Aethelread v Antidepressants

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.

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12 Responses to Aethelread v Antidepressants

  1. Kate says:

    While I do agree with your placebo hypothesis and the idea that anti-depressants have only a mild neurochemical impact on some people, I personally experienced what i can only assume to be a very extreme response (undoubtedly neurochemical) when i was mis-diagnised with depression rather than bipolar. Within 2 days i became more manic than i have ever known either previously or subsequently. The agitation and hallucinations were so intense I very nearly killed myself. This occured after both citalopram and fluoxetine and I don’t believe it was a coincidence. Within 24-48 hours of stopping both meds, I was back to normal again (if somewhat exhausted and mildly depressed). Pergaps I’m unusual but i would argue that such a strong reaction would indicate that, for some people at least, these drugs can have a very potent effect.

  2. I am not sure you want to hear this, but I wanted to repeat what I said in my last comment, putting it in your terms.

    I had tried:

    SSRIs (Selective Serotonin Re-uptake Inhibitors)

    * Fluoxetine
    * Citalopram

    SNRIs (Serotonin Norepinephrine Re-uptake Inhibitors)

    * Duloxetine
    * Venlafaxine

    SARIs (Serotonin Antagonist and Re-uptake Inhibitors)

    * Trazodone

    TCAs (Tri-Cyclic Antidepressants)


    and ECT.

    At this point it was decided by my old psychiatrist that there was a high chance antidepressants wouldn’t work for me and they gave up. The theory was, if ECT didn’t work, possibly the most effective AD of all, then I didn’t really stand a chance.

    I also tried various antipsychotics/mood stabilisers along the way:


    (plus various benzos and things for anxiety/sleep etc).

    The only thing that had helped from that list was the Lamotrigine, which had helped take the edge off things and slowed down the mood swings.

    Then I tried to kill myself again back in January and my new psych decided to try the ADs again. She chose an NRI this time – Reboxetine.

    I never believed it would. I told her I didn’t want to try it because I didn’t see the point. There was no placebo effect for me, because I had no faith at all. I had no faith in the psychiatrist at all, let alone the drug. I was in hospital and just waiting for the opportunity to kill myself

    The side effects sucked at first and I considered stopping it, but I decided to persevere as I didn’t really have anything to lose or much choice in the matter, being in hospital. If I refused treatment it would have probably been enforced.

    Slowly I started to get signs it might be working, although I felt physically awful from the side effects a lot of the time. At this point my psychiatrist was considering taking me off it and trying something else because I felt so bad, but I told her the small signs of improvement were enough to keep trying as I was loathe to give up on another drug due to side effects. I’m glad I pushed through the nastiness as the improvements continued and I’m now so much better.

    I do understand that you are sceptical and rightly so. After trying so many it is easy to lose faith. The thing is there really are hundreds of drugs and they all affect everyone differently. There are strange groups that hardly ever get used and there are drugs within groups that behave differently to others.

    You haven’t tried the NRIs or the NDRIs (Reboxetine or Bupropion). My psych thinks that these tend to be more effective for chronic treatment-resistent depression and those of us to a tendancy towards dysthymia and the fact it has helped me may support her theory.

    I now believe there is a combination out there for everyone and it is just a case of finding it. That can be a painful experience, but you may get lucky.

    I am pleased to hear by your previous post that things have improved a little, but if they go downhill or don’t, you don’t have much to lose by giving drugs another go?

  3. gun street girl says:

    People misunderstand what “placebo effect” means. It doesn’t mean the pills you are taking are as inert as sugar pills, with no effect at all. It means that any perceived improvement in symptoms of your disorder is not due to the active ingredients in the medicine but rather to your own expectations of what the medicine will do.

    Psychotropic drugs are made to alter brain chemistry. They are generally pretty effective at that, thus all the side effects, large and small, that people report. What the meds may or may not do is actually make you better.

    I took Prozac for a long time back when it was new on the market and can’t honestly say whether it helped or not. I experienced next to no side effects on it but also didn’t really notice any improvement in my depression that seemed. This last go-round my doctors put me on all sorts of stuff that scared me. Really really scared me. The side effects were horrible enough that there was no way I could make the 4-6 weeks necessary for the meds to work (why is that anyways? shouldn’t they work immediately, biochemically speaking?) Eventually I said “Enough. If I’m doing this, I’m doing it med-free. I can’t take this anymore.” And I immediately became a “bad patient” and “noncompliant.” I found it almost impossible to find an outside therapist that would treat me if I wasn’t taking something. So yeah.. med-free and therapy-free.

    I’m like you, I read too much. :)

    I’ve not only been certifiable on and off for decades, I have degrees in psychology. I read whatever I can about depression and medications. And everything I read just increases my doubt and confusion and strengthens my resolve to stay away from it until they can 1) show me the biochemical basis of my disorder; and 2) show me that the meds they want me to take will actually fix the problem.

  4. pirate says:

    Its weird how depression makes us all read – everything ever written on the subject! I’m working on a biology degree which I started as a way of trying to understanding what the hell was happening to me.
    Antidepressants stopped me acting on my suicidal tendencies – but that would be because after I stopped taking them I blamed them for every suicidal thought I had for the next couple of months!. (and no, in hindsight i don’t think they were responsible in the least.)

    Generally i’m promedication and think the antidepressants can work for most people with severe depresssion (but not all). I’m also generally against therapy etc.

    When i was severly depressed i started to do soduko (yes i really said that), the easy version would take me all day, especially as i would forget what i’d already tried etc, and i would beat myself up endlessly about how useless i was at -thick, stupid etc etc. But in hindsight i think i accidentally found something that worked for me, it forced me to think logically (something that can be hard to do when i’m depressed) and it was non emotional, at least whilst i actually concentrated on the puzzle. In fact now i tend to believe that for me at least, occupying my mind with a puzzle enabled mymood to get a bit more undercontrol as it gave my mind a break from the usual round of obsessive negative thoughts and images of suicide that was plaguing it.

    If the depression comes back, i will definitely, definitley be looking for something logical and hard to try and focus on as a way of short circuiting the negative focus. Hard by the way is a very flexible concept, i have never found anything as hard as those easy soduku puzzels were at the time – as now i can do them in about 5 minutes.

    Whatever you decide to do next – good luck athelread.

  5. Josie says:

    I am actually going to be incredibly annoying and also suggest not giving up on antidepressants. I used to have opinions just like yours – i read around the subject and from experience (trying 7 antidepressants over a number of years), and i concluded antidepressants just wouldn’t work for me. But then out of total desperation i tried one more (after many tearful fights with my psychiatrist) and to my absolute shock it’s worked. And it’s my 3rd SSRI too.

  6. aethelreadtheunread says:

    Thanks for the comments. intothesystem, sorry for the long delay in your comment appearing – wordpress decided it was spam for some reason, and i was very bad at checking yesterday.

    Kate – Sorry to hear about your bad experience on ADs. They certainly are notorious for their negative impact on people with bipolar. I agree your experiences are extremely unlikely to have been coincidence, and it also seems very likely to me that the capability of ADs to trigger mania/hypomania in susceptible people is related to the non-placebo part of their effect on unipolar depression. As to whether that’s ‘undoubtedly neurochemical’ well, i don’t know, but, if i’m interpreting it right, the evidence would pretty much overwhelmingly mean that it isn’t, but rather the result of some other, as yet unexplained, mechanism.

    intothesystem – I am so glad to hear that you’ve found something that works. :o) As i said, i do realise that i haven’t exhausted the possibilities for drug treatment of my depression, and it’s certainly possible that there’s a drug, or combination of drugs, out there that will work brilliantly for me, although i remain sceptical – i’m too much of an empiricist not to!

    FWIW, i think your good experience may not have been down to the drug alone, but a combination of the effect of the drug and the benefits of the other interventions you received while you were in hospital and the fact that depression is somewhat cyclical – after a crashing low there’s usually a return to a lighter mood even in the absence of any treatment whatsoever. I’m not saying the drug wasn’t important – i’m sure it was an absolutely crucial part of your recovery – but i also think it’s likely that your recovery wasn’t down to the drug alone, but to the drug enhanced by other factors. Depression is a very complicated, multi-factoral thing, and the recovery from it can be equally complex and multi-factoral, i think.

    But that’s all pretty academic when it’s set against the fact that you’ve recovered – that’s the important thing! :o)

    gun street girlPeople misunderstand what “placebo effect” means.

    They certainly do, although i hope i’m not one of them! :o) I know it can be incredibly powerful, especially in conditions like depression. Really my only point is that it’s modulated by faith – i have to believe a medicine (or a placebo given as though it were medicine) will help me in order to benefit fully from the placebo effect.

    This last go-round my doctors put me on all sorts of stuff that scared me. Really really scared me. The side effects were horrible enough that there was no way I could make the 4-6 weeks necessary for the meds to work (why is that anyways? shouldn’t they work immediately, biochemically speaking?) Eventually I said “Enough. If I’m doing this, I’m doing it med-free. I can’t take this anymore.” And I immediately became a “bad patient” and “noncompliant.”

    I’m really sorry to hear about your bad experiences. I have also been labelled a bad patient because i didn’t just unthinkingly swallow whatever was put in front of me, so i sympathise with the difficulties this has caused you. The fact that drugs which affect brain chemistry rapidly take far longer to affect mood is one of the things that undermines the neurotransmitter hypothesis.

    everything I read just increases my doubt and confusion and strengthens my resolve to stay away from it until they can 1) show me the biochemical basis of my disorder; and 2) show me that the meds they want me to take will actually fix the problem.

    It sounds as though you and i are coming from pretty much the same place. :o)

    pirateIts weird how depression makes us all read – everything ever written on the subject!

    It is, isn’t it? :o) Personally i think it’s something to do with the fact that doctors’ explanations are a little vague (as they have to be, because no-one’s quite sure how it all works), so we go looking fur more information and quickly realise that it’s a bottomless pit… ;o)

    Generally i’m promedication and think the antidepressants can work for most people with severe depresssion (but not all). I’m also generally against therapy etc.

    I’d definitely tell anyone struggling with severe depression to try the meds – they work for lots of people, and cases like mine that are treatment-resistant are the execption rather than the rule. I’m not completely hostile to therapy either, having achieved some definite benefits from my 20 weeks of psychodynamic psychotherapy. I definitely think, though, that therapy’s role is in helping people to understand the way their illness manifests (i’m much clearer that the physical symptoms of depression and anxiety are mental rather than physical in origin than i was before i began therapy), and in developing more effective coping strategies, rather than actually treating the underlying problem.

    On the issue of sudoku puzzles – i always make sure i have a book of them around, because i find them a very effective way of channeling my focus onto something other than the way i’m thinking. I find them particularly useful for anxiety – when i’m depressed i’m more likely to go for something that involves less mental effort – but i definitely agree with you that they can be a very useful tool. :o)

    Josie – Don’t worry, you’re not being the least bit annoying! I’m really glad you’ve found something that works for you. :o)

  7. Thanks. I am glad I’ve found something to help too.

    I do laugh at the suggestion of other interventions whilst I was in hospital though! If other interventions include terrible food, an occasional game of scrabble and the sound of panic alarms, then maybe it is time for a whole new strategy to depression! That place was only good for one thing and that was locking me up somewhere where it was unlikely I could do much damage to myself.

    In all seriousness though – I get what you are saying. I have come out of depression during my teens without intervention so it could have happened again, but I’d been seriously depressed without respite for almost 2 years. Improvements were felt within a few weeks of starting the meds and have continued since. The couple of times I’ve missed the dose accidentally I have felt a drop in mood pretty rapidly unfortunately, which has lasted for a couple of days even after resuming meds – more than likely down to withdrawals and resumption of side effects, but it also makes it pretty clear it is doing something to my mood.

    I’m probably still vaguely mildly depressed, but I suspect that’s my baseline really. Maybe it will keep going and my mood will improve more, or maybe this is the best I can hope for, but I’m glad of the changes.

  8. Meds and therapy aren’t the only choices. There’s ECT and there’s DBS.

    Note that it’s very typical of depressives to quickly acknowledge that other people deserve relief for their suffering but to choose nobly enduring when it’s their own turn.

  9. Adair says:

    Now I’m curious: What is the scientific evidence for and against the hypothesis of individualized drug regimes being effective? Obviously this is a different question than rather a given drug works well statistically for a random sample of the population. Equally obvious is the fact that eliminating confounding effects is much harder with this hypothesis, but that doesn’t mean it’s justified to write off all the anecdotal evidence as regression to the mean or whatnot. Surely many clever sciencey type people have come up with testable predictions from this hypothesis and then compared to the data?

    Also, interesting difference in psych treatment cultures with your therapists and psychiatrists seeing each other as mutually exclusive. Mine always want me to concurrently be in therapy and on meds, which is very different from my own tendency to want neither.

  10. Neuroskeptic says:

    I’m going to be annoying too…

    There are a number of options you haven’t tried yet:

    Most importantly MAOis – don’t write these off. The side effects are an issue, but when they work, they work really well, and if they stop you being depressed, you’ll be able to live with the side effects. It’s at least worth a shot. You’ll be kicking yourself if you try one in say 5 years and it works…

    Combination treatment – I’m surprised this hasn’t been tried yet. In my neck of the woods it’s the first thing they do in “treatment resistant” depression.

    What dose of mirtazapine did you take? I was prescribed 30 mg for a couple of months which did little more than make me sleep and eat. But when it was raised to 45 mg, the sedation disappeared – there’s a pharmacological reason for this – in my opinion doctors generally prescribe this at a too low of a dose.

    What about venlafaxine? Again, in my experience you need to take it at a high dose; at low doses it’s just an SSRI, but at higher doses (e.g. 225 mg or 300 mg in most people) it’s also an NRI. In theory it’s no different to duloxetine, but it is, because it has fewer side effects (duloxetine is notoriously unpleasant); the combination with mirtazapine is becoming very popular.

    Of course maybe nothing will work, but it really doesn’t sound like you’ve exhausted the possibilities and to be honest it sounds like your prescribers have overlooked some of the obvious ones (most notably augmentation)…

  11. Pingback: Antidepressants and the ‘anti-placebo’ effect | Aethelread the Unread

  12. Cyndi says:

    I was forcibly drugged for depression between age 13 and 18. By the time I was 21, I had tried 47 psychotropic drugs. Only two of them made a difference, and it was negligable. In all honesty, nothing helps if you are stuck in a negative thinking pattern. It’s a constant process of sorting out reailty from introjection and projection, prioritizing things in life, and figuring out what I want, why I want it, and what I am doing to achieve it. No drug or therapist in the world can help you out of a depression, they can only serve as support if you believe they are helping you out. You have to figure out what is mentally healthy for you, because no one knows you better than yourself. Best of luck to you.

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