Real vs Placebo Coffee

Coffee contains caffeine, and as everyone knows, caffeine is a stimulant. We all know how a good cup of coffee wakes you up, makes you more alert, and helps you concentrate - thanks to caffeine.


Or does it? Are the benefits of coffee really due to the caffeine, or are there placebo effects at work? Numerous experiments have tried to answer this question, but a paper published today goes into more detail than most. (It caught my eye just as I was taking my first sip this morning, so I had to blog about it.)

The authors took 60 coffee-loving volunteers and gave them either placebo decaffeinated coffee, or coffee containing 280 mg caffeine. That's quite a lot, roughly equivalent to three normal cups. 30 minutes later, they attempted a difficult button-pressing task requiring concentration and sustained effort, plus a task involving mashing buttons as fast as possible for a minute.

The catch was that the experimenters lied to the volunteers. Everyone was told that they were getting real coffee. Half of them were told that the coffee would enhance their performance on the tasks, while the other half were told it would impair it. If the placebo effect was at work, these misleading instructions should have affected how the volunteers felt and acted.

Several interesting things happened. First, the caffeine enhanced performance on the cognitive tasks - it wasn't just a placebo effect. Bear in mind, though, that these people were all regular coffee drinkers who hadn't drunk any caffeine that day. The benefit could have been a reversal of caffeine withdrawl symptoms.

Second, there was a small effect of expectancy on task performance in the placebo group - but it worked in reverse. People who were told that the coffee would make them do worse actually did better than those who expected the coffee to help them. Presumably, this is because they put in extra effort to try to overcome the supposedly negative effects. This paradoxical placebo response reminds us that there's more to "the placebo effect" than meets the eye.

Finally, no-one who got the decaf noticed that it didn't actually contain caffeine, and the volunteer's ratings of their alertness and mood didn't differ between the caffeine and placebo groups. So, this suggests that if you were to secretly replace someone's favorite blend with decaf, they wouldn't notice - although their performance would nevertheless decline. Bear that in mind when considering pranks to play on colleagues or flatmates.

It looks like science has just confirmed another piece of The Wisdom of Seinfeld:

Elaine: Jerry likes Morning Thunder.
George: Jerry drinks Morning Thunder? Morning Thunder has caffeine in it. Jerry doesn't drink caffeine.
Elaine: Jerry doesn't know Morning Thunder has caffeine in it.
George: You don't tell him?
Elaine: No. And you should see him. Man, he gets all hyper, he doesn't even know why! He loves it. He walks around going, "God, I feel great!"
- Seinfeld, "The Dog"

[BPSDB]

Harrell PT, & Juliano LM (2009). Caffeine expectancies influence the subjective and behavioral effects of caffeine. Psychopharmacology PMID: 19760283

A Weighty Issue

The BBC asks - "Why are fat people abused? Why is "fattism" seen by many as an acceptable prejudice?"

Psychoanalyst Susie Orbach explains or tries to:

Often the assumption is that overweight people have lost their self-control. That frightens society because there is so much emphasis on being slim, she says.

"Often it's not the larger person's excess weight that is the problem, it's the other people's obsession with being thin. Most people want to be slim, but this perceived physical perfection is difficult to hold on to and they fear losing control of it. Women and men can be on diets their whole lives and it's utterly miserable. They project that fear and unhappiness on to people who are bigger and that often translates into abuse and attacks. It's a way of people disassociating themselves from what they fear the most - getting fat."

But this is pure psychobabble. Like saying that all homophobes are repressed homosexuals, it's satisfying, but not true. (Although...) Most people fear cancer, but we don't "project" this fear onto others by accusing them of having it, or hating people who do have it. Orbach seems to still adhere to the Freudian idea that obvious explanations of human behaviour are usually wrong, and that people's true motives are unconscious, and usually embarrassing.

The truth is more straightforward. For various cultural and historical reasons most of us prefer thinness to fatness. And crucially we see weight as something people have personal control over. Far from fearing that overweight people have lost their self-control, we think they choose not to use it.

This is why it's "OK" to not like fat people; just as it's OK to not like criminals, selfish people, racists, etc. It's "their fault". Whereas it's not OK to make fun of people with one leg, deaf people, people with genetic disorders and so on. They "can't help it".

But there are grey areas, and this is where it gets interesting. People with cancer deserve sympathy... unless perhaps it's "their fault" for getting it, e.g. lung cancer from heavy smoking. Paedophiles deserve severe punishment... unless perhaps it's not their fault. How could it not be? How about if they developed a compulsive urge to view child porn due to the medication they were taking for Parkinson's disease? Or if they started abusing their daughter because of a brain tumour?

This is why one Kathryn Szrodecki, who campaigns on behalf of overweight people, is quoted by the BBC as saying

"We're simply not all built to be slim, our genetic make-ups are all different."

In other words: actually it's not our fault. Likewise, conservatives say homosexuality is a choice; liberals say it's something you're born being. Both sides implicitly agree that if something's not a choice, it's wrong to treat people badly for it. In an attempt to destigmatize clinical depression, a billboard famously proclaimed that "Depression is a flaw in chemistry not character" - it's not your fault.

The trend at the moment is towards things being no-one's fault. It's happened to everything from drug and alcohol addiction to antisocial and criminal behaviour (as ADHD, Conduct Disorder, Personality Disorders, etc.) By contrast, I can't think of anything which has moved in the other direction. Of course, not everyone accepts that, say, addiction is a disease. Many people still think it's a moral issue. But they're on the back foot. The wind is blowing in the other direction.

We can expect even more of this in the future, as neuroscience and genetics find biological causes and correlates of ever more behaviours. Brain scans in particular have a seductive allure when it comes to making things seem to be outside the sphere of choice. As for how valid any of this is, well, that's another story. But if the fat acceptance movement wants to advance their cause, finding a few fMRI scans might be the best way to do it.

More Antidepressant Debates

Six months ago, I asked What's The Best Antidepressant?, and I discussed a paper by Andrea Cipriani et al. The paper claimed that of the modern antidepressants, escitalopram (Lexapro) and sertraline (Zoloft) offer the best combination of effectiveness and mild side effects, and that sertraline has the advantage of being much cheaper.

The Cipriani paper was a meta-analysis of trials comparing one drug against another. With a total of over 25,000 patients, it boasted an impressively large dataset, but I advised caution. Their method of crunching the numbers (indirect comparisons) was complex, and rested on a lot of assumptions.

I wasn't the only skeptic. Cipriani et al has attracted plenty of comments in the medical literature, and they make for some fascinating reading. Indeed, they amount to crash-course in the controversies surrounding antidepressants today - a whole debate in microcosm. So here's the microcosm, in a nutshell:

*

In The Lancet, the original paper was accompanied by glowing praise by one Sagar Parikh:

Free of any potential funding bias... Now, the clinician can identify the four best treatments... A new gold standard of reliable information has been compiled for patients to review.

But critical comments swiftly appeared in the Lancet's letters pages. While not accusing Cipriani and colleagues themselves of bias or conflicts-of-interest, Tom Jefferson noted that way back in 2003, David Healy drew attention to:

documents that a communications agency acting on behalf of the makers of sertraline were forced to make available by a US court. Among them was a register of completed sertraline studies awaiting to be assigned to authors. This practice (rent-a-key-opinion-leader) is of unknown prevalence but it undermines any attempt at reviewing the evidence in a meaningful way.

This is what's known as medical ghostwriting, and it is indeed a scandal. However, by itself, ghostwriting doesn't distort evidence as such. It's what's published - or not published - that counts. Almost all antidepressant trials are run and funded by drug companies. All too often, they just don't publish data showing their products in an unfavourable light. The fearsome John Ioannidis - known for writing papers with titles like Why most published research findings are false - pulled no punches in reminding readers of this, in his letter:

Among placebo controlled antidepressant trials registered with the US FDA, most negative results are unpublished or published as positive. Take sertraline, which Cipriani and colleagues recommend as the best ... of five FDA-registered trials, the only positive trial was published, one negative trial was published as positive, and three negative trials were unpublished. Head-to-head comparisons can suffer worse bias, since regulatory registration is uncommon. Meta-analysis of published plus industry-furnished data could spuriously suggest that the best drugs are those with the most shamelessly biased data ...

Ioannidis also noted that Cipriani did not include placebo-controlled trials in their analysis. He helpfully provided a table showing that if you do include these trials, the ranking of antidepressants is very different:

Of course, Ioannidis was not saying that the drug-vs-placebo data is better than the drug-vs-drug trials. After all, he had just declared it to be biased. But neither is it necessarily worse, and there's no good reason not to consider it.

Cipriani et al's response to their critics was a little light on detail. In response to concerns of industrial publication bias, they said that:

we contacted the original authors and pharmaceutical companies to obtain further data or to confirm reported figures.

But of course the pharmaceutical companies were under no obligation to play ball. They could just have chosen not to reveal embarrassing data. Rather more reassuring is the fact that the original paper did look for correlations between the drug company running each trial, and the results of the trial; they didn't find any. Rather cheekily, Cipriani et al then went on to suggest that they were the ones who were sticking it to Big Pharma:

The standard thinking has become that most antidepressants are of similar average efficacy and tolerability ... In some ways, this is a comfortable position for industry and its hired academic opinion leaders—it sets a low threshold for the introduction of new agents which can initially be marketed on the basis of small differences in specific adverse effects rather than on clear advantages in terms of overall average efficacy and acceptability.

They certainly have a point here. If aspiring antidepressants had to be proven better than existing ones in order to be sold, instead of just as good, there would probably have been no new antidepressants since Prozac in 1990. (And Prozac is only "better" than the drugs available in 1960 in that it's safer and has fewer side effects; it's no more effective.)

But this is not really relevant to whether the Cipriani analysis is valid. And in The Lancet letters, the authors did not address some of the criticisms, such as Ioannidis's point about including placebo-controlled trials, at all. They do point out that their raw data is available online for anyone to play around with.

The debate continued in the pages of Evidence Based Mental Health. In 2008, Gerald Gartlehner and Bradley Gaynes conducted a rather similar meta-analysis, but they reached very different conclusions. They declared that all post-1990 antidepressants are equally effective (or ineffective).

In their comments on the Cipriani paper, Gartlehner and Gaynes say that they were just more cautious in interpreting the results of a complex and problematic statistical process:

Ranking sertraline and escitalopram higher than other drugs conveys a precision
and existence of clinically important differences that is not reflected in the body of evidence. ...for sertraline and escitalopram the range of probabilities actually extends from the first to the eighth rank for both efficacy and acceptability... the validity of results of indirect comparisons depends on various assumptions, some of which are unverifiable ... We simply took underlying uncertainties into greater consideration and interpreted findings more cautiously than Cipriani and colleagues.

They also accuse Cipriani et al of various technical shortcomings - and in a meta-analysis, such 'technicalities' can often greatly the skew the results:

they included studies with very different populations such as frail elderly, patients with accompanying anxiety and inpatients as well as outpatients ... the effect measure of choice was odds ratios rather than relative risks. Odds ratios have mathematical advantages that statisticians value. Practitioners, however, frequently overestimate their clinical importance...

Cipriani et al respond to some of these technical criticisms, while admitting that their analysis has limitations. But, they say, even an imperfect ranking of antidepressants is better than none at all:

We have a choice. We may either make the best use of the available randomised evidence or we essentially ignore it. We believe that it is better to have a set of criteria based on the available evidence than to have no criteria at all... We believe that, despite the likely biases of the included trials, and the limitations of our approach, our analysis makes the best use of the randomised evidence, providing clinicians with evidence based criteria that can be used to guide treatment choices.

*

What are we to make of all this? Here's my two cents. It's implausible that all antidepressants are truly equally effective. They affect the brain in different ways. The pharmacological differences between SSRIs such as Prozac, Zoloft and Lexapro are minimal at best but mirtazapine and reboxetine, say, target entirely different systems. They work differently, so it would be odd if they all worked equally well.

The search phrase that most often leads people to this blog is "best antidepressant". People really want to know which antidepressant is most likely to help them. In truth, everyone responds differently to every drug, so there is no one best treatment. But Cipriani et al are quite right that even a roughly correct ranking could help improve the treatment of people with depression, even if the differences are tiny. If Drug X helps 1% more people than Drug Y on average, that's a lot of people when 30 million Americans take antidepressants every year.

So, what is the best antidepressant, on average? I don't know. But maybe it's escitalopram or sertraline. Stranger things have happened.

Ioannidis JP (2009). Ranking antidepressants. Lancet, 373 (9677) PMID: 19465221

Gartlehner, G., & Gaynes, B. (2009). Are all antidepressants equal? Evidence-Based Mental Health, 12 (4), 98-100 DOI: 10.1136/ebmh.12.4.98

Barack Obama Boosts Testosterone

But only if you voted for him, and only if you're a man. That's according to a PLoS One paper called Dominance, Politics, and Physiology.

It's already known that in males, winning competitions - achieving "dominance" - causes a rapid rise in testosterone release, whilst losing does the opposite. That's true in humans, as well as in other mammals. The authors wondered whether the same thing happens when men "win" vicariously - i.e. when someone we identify with triumphs.

What better way of testing this than the U.S. Presidential Election? The authors took 163 American voters, and got them to provide saliva samples before, during and after the results came in on the night of the 4th November. Here's what happened -

In Obama supporters (the blue line, natch), salivary testosterone levels stayed flat throughout the crucial hours. But supporters of John McCain or Libertarian candidate Bob Barr, suffered a testosterone crash after Obama's victory became apparent. That was only true in men, though; in women, there was no change.

Heh. Of course, we hardly needed biology to tell us that people often identify strongly with their preferred political parties, and the fact that social events cause hormonal changes shouldn't surprise anyone - the brain controls the secretion of most hormones.

The gender difference is interesting, though. Does this mean that men identify closer with politicians? Or maybe only with male ones - what would have happened if Hilary had won... or Palin? It could be that the testosterone surge accompanying success is strictly a man thing, although it's been shown to occur in women in some studies, but not consistently.

Finally, I should mention that this paper contains some excellent quotes, such as "...Robert Barr, who arguably did not have a chance of winning...", "In retrospective reports of their affective state upon the announcement of Obama as the president-elect, McCain and Barr voters felt significantly more unhappy" and my favourite, "men who voted for John McCain or Bob Barr (losers)". That last one may be taken slightly out of context.

Stanton, S., Beehner, J., Saini, E., Kuhn, C., & LaBar, K. (2009). Dominance, Politics, and Physiology: Voters' Testosterone Changes on the Night of the 2008 United States Presidential Election PLoS ONE, 4 (10) DOI: 10.1371/journal.pone.0007543

Deep Brain Stimulation for Depressed Rats

Deep-brain stimulation (DBS) is probably the most exciting emerging treatment in psychiatry. DBS is the use of high-frequency electrical current to alter the function of specific areas of the brain. Originally developed for Parkinson's disease, over the past five years DBS has been used experimentally in severe clinical depression, OCD, Tourette's syndrome, alcoholism, and more.

Reports of the effects have frequently been remarkable, but there have been few scientifically rigorous studies, and the number of psychiatric patients treated to date is just dozens. So the true usefulness of the technique is unclear. How DBS works is also a mystery. Even the most basic questions - such as whether high-frequency stimulation switches the brain "on" or "off" - are still being debated.

Recent data from rodents sheds some important light on the issue: Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats. The authors took rats, and implanted DBS electrodes in the infralimbic cortex. This area is part of the vmPFC. It's believed to be the rat equivalent of the human region BA25, the subgenual cingulate cortex, which is the most common target for DBS in depression. The current settings (100 microA, 130 Hz, 90 microsec) were chosen to be similar to the ones used in humans.

In a standard rat model of depression, the forced-swim test, infralimbic DBS exerted antidepressant-like effects. DBS was equally as effective as imipramine, a potent antidepressant, in terms of reducing "depression-like" behaviours, namely immobility.

This is not all that surprising. Almost everything which treats depression in humans also reduces immobility in this test (along with few things which don't treat it). Much more interesting is what did and did not block the effects of DBS in these rats.

First off, DBS worked even when the rat's infralimbic cortex had been destroyed by the toxin ibotenic acid. This strongly suggests that DBS does not work simply by activating the infralimbic cortex, even though this is where the electrodes were implanted.

Crucially, infralimbic lesions did not have an antidepressant effect per se, which also rules out the theory that DBS works by inactivating this region. (Infralimbic lesions produced by other methods did have a mild antidepressant effect, but it was smaller than the effect of DBS. This may still be important, however.)

What did block the effects of DBS was the depletion of serotonin (5HT). Serotonin is known to its friends as the brain's "happy chemical", although it's a bit more complicated than that. Most antidepressants target serotonin. And rats whose serotonin systems had been lesioned got no benefit from DBS in this study.

So this suggests that DBS might work by affecting serotonin, and indeed, DBS turned out to greatly increase serotonin release, even in a distant part of the brain (the hippocampus). Interestingly this lasted for nearly two hours after the electrodes were switched off.

Depletion of another neurotransmitter, noradrenaline, did not alter the effects of DBS.

Overall, it seems that infralimbic DBS works by increasing serotonin release, but that this is not because it activates or inactivates the infralimbic cortex itself. Rather, nearby structures must be involved. The most likely explanation is that DBS affects nearby white-matter tracts carrying signals between other areas of the brain; the infralimbic cortex might just happen to be "by the roadside". Many researchers believe that this is how DBS works in humans, but this is the first hard evidence for this.

Of course, evidence from rats is never all that hard when it comes to human mental illness. We need to know whether the same thing is true in people. As luck would have it, you can temporarily reduce human serotonin levels with a technique called acute tryptophan depletion This reverses the effects of antidepressants in many people. If this rat data is right, it should also temporarily reverse the benefits of DBS. Someone should do this experiment as soon as possible - I'd like to do it myself, but I'm British, and all the DBS research happens in America. Bah, humbug, old bean.

There's a couple of others things to note here. In other behavioural tests, infralimbic DBS also had antidepressant-like effects: it seemed to reduce anxiety, and it made rats more resistant to the stress of having electrical shocks (although only slightly.) Finally, DBS in another region, the striatum, had no antidepressant effect at all. That's a bit odd because DBS of the striatum does seem to treat depression in humans - but the part of the striatum targeted here, the caudate-putamen, is quite separate to the one targeted in human depression, the nucleus accumbens.

Hamani, C., Diwan, M., Macedo, C., Brandão, M., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A., Fletcher, P., & Nobrega, J. (2009). Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats Biological Psychiatry DOI: 10.1016/j.biopsych.2009.08.025