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:

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.

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.

Among placebo controlled antidepressant trials registered with the US FDA, most negative results are unpublished or published as positive.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the only positive trial was published, one negative trial was published as positive, and three negative trials were unpublished.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 ...

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

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.

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 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...

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.

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

Antidepressant sales are rising in most Western countries, and they have been for at least a decade. Recently, we learned that the proportion of Americans taking antidepressants in any given year nearly doubled from 1996 to 2005.

The situation has been thought to be similar in the UK. But a hot-off-the-press paper in the British Medical Journal reveals some surprising facts about the issue: Explaining the rise in antidepressant prescribing.

The authors examined medical records from 1.7 million British patients in primary care (General Practice, i.e. family doctors.) They found that antidepressant sales rose strongly between 1993 and 2005, not because more people are taking these drugs, but entirely because of an increase in the duration of treatment amongst the antidepressant users. It's not that more people are taking them, it's that people are taking them for longer.

In fact, the number of people being diagnosed with depression and prescribed antidepressants has actually fallen over time. The rate of diagnosed depression remained steady from 1993 to about 2001, and then fell markedly, by about a third, up to 2005. This trend was seen in both men and women, but there were age differences. In 18-30 year olds, there was a gradual increase in diagnoses before the decrease. (Note that these graphs show the number of people getting their first ever diagnosis of depression in each year.)
The likelihood of being given antidepressants for a diagnosis of depression stayed roughly constant, at about 75-80% across the years. However, the average duration of treatment increased over time -

The change doesn't look like much, but remember that even a small change in the number of long-term users translates into a large effect on the total number of sales, because each long-term user takes a lot of pills. The authors conclude

Last month Wired, announced that Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why.

The article's a good read, and the basic story is true, at least in the case of psychiatric drugs. In clinical trials, people taking placebos do seem to get better more often now than in the past (paper). This is a big problem for Big Pharma, because it means that experimental new drugs often fail to perform better than placebo, i.e. they don't work. Wired have just noticed this, but it's been being discussed in the academic literature for several years.

Why is this? No-one knows. There have been many suggestions - maybe people "believe in" the benefits of drugs more nowadays, so the placebo effect is greater; maybe clinical trials are recruiting people with milder illnesses that respond better to placebo, or just get better on their own. But we really don't have any clear idea.

What if the confusion is because of the very concept of the "placebo"? Earlier this year, the BMJ ran a short opinion piece called It’s time to put the placebo out of our misery. Robin Nunn wants us to "stop thinking in terms of placebo...The placebo construct conceals more than it clarifies."

The placebo is the most talked-about treatment in medicine.

Everyone's heard of the "placebo effect", by which pills containing no drugs at all, just chalk and sugar, often seem to make people feel better. But if the mere expectation of improvement can produce improvement, then the expectation of unpleasant consequences, such as side effects, should make people feel worse. This is sometimes called the "nocebo" effect.

Two recently published papers tried to measure it. They looked at people who took part in randomized controlled trials of various drugs, and who were given placebos. Because different drugs have different known side effects, if the nocebo effect is real, the side effects reported by the placebo group should depend on the drug they think they might be taking. As the authors of one of the papers put it:

"Statistically, airplane travel is safer than driving..." "Statistically, you're more likely to be struck by lightning than to..." "Statistically, the benefits outweigh the risks..."

What does statistically mean in sentences like this? Strictly speaking, nothing at all. If airplane travel is safer than driving, then that's just a fact. (It is true on an hour-by-hour basis). There's no statistically about it. A fact can't be somehow statistically true, but not really true. Indeed, if anything, it's the opposite: if there are statistics proving something, it's more likely to be true than if there aren't any.

But we often treat the word statistically as a qualifier, something than makes a statement less than really true. This is because psychologically, statistical truth is often different to, and less real than, other kinds of truth. As everyone knows, Joseph Stalin said that one death is a tragedy, but a million deaths is a statistic. Actually, Stalin didn't say that, but it's true. And if someone has a fear of flying, then all the statistics in the world probably won't change that. Emotions are innumerate.

A study claims that it's possible to immunize against cocaine: Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone-Maintained Patients. But does it work? And will it be useful?
The idea of an anti-drug vaccine is not new; as DrugMonkey explains in his post on this paper, monkeys were being given experimental anti-morphine vaccines as long ago as the 1970s. This one has been under development for years, but this is the first randomized controlled trial to investigate whether it helps addicts to use less of the drug.

Martell et al, a Yale-based group, recruited 115 patients. They all used both cocaine and opiates, and were given methadone treatment to try to reduce their opiate use. The reason why the authors chose to focus on these patients is that the methadone keeps people coming back for more and makes them less likely to drop out of the study, or as they put it, "retention in methadone maintenance programs is substantially better than in primary cocaine treatment programs. We also offered subjects $15 per week to enhance retention."

The vaccine consists of a bacterial protein (cholera toxin B-subunit) chemically linked to a cocaine-like molecule, succinylnorcocaine. Like all vaccines, it works by provoking an immune response. The bacterial protein triggers the production of antibodies, proteins which recognize and bind to specific targets.

In this case, the antibodies bind cocaine (anti-cocaine IgG) because of the succinylnorcocaine in the vaccine. Once a molecule of cocaine is bound to the antibody, it's effectively out of commission, as it cannot enter the brain. So, the vaccine should reduce or abolish the effects of the drug. The control group were given a dummy placebo vaccine.

The results? Biologically speaking, the vaccine worked, but in some people more than others. Out of the 55 subjects who were given the active vaccine, all but one produced anti-cocaine IgG. However, the amount of antibodies produced varied widely. Also, the response was short-lived. The vaccine was given 5 times over the first 12 weeks, but antibody levels did not peak until week 16, after which they fell rapidly.
And the key question - did it reduce cocaine use? Well, sort of. The authors measured drug use in terms of the proportion of urine samples which were cocaine-free. In the active vaccine group, the proportion of drug-free urine samples was higher over weeks 9 to 16, when the antibody levels were high, and this was statistically significant (treatment x time interaction: Z=2.4, P=.01). As expected, the benefit was greater in the people who made lots of antibodies (43 μg/mL) (treatment x time interaction: Z=4.8, P less than .001). But the effect was pretty small:

The bottom line was about 10% more urine samples testing negative, and even that was only true in the minority (38%) of people who responded well to the vaccine! Not very impressive, but on the other hand, the number of drug-free urine tests is a very crude measure of cocaine use. It doesn't tell us how much coke the patients used at a time, or how many times they used it per day.

Also, bear in mind that if it works, this vaccine might increase cocaine use in some people, at least at first. By binding and inactivating some of the cocaine in the bloodstream, the vaccine would mean you'd need to take more of the drug in order to feel the effects. It's curious that the authors relied on just one crude outcome measure and didn't ask the patients to describe the effects in more detail.

So, these are some interesting results, but the vaccine clearly needs a lot of work before it becomes clinically useful, as the authors admit - "Attaining high (43 μg/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters." Quite an admission given that this study was partially funded by Celtic Pharmaceuticals, who make the vaccine.

It's also questionable whether any vaccine will be truly beneficial in treating cocaine addiction. Such a vaccine would be a way of reducing the temptation to use cocaine. In this sense, it would be just like naltrexone for heroin addicts, which blocks the effects of the drug. Or disulifram (Antabuse) for alcoholics, which makes drinking alcohol cause horrible side effects. Essentially, these treatments are ways of artificially boosting your "self-control", and they work.

But we've had naltrexone and disulifram for many years. They're cheap and safe. But we still have heroin addicts and alcoholics. This is not to say that they're never helpful - some people find them very useful. But they haven't eradicated addiction because addiction is not something that can be cured with a pill or an injection.

Addiction is a pattern of behaviour, and medications might help people to break free of it, but the causes of addiction are social, economic and psychological as well as biological. People turn to drugs and alcohol when there's nowhere else to turn, and unfortunately, there's no vaccine against that.

Martell BA, Orson FM, Poling J, Mitchell E, Rossen RD, Gardner T, & Kosten TR (2009). Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. Archives of general psychiatry, 66 (10), 1116-23 PMID: 19805702

Freudian psychoanalysis is the key to treating depression, especially the post-natal kind (depression after childbirth). That's according to a Guardian article by popular British psychologist and author Oliver James. He says that recent research has proven Freud right about the mind, and that psychoanalysis works better than other treatments, like cognitive-behavioural therapy (CBT).

Neuroskeptic readers have encountered James before. He's the person who thinks that Britain is the most mentally-ill country in Europe. I disagree, but that's at least a debatable point. This time around, James's claims are just plain wrong.

So, some corrections. We've got a lot to cover, so I'll keep it brief:

"10% [of new mothers] develop a full-blown depression...which therapy should you opt for? [antidepressants] rule out breastfeeding" - No, they don't. Breast-feeding mothers are able to use antidepressants when necessary, according to the British medical guidelines and others:

Limited data on effects of SSRI exposure via breast milk on weight gain and infant development are encouraging. If a woman has been successfully treated with a SSRI in pregnancy and needs to continue therapy after delivery, there is no need to change the drug, provided the infant is full term, healthy and can be adequately monitored...