaint which is common all over the world and for which reasonably effective treatment is available. But depression has not been dumped in the dustbin of history, it is still around and there is still plenty of room for the magic bullet. One of which got a place at the very end of reference 1.

So I imagine that there are research laboratories and research teams all over the world, beavering away, trying for find fame and fortune by coming up with the next magic bullet. At the very least, increasing our knowledge of depression, if not actually reducing the amount of misery that it causes.

On the assumption that we have a chemical rather than a talk orientated team, this work must involve at least three components. Scan the catalogue for a chemical worth checking out. Having come up with one, scan the literature to see who else has looked at it and what, if anything, they came up with. Then, if the lights are still green, mount your own trial. This last being the expensive bit. 

So this team, brought to me by Medscape, is from the University of Reading here in the UK, and has been looking at Vitamin B supplements, maybe even the humble Marmite, said to be a good source of Vitamin B. With a downside being that it is also a good source of salt, something that most of us consume far too much of for our own good. The team have reported at reference 3.

Step 1

Vitamin B – or perhaps the vitamin B complex as is was known when I did chemistry, a long time ago now – is involved in the regulation of relevant neural activity, in particular with the important neural inhibitor called γ-aminobutyric acid  or GABA for short. In getting the right balance between excitation and inhibition – disturbances in which balance appear to be involved in various mental disorders, including depression. With, very roughly speaking, the more GABA in the system, the more inhibition. The system is calmed down a bit.

Enough people think GABA is important for lots of GABA supplements to be sold in health food outlets, even though it is not yet clear that it is doing much good. There are even doubts about whether it can get across the blood-brain barrier.

Step 2

Over the last decade, there has been a lot of work on the place of vitamins B6 and B12 in the brain, in particular in neural inhibition in the brain. See, for example, reference 4. Work which was promising but inconclusive, and there was room for another trial.

Step 3

A study involving near 500 subjects – BSc and MSc students – over five years. B6 supplement, B12 supplement and placebo. Quite a good sized sample compared with some that one comes across – with large samples often being neither practical nor affordable. Each subject took his or her medication for around 35 days, after which he or she was assessed.

Assessment by means of a combination of two questionnaires (first two rows in the table above) and eight physiological tests (the remaining rows). A study complicated by COVID and the consequent move online. All these tests are well-established in the field, all thought to be relevant in the present context. 

I don’t know what the last column on the right is about, beyond it looking to be something to do with knowing whether any effect that one sees can be trusted or not; whether it is something real going on or just chance.

SCAARED is a 44 question screening questionnaire for adult anxiety related disorders to be completed by the patient. While MFQ, the mood and feelings questionnaire is a 33-item questionnaire based on DSM-III-R criteria for depression. So the MFQ consists of a series of descriptive phrases regarding how the subject has been feeling or acting recently. Coding reflect whether the phrase was descriptive of the subject most of the time, sometimes, or not at all in the past two weeks. My understanding is that patient completed questionnaires of this sort are widely used for screening purposes. Perhaps on presentation at A&E, at a general practitioner or at a psychiatric service.

Turning to the physiological tests, by way of example, I look at visual contrast detection, some work on which is reported at reference 5. In the figure above, brightness induction is thought to be a function of retinal processing, contrast suppression a function of cortical processing. In both cases the centres are identical but are made to appear different by their different surrounds. The idea is to tweak the surrounds until the centres appear to be identical. There appears to be plenty of evidence that this sort of thing can be affected by depression, and the finding of reference 5 is that brightness induction in the retina is not, while contrast suppression in the cortex is. Suggesting that depression is doing something to the relevant circuits in the brain, rather than in the eyes. With GABA firmly in the frame.

The summary of the results of the present study was that: ‘vitamin B6 supplementation reduced self‐reported anxiety and induced a trend towards reduced depression, as well as increased surround suppression of visual contrast detection, but did not reliably influence the other outcome measures. Vitamin B12 supplementation produced trends towards changes in anxiety and visual processing’. I did not follow the chain of argument from what looked to me like very small differences between the different bars of various bar charts.

Systems

But I was provoked to think in terms of systems. 

By organic standards GABA itself is a relatively small molecule and in the ball and stick figure above we have: GABA = 4×Carbon=black + 9×Hydrogen=white + 2×Oxygen=red + 1×Nitrogen=blue.

However, the systems around it are quite complicated. Bing turned up the graphic above by way of example. Something to do with GABA shunts in fungal processes. While in Wikipedia there is talk of two classes of GABA receptors, which presumably means a lot more different kinds of GABA receptors.

You then insert complicated GABA sub-systems into even an more complicated host system, as suggested in the graphic above, adapted from a systems model of the Flemish economy.

It then seems rather unlikely, at least to me, that by tweaking GABA operations in a one dimensional way, say cranking it up or down, that you are going to achieve anything useful. Maybe you will do some good in one area, but at the cost of massive disruption elsewhere. Systems of this sort are apt to be finely tuned – think of the amount of work involved in working up a power station to operational status – and may not be in very stable equilibria: give them a push and they slide off to somewhere bad, rather than just drifting back to their comfort zone, to their start point.

On the other hand, suppose that, for some physiological reason, GABA activity across the board has been reduced below its proper level. This might cause all kinds of problems, some serious, others not serious enough to register. But pushing it back towards its proper level might well be helpful. The catch here might be that you are only pushing one sort of GABA activity, of the many varieties available and in use across the brain. Which takes us back to the first point.

So I imagine, at the present state of knowledge, it is hard to know what the overall effect of tinkering with one of the many GABA pathways is going to be. You might identify candidate tinkers, but you have to design and execute a series of trials involving real people to know for sure. 

A chancy and expensive business, as drug companies well know: it is the justification for the fancy prices they charge for the magic bullets which do make the cut.

Conclusions

I think I am a bit too old for all the slog and luck involved in poking around in this particular hay stack. You need to be young and hungry.

References

Reference 1: https://psmv5.blogspot.com/2022/06/a-cure-for-darkness.html. 

Reference 2: https://en.wikipedia.org/wiki/Marmite. 

Reference 3: High‐dose  Vitamin B6 supplementation reduces anxiety and strengthens visual surround suppression – David T. Field, Rebekah O. Cracknell, Jessica R. Eastwood. Peter Scarfe, Claire M. Williams, Ying Zheng, Teresa Tavassoli – 2022.

Reference 4: GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia - Meng-yi Xu, Albert H C Wong – 2018.

Reference 5: Reduced visual contrast suppression during major depressive episodes - Salmela, V., Socada, L., Söderholm, J., Heikkilä, R., Lahti, J., Ekelund, J., Isometsä, E. - 2021.