ECT in Nixonland

I've just finished Nixonland, Rick Perlstein's history of the 1960s. Some things I learned: Richard Nixon was a genius, albeit an evil one; the 1960s never ended; Rick Perlstein is my new favourite political author.

The book also reminded me of a sad episode in the history of psychiatry.

George McGovern ran against Nixon as the Democratic candidate for President in 1972. He was essentially the Obama of the 60s generation: unashamedly liberal and intellectual, he unseated the "established" candidate, Hubert Humphrey, to clinch the Democrat's nomination after a bitter primary campaign thanks to his idealistic young grass-roots.

McGovern had difficulty choosing his vice-presidential running mate, and eventually chose a little-known Senator from Missouri, Thomas Eagleton (left in the photo). It seemed a safe enough choice. Until Eagleton's first press conference.

Eagleton revealed that he'd been treated in a psychiatric hospital for "exhaustion" - everyone knew he meant clinical depression - three times, and that he had received electroconvulsive therapy twice. McGovern hadn't known this when he picked him.

From there it was all downhill. McGovern initially said he backed Eagleton "1000%". But to some, the idea of putting someone who'd had shock therapy a heartbeat away from the Presidency was unacceptable, and after two weeks of gossip, McGovern dropped him from the ticket.

Perlstein notes that this move wrecked McGovern's image as the idealistic and authentic alternative to politics-as-usual. Polls showed that Americans overwhelmingly trusted Nixon over McGovern, even as the facts about Watergate were emerging. Nixon won a landslide.

Good News for Armchair Neuropathologists

Ever wanted to crack the mysteries of the brain? Dreamed of discovering the cause of mental illness?

Well, now, you can - or, at any rate, you can try - and you can do it from the comfort of your own home, thanks to the new Stanley Neuropathology Consortium Integrative Database.

Just register (it's free and instant) and you get access to a pool of data derived from the Stanley Neuropathology Consortium brain collection. The collection comprises 60 frozen brains - 15 each from people with schizophrenia, bipolar disorder, and clinical depression, and 15 "normals".

In a Neuropsychopharmacology paper announcing the project, administrators Sanghyeon Kim and Maree Webster point out that

Data sharing has become more important than ever in the biomedical sciences with the advance of high-throughput technology and web-based databases are one of the most efficient available resources to share datasets.
The Institute's 60 brains have long been the leading source of human brain tissue for researchers in biological psychiatry. Whenever you read about a new discovery relating to schizophrenia or bipolar disorder, chances are the Stanley brains were involved. The Institute provide slices of the brains free of charge to scientists who request them, and they've sent out over 200,000 to date.

Until now, if you wanted to find out what these scientists discovered about the brains, you'd have to look up the results in the many hundreds of scientific papers where the various results were published. If you knew where to look, and if you had a lot of time on your hands. The database collates all of the findings. That's a good idea. To ensure that they get all of the results, the Institute have another good idea:
Coded specimens are sent to researchers with the code varying from researcher to researcher to ensure that all studies are blinded. The code is released to the researcher only when the data have been collected and submitted to the Institute.
The data we're provided about the brains is quite exciting, if you like molecules, comprising 1749 markers from 12 different parts of the brain. Markers include levels of proteins, RNA, and the number and shape of various types of cells.

It's easy to use. While waiting for my coffee to brew, I compared the amount of the protein GFAP76 in the frontal cortex between the four groups. There was no significant difference. I guess GFAP76 doesn't cause mental illness - darn. So much for my Nobel Prize winning theory. But I did find that levels of GFAP76 were very strongly correlated with levels of another protein, "phosphirylated" (I think they mean "phosphorylated") PRKCA. You read it here first.

In the paper, Kim and Webster used the Database to find many differences between normal brains and diseased brains, including increased levels of dopamine in schizophrenia, and increased levels of glutamate in depression and bipolar. And decreased GAD67 proteins in the frontal cortex in bipolar and schizophrenia. And decreased reelin mRNA in the frontal cortex and cerebellum in bipolar and schizophrenia. And...

This leaves open the vital questions of what these differences mean, as I have complained before. And the problem with giving everyone in the world the results of 1749 different tests, and letting us cross-correlate them with each other and look for differences between 4 patient groups, is that you're making possible an awful lot of comparisons. With only 15 brains per group, none of the results can be considered anything more than provisional, anyway - what we really need are lots more brains.

But this database is still a welcome move. This kind of data pooling is the only sensible approach to doing modern science, and it's something people are advocating in other fields of neuroscience as well. It just makes sense to share results rather than leaving everyone to do there own thing in near-isolation from each other, now that we have the technology to do so. In fact, I'd say it's a... no-brainer.

ResearchBlogging.orgKim, S., & Webster, M. (2009). The Stanley Neuropathology Consortium Integrative Database: a Novel, Web-Based Tool for Exploring Neuropathological Markers in Psychiatric Disorders and the Biological Processes Associated with Abnormalities of Those Markers Neuropsychopharmacology, 35 (2), 473-482 DOI: 10.1038/npp.2009.151

Two Drugs Are Better Than One?

According to a study just out in the American Journal of Psychiatry, starting depressed people on two antidepressants leads to much better results than starting them on just one - Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder. But how reliable is it?

Currently accepted practice is to prescribe one antidepressant to begin with, and if the patient doesn't feel better after about 6 weeks, to either change to a different antidepressant (switching) or add a second drug while continuing the first (augmentation).

But in clinical trials and also in "real life", the proportion of depressed people who achieve "remission", meaning that they're fully or almost fully recovered, with their first antidepressant is rarely more than 1 in 3. Some antidepressants may be slightly better than others as first-line treatments, but any such differences are small.

Do two mediocre drugs combined add up to one good treatment? In this study, Blier et al. took 105 depressed people and gave them either one antidepressant or two. The one antidepressant was fluoxetine (Prozac) 20mg, and the two was mirtazapine 30mg and either fluoxetine 20mg, venlafaxine 225mg, or buproprion 150mg. The study was double-blind; patients didn't know which drug(s) they were on. There was no placebo group, however.

Mirtazapine (Remeron) is an antidepressant which is commonly used as an add-on treatment in depression, because it can be safely combined with most other drugs. So it makes sense to use mirtazapine in research like this, but take note: this study was "supported by Organon Pharmaceuticals", who make... mirtazapine.

What happened? All three combinations of two antidepressants were equally effective, and all three were considerably better than just Prozac alone, in the initial 6 week phase of the trial. The difference was massive by the standards of antidepressants - about 5 Hamilton scale points, considerably larger than the average benefit of an antidepressant over placebo.

There was also a 6 month follow-up phase to the study in which everyone who had been taking two antidepressants had one of them replaced by placebos, so everyone ended up only taking one drug (either fluoxetine or mirtazapine). Discontinuing one antidepressant seemed to cause relapse in about 40-50% of the people who were taking two, as opposed to a 25% relapse rate in the people who started on just fluoxetine and kept taking it. If you believe it, this is further evidence that two drugs are better than one, although the total sample size was just 66 for this bit, and I'm not sure I do.

What are we to make of all this? This study joins a previous one finding that mirtazapine plus paroxetine is better than either drug alone as a starting treatment. But that paper was also by Blier et al and it was "fully funded by Organon Pharmaceuticals" although apparently "The sponsor had no role in the study design, in the collection and interpretation of the data, in the preparation of this report, and in the decision to publish this manuscript".

Personally, I'm not so much troubled by the industry sponsorship in these studies as I am by the nature of the add-on treatment, mirtazapine. Mirtazapine is an unusual drug, with a pharmacological profile very different to that of most antidepressants. Notably, it's a powerful hypnotic - it makes you sleep - and it increases appetite. Patients on mirtazapine in the present study put on over 2kg in 6 weeks.

Why does this matter? Because the two scales used to rate depression in this study, the Hamilton Scale and the Montgomery-Asberg Scale, both count reduced appetite and sleeplessness as symptoms of depression. If you're on mirtazapine, you're unlikely to have either problem - you'll be more worried about the exact opposite, insatiable hunger and drowsiness. So mirtazapine could reduce your total score on these scales even if it didn't change your mood. I have no idea to what extent this is a factor in these results, but it could be important.

So, are two drugs better than one? Should antidepressants come with a side-order of mirtazapine as standard? Maybe. But it's far from proven.

ResearchBlogging.orgBlier, P., Ward, H., Tremblay, P., Laberge, L., Hebert, C., & Bergeron, R. (2009). Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder: A Double-Blind Randomized Study American Journal of Psychiatry DOI: 10.1176/appi.ajp.2009.09020186

Gamma Knives Out

The Guardian covers contemporary psychosurgery - in their "Life and Style" section, believe it or not -

A radical treatment for Obsessive-compulsive disorder patients
The treatment being "gamma knife" lesions in OCD. Surgeons use a gamma knife to destroy part of the brain by aiming several beams of gamma rays at it from different angles. At the point of the target the beams overlap, and the total radiation level is intense enough to kill cells. Other parts of the brain only get hit by one beam, which is, hopefully, harmless. It's quite a clever technique, although it's not exactly brain surgery. (Sorry...)

Unlike actual surgery, the gamma knife doesn't involve cutting holes in people. This makes it safer, because any neurosurgery carries risks of infection or haemorrhage. But functionally, it's exactly the same as physically removing the tissue with a scalpel. It's hardly "non-invasive", which is what the Guardian call it (twice). Maybe technically, in the sense that it doesn't break the skin, but it does permanently destroy a substantial part of the brain. That's rather more invasive than, say, getting a tattoo, if you ask me.

Lesioning the brain to treat severe OCD has a long history. In the past couple of decades, it's been done on some dozens of patients at a few hospitals such as the Karolinska Institute in Sweden, Brown University in the US, Spain, China and South Korea.

Does it work? Some reports say that about 60% of OCD patients experience a good response others put the rate at more like 40%. So it doesn't work for everyone although given that the patients who get psychosurgery are severely ill and have not benefited from other treatments (medication and therapy), it's not so bad. But it's impossible to know how much of the improvement is a placebo effect, because there's never been a placebo controlled trial of any kind of psychosurgery for OCD, including gamma knife. This is something that the Guardian unfortunately doesn't mention.


Newspapers at the moment are pretty keen on neurosurgery for mental illness. Deep brain stimulation (DBS) has been getting positive coverage for years, and psychosurgery is also becoming popular nowadays. The NYT recently ran a cautious, but generally positive, piece on it.

There seems to be an unwritten rule that every such article has to include a bit reassuring us that today's psychosurgery is Not Like In One Flew Over the Cuckoo's Nest. Hence The Guardian:
The technique certainly could not be further from the brutal lobotomies made famous by Ken Kesey's novel, One Flew Over the Cuckoo's Nest. While the frontal lobotomy essentially destroys part of the brain, Gamma Knife is highly accurate and non-invasive, damaging only a minute area - 100 millimeters square - of brain tissue. It is usually done as an out-patient procedure. Some might experience a mild headache afterwards, but most report no physical problems at all.
And the NYT:

In the early days of psychosurgery doctors published scores of papers detailing how lobotomy relieved symptoms of mental distress. But careful follow-up painted a darker picture: of people who lost motivation, who developed the helpless indifference dramatized by the post-op rebel McMurphy in Ken Kesey’s novel “One Flew Over the Cuckoo’s Nest”... The newer operations pinpoint targets on specific, precisely mapped circuits, whereas the frontal lobotomy amounted to a crude slash into the brain behind the eyes, blindly mangling whatever connections and circuits were in the way.
This old bad, new good message is simplistic and misleading. The old (1930s-1940s) psychosurgery didn't consist of "blindly mangling" the brain. At least at first, it was targeted as precisely as the technology and neuroanatomy at the time allowed. And although some psychosurgeons used it in a cavalier way, there is no doubt that it often seemed to produce dramatic benefits; the contemporary testimonials of patients and their families are proof of that.

Today's surgery allows more accurate (and smaller) lesion placement, thanks to advances in stereotactic techniques and now the gamma knife. But we still have no solid understanding of the brain circuits underlying mental illness. We still don't know why destroying certain frontal white matter pathways in the brain alleviates symptoms. We still don't know why it works in some people and not others.

There's not even much agreement on which parts of the brain to hit; the most popular surgical target for OCD is the anterior limb of the internal capsule (capsulotomy) although cingulotomy has also been used, and for depression there are a handful. To say that "The newer operations pinpoint targets on specific, precisely mapped circuits" is true only in the sense that if a modern surgeon tries to destroy the anterior limb of the internal capsule, they will probably do it.

None of this means that psychosurgery doesn't work. It probably does - or rather, it certainly does, and it's probably not just a placebo. (For one thing the fact that accidental brain damage to the same regions also seems to reduce emotional distress is very promising.) But it's not so different to what was going on in the 1930s. It's still, basically, a stab in the dark.

Link: The Lobotomist and Last Resort are excellent books on the history of psychosurgery.

In the Brain, Acidity Means Anxiety

According to Mormon author and fruit grower "Dr" Robert O. Young, pretty much all diseases are caused by our bodies being too acidic. By adopting an "alkaline lifestyle" to raise your internal pH (lower pH being more acidic), you'll find that

if you maintain the saliva and the urine pH, ideally at 7.2 or above, you will never get sick. That’s right you will NEVER get sick!
Wow. Important aspects of the alkaline lifestyle include eating plenty of the right sort of fruits and vegetables, ideally ones grown by Young, and taking plenty of nutritional supplements. These don't come cheap, but when the payoff is being free of all diseases, who could complain?

Young calls his amazing theory the Alkavorian Approach™, aka the New Biology. Almost everyone else calls it quack medicine and pseudoscience. Because it is quack medicine and pseudoscience. But a paper just published in Cell suggests an interesting role for pH in, of all things, anxiety and panic - The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior.

The authors, Ziemann et al, were interested in a protein called Acid Sensing Ion Channel 1a, ASIC1a, which as the name suggests, is acid-sensitive. Nerve cells expressing ASIC1a are activated when the fluid around them becomes more acidic.

One of the most common causes of acidosis (a fall in body pH) is carbon dioxide, CO2. Breathing is how we get rid of the CO2 produced by our bodies; if breathing is impaired, for example during suffocation, CO2 levels rise, and pH falls as CO2 is converted to carbonic acid in the bloodstream.

In previous work, Ziemann et al found that the amygdala contains lots of ASIC1a. This is intriguing, because the amygdala is a brain region believed to be involved in fear, anxiety and panic, although it has other functions as well. It's long been known that breathing air with added CO2 can trigger anxiety and panic, especially in people vulnerable to panic attacks.

What's unclear is why this happens; various biological and psychological theories have been proposed. Ziemann et al set out to test the idea that ASIC1a in the amygdala mediates anxiety caused by CO2.

In a number of experiments they showed that mice genetically engineered have no ASIC1a (knockouts) were resistant to the anxiety-causing effects of air containing 10% or 20% CO2. Also, unlike normal mice, the knockouts were happy to enter a box with high CO2 levels - normal mice hated it. Injections of a weakly acidic liquid directly into the amygdala caused anxiety in normal mice, but not in the knockouts.

Most interestingly, they found that knockout mice could be made to fear CO2 by giving them ASIC1a in the amygdala. Knockouts injected in the amygdala with a virus containing ASIC1a DNA, which caused their cells to start producing the protein, showed anxiety (freezing behaviour) when breathing CO2. But it only worked if the virus was injected into the amygdala, not nearby regions.

This is a nice series of experiments which shows convincingly that ASIC1a mediates acidosis-related anxiety, at least in mice. What's most interesting however is that it also seems to involved in other kinds of anxiety and fear. The ASIC1a knockout mice were slightly less anxious in general; injections of an alkaline solution prevented CO2-related anxiety, but also reduced anxiety caused by other scary things, such as the smell of a cat.

The authors conclude by proposing that amygdala pH might be involved in fear more generally
Thus, we speculate that when fear-evoking stimuli activate the amygdala, its pH may fall. For example, synaptic vesicles release protons, and intense neural activity is known to lower pH.
But this is, as they say, speculation. The link between CO2, pH and panic attacks seems more solid. As the authors of another recent paper put it
We propose that the shared characteristics of CO2/H+ sensing neurons overlap to a point where threatening disturbances in brain pH homeostasis, such as those produced by CO2 inhalations, elicit a primal emotion that can range from breathlessness to panic.
ResearchBlogging.orgZiemann, A., Allen, J., Dahdaleh, N., Drebot, I., Coryell, M., Wunsch, A., Lynch, C., Faraci, F., Howard III, M., & Welsh, M. (2009). The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit Fear Behavior Cell, 139 (5), 1012-1021 DOI: 10.1016/j.cell.2009.10.029

That Sinking Feeling?

Sinking and Swimming is a paper just out from the Young Foundation, a British think-tank. It "explores how psychological and material needs are being met and unmet in Britain." I'm not sure how useful their broad concept of "unmet needs" is, but there's some rather interesting data in this report.

On page 238, and prominently in the executive summary, we find the following terrifying graph, which comes with warnings like "anxiety and depression looks set to double during the course of a single generation..."

The % of the population self-reporting suffering from depression or anxiety seems to have been consistently rising since 1990, from less than 6% to almost 10% today. And the line continues ever upwards. Eeek!

Is Britain really becoming more depressed and anxious? No, and that's what makes this graph terrifying. According to the large government Adult Psychiatric Morbidity Survey, the prevalence of self-reported depression and anxiety symptoms rose slightly from 1993 to 2000 (15.5% to 17.5%) and then stayed level up to 2007 (17.6%). Not very scary. Even the Young Foundation note (on page 80) that when you look at "well-being"

analysis of the English health survey that uses a variation of GHQ [General Health Questionnaire] suggested that the proportion of the working age population with poor psychological well-being decreased from 17% in 1997 to 13% in 2006.
On that measure, we're getting happier. And the rate of new diagnoses of clinical depression fell over the past decade.

So what about that ominous line? Well, that graph was based on "self-reported anxiety or depression", but in a specific sense. People were not reporting feeling scared or unhappy (see above for the data on that), but rather, reporting having anxiety or depression as medical disorders. Curiously the % of people reporting having every other sort of health problems (except with vision) increased from 1991 to 2007 as well:

What seems to be happening is that British people are becoming more willing to label our problems as medical illnesses, although in fact our mental health has not changed much over the past two decades, and may even have improved slightly. This is what's terrifying, because medicalizing emotional issues is a bad idea.

Mental illness does exist, and medicine can help treat it, but medicine can't resolve non-medical problems even if they're labelled as illnesses. Antidepressants, for example, are (imperfectly) effective for severe clinical depression but probably not for "mild depression"; much of what is labelled "mild depression" is probably not, in any meaningful sense, an illness.

Why does this matter? Drugs have side effects, and psychotherapy is expensive. The cost-benefit profile of any treatment is obviously negative when there are no benefits because the treatment is being used inappropriately. My biggest concern, though, is that if someone is unhappy because of tensions in their marriage or because they're in the wrong job, they don't need treatment, they need to do something about it. Labelling a problem as an illness and treating it medically may, in itself, make that problem harder to overcome.


Psychiatrist, Drug Thyself

Psychiatrists give their patients all kinds of drugs, but in most cases, they do so without ever taking any themselves. Some French psychiatrists found an excuse to try out some drugs in the name of science, and the results are published in a paper just out - Besnier et al's Effects of paroxetine on emotional functioning and treatment awareness.

Thirty healthy psychiatrists and clinical psychologists took paroxetine 20mg per day, or placebo pills, for 4 weeks. Paroxetine (Paxil, Seroxat) is a popular SSRI antidepressant - popular with doctors, at least. It has a bad reputation amongst users as causing serious withdrawl symptoms, even compared to other SSRIs. These psychiatrists decided to wean themselves off with a week at a reduced dose of 10mg before stopping completely - after just one month on it! Make of that what you will.

Anyway, what happened? The participants experienced no changes in mood or anxiety, although since they weren't depressed or anxious to begin with, this is not surprising. However, the people taking paroxetine did report reduced "Internal Emotional Experience" as measured with the Emotional State Questionnaire (designed by the same people who ran this study.) That means they were less likely to answer yes to questions like “Do you feel anger when faced with a familiar face with expressed anger?”

This sounds as though they experienced the "emotional blunting" reported by some people who take SSRIs, although it's not clear what exactly this questionnaire is measuring, or how powerful the effect was. The paroxetine group also reported feeling sedated and suffered many more side effects - 70% of participants presented with an adverse event for more than 3 weeks, vs 20% of placebo.

Most described adverse events were psychiatric (sleepiness disorders, libido decreased), gastrointestinal (nausea, diarrhea), or neurological signs (headache).
There's a twist, though, in that while 20 of the subjects got placebo or paroxetine in a double-blind manner (10 each), the other 10 got paroxetine unblinded, i.e. they knew they were not going to get placebo. Strangely, the unblinded group experienced much weaker effects than the double-blind paroxetine group, including many fewer side effects. What's up with that? It's hard to say. It doesn't make much sense. To be honest, with just 10 people in each group, any or all of these results could be random chance anyway.

Still, I do like the idea of psychiatrists self-experimenting. Sadly we're not told whether they were more or less likely to prescribe paroxetine after taking it themselves! Still, I have a bit of anecdotal evidence here. I was talking to a French psychiatrist a while ago who said he'd self-prescribed the SSRI antidepressant citalopram and thought it was brilliant. But one day he accidentally picked up a box of chlorpromazine instead (they were next to each other on the shelf) and that wasn't much fun at all...

Freudian psychoanalysis requires trainee therapists to undergo a full course of therapy themselves before they get to inflict it on their patients. Maybe psychiatrists should have to take courses of antidepressants and antipsychotics as part of their training? Or as the psychopathic bounty hunter said to the doctor in Joss Whedon's Firefly -
Jubal Early: You ever been shot?
Dr Simon Tam
: No.
Jubal Early
: You oughta be shot. Or stabbed. Lose a leg. To be a surgeon, you know? Know what kind of pain you're dealing with. They make psychiatrists get psychoanalyzed before they can get certified, but they don't make a surgeon get cut on. That seem right to you?
- Firefly
ResearchBlogging.orgBesnier N, Cassé-Perrot C, Jouve E, Nguyen N, Lançon C, Falissard B, & Blin O (2009). Effects of paroxetine on emotional functioning and treatment awareness: a 4-week randomized placebo-controlled study in healthy clinicians. Psychopharmacology PMID: 19826792

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