A 45 year old female teacher had a history of severe obsessive-compulsive disorder, along with other problems including ADHD. Her daughter, and many other people in her family, had suffered the same problems and in a few cases had Tourette's Syndrome.But all that changed - when she suffered a stroke. This is according to a brief case report from Drs. Diamond and Ondo of Texas:
[she] had a long history of constant intrusive and obsessive thoughts that interrupted her daily activities and sleep. She had constant unfounded fears that something bad would happen to her family and had persistent violent thoughts of using knives to harm family members. She would check the door locks up to 15 times a day. In addition to her OCD symptoms, she had ... inattention, poor concentration, and difficulty sitting still.
She had never been treated for the OCD, despite how it interfered with her life, because she feared losing her job as a teacher if she sought psychiatric help. But then...
Nine months before approaching us, she developed the acute onset of paresthesia [weird sensations] and weakness in the left upper extremity and face, associated with slurred speech. Initially, she was unable to lift her arm against gravity.
These are classic signs of a stroke, but it was a very mild one, because the symptoms only lasted a few minutes and were pretty much gone even before she arrived at the emergency room. She made a full recovery. More than a full recovery in fact:
Within weeks of her stroke, she realized that her obsessive and intrusive thoughts, fears, rituals, and impulsive behavior had completely resolved. In addition, there was some improvement in her temperament. There was no improvement in attention or concentration. Owing to her improvement in neuropsychiatric symptoms, she strongly felt that her stroke was beneficial. These benefits have persisted for 24 months.
Most medical case reports concern patients who died, or got really sick, in a particularly interesting fashion, but this one has a happy ending. Strokes can be devastating, of course, although people also make full recoveries - it all depends on the severity of the stroke, and whether they get prompt treatment.
There have been a few other cases of brain damage which brought unexpectedly beneficial effects. In Vietnam veterans, for example, people with damage to the vmPFC due to combat trauma seemed to be protected from depression.
Whether the stroke really cured her, or whether it was some kind of psychological "placebo" effect, we'll never know. It's hard to see why a stroke would have a placebo effect, but on the other hand, an MRI scan revealed that the stroke occured in an area of the brain - the right frontoparietal cortex - which is fairly low down on the list of "OCD-ish" areas.
The authors make some vague comments about "modulation of the cortical–subcortical circuits" but this is really the neuroscientific equivalent of saying "We guess it did something", because the entire brain is made of cortical-subcortical circuits, given that the cortex is at the top and everything else is, by definition, the sub-cortex. It's quite possible. But we really can't tell.
Diamond A, & Ondo WG (2011). Resolution of Severe Obsessive-Compulsive Disorder After a Small Unilateral Nondominant Frontoparietal Infarct. The International journal of neuroscience PMID: 21426244
Paroxetine, aka Paxil aka Seroxat, is an SSRI antidepressant.
Like other SSRIs, its reputation has see-sawed over time. Hailed as miracle drugs in the 1990s and promoted for everything from depression to "separation anxiety" in dogs, they fell from grace over the past decade.
First, concerns emerged over withdrawal symptoms and suicidality especially in young people. Then more recently their antidepressant efficacy came into serious question. Paroxetine has arguably the worstimage of all SSRIs, although whether it's much different to the rest is unclear.
Now a new paper claims to provide a definitive assessment of the safety and efficacy of paroxetinein adults (age 18+). The lead authors are from GlaxoSmithKline, who invented paroxetine. So it's no surprise that the text paints GSK and their product in a favourable light, but the data warrant a close look and the results are rather interesting - and complicated.
They took all of the placebo-controlled trials on paroxetine for any psychiatric disorder - because it wasn't just trialled in depression, but also in PTSD, anxiety, and more. They excluded studies with fewer than 30 people; this makes sense though it's somewhat arbitrary, why not 40 or 20? Anyway, they ended up with 61 trials.
First they looked at suicide. In a nutshell paroxetine increased suicidal "behaviour or ideation" in younger patients (age 25 or below) relative to placebo, whether or not they were being treated for depression. In older patients, it only increased suicidality in the depression trials, and the effect was smaller. I've put a red dot where paroxetine was worse than placebo; this doesn't mean the effect was "statistically significant", but the numbers are so small that this is fairly meaningless. Just look at the numbers.
This is not very new. It's been accepted for a while that broadly the same applies when you look at trials of other antidepressants. Whether this causes extra suicides in the real world is a big question.
When it comes to efficacy, however, we find some rather startling info that's not been presented together in one article before, to my knowledge. Here's a graph showing the effect of paroxetine over-and-above placebo in all the different disorders, expressed as a proportion of the improvement seen in the placebo group.
Now I should point out that I just made this measure up. It's not ideal. If the placebo response is very small, then a tiny drug effect will seem large by comparison, even if what this really means is that neither drug nor placebo do any good.
However the flip side of that coin is that it controls for the fact that rating scales for different disorders might be just more likely to show change than others. The d score is a more widely used standardized measure of effect size - though it has its own shortcomings - and I'd like to know those, but the data they provide don't allow us to easily calculate it. You could do it from the GSK database but it would take ages.
Anyway as you can see paroxetine was better, relative to placebo, against PTSD, PMDD, obsessive-compulsive disorder, and social anxiety, than it was against depression measured with the "gold-standard" HAMD scale! In fact the only thing it was worse against was Generalized Anxiety Disorder. Using the alternative MADRS depression scale, the antidepressant effect was bigger, but still small compared to OCD and social anxiety.
This is rather remarkable. Everyone calls paroxetine "an antidepressant", yet at least in one important sense it works better against OCD and social anxiety than it does against depression!
In fact, is paroxetine an antidepressant at all? It works better on MADRS and very poorly on the HAMD; is this because the HAMD is a better scale of depression, and the MADRS actually measures anxiety or OCD symptoms?
That's a lovely neat theory... but in fact the HAMD-17 has two questions about anxiety, scoring 0-4 points each, so you can score up to 8 (or 12 if you count "hypochondriasis", which is basically health anxiety, so you probably should), out of a total maximum of 52. The MADRS has one anxiety item with a max score of 6 on a total of 60. So the HAMD is more "anxious" than the MADRS.
This is more than just a curiosity. Paroxetine's antidepressant effect was tiny in those aged 25 or under on the HAMD - treatment just 9% of the placebo effect - but on the MADRS in the same age group, the benefit was 35%! So what isthe HAMD measuring and why is it different to the MADRS?
Honestly, it's hard to tell because the Hamilton scale is so messy. It measures depression and the other distressing symptoms which commonly go along with it. The idea, I think, was that it was meant to be a scale of the patient's overall clinical severity - how seriously they were suffering - rather than a measure of depression per se.
Which is fine. Except that most modern trials carefully exclude anyone with "comorbid" symptoms like anxiety, and on the other hand, recruit people with symptoms quite different to the depressed inpatients that Dr Max Hamilton would have seen when he invented the scale in 1960.
Yet 50 years later the HAMD17, unmodified, is still the standard scale. It's been repeatedly shown to be multi-factorial (it doesn't measure one thing), no-one even agrees on how to interpret it, and a "new scale", the HAMD6, which consists of simply chucking out 11 questions and keeping the 6 that actually measure depression, has been shown to be better. Yet everyone still uses the HAMD17 because everyone else does.
Link: I recently covered a dodgy paper about paroxetine in adolescents with depression; it wasn't included in this analysis because this was about adults.
Carpenter DJ, Fong R, Kraus JE, Davies JT, Moore C, & Thase ME (2011). Meta-analysis of efficacy and treatment-emergent suicidality in adults by psychiatric indication and age subgroup following initiation of paroxetine therapy: a complete set of randomized placebo-controlled trials. The Journal of clinical psychiatry PMID: 21367354
“Mr. A” was a 43-year-old man...His most pressing medical complaint was worrisome fatigue. He was not depressed...had no formal psychiatric history, no family psychiatric history, and he was a successful businessman.
He was referred to the psychiatry department by his primary-care physician (PCP) because of a 2-year-long complaint of pruritus [itching] accompanied by the belief of being infested with parasites. Numerous visits to the infectious disease clinic and an extensive medical work-up...had not uncovered any medical disorder, to the patient’s great frustration.
Although no parasites were ever trapped, Mr. A caused skin damage by probing for them and by applying topical solutions such as hydrogen peroxide to “bring them to the surface.” After reading about Morgellons disease on the Internet, he “recalled” extruding particles from his skin, including “dirt” and “fuzz.”
During the initial consultation visit with the psychiatrist, Mr. A was apprehensive but cautiously optimistic that a medication could help. The psychiatrist had been forewarned by the PCP that the patient had discovered a website describing Morgellons and “latched onto” this diagnosis.
However, it was notable that the patient allowed the possibility (“30%”) that he was suffering from delusions (and not Morgellons), mostly because he trusted his PCP, “who has taken very good care of me for many years.”
The patient agreed to a risperidone [an antipsychotic] trial of up to 2 mg per day. [i.e. a lowish dose]. Within weeks, his preoccupation with being infested lessened significantly... Although not 100% convinced that he might not have Morgellons disease, he is no longer pruritic and is no longer damaging his skin or trying to trap insects. He remains greatly improved 1 year later.
(Mr A. had also been HIV+ for 20 years, but he still had good immune function and the HIV may have had nothing to do with the case.)
"Morgellons" is, according to people who say they suffer from it, a mysterious disease characterised by the feeling of parasites or insects moving underneath the skin, accompanied by skin lesions out of which emerge strange, brightly-coloured fibres or threads. Other symptoms include fatigue, aches and pains, and difficulty concentrating.
According to almost all doctors, there are no parasites, the lesions are caused by the patient's own scratching or attempts to dig out the non-existent critters, and the fibres come from clothes, carpets, or other textiles which the patient has somehow inserted into their own skin. It may seem unbelievable that someone could do this "unconsciously", but stranger things have happened.
As the authors of this paper, Freudenreich et al, say, Morgellons is a disease of the internet age. It was "discovered" in 2002 by a Mary Leitao, with Patient Zero being her own 2 year old son. Since then its fame, and the reported number of cases, has grown steadily - especially in California.
Delusional parasitosis is the opposite of Morgellons: doctors believe in it, but the people who have it, don't. It's seen in some mental disorders and is also quite common in abusers of certain drugs like methamphetamine. It feels like there are bugs beneath your skin. There aren't, but the belief that there are is very powerful.
This then is the raw material in most cases; what the concept of "Morgellons" adds is a theory, a social context and a set of expectations that helps make sense of the otherwise baffling symptoms. And as we know expectations, whether positive or negative, tend to be become experiences. The diagnosis doesn't create the symptoms out of nowhere but rather takes them and reshapes them into a coherent pattern.
As Freudenreich et al note, doctors may be tempted to argue with the patient - you don't have Morgellons, there's no such thing, it's absurd - but the whole point is that mainstream medicine couldn't explain the symptoms, which is why the patient turned to less orthodox ideas.
Remember the extensive tests that came up negative "to the patient’s great frustration." And remember that "delusional parasitosis" is not an explanation, just a description, of the symptoms. To diagnose someone with that is saying "We've no idea why but you've imagined this". True, maybe, but not very palatable.
Rather, they say, doctors should just suggest that maybe there's something else going on, and should prescribe a treatment on that basis. Not rejecting the patient's beliefs but saying, maybe you're right, but in my experience this treatment makes people with your condition feel better, and that's why you're here, right?
Whether the pills worked purely as a placebo or whether there was a direct pharmacological effect, we'll never know. Probably it was a bit of both. It's not clear that it's important, really. The patient improved, and it's unlikely that it would have worked as well if they'd been given in a negative atmosphere of coercion or rejection - if indeed he'd agreed to take them at all.
Morgellons is a classic case of a disease that consists of an underlying experience filtered through the lens of a socially-transmitted interpretation. But every disease is that, to a degree. Even the most rigorously "medical" conditions like cancer also come with a set of expectations and a social meaning; psychiatric disorders certainly do.
I guess Morgellons is too new to be a textbook case yet - but it should be. Everyone with an interest in the mind, everyone who treats diseases, and everyone who's ever been ill - everyone really - ought to be familiar with it because while it's an extreme case, it's not unique. "All life is here" in those tangled little fibres.
Freudenreich O, Kontos N, Tranulis C, & Cather C (2010). Morgellons disease, or antipsychotic-responsive delusional parasitosis, in an hiv patient: beliefs in the age of the internet. Psychosomatics, 51 (6), 453-7 PMID: 21051675
Some ideas seem so nice, so inoffensive and so harmless, that it seems a shame to criticize them.
Take the idea that exercise is a useful treatment for depression. It's got something for everyone.
For doctors, it's attractive because it means they can recommend exercise - which is free, quick, and easy, at least for them - instead of spending the time and money on drugs or therapy. Governments like it for the same reason, and because it's another way of improving the nation's fitness. For people who don't much like psychiatry, exercise offers a lovely alternative to psych drugs - why take those nasty antidepressants if exercise will do just as well? And so on.
The authors took a large community sample of Norwegian people, the HUNT-2 study, which was done between 1995 and 1997. Over 90,000 people were invited to take part and full data were available from over 40,000.
What they found was that there was an association between taking part in physical exercise as a leisure activity, and lower self-reported symptoms of depression. It didn't matter whether the activity was intense or mild, and it didn't really matter how often you did it: so long as you did it, you got the benefit.
Crucially, however, the same was not true of physical exercise which was part of your job. That didn't help at all, and indeed the most strenuous jobs were associated with more depression (but less anxiety, strangely).
How does this fit with the verypopular idea that exercise helps in depression? Well, many randomized trials have indeed shown exercise to be better than not-exercize for depression, but the problem is that these trials are never really placebo controlled. You can usually tell whether or not you're going jogging in the park every morning.
So the direct effects of exercise per se are hard to distinguish from the social and psychological meaning of "exercise".Knowing that you're starting a program of exercise could make you feel better: you're taking positive action to improve your life, you're not helpless in the face of your problems. By contrast, doing heavy work as part of your job, while physiologically beneficial, is unlikely to be so much fun.
This doesn't mean that telling people to get more exercise isn't a good idea, but if the meaning of exercise is more important than the physiology, that has some big implications for how it ought to be used.
It's good news for people who just can't take part in strenuous physical exercise because of physical illness or disability, something which is quite common in mental health. It suggests that these people could still get the benefits attributed to exercise even if they did less demanding forms of meaningful activity.
But it's bad news for doctors tempted to default to "get out and go jogging" whenever they see a potentially depressed person. Because if it's the meaning of exercise that counts, and you recommend exercise in a way which sounds like you're dismissing their problems, the meaning will be anything but helpful.
In clinical trials of exercise, the exercise program has, almost by definition, a positive value: it's the whole point of the trial. And the participants just wouldn't have volunteered for the trial if they didn't, on some level, think it would make them feel better.
But not everyone thinks that way. If you go to your doctor looking to get medication, or psychotherapy, or something like that, and you're told that all you need to do is go and get more exercise, it would be easy to see that as a brush-off, especially if it's done unsympathetically. The point is, if exercise doesn't feel like a positive step, it probably won't be one.
Harvey SB, Hotopf M, Overland S, & Mykletun A (2010). Physical activity and common mental disorders. The British journal of psychiatry : the journal of mental science, 197, 357-64 PMID: 21037212
The characters are going about their lives, blissfully unaware that something horrifying is about to happen. You the viewer know that things are going to end badly, though, because you know it's a horror movie.
Someone opens a closet - a bloody corpse could fall out!Or they're drinking a glass of water - which could be infected with a virus! Or they're talking to some guy - who's probably a serial killer!And so on.
The effect of this - and a good director can get a lot of mileage from it - is that scenes which would otherwise be entirely mundane, are experienced as scary, purely because you know that something scary is going to happen, so you see potential horror in every innocent little thing. An expectation as to what's going to happen, leads to you interpreting events in a certain way, and this creates certain emotions.
In a medical context, that would be called a placebo effect. Or a nocebo effect when expectations make people feel worse rather than better.
The horror movie analogy is useful, because it shows that placebo effects don't just happen to other people. We all like to think that if we were given a placebo treatment, we wouldn't be fooled. Unlike all those silly, suggestible, placebo responders, we'd stay as sick as ever until we got a proper cure.
I wouldn't be so sure. We're always interpreting the world around us, and interpreting our own thoughts and feelings, on the basis of our expectations and beliefs about what's going on. We don't suddenly stop doing this when it comes to health.
Suppose you have the flu. You feel terrible, and you're out of aspirin. You don't think you'll be able to make that meeting this afternoon, so you phone in sick.
Now, clearly, flu is a real disease, and it really does make you feel ill. But how do you know that you wouldn't be able to handle the meeting? Unless you have an extensive history of getting the flu in all its various forms, this is an interpretation, a best guess as to what you'll feel in the future, and it might be too pessimistic.
Maybe, if you tried, you'd get on OK. Maybe if you had some aspirin that would reassure you enough to give it a go. And just maybe it would still have worked even if those "aspirins" were just sugar pills... Link: See my previous posts I Feel X, Therefore Y and How Blind is Double Blind?
Bear with me and I'll explain. It's less boring than it looks, trust me.
The Hamilton Scale (HAMD) is the most common system for rating the severity of depression. If you're only a bit down you get a low score, if you're extremely ill you get a high one. The maximum score's 52 but in practice it's extremely rare for someone to score more than 30.
First published in 1960, the HAMD is used in most depression research including almost all clinical trials of antidepressants. It's come under much criticism recently, but that's not the point here. The authors of the new paper, Kristen & von Wolff, simply asked: what does a given HAMD score mean in terms of severity?
It turns out that people have proposed no less than 5 different systems for interpreting HAMD scores. Do they all agree? Ha. Guess.
The pretty colors are mine. Just a glance shows a lot of variability, but the obvious outlier is the second one. That's the American Psychiatric Association (APA)'s official 2000 recommendations. Their interpretations of a given point on the scale tend to be worse than everyone else's.
This is most apparent at the top end. The APA use the terminology "Very Severe", which doesn't even appear on other scales. Much of what they class as "Very Severe" (23-26), two other scales class as "Moderate" depression! Amusingly, British authorities NICE seem to have been so unimpressed with this that they simply copied the APA's scale and toned everything down a notch for their 2009 criteria.
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Why does this purely terminological debate matter? Well. A number of recent studies, most notoriously Kirsch et al (2008), have shown that antidepressants work better in more severe cases. The cut-off for antidepressants being substantially better than placebo generally comes out as about 26 on the HAMD in these studies.
Under the APA's 2000 terminology, this is well into the "Very Severe" band. Hence why Kirsch et al wrote - in a phrase that launched a thousand "Prozac Doesn't Work" headlines -
antidepressants reach... conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category.
But for Bech, 26 is simply middle-of-the-road "major depression". For Furukawa, it's borderline "moderate" or "severe". Hmm. So if they'd gone with those criteria, Kirsch et al would have written instead
antidepressants reach... conventional criteria for clinical significance only for patients with major depression, of moderate-to-severe severity.
All of these terminological criteria are arbitrary, so this isn't necessarily more accurate, but it's no less so. The irony of the fact that Kirsch et al used the American Psychiatric Associations own criteria to skewer modern psychiatry isn't lost on me and probably wasn't lost on them either.
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But where did the APA get their system from? This is the most extraordinary thing. Here's the paper they based their approach on. It's an 1982 British study by Kearns et al. The authors wanted to see how the HAMD compared to other depression scales. So they used lots of scales on the same bunch of depressed patients and compared them to each other, and to their own judgments of severity. Here's what they found:
You'll recognize the APA's categories, kind of, but they're all shifted. Why? We can only guess. Here's my guess. The scores in that Kearns et al graph were the average HAMD scores of people who fell into each severity band. The APA must have decided that they could use these to create cutoffs for severity.
How? It's not at all clear. The mean score for "Moderate" was 18, but that's the topend of Moderate in the APA's book; ditto for "Mild". The average "Very Severe" was 30 and the average "Severe" was 21 so the cut-off should have been 25 or 26 if you just went for the midpoint, in fact the APA went with 23. And so on.
That's before we get into the question of whether you should be using these results to make cutoffs at all (you shouldn't.) And the APA seem to have ignored the fact that the HAMD did not statistically significantly distinguish between "Severe" and "Moderate" depression anyway (p=0.1). Kearns et al's graph shows that other scales, like the Melancholia Subscale ("MS"), would be better. But everyone's been using the HAMD for the past 50 years regardless.
In Summary: Interpreting the Hamilton Scale is a minefield of controversy and the HAMD is far from a perfect scale of depression. Yet almost everything we know about depression and its treatment relies on the HAMD. Don't believe everything you read.
Kriston, L., & von Wolff, A. (2010). Not as golden as standards should be: Interpretation of the Hamilton Rating Scale for Depression Journal of Affective Disorders DOI: 10.1016/j.jad.2010.07.011
Kearns, N., Cruickshank, C., McGuigan, K., Riley, S., Shaw, S., & Snaith, R. (1982). A comparison of depression rating scales The British Journal of Psychiatry, 141 (1), 45-49 DOI: 10.1192/bjp.141.1.45
I'm reading Le Rouge et le Noir ("The Red and the Black"), an 1830 French novel by Stendhal...
One passage in particular struck me. Stendhal is describing two characters who are falling in love (mostly); both are young, have lived all their lives in a backwater provincial town, and neither has been well educated.
In Paris, the nature of [her] attitude towards [him] would have very quickly become plain - but in Paris, love is an offspring of the novels. In three or four such novels, or even in a couplet or two of the kind of song they sing at the Gymnase, the young tutor and his shy mistress would have found a clear explanation of their relations with each other. Novels would have traced out a part for them to play, given them a model to imitate.
The idea that reading novels could change the way people fall in love might strange today, but remember that in 1830 the novel as we know it was still a fairly new invention, and was seen in conservative quarters as potentially dangerous. Stendhal was of course pro-novels (he was a novelist), but he accepts that they have a profound effect on the minds of readers.
Notice that his claim is not that novels create entirely new emotions. The two characters had feelings for each other despite never having read any. Novels suggest roles to play and models to follow: in other words, they provide interpretations as to what emotions mean and expectations as to what behaviours they lead to. You feel that, therefore you'll do this.
This bears on many things that I've written about recently. Take the active placebo phenomenon. This refers to cases in which a drug creates certain feelings, and the user interprets these feelings as meaning that "the drug is working", so they expect to improve, which leads them to feel better and behave as if they are getting better.
As I said at the time, active placebos are most often discussed in terms of drug side effects creating the expectation of improvement, but the same thing also happens with real drug effects. Valium (diazepam) produces a sensation of relaxation and reduces anxiety as a direct pharmacological effect but if someone takes it expecting to feel better, this will also drive improvement via expectation: the Valium is working, I can cope with this.
The same process can be harmful, though, and this may be even more common. The cognitive-behavioural theory of recurrent panic attacks is that they're caused by vicious cycles of feelings and expectations. Suppose someone feels a bit anxious, or notices their heart is racing a little. They could interpret that in various ways. They might write it off and ignore it, but they might conclude that they're about to have a panic attack.
If so, that's understandably going to make them more anxious, because panic is horrible. Anxiety causes adrenaline released, the heart beats ever faster etc., and this causes yet more anxiety until a full-blown panic attack occurs. The more often this happens, the more they come to fear even minor symptoms of physical arousal because they expect to suffer panic. Cognitive behavioural therapy for panic generally consists of breaking the cycle by changing interpretations, and by gradual exposure to physical symptoms and "panic-inducing" situations until they no longer cause the expectation of panic.
This also harks back to Ethan Watters' book Crazy Like Us which I praised a few months back. Watters argued that much mental illness is shaped by culture in the following way: culture tells us what to expect and how people behave when they feel distressed in certain ways, and thus channels distress into recognizable "syndromes" - a part to play, a model to imitate, though probably quite unconsciously. The most common syndromes in Western culture can be found in the DSM-IV, but this doesn't mean that they exist in the rest of the world.
Like Stendhal's, this theory does not attempt to explain everything - it assumes that there are fundamental feelings of distress - and I do not think that it explains the core symptoms of severe mental illness such as bipolar disorder and schizophrenia. But people with bipolar and schizophrenia have interpretations and expectations just like everyone else, and these may be very important in determining long-term prognosis. If you expect to be ill forever and never have a normal life, you probably won't.
An unexpected gem from last year's Journal of the American Psychoanalytic Association:Mind over medicine.
Surprisingly, it has nothing to do with psychoanalysis. Rutherford and colleagues performed a meta-analysis of lots of clinical trials of antidepressants. Neuroskeptic readers will be all too familiar with these. But they did an interesting thing with the data: they compared the benefits of antidepressants in trials with a placebo condition, vs. trials with no placebo arm, such as trials comparing one drug to another drug.
Why do that comparison? Because the placebo effect is likely to be stronger in trials with no placebo condition. If you volunteer for a placebo controlled trial, you'll know that you've got (say) a 50-50 chance of getting inactive sugar pills. You'll probably be uncertain whether or not you'll get better, maybe even quite worried. On the other hand if you're in a trial where you definitely will get a real drug, you can rest assured that you'll feel better - and that in itself might make your depression improve.
The paper only presents very preliminary results, but they say that:
Our group at Columbia has completed preliminary work involving metaanalyses of randomized controlled trials comparing antidepressant medications to a placebo or active comparator in geriatric outpatients with Major Depressive Disorder (Sneed et al. 2006). In placebo controlled trials, the medication response rate was 48% and the remission rate 33%, compared to a response rate of 62% and remission rate of 43% in the comparator trials (p < .05). The effect size for the comparison of response rate to medications in the comparator and placebo controlled trials was large (Cohen’s d = 1.2).
They only looked at trials of old age patients, but the same probably applies to everyone else.
Why does this matter? The authors suggest one very important implication. There are quite a few trials nowadays comparing the effects of psychotherapy, medication, neither, or both. How it works is that everyone gets pills, 50% of them real drugs and 50% placebos; also, half the people get psychotherapy while the others remain on the waiting list.
These trials often find that medication plus psychotherapy is better than just medication alone. This has led to the idea that therapy and drugs should be combined in clinical practice, a message which goes down really well, because it gives both psychopharmacologists and therapists the feeling that they have an important job to do. An example of this kind of trial is the influential TADS from 2004, finding that Prozac and therapy both work in depressed teens, and combining them is best. Everyone's a winner.
But as Rutherford et al. point out, there's a problem with this reasoning. The people who only get antidepressants don't know that they're getting any treatment, because they might be getting placebo. But the people who get antidepressants and therapy know that they're getting at least one real treatment (therapy). This is likely to improve their outcome through an expectation effect. (In fact, for some reason, in TADS, the people on combination treatment were told that they were getting both - they specifically knew they would never get dummy pills - which will have made this even worse.)
Now you could say that this doesn't matter: TADS and similar studies show that therapy and medication is better than just medication, and it's purely academic whether that's "just a placebo effect". But the key point is that in real life people always get medication knowing that it's real - so, like the therapy plus medication people in the trials, they get the benefit of the certainty that they are getting a real treatment. In the trials the medication-only group don't know that, but in real life they do - so the benefits of adding psychotherapy might be less, or even zero, in real life.
The authors of the TADS study did acknowledge this in their original paper, but only very briefly - here's all they say about it:
Blinding patients in the placebo and fluoxetine alone groups but not in the CBT alone group (participants knew they would not be receiving fluoxetine) and the fluoxetine combined with CBT group (participants knew that they would be receiving fluoxetine) may have interacted with expectancy effects regarding improvement and acceptability of treatment assignment.
Yet this limitation means they, strictly speaking, all TADS showed is that Prozac works in this group. It doesn't prove that adding (very expensive) therapy benefits anyone, in the real world. This is not to say that psychotherapy doesn't work of course, maybe it does, but the point is that therapy + medication trials may be best without a placebo.
Rutherford, B., Roose, S., & Sneed, J. (2009). Mind Over Medicine: the Influence of Expectations on Antidepressant Response Journal of the American Psychoanalytic Association, 57 (2), 456-460 DOI: 10.1177/00030651090570020909
Generally, when the list of the authors' conflicts of interest (550 words) is nearly as long as the text of the paper (740 words), it's not a good sign, but this one isn't bad. Perlis et al remind us that if you do a double-blind placebo controlled trial:
The blind may be compromised in a variety of ways, however, beginning with differences in medication taste or smell. Of particular concern may be the emergence of adverse effects, particularly when those adverse effects are known to be associated with a specific medication ... Indeed, when the degree of unblinding is assessed in antidepressant trials, multiple reports suggest that it is extensive: at least three-quarters of patients are typically able to correctly guess at their treatment assignment.
The point of a placebo-controlled trial is that neither the patients nor their doctors know whether they're getting the placebo or the real drug. Hence the strength of the placebo effect should be the same in each group, allowing the "real" drug effect to be measured.
But if the drug causes side effects, as pretty much all do, then people could work out which group they're in by noticing whether they're feeling side effects or not. This might enhance the placebo effect in the drug group, and make the drug seem to work better than it really does. Or it might not. But the possibility that it might is worrying.
This is called the active placebo effect. It's why I'm skeptical of claims that scopolamine and ketamine have rapid-acting but short lived antidepressant effects. I may be wrong, but while both of these drugs have been shown to work better than placebo, bothhave very pronounced subjective effects, so there's no chance the blind will have been intact.
Whether the active placebo effect also underlies the efficacy of established antidepressants like Prozac is very controversial. There have been 9 trials comparing antidepressants to active placebos, i.e. drugs that have similar side effects to antidepressants and that should therefore help to preserve the blind. (The active placebos were all atropine which is basically the same as scopolamine.)
The trials were reviewed by antidepressant critic Joanna Moncrieff et al who found that the overall effect size of antidepressants vs. active placebos was d = 0.39. That's not very high, although it's not too bad, and ironically it's actually higher than the effect that Moncrieff's friend and fellow Prozac-baiter Irving Kirsch found in his famous 2008 antidepressant vs. sugar pill placebo meta-analysis, d=0.32. So if you take that seriously, the active placebo effect plays no part in antidepressant efficacy. However the active placebo trials are mostly small and old, so to be honest, we don't really know.
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A point that's often overlooked is that a drug could have an active placebo effect via having a "real" psychoactive treatment effect. Diazepam (Valium), for example, has basically no peripheral side effects at all: unlike scopolamine it doesn't cause dry mouth, nausea, etc. But it is a tranquillizer; it causes calmness and, at higher doses, sleep. They're pretty noticeable. So if you were to give a depressed person Valium and tell them that it's not only a tranquillizer, it's an antidepressant, then the active placebo problem would arise.
In fact, any active drug will also produce active placebo effects - almost by definition, if you think about it. These may be hard to disentangle from the "real" effects. Say you're anxious about giving a speech so you take some diazepam hoping to feel calmer. A short while later you feel the lovely warm tranquillizing feeling setting in. Phew, you're calm now, anxiety's gone, the speech will be no worry. That thought might well be tranquillizing in itself. In other words the anti-anxiety effects of diazepam are partially driven by active placebo responses due to... the anti-anxiety effects of diazepam.
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This leads onto another point. Suppose a drug has a genuine effect which improves some of the symptoms of a disease. Does that drug "treat" that disease? In a weak sense, yes, and it might be a helpful drug, but it's not a specific treatment. Morphine's very helpful in cancer, because it treats pain, but it doesn't cure cancer. Likewise insomnia is a symptom of depression, but we feel that in order to qualify as an antidepressant a drug has to treat the core symptoms: mood, anxiety, etc. rather than just being a sleeping pill.
But suppose someone suffered from low mood and you gave them a treatment which stopped them feeling any moods or emotions. That solves their low mood problem: no mood, no problem. But is that a specific treatment for depression? It's a bit of a grey area, but many would say no.
Many people say that this is exactly what SSRI antidepressants do: they blunt your emotions. That doesn't mean they're not helpful in depression: a lot of people find them very useful. I did. But then are they really "antidepressants", or just anti-mood? SSRIs are the drugs of choice not just for depression but also most anxiety disorders, and obsessive-compulsive disorder, etc. In fact they work better in OCD than they do in depression, relative to placebo. So are SSRIs actually antiobsessives that happen to be helpful in some cases of depression? Good question.
Here's Chris Rock on the issue of non-specific effects...
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Perhaps an ideal clinical trial of a drug for a psychiatric condition should have 4 groups: the drug you're studying, another psychotropic with non-specific effects (e.g. Valium, or caffeine if you want a stimulant), an active placebo with purely peripheral side effects, and sugar pills. But even then, if the active drug performed better than the other 3 groups, a die-hard skeptic could say that maybe it's just more effectively causingnon-specific sedation, or blunting, or whatever, than the Valium. Ultimately, a randomized controlled trial can never prove that a psychotropic drug has a specific as opposed to a non-specific effect.
So where do we stand? Does that mean we don't know what drugs do? No - unless we're some cloistered soul who only reads papers as opposed to talking to people, reading subjective reports, or taking drugs themselves. I know what alcohol does, not because I've read papers about it, but because I've drunk it. I've also been depressed and taken antidepressants, and for what it's worth, in my experience, some of the drugs currently marketed as antidepressants do have a specific anti-depression effect, although others don't. Overall, though, my view is that we know surprisingly little about what antidepressants actually do.
Perlis RH, Ostacher M, Fava M, Nierenberg AA, Sachs GS, & Rosenbaum JF (2010). Assuring that double-blind is blind. The American journal of psychiatry, 167 (3), 250-2 PMID: 20194487
Moncrieff J, Wessely S, & Hardy R (2004). Active placebos versus antidepressants for depression. Cochrane database of systematic reviews (Online) (1) PMID: 14974002
Imagine there was a nasty disease that affected 1 in 100 people. And imagine that someone invented a drug which treated it reasonably well. Good work, surely.
Now imagine that, for some reason, people decided that 10% of the population need to be taking this drug, instead of 1%. So sales of the drug sky-rocket. Eventually some clever person comes along and asks "This is one of the biggest selling drugs in the world - but does it work?" They look into it, and find that it doesn't work very well at all. For about 9 out of 10 people, it's completely useless! What a crap drug.
Of course the drug hasn't changed, and what's crap was the decision to prescribe it to so many people.
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Back to reality. According to accepted DSM-IV diagnostic criteria, close to 50% of people suffer from a mental illness at some point; a large fraction of this being depression. 10% of Americans took antidepressants last year according to the best estimates.
Guess what? Clever people have started asking "Antidepressants are amongst the biggest selling drugs in the world - but do they work?"And their answer is - not very well. The latest such claim came from Fournier et al and appeared in JAMA a couple of weeks ago: Antidepressant Drug Effects and Depression Severity.
These researchers re-analysed the data from six clinical trials testing antidepressants against placebo pills. The drugs were the tricyclic imipramine and the newer SSRI paroxetine. The total sample size was a respectable 718, and most trials lasted 8 weeks, which is longer than average for this kind of study. Here's what they found -
Grey circles are people on antidepressants, white circles people on placebo. What this shows is that the more severe the patient's depression, the more they get better - when they're given either drugs or placebos. However, because the improvement on antidepressants rises more steeply, the benefit of antidepressants versus placebos correlates with severity. The thin blue line marks the minimum severity for which the average effect of the drugs over placebo was "clinically significant" according to NICE criteria (although these are arbitrary).
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So, this study says that antidepressants work better in more severe depression. This is not a new claim - Kirsch et al (2008) famously found the same thing, and long before that so did Khan et al (2002). However this new analysis has some advantages over previous ones. First, Fournier et al looked at what happened to each patient individually, whereas the previous studies found that in trials where the patients were more severely depressed, on average, antidepressants worked better.
Second, the patients in this analysis spanned a wide range of severity scores, from 10 points on the Hamilton Scale to nearly 40. In Kirsch et al almost all the trials had average severities in the narrow range of 22 to 29. Finally, none of the trials in the new paper used a placebo run-in period. These are meant to exclude people from the trial if they improve "too well" during an initial week or so of placebo pills. In theory, they bias trials against finding large placebo effects; it's not clear they actually work, but either way, it's good to know it wasn't a factor.
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Overall, the evidence all seems to point to the idea that people with more serious clinical depression respond better to antidepressants vs. placebos in clinical trials. The exact details are debatable, there's the issue of whether antidepressant clinical trials are realistic, and the question of how clinically effective antidepressants are is also controversial, but I'm not aware of any studies which have contradicted this central claim.
But when you start to think about it, this is a very odd result. Fournier et al say that
The general pattern of results reported in this work is not surprising. As early as the 1950s, researchers conducting controlled investigations of treatments for a wide variety of medical and psychiatric conditions described a phenomenon whereby patients with higher levels of severity showed greater differential (i.e., specific) benefit from the active treatments.
and refer to a couple of papers from the 1960s. But I must admit that I do find this very surprising. We don't wait until someone's nearly dead from a bacterial infection before we give them antibiotics, we give them early, when the disease is still mild. Doctors unfortunately don't tell people "Good news! You've got advanced-stage cancer - just the kind where drugs work best." Why is depression so different?
Look a little closer, and a possible answer emerges. Severity, in all of these studies, was measured using the Hamilton Rating Scale for Depression (HAMD). The HAMD has 17 items, and each asks whether you're suffering from certain symptoms; the more symptoms you have, and the more pronounced they are, the higher your total score. You get 1 point if you have "occasional difficulty falling asleep", 2 points for "nightly difficulty falling asleep", 4 points for "Hand wringing, nail biting, hair-pulling, biting of lips". Here's the whole thing.
The HAMD was designed in 1960 by a psychiatrist, Max Hamilton, and it was originally intended for use by staff at psychiatric hospitals for use on depressed inpatients. So it's not a measure of severity per se: it's a measure of how well your symptoms match those considered to be characteristic of severe depression in 1960.
Psychiatry's concept of depression - not to mention the wider culture's - has changed greatly since then. 1960 was a full 20 years before the DSM-III criteria of depression were published, which form the basis for today's DSM-IV criteria. A quick comparison of the DSM-IV alongside the HAMD reveals a lot of differences. It's quite possible to meet DSM-IV criteria for "Major Depressive Disorder" yet score low on the HAMD.
Which brings us back to the imaginary scenario at the start of this post. My personal interpretation of results like those of Fournier et al is this: antidepressants treat classical clinical depression, of the kind that psychiatrists in 1960 would have recognized. This is the kind of depression that they were originally used for, after all, because the first antidepressants arrived in 1953, and modern antidepressants like Prozac target the same neurotransmitter systems.
Yet in recent years "clinical depression" has become a much broader term. Many people attribute this to marketing on the part of pharmaceutical companies. Whatever the cause, it's almost certain that many people are now being prescribed antidepressants for emotional and personal issues which wouldn't have been considered medical illnesses until quite recently. (Antidepressants also have a long history of use for other conditions, like OCD, but this is a separate issue.)
My imaginary story used made up numbers: I'm not saying that only 10% of the people on antidepressants have "classic" depression. I don't know what the % is. But apart from that, in my opinion (and I don't think I'm alone), it's far from fantasy.
Fournier, J., DeRubeis, R., Hollon, S., Dimidjian, S., Amsterdam, J., Shelton, R., & Fawcett, J. (2010). Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis JAMA: The Journal of the American Medical Association, 303 (1), 47-53 DOI: 10.1001/jama.2009.1943
As I described last week, Desiree Jennings is a young woman from Virginia who developed horrible symptoms, including muscle spasms and convulsions, after getting a flu vaccine. It looked a bit like a form of brain damage called dystonia.
Numerous neurologists concluded that her illness was mostly or entirely psychogenic. A certain Dr Rashid Buttar, however, said that she was suffering from neurological damage caused by toxins in the flu vaccine.
Buttar gave her chelation therapy to flush the toxins out. Within 15 minutes, she was cured. Biologically speaking, this is ludicrous. It's flat-out impossible that chelation could reverse brain damage in 15 minutes, even if Jennings did have brain damage in the first place.
But Buttar's treatment worked, amazingly well by all accounts. This is not surprising, because the illness was psychological in nature, and Dr Buttar's treatment was, psychologically, very effective. Jennings was admitted to Dr Buttar's private clinic; she had IV lines put in to her arm; Dr Buttar attached the chelation treatment to the IV drip and, in a textbook example of how to produce a placebo effect:
The magic did indeed happen, precisely because Dr Buttar convinced Jennings that it would.
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What would have happened to Jennings if there were no Dr Buttars in the world? Her doctors would have run scans and tests to check if Jennings had any neurological damage. The results would have been normal. Jennings would probably have interpreted this as "We don't know what's wrong with you", although experts would have suspected that the symptoms were most likely psychogenic.
At some point, someone would have had to raise that possibility with her. But the point about psychogenic illness is that it's not "faking", "acting" or "made up" - the patient believes they are ill. The symptoms don't feel psychogenic. This is why people often interpret the suggestion that symptoms are psychogenic as saying "you're not really ill" and hence "you're either lying, or crazy". Of course, patients suffering from psychogenic illness are neither, and they know it.
So, without complementary and alternative medicine, Jennings might have ended up believing herself to be suffering from an illness so obscure that doctors were unable to diagnose it, and hence, unable to cure it. A hopeless situation. A worse thing for someone with psychogenic symptoms to believe is hard to imagine.
Dr Buttar's treatment was psychologically very powerful - precisely because he believed in it, so he was able to convince Jennings to believe in it. A doctor who realized that Jennings' symptoms were psychogenic would have found it much harder to achieve the same result. In order to do so, they would have to lie to her, by pretending to believe in a treatment which they knew was just a placebo. This is hard - the doctor would need to be an excellent actor as well as a medic - not to mention ethically tricky.
Interestingly, 100 years ago, this problem wouldn't have arisen. Doctors knew much less about diagnosis and there were few laboratory tests or scans in those days, so there was usually no way to prove that some symptoms were organic and others were psychogenic. Everyone got the same treatment. Of course, the treatments back then were less good at treating organic illnesses, but that wouldn't necessarily have made them any worse as placebos. Ironically, as mainstream medicine gets better and better at diagnosing and treating disease, it may be getting worse at dealing with psychogenic symptoms. [BPSDB]
Previously I wrote about a small study finding that smoked marijuana helps with HIV-related pain. In the last month, two more clinical trials of medical marijuana - or rather, marijuana-based drugs - for pain have come out.
First, the good news. Johnson et al tested a mouth spray containing the two major psychoactive chemicals in marijuana, THC and CBD. Their patients were all suffering from terminal cancer, which believe it or not, is quite painful. Almost all of the subjects were already taking high doses of strong opiate painkillers: a mean of 270 mg morphine or equivalent each day, which is enough to kill someone without a tolerance. (A couple of them were on an eye-watering 6 grams daily). Yet they were still in pain.
Patients were allowed to use the cannabinoid spray as often as they wanted for 2 weeks. Lo and behold, the THC/CBD spray was more effective than an inactive placebo spray at relieving pain. The effect was modest, but statistically significant, and given what these people were going through I'm sure they were glad of even "modest" effects. A third group got a spray containing only THC, and this was less effective than the combined THC/CBD - on most measures, it was no better than placebo. THC is often thought of as the single "active ingredient" in marijuana, but this suggests that there's more to it than that. This was a relatively large study - 177 patients in total - so the results are pretty convincing, although you should know that it was funded and sponsored by GW Pharma, whose "vision is to the global leader in prescription cannabinoid medicines". Hmm.
The other trial was less promising, although it was in a completely different group - patients with painful diabetic neuropathy. The people in this study were in pain despite taking tricyclic antidepressants, which, curiously, are quite good at relieving neuropathic pain. Again, the treatment was a combined CBD/THC spray, and this trial for lasted 12 weeks. The active spray was no more effective than the placebo spray this time around - both groups improved a lot. This was a small trial (just 29 patients), so it might just have not been big enough to detect any effect. Also, this one wasn't funded by a pharmaceutical company.
Overall, this is further evidence that marijuana-based drugs can treat some kinds of pain, although maybe not all of them. I have to say, though, that I'm not sure that we needed a placebo-controlled trial to tell us that terminal cancer patients can benefit from medical marijuana. If someone's dying from cancer, I say let them use whatever the hell they want, if they find it helps them. Dying patients used to be given something called a Brompton cocktail, a mixture of drugs that would make Keith Richards jealous: heroin, cocaine, marijuana, chloroform, and gin, in the most popular variant.
And why not? There were no placebo-controlled trials proving that it worked, but it seemed to help, and even if it was just a placebo (which seems unlikely), placebo pain relief is still pain relief. I'm not saying that these kinds of trials aren't valuable, but I don't think we should demand cast-iron proof that medical marijuana works before making it available to people who are suffering. People are suffering now, and trials take time.
Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, & Fallon MT (2009). Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study of the Efficacy, Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients With Intractable Cancer-Related Pain. Journal of pain and symptom management PMID: 19896326
Selvarajah D, Gandhi R, Emery CJ, & Tesfaye S (2009). A Randomised Placebo Controlled Double Blind Clinical Trial of Cannabis Based Medicinal Product (Sativex) in Painful Diabetic Neuropathy: Depression is a Major Confounding Factor. Diabetes care PMID: 19808912
13.15
wsn
But all that changed - when she suffered a stroke. This is according to a brief case report from Drs. Diamond and Ondo of Texas:
The authors make some vague comments about "modulation of the cortical–subcortical circuits" but this is really the neuroscientific equivalent of saying "We guess it did something", because the entire brain is made of cortical-subcortical circuits, given that the cortex is at the top and everything else is, by definition, the sub-cortex. It's quite possible. But we really can't tell.
Diamond A, & Ondo WG (2011). Resolution of Severe Obsessive-Compulsive Disorder After a Small Unilateral Nondominant Frontoparietal Infarct. The International journal of neuroscience PMID: 21426244
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