Quite often, when I write about antidepressants not working for me, I get friendly and helpful comments left by people telling me that they do work, and that all I need to do is stick with it, and eventually I’ll find the drug that works for me. It happened most recently on my ‘Slough of despond’ post, where two separate people told me this very thing. I’m not complaining about the comments; far from it, I’m very grateful for them, as I am for all the comments I get, and I also recognise that those people specifically were trying to buoy me up with stories from their own life that suggest that there are reasons for me to remain hopeful of a cure. (Re-reading that, it sounds fake, but it isn’t – it means a huge amount to get friendly, hope-filled messages at a time like that, and I really am grateful.)
But the thing is, while I do understand that antidepressants work for a lot of people, and while I recognise that my air of hopeless resignation was partly just the depression talking, I do have good reason to believe that they are unlikely to work for me. You see, I didn’t give up at the first hurdle when it came to trying drug treatments for my depression, but only after a long, painful slog. Over the course of a period of about five years, I was prescribed several different drugs by both my GP and also a psychiatrist I was referred to in order to find an effective antidepressant. The approach was somewhat scattershot, but over the course of the period as a whole I ended up trying at least one drug from pretty much every class of antidepressant:
SSRIs (Selective Serotonin Re-uptake Inhibitors)
SNRIs (Serotonin Norepinephrine Re-uptake Inhibitors)
SARIs (Serotonin Antagonist and Re-uptake Inhibitors)
NaSSAs (Noradrenergic and Specific Serotonergic Antidepressants)
TCAs (Tri-Cyclic Antidepressants)
Between them, these drugs account for pretty much every class of antidepressant there is. In fact, when I sat down to write this post, I was only aware of one major class of antidepressants that I hadn’t tried, the MAOIs (Monoamine Oxidase Inhibitors), which, so far as I can tell, are pretty much never prescribed these days. It turns out there are other classes of antidepressants listed on Wikipedia, but it would seem that these are also rarely prescribed, at least in the UK. As my GP told me when she was explaining why I hadn’t been prescribed some well-known drugs, because antidepressants are classified on the basis of the mechanism by which they affect brain chemistry, it’s reasonable to assume that if one drug in a particular class is ineffective the others in that class will also be ineffective. This is why, having tried such a wide range of drugs with very little to show for it, it’s reasonable to assume that antidepressants aren’t likely to be effective for me.
Not all the drugs were equally ineffective. I did have some response to Lofepramine, but only at a very high dose (280mg/day – 70mg above the official maximum dose), and even then it gradually stopped working. Assuming I wanted to try it again, I’m not sure I would find a doctor prepared to prescribe it to me at the dosage that was required for me to benefit, since, apart from the doctor who signed the prescriptions, everyone I’ve seen has expressed horror that I was given a dose so high. If someone was prepared to prescribe me another TCA I’d probably be inclined to give it a go, on the basis that was the class of medication I responded to before. Whenever I’ve raised that as a possibility, though, I’ve always been stonewalled, I think probably because all the other TCAs besides Lofepramine tend to be fairly toxic in overdose.
It’s certainly true to say that I haven’t completely exhausted the theoretical possibilities of drug treatment for my depression. In particular, I’ve never tried taking more than one antidepressant simultaneously, which is sometimes effective in cases that don’t respond to a single medication, and I’ve also never been prescribed any other sorts of medication which are sometimes effective in depression (mood stabilisers, for example), either as an adjunct to an antidepressant, or on their own. The thing is, though, when I say that antidepressants don’t work for me I’m not just spouting nonsense. I have tried really quite a lot of antidepressants, most for several months at a time, and I’ve been officially told that my depression is treatment-resistant. Psychiatrists, who specialise in medication, have told that I’m unlikely to benefit from their approach and that I should try therapy instead, while the psychologists who might offer me therapy have refused to tackle my depression because they see it as endogenous, and so not amenable to the therapeutic approach. In other words, I’m piggy in the middle.
I could, of course, fight this. In particular, I could push for exploration of more aggressive drug regimes. From reading various blogs written by GPs it seems like it’s by no means unusual for MH patients to be returned from secondary care with ‘Incurable’ stamped on their foreheads, and for the GPs rather than the supposed experts to have to establish an effective treatment regime by trial and error, so if I did go back to my GP I think I’d be part of a trend rather than anything more unusual. But the truth is, I don’t really see the point.
Everything I’ve read about antidepressants leads me to think that they work predominantly by the placebo effect, with perhaps a very small biochemical effect on top of that. Insofar as I understand the research (and I’m very far from being an expert – my highest scientific qualification is a D at A-level biology), the most reliable studies show that antidepressants are effective over-and-above placebo in severe depression, but only by a very narrow margin: so narrow that, in some cases, it’s perilously close to being clinically insignificant. Just this week, Neuroskeptic discussed a meta-analysis which seems, to my wildly inexpert eye, to imply that much of the benefit seen in clinical trials of antidepressants comes down to a design feature of the trials which significantly enhances the placebo effect, rather than the effects of the drugs themselves. Then again, as I understand it, no-one has been able to establish a robust correlation between fluctuations in neurotransmitter levels and fluctuations in mood, or between antidepressant use and neurotransmitter levels. So far as I’m aware, even researchers who think antidepressants are effective think that their effectiveness is unrelated to the neurotransmitter hypothesis, which was in any case just a hunch, a best guess as to why drugs designed to treat TB had the unexpected side effect of making sad people smile.
This is the root of the problem, I think. Everything I read tells me that no-one understands what causes those cases of depression which, like mine, are not the result of negative life events. Everything I read tells me that all the drugs designed over the last 60-odd years to target clinical depression are based on the assumption that mood disorders are caused by neurotransmitter imbalances, but that’s increasingly looking like it was a bad hunch. Everything I read tells me that antidepressants have a significant placebo effect, but only a very small ‘real’ impact. In itself, that shouldn’t be a problem – a small benefit is still a benefit, after all. The trouble is that I know perfectly well that the effect of ‘mind over matter’ in physiological ill-health has been well established – people with an optimistic mindset do measurably better than people with a pessimistic one. So this is the problem:
Someone like me who, thanks to a combination of first-hand experience and reading around the subject, knows that any new antidepressant he tries will have, at the very best, only a minimal effect on his depression will inevitably start taking the drug with a pessimistic mindset, an expectation that this drug will fail to lift his mood, just like all the others did. Straight off the bat, this means the placebo effect is greatly reduced, or even wholly absent, and thus the greater part of the potential benefits of taking the drug are unavailable. But having so negative a mindset means that the very fragile part of the response to the drug that is not a result of the placebo effect – that very slight impact on mood – is at great risk of being overwhelmed and rendered invisible by the weight of negative expectation that surrounds it. It’s not just a question of the placebo effect failing to function, but of a kind of negative-placebo-effect* taking its place.
I think this is probably a positive feedback loop, both ways round. If I believe the drug will work, this enhances its effectiveness once I start taking it, which increases my belief that it’s working still further, which further enhances its effectiveness – and so on. Conversely, if I believe the drug won’t work, this reduces its effectiveness once I start taking it, which damages my perception of its effectiveness still further, which further reduces its effectiveness – and so on. Basically, I’m caught in a vicious circle, and there’s no way, thanks to my experiences and my knowledge, that I can make the leap to a virtuous one, no matter how much I wish I could. This, then, is what I mean when I say that I would need to believe in antidepressants in order for them to work: not just so that I might experience the positive impact of the placebo effect, but so that I might also overcome the negative effects of its opposite. Basically, I sabotage myself before I even begin, and, so far as I can see, there’s nothing I can do about it.
* – I don’t know the correct term; I don’t think nocebo is quite right, since the expectation is that the drug is useless, not harmful.