Ring the alarm!

My twitter feed has been somewhat abuzz today with this story about the ‘discovery’ of the chemical responsible for depression and anxiety, dubbed the ‘misery molecule’ by various sections of the press and reported on in a confused and hard-to-follow manner, with the main take home message being ‘more drugs (maybe)’.

First things first – I know this may come as a shock to many of you, but the reporting of this in the media is overblown and misguided. The headline from the Independent serves as a good guide to the misunderstandings present in the reporting of this story:

Scientists discover the molecule responsible for causing feelings of depression 

From this you might surmise that a new molecule has been discovered, and that it is responsible for causing feelings of depression; the implication of the rest of the article is that this molecule has a role to play in pathological depression. Lest you think I’m being too harsh (journalists aren’t responsible for headlines, after all), the body of the article contains the sentence

…scientists have now discovered that the protein receptor CRF1 is responsible for releasing hormones which can cause anxiety and depression over extended periods of time

Similar stories have cropped up in the Times, the Daily Mail, and various other news sources (notably, the reporting in the Financial Times was much better).

Unfortunately for these stories, this is not a previously unknown molecule, and it’s role in either feelings of depression or depressive disorder is  complicated and uncertain.

Human experience, complex emotions and mental health not reducible to a single molecule – surprise!

What has been discovered is the structure of the molecule – this gives us a better chance at figuring out how it works and makes designing drugs which work on it easier. The molecule in question is called CRF1, and it’s a receptor – it sits on the surface of cells and transmits information from outside the cell to inside it. Even on a very reductionist understanding, it is not responsible for feelings of depression, any more than your tongue is responsible for the taste of sugar.

CRF1 is part of a pathway called the Hypothalamic Pituitary Adrenal (HPA) axis. The interaction of all the bits and pieces of this pathway are involved in the ‘stress’ response; it’s a good example of how the brain and rest of the body work together, and it’s a pathway which is often found to be disrupted not only in people with depression, but also in those with psychosis. It involves – as you might expect – the hypothalamus, the pituitary, and the adrenal glands.

The hypothalamus is a small structure which sits deep in your brain and is a kind of ‘master switch’ for all the body’s hormones – long-distance messengers which diffuse signals throughout the body. One of the hormones controlled by the hypothalamus is cortisol, although this being biology nothing is simple; cortisol is not released by the hypothalamus, or even by the brain, but by the adrenal glands which sit atop the kidneys. The hypothalamus itself, while it acts as a master switch, gets it’s neighbour – the pituitary – to do most of the heavy lifting.

Various other parts of the brain, notably the amygdala and the hippocampus, send signals to the hypothalamus which provide information about any potential threats. If it gets such a signal, the hypothalamus releases a chemical messenger known as Corticotrophin Releasing Factor (CRF), which tells the pituitary to release a further messenger, Adrenocorticotropin Releasing Hormone (ACTH), into the bloodstream. ACTH acts on receptors on the adrenal cortices – remember these are the glands which sit on top of the kidneys, and which release cortisol in response to ACTH. Cortisol goes on to have many, many effects on various tissues throughout the body, effects which are mediated through a couple of receptors called the Glucocorticoid Receptor (GR) and the Mineraloreceptor (MR).

You might think this is a roundabout way of doing things (and you’d be right), but each additional step allows for modulation and modification of the signal – in biology, more steps make for a better dance.

So – what’s this all got to do with depression? Well, being constantly stressed all the time isn’t nice, and nor is it good for the brain – cortisol is great for adding a boost to the engine, but you’d soon wear the machine out if the boost was constantly applied. To prevent this from happening, neurons in both the hypothalamus and the pituitary express glucocorticoid receptors; when cortisol acts on these receptors, the activity of the HPA axis is inhibited. This ensures the cortisol alarm is short lived – so long as the receptors on the hypothalamus and pituitary are doing their job.

As you might have guessed, in at least some types of depression this feedback loop fails. There are good reasons for thinking that when this system malfunctions, it’s the glucocorticoid receptors which are the weak link in the chain, and this leads to abnormally long ‘recovery times’ after stress exposure. It’s as if, when it comes to the racket made by the cortisol alarm, your brain is a little bit deaf. The alarm keeps on going on, and on, and on.

Worse, the cortisol alarm actually seems to damage cells in the hippocampus, leading to lower hippocampal volume in some depressed patients. The hippocampus is best known for its role in memory formation but, as I say, it also sends input to the hypothalamus. The nature of this input is inhibitory – that is, it helps turn down the alarm (the amygdala, meanwhile, helps turn it up – which makes sense when you think about the amygdala’s role in fear and anxiety). Of course, if pathologically raised levels of cortisol are damaging the hippocampus, that could well damage its ability to turn down the alarm. As the amygdala doesn’t appear to experience any such damage, you end up with a circuit which is easy to turn on and easily turned up, but resists being turned down or off. Can you imagine a car alarm like that?!

(As an aside, memory problems are a known symptom of major depressive disorder, and it’s extraordinarily tempting to link the lower hippocampal volume seen in depressed individuals with these memory problems; it’s certainly not going to help, but just as there’s more to mood than molecules, there’s more to memory than the hippocampus; depressed individuals also have problems with attention and concentration, both of which could conceivably lead to problems with memory via a different route).

What are the wider effects of this raised alarm? That is a trickier question to answer; the safest response is that there is an association between disrupted cortisol regulation and some (but not all) forms of depression. Current antidepressants do not act directly on the HPA axis, although successful treatment with them seems to have beneficial effects on both the cortisol response and hippocampal volume (we really don’t know much about their mechanisms of action at all, either on the HPA axis or on the brain more generally – a post for another time, perhaps).  Wouldn’t it be great if we could design some drugs which could turn off this runaway alarm directly, and so maybe resolve depression?

And here, at last, we get to the point of this paper. The receptor CRF1 is found on cells of the pituitary gland; they respond to the first ‘go’ signal from the hypothalamus, the chemical messenger CRF (CRF binds to CRF1, see?). Knowing the structure of this receptor makes it a lot easier to design drugs that can inhibit it’s function, working to turn down the alarm. The reasoning goes lower HPA axis activity, a miracle happens, then no depression.

As you can see, it’s a theory that needs a bit of work. But hey – you never know until you try.

Hiding behind the sofa

Sack person from Little Big PlanetMy little niece has just started playing Little Big Planet on the PS3, I’m told she runs for cover when any lava comes on screen. It’s cute.

And it’s strange, isn’t it?

Maybe you don’t think it’s strange, maybe you’re so used to kids hiding behind the sofa that you think it the most pedestrian thing in the world.

I think it’s strange.

And then I think of watching a film though fingers, or turning away during the gruesome bits; it hits me, and I think ‘that’s strange, too’.

Because there is nothing to be frightened of. And we know there is nothing to be frightened of. We experience, again and again, complete safety when we watch these things, when we play these games. We look at toddlers and smile that they’re so scared of the in-game hot lava that they’ll drop the controller and run for safety. At kids who run from the monsters in Doctor Who, as if – we tell ourselves – as if they think the monsters might come out of the TV and get them for real.

As if!

But we know better, we know where the real monsters lie in wait, and we know they’re not in the TV. But still we watch, sometimes, through fingers.

Isn’t it strange?

Why do we do it? Why do they do it? You’ve got to be so careful interpreting what children say – or maybe just as careful as you are with adults, but in a different way; do children understand what you’re asking when you ask if they’re scared of the lava on the screen? Do they understand what they’re saying, when they say ‘yes’? Because of course they are, otherwise they wouldn’t hide! (What peculiar questions these grown ups ask!).

Do you get more specific, and ask them if they’re scared of the lava coming out of the TV and hurting them?

(When I was a kid, I used to be frightened of being upstairs in our house on my own. One of my elder brothers once asked, mockingly, ‘What are you so afraid of? That your toys will come to life and come to get you?!’.

And I thought, ‘well I am now!’).Phrenology head and almonds

Inside your brain you’ve got two ovoid structures called the amygdalae; they’ve got close connection with your two hippocampi, structures which we know are vital for ‘memory’, as we commonly understand the word. The amygdala seems to get especially excited when we’re in danger, or if we perceive a threat. Its close connections with the hippocampus act as a kind of ‘notice this!’ signal, ensuring you remember situations when bad things happened and thus allowing you to avoid them in future.

Undergrad textbooks sometimes take this and conclude that you need the amygdala for fear processing; that the visceral, panic sensation of fear somehow is part of the amygdala’s functioning. Myself, I keep thinking also of the remark in ‘Into the Silent Land‘ that the amygdala is possibly more involved in contextualising fear; thinking of the woman who, deprived of its processing, would stand passive and smiling through a mugging but could also be pinned to the armchair in fear’s grip while watching TV.

(As an aside, the word ‘amygdala’ comes from ancient greek and means ‘almond’, and the amygdala looks like an almond; ‘hippocampus’ comes from the ancient greek ‘hippokampos’, which means sea-horse, and the hippocampus looks nothing like a sea-horse, not even like the crazy-ass sea-horses the Greeks imagined. So long as you remember that anatomical terms either do make sense or do not make sense, you’ll have no problem remembering them)

Often we talk about ‘higher’ and ‘lower’ brain functions; the amygdalae sit at the lower end, apparently driving primal emotional responses which are then modified, modulated and given texture and nuance by the ‘higher’ centres, up and out in the wrinkly cortex. It’s tempting to say that as children we have less control over these ‘lower’ centres – certainly the circuitry of the prefrontal cortex is underdeveloped compared to an adults, and these areas do send many projections deep into the lower processing centres. It’s nice and neat to say that without enough control, or with too much stimulation, or both, our rational selves are displaced, leaving us frightened even when we know we’ve nothing to be scared of.

I’m lured by this explanation, but I’m wary; I’m wary of the Cartesian confusion we can slip into when talking about competing drives and desires inside a single soul; I’m wary of this ‘higher v lower’ dichotomy, which carries so much historical, moralistic baggage. Plato and Freud both thought we had three parts to our selves, which to me seems at least two too many. Besides, as any of my ex’s will attest, I am not good with nice and neat. I don’t trust it; I’ve been let down too many times in the past. Brains are complicated and people even, even more so. Our desires and knowledge and behaviours bleed into one another, from it all we emerge, often unsure of ourselves and our reasons why. We find ourselves on a diet, scooping ice cream into our mouths; promising never to drink again, again; find ourselves watching, frightened and delighted, through tight fingers.

Strange, isn’t it?