The Decline and Fall of the Cannabinoid Antagonists

Cannabinoid Receptor, Type 1 (CB1) antagonists were supposed to be the next big thing.

They're weight loss drugs, and with obesity rates rising and the diet craze showing no signs of abating, that's a large and growing market (...sorry). They worked, at least in the short term, and they were at least as effective as existing pills. They may even have had health benefits over and above promoting weight loss, such as improving blood fat and sugar levels through metabolic effects.

It all started off well. Rimonabant, manufactured by Sanofi, was the first CB1 antagonist to become available for human use: it hit the European market in 2006, as Acomplia. Four large clinical trials showed convincingly that it helped people lose weight. Rival drug companies were hard at work developing other CB1 antagonists, and inverse agonists (similar, but even more potent). The "bants" included Merck's taranabant, Pfizer's otenabant, and more.

Even more excitingly, there were indications that CB1 antagonists could do more than help people lose weight: they might also be useful in helping people quit smoking, alcohol or drugs. The animal evidence that CB1 antagonists did this was strong. Human trials were underway. Optimists saw rimonabant and related drugs as offering something unprecedented: self-control in a pill, abstinence on demand.

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But it ended in tears, literally. Rimonabant was pulled from the European market in late 2008; it was never approved in the USA at all. After rimonabant was withdrawn, drug companies abandoned the development of other CB1 antagonists.

The problem was that they made people depressed. In several large clinical trials of rimonabant it raised the risk of suffering depression and other psychiatric problems, like anxiety and irritability, compared to placebo. The reported rates of these symptoms ranged from a few % up to over 40% depending upon the population, but there have been no trials (except very small ones) in which these effects weren't seen. This means that CB1 antagonists cause depression rather more consistently than antidepressants treat it.

Merck have just released the data from a trial of taranabant: A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients. It makes a fitting epitaph to the CB1 antagonists. They gave taranabant, at a range of doses, or placebo, to overweight people to go alongside diet and exercise to help them lose weight. The results were extremely similar to those seen with rimonabant; the drug worked:

But there were side effects. Alongside things like nausea, vomiting, and sweating, about 35% of people taking high doses of taranabant reported "psychiatric disorders". 20% of people on placebo also did, so this is not quite as bad as it first appears, but it's still striking, especially since a number of people on high doses of taranabant reported suicidal thoughts or behaviours...

Suicidal ideation was reported in three patients in the taranabant 6-mg group in year 1 and in one patient in the 4-mg group in year 2. There was one suicide attempt reported in a patient with a previous history of suicide attempts in the 6/2-mg group while the patient was receiving 2-mg, and one episode of suicidal behavior reported in a patient in the 6/2-mg group while the patient was receiving 6-mg. There were no completed suicides. The adjudication of possibly suicide-related adverse experiences during years 1 and 2 indicated an increased incidence of suicidality in the taranabant groups...

This is the kind of thing that gives drug companies nightmares, especially today, in the post-SSRI lawsuits era. This is why rimonabant was removed from the EU market in 2008 and why it was never approved in the US.

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Safety concerns have plagued weight loss medications for decades. The problem is not that they don't work: plenty of drugs cause weight loss, at least for as long as you keep taking them. But unfortunately, there's always a 'but'.

Fenfluramine worked, but it caused heart valve defects, and was banned. Sibutramine works, but it's just been suspended from the European market due to concerns over heart disease (a different kind). Amphetamine-like stimulants such as phentermine work, but they're addictive and liable to abuse. What with rimonabant and sibutramine are gone, the only weight-loss drug approved for use in Europe is orlistat, which seems to be safe, but has some very unpleasant side effects...

Still, CB1 antagonists have a unique mechanism of action: they block the CB1 receptor, which is what gets activated by the cannabinoid ingredients in marijuana, and also the brain's own cannabinoids neurotransmitters (endocannabinoids). The past five years has seen a huge amount of research showing that the CB1 receptor is involved in everything from memory and emotion to motivation, pain sensation and hormone secretion. We recently learned that there are even CB1 receptors on the tongue that regulate taste.

CB1 is able to do all this because it's found almost everywhere in the brain. To simplify, but only a little, the endocannabinoid system is a general feedback mechanism, which allows cells on the receiving end of neural transmission to "talk back" to the neuron sending them signals; if they're receiving lots of input, they tell the cell sending the signals to quiet down. In other words, endocannabinoids regulate the release of just about every other neurotransmitter. To be honest, given how important the system is in the brain, it's surprising that depression and anxiety are the biggest problems with CB1 antagonists.

For all that, we still don't know why they cause psychiatric symptoms, although a number of mechanisms have been suggested. Hopefully, someone will work this out sooner or later, since that would add an important piece to the puzzle of what goes on in the brain during depression...

Aronne, L., Tonstad, S., Moreno, M., Gantz, I., Erondu, N., Suryawanshi, S., Molony, C., Sieberts, S., Nayee, J., Meehan, A., Shapiro, D., Heymsfield, S., Kaufman, K., & Amatruda, J. (2010). A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study International Journal of Obesity DOI: 10.1038/ijo.2010.21

More on Deep Brain Stimulation for OCD

Over the past few years, deep brain stimulation (DBS) has emerged as a promising treatment for severe psychiatric disorders that haven't responded to conventional approaches. A new paper from the University of Florida reports on a trial of DBS in obsessive-compulsive disorder (OCD), and unlike most DBS studies, it was placebo-controlled: Deep Brain Stimulation for Intractable Obsessive Compulsive Disorder.


Six patients were implanted with electrodes in the "ventral capsule/ventral striatum" (VC/VS). This area has previously been used as a DBS target for OCD. The original reason for choosing to implant electrodes in this region was that it's long been known that destroying the anterior limb of the internal capsule (capsulotomy) alleviates OCD symptoms in many cases, especially if the ventral (lower) part is removed.

Did it work? Yes, but not for everyone. Out of the 6 patients who entered the trial, all of whom were extremely ill despite having tried multiple medications and psychotherapy, 4 (66%) eventually responded well. The other 2 unfortunately got little or no benefit over the 12 month trial period.

The study had a double-blind, placebo-controlled phase: the patients weren't told when the DBS electrodes were going to be switched on. As the graphs show, in the 3 patients who were randomly selected to have them switched on early, 2 responded pretty much immediately, while in the 3 patients whose electrodes were left off, none responded until they were turned on 30 days later, although the response at this point was fairly gradual.

One person (S1), who responded very well initially, suddenly relapsed about a year later. Upon investigation, it turned out that the battery powering their electrodes had worn out, although no-one knew this until the OCD symptoms returned, so this can't have been a placebo effect. They recovered after getting a new battery.

Overall there are few surprises here. These results confirm what we already knew about DBS: it works in many people, but not all, with response rates of around 60%; When it works, it works very well; but sometimes the effects take weeks or months to become fully apparent. This could be either because DBS starts some gradual process of change in the brain which takes time to work; or it could be that it often takes a long time to find the right stimulation parameters (voltage, frequency, etc.) which provide a good response, since this has to be done by trial-and-error. Most likely, it's a bit of both.

What I found most interesting was that the VC/VS stimulation didn't just treat people's obsessions and compulsions. It also had a mood-improving effect, and crucially, it sounds as though mood was the first thing to improve, with OCD symptoms following days or weeks later:

Finding the optimal settings for an individual subject proved challenging...unlike other experiences with DBS, there is not a clear positive symptom (e.g., tremor improvement) to gauge settings. In this study... the goal was to select parameters that produced some benefit in mood or anxiety symptoms acutely, with minimal side effects.

and mood was the first thing that got worse when the DBS was accidentally turned off for whatever reason:

Worsening in mood or increased anxiety were typically the first symptoms reported following battery depletion or inadvertent inactivation by metal detectors. Other signs of depression, such as diminished energy or interest, also emerged within days of device interruption... Exacerbation of OCD symptoms generally lagged the emergence of affective or anxiety symptoms.

And in fact, four people experienced temporary hypomania, i.e. abnormally elevated mood, which is usually seen in bipolar disorder, although none of the patients in this study had a history of bipolar. People also commonly reported increased alertness, motivation, and difficulty falling asleep.

This all fits with the fact that VC/VS stimulation has been used as a DBS target for clinical depression, as well as for OCD. Indeed, this suggests that DBS probably works in essentially the same way in both conditions. The drugs that are used to treat OCD are all antidepressants - specifically serotonin-based ones - so this makes sense too.

With luck, research on DBS in animals and humans will finally allow us to understand the neural basis of mood states like depression, and mania - something which, despite decades of research on drugs like antidepressants and mood stabilizers, is still deeply mysterious...

Goodman, W., Foote, K., Greenberg, B., Ricciuti, N., Bauer, R., Ward, H., Shapira, N., Wu, S., Hill, C., & Rasmussen, S. (2010). Deep Brain Stimulation for Intractable Obsessive Compulsive Disorder: Pilot Study Using a Blinded, Staggered-Onset Design Biological Psychiatry, 67 (6), 535-542 DOI: 10.1016/j.biopsych.2009.11.028

Scannerphobia

Science informs us of about a tricky problem facing Chinese neuroscientists: Fear of MRI Scans Trips Up Brain Researchers.

Apparently, many parents are concerned about the possible impact of strong magnetic fields on children, and are unwilling to allow their children to get MRI scanned for research purposes; the article reports on two Chinese neuroscientists who were unable to find healthy children to volunteer for their MRI studies.

“I would not dare to allow my children to be tested by MRI,” says radiologist Han Hongbin of Peking University Third Hospital. “Nobody can ensure that there is no potential danger,” such as during nonroutine MRI scans that use extremely powerful magnetic fields, he says.

This is not a problem I've heard of amongst Western researchers, but on the other hand, it's not all that bizarre. In Britain, and as far as I know elsewhere too, standard practice is never to include women who are (or might be) pregnant in fMRI studies. This is not because strong magnetic fields have any known risks for unborn babies, or indeed anyone else. It's purely a better-safe-than-sorry precaution. But it sounds as though the concerns of Chinese parents are of that kind as well.

MRI safety is an interesting topic. Used incorrectly, an MRI scanner could, in theory, harm you in quite a few ways, from heating you up due to radiofrequency energy transfer, to stopping your heart by inducing an electric current in it (although I don't think that's ever actually happened, it is a theoretical concern). Fortunately, by sensible selection of the scan parameters, these risks can be avoided.

The only real danger is that posed by metal objects (specifically ferromagnetic ones), which in the presence of a strong magnetic field become deadly projectiles. This is why it's a bad idea to carry that pair of scissors into the scanner room. Remember: the magnet is always on...

Drunk on Alcohol?

When you drink alcohol and get drunk, are you getting drunk on alcohol?

Well, obviously, you might think, and so did I. But it turns out that some people claim that the alcohol (ethanol) in drinks isn't the only thing responsible for their effects - they say that acetaldehyde may be important, perhaps even more so.

South Korean researchers Kim et al report that it's acetaldehyde, rather than ethanol, which explains alcohol's immediate effects on cognitive and motor skills. During the metabolism of ethanol in the body, it's first converted into acetaldehyde, which then gets converted into acetate and excreted. Acetaldehyde build-up is popularly renowned as a cause of hangovers (although it's unclear how true this is), but could it also be involved in the acute effects?

Kim et al gave 24 male volunteers a range of doses of ethanol (in the form of vodka and orange juice). Half of them carried a genetic variant (ALDH2*2) which impairs the breakdown of acetaldehyde in the body. About 50% of people of East Asian origin, e.g. Koreans, carry this variant, which is rare in other parts of the world.

As expected, compared to the others, the ALDH2*2 carriers had much higher blood acetaldehyde levels after drinking alcohol, while there was little or no difference in their blood ethanol levels.

Interestingly, though, the ALDH2*2 group also showed much more impairment of cognitive and motor skills, such as reaction time or a simulated driving task. On most measures, the non-carriers showed very little effect of alcohol, while the carriers were strongly affected, especially at high doses. Blood acetaldehyde was more strongly correlated with poor performance than blood alcohol was.

So the authors concluded that:

Acetaldehyde might be more important than alcohol in determining the effects on human psychomotor function and skills.

So is acetaldehyde to blame when you spend half an hour trying and failing to unlock your front door after a hard nights drinking? Should we be breathalyzing drivers for it? Maybe: this is an interesting finding, and there's quite a lot of animal evidence that acetaldehyde has acute sedative, hypnotic and amnesic effects, amongst others.

Still, there's another explanation for these results: maybe the ALDH2*2 carriers just weren't paying much attention to the tasks, because they felt ill, as ALDH2*2 carriers generally do after drinking, as a result of acetaldehyde build-up. No-one's going to be operating at peak performance if they're suffering the notorious flush reaction or "Asian glow", which includes skin flushing, nausea, headache, and increased pulse...

Kim SW, Bae KY, Shin HY, Kim JM, Shin IS, Youn T, Kim J, Kim JK, & Yoon JS (2009). The Role of Acetaldehyde in Human Psychomotor Function: A Double-Blind Placebo-Controlled Crossover Study. Biological psychiatry PMID: 19914598

The Case of the Missing Retrovirus

In October 2009, a team led by Vincent C. Lombardi of the Whittemore Peterson Institute reported the presence of a recently discovered virus, XMRV, in 67% of the blood samples from 101 American patients with chronic fatigue syndrome (CFS). XMRV had previously been linked to some cases of prostate cancer.

This sparked intense interest amongst many people and much discussion. But in January this year, Erlwein et al reported that they did not find any evidence of XMRV in the blood of 186 British CFS patients (my post).

Now, a second British study has appeared, and the results are also negative. The paper is Groom et al's Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. They found no XMRV in 170 British CFS patients or 395 healthy controls. VirologyBlog has an excellent summary of the latest paper.

In order to help people interested in this topic, I've put together a quick summary of all the data on XMRV infection in humans. If I've left anything out or made any mistakes, let me know in the comments. I'll try to keep this list up to date with every new publication - because there are sure to be plenty more.

Overall, the most striking thing about these results is the national differences. XMRV has been detected in 67% of American CFS patients, in 10-25% of American prostate cancer cases, and in 3-4% of healthy Americans. By contrast, in Germany, Britain and Ireland, it's only been detected in 2 Germans, out of a grand total of 1,300 or so European people who have been tested so far using a variety of methods. The situation elsewhere is unclear; one study claimed to detect XMRV in 1.5% of healthy Japanese blood donors but this is unpublished, and the methodology is unclear.

Other than that, it's not clear what's going on here, and it seems to me that it would be premature to conclude anything about XMRV and CFS (or, indeed, cancer) at this stage.

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Last Updated: 06 July 2010
Please let me know if I have omitted any data (published or unpublished)

Published Papers - CFS

1. Lombardi et al 2009

• Patients: "CDC Fukuda Criteria and the 2003 Canadian Consensus Criteria... presenting with severe disability... their diagnosis of CFS is based upon prolonged disabling fatigue ... cognitive deficits and reproducible immunological abnormalities ... impaired exercise performance with extremely low VO2 max measured on stress testing."
• Origin: USA
• Method A: PCR of DNA from PBMCs
• Result: 68 of 101 patients (67%), 8 of 218 controls (3.7%)
• Method B: PBMC reactivity to anti-MLVp30Gag antibodies
• Result: 19 of 30 patients (63%), 0 of 16 controls (0%)
• Method C: Plasma immunoreactivity to SFFV-Env
• Result: 9 out of 18 patients with XMRV, 0 out of 7 controls

2. Erlwein et al 2010

• Patients: CDC Fukeda criteria "markedly unwell. Few were working, and 19% were members of patient support groups for CFS/ME... The levels of fatigue in this sample were high ... as were levels of disability"
• Origin: London, UK
• Method: PCR of DNA from whole blood
• Result: 0 out of 186 patients (0%)
  

3. Groom et al 2010

• Patients: CDC Fukeda criteria
• Origin: Bristol, Dorset, London, Birmingham, Norfolk and Epsom, UK
• Method A: PCR of gDNA from PBMCs
• Result: 0 of 48 patients (0%)
• Method B: PCR of gDNA, cDNA, or both from PBMCs
• Result: 0 out of 142 patients (0%), and 157 controls (0%)
• Method C: Serum immunoreactivity to XMRV
• Result: 1 out of 160 patients; 25 out of 395 controls; but positives were not considered specific to XMRV, as they also reacted to and neutralized other viruses.

4. Switzer et al 2010 "CDC study"

• Patients: Recruited by random population telephone screening and symptom quizzing (unlike other studies). CDC Fukeda 1994 criteria (but also referred to in the abstract as the "revised" 1994 CDC criteria) and symptoms not better accounted for by medical illness or "current psychiatric disorders considered exclusionary for CFS, which included current melancholic depression, current or lifetime bipolar disorder or psychosis, substance abuse within 2 years and eating disorders within 5 years".
• Origin: Wichita, Kansas, USA and Georgia, USA.
• Method A: Western blotting serology for anti-XMRV antibodies in plasma
• Result: 0 of 51 patients (0%) and 0 of 53 controls (0%)
• Method B: ELISA serology for anti-XMRV gag and pol antibodies in plasma, performed by RKI.
• Result: 0 of 51 patients (0%) and 0 of 53 controls (0%)
• Method C: PCR of DNA from PBMCs or whole blood for XMRV gag and pol
  
• Result: 0 of 50 patients (0%) and 0 of 97 controls (0%)
• Method D: PCR of DNA for XMRV gag, performed by BSRI.
  
• Result: 0 of 50 patients (0%) and 0 of 56 controls (0%)

5. van Kuppeveld et al 2010 "Dutch study"

• Patients: Oxford Criteria
  
• Origin: Netherlands. Recruited and samples taken 1991-1992
  
• Method: PCR of cDNA from PBMCs for XMRV integrase and gag
  
• Result: 0 of 32 patients (0%), 0 of 43 controls (0%)
  

Published Papers - Prostate Cancer

6. Urisman et al 2006

• Patients: Familial Prostate Cancer
• Origin: Cleveland, USA
• Method: PCR on prostate cell DNA
  
• Result: 9 of 86 (10.4%); associated with R462Q QQ genotype

7. Schlaberg et al 2009

• Patients: Prostate Cancer
• Origin: Columbia University Medical Center, USA
  
• Method A: PCR on prostate cell DNA
  
• Results: 14/223 prostate cancer patients (6.2%), 2/101 non-cancer prostate controls (2.0%). Not associated with R462Q QQ genotype.
• Method B: XMRV protein expression (cell reactivity to anti-XMRV serum)
  
• Results: XMRV protein expression in 54/223 (23%) cases with prostate cancer and in 4/101 (4%) controls. Not associated with R462Q QQ genotype.

8. Hohn et al 2009

• Patients: Prostate Cancer
  
• Origin: Berlin, Germany
• Method: PCR on prostate cell DNA
  
• Result: 0 out of 589 (0%)
• Method: Serum immunoreactivity to XMRV proteins (gp70 and Gag)
  
• Result: 0 out of 146 patients, 0 out of 5 controls (0%)
  

9. Fischer et al 2008

• Patients: Non-familial Prostate Cancer
• Origin: Hamburg, Germany
• Method: PCR of prostate cell RNA
• Results: 1/105 patients (0.95%), 1/70 healthy controls (1.42%).
  

Unpublished Data

10. D'Arcy et al 2008

• Patients: Prostrate Cancer
• Origin: Dublin, Ireland
  
• Method A: PCR of prostate cell RNA
• Results: 0 out of 9 (7 R462Q QQ genotype, 2 others) (0%)
  
• Notes: Unpublished data presented at a conference.

11. Furata et al 2009

• Patients: n/a
• Origin: Japan
• Method: "antibodies [to XMRV]"
• Result: 5/300 controls (healthy blood donors) (1.5%)
• Note: Unpublished data presented at a conference - I can't access the abstract and am relying on Erlwein et al's summary. In the light of Groom et al, we really need to know whether the antibodies were truly specific to XMRV.

12. "The Harvey Alter NIH/FDA Paper"

• Patients: CFS?
• Origin: ?
• Method: ?
• Result: "We (FDA & NIH) have independently confirmed the Lombardi group findings." according to a conference presentation by Harvey Alter: see here.
• Notes: Rumored as of 5th July 2010 to be about to appear in PNAS.

13. Qui et al 2010

• Patients: n/a
• Origin: U.S. blood donors
• Method: Blood immunoreactivity to XMRV env, gag, and p15E.
• Result: "reactivity to all 3 antigens in a low proportion (~0.1%) of US blood donors." n=?
  
• Notes: Conference presentation given at the 17th Conference on Retroviruses and Opportunistic Infections 2010.

Harriet Groom, et al. (2010). Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome Retrovirology

DSM-V: Change We Can Believe In?

So the draft of DSM-V is out.

If, as everyone says, the Diagnostic and Statistical Manual is the Bible of Psychiatry, I'm not sure why it gets heavily edited once every ten years or so. Perhaps the previous versions are a kind of Old Testament, and only the current one represents the New Revelation from the gods of the mind?

Mind Hacks has an excellent summary of the proposed changes. Bear in mind that the book won't be released until 2013. Some of the headlines:

• Asperger's Syndrome is out - everyone's going to have an "autistic spectrum disorder" now.
  
• Personality Disorders are out - kind of. In their place, there's 5 Personality Disorder Types, each of which you can have to varying degrees, and also 6 Personality Traits, each of which you can have to varying degrees.
• Hypoactive Sexual Desire Disorder - the disease which failed-antidepressant-turned-aphrodisiac flibanserin is supposed to treat - is out, to be replaced by Sexual Interest and Arousal Disorder.
• Binge Eating Disorder, Hypersexuality Disorder, and Gambling Addiction are in. Having Fun is not a disorder yet, but that's on the agenda for DSM-VI.

More important, at least in theory, are the Structural, Cross-Cutting, and General Classification Issues. This is where the grand changes to the whole diagnostic approach happen. But it turns out they're pretty modest. First up, the Axis system, by which most disorders were "Axis I", personality disorders which were "Axis II", and other medical illnesses "Axis III", is to be abolished - everything will be on a single Axis from now on. This will have little, if any, practical effect, but will presumably make it easier on whoever it is that has to draw up the contents page of the book.

Excitingly, "dimensional assessments" have been added... but only in a limited way. Some people have long argued that having categorical diagnoses - "schizophrenia", "bipolar disorder", "major depression" etc. - is a mistake, since it forces psychiatrists to pigeon-hole people, and that we should stop thinking in terms of diagnoses and just focus on symptoms: if someone's depressed, say, then treat them for depression, but don't diagnose them with "major depressive disorder".

DSM-V hasn't gone this far - the categorical diagnoses remain in most cases (the exception is Personality Disorders, see above). However, new dimensional assessments have been proposed, which are intended to complement the diagnoses, and some of them will be "cross-cutting" i.e. not tied to one particular diagnosis. See for example here for a cross-cutting questionnaire designed to assess common anxiety, depression and substance abuse symptoms.

Finally, the concept of "mental disorder" is being redefined. In DSM-V a mental disorder is (drumroll)...

A. A behavioral or psychological syndrome or pattern that occurs in an individual

B. The consequences of which are clinically significant distress (e.g., a painful symptom) or disability (i.e., impairment in one or more important areas of functioning)

C. Must not be merely an expectable response to common stressors and losses...

D. That reflects an underlying psychobiological dysfunction

E. That is not primarily a result of social deviance or conflicts with society

The main change here is that now it's all about "psychobiological dysfunction", whereas in DSM-IV, it was about "behavioral, psychological, or biological dysfunction". Hmm. I am not sure what this means, if anything.

But read on, and we find something rather remarkable...

J. When considering whether to add a mental/psychiatric condition to the nomenclature, or delete a mental/psychiatric condition from the nomenclature, potential benefits (for example, provide better patient care, stimulate new research) should outweigh potential harms (for example, hurt particular individuals, be subject to misuse)

This all sounds very nice and sensible. Diagnoses should be helpful, not harmful, right?

No. Diagnoses should be true. The whole point of the DSM is that it's supposed to be an accurate list of the mental diseases that people can suffer from. The diagnoses are in there because they are, in some sense, real, objectively-existing disorders, or at least because the American Psychiatric Association thinks that they are.

This seemingly-innocuous paragraph seems to be an admission that, in fact, disorders are added or subtracted for reasons which have little to do with whether they really, objectively exist or not. This is what's apparently happened in the case of Temper Dysregulation Disorder with Dysphoria (TDDD), a new childhood disorder.

TDDD has been proposed in order to reduce the number of children being diagnosed with pediatric bipolar disorder. The LA Times quote a psychiatrist on the DSM-V team:

The diagnosis of bipolar [in children] "is being given, we believe, too frequently," said Dr. David Shaffer, a member of the work group on disorders in childhood and adolescence. In reality, when such children are tracked into adulthood, very few of them turn out to be bipolar, he said.

And the DSM-V website has a lengthy rationale for TDDD, to the same effect.

Now, many people agree that pediatric bipolar is being over-diagnosed. As I've written before, pediatric bipolar was considered to be a vanishingly rare disease until about 10 years ago, it still is pretty much everywhere outside the USA.

So we can all sympathize with the sentiment behind TDDD - but this is fighting fire with fire. Is the only way to stop kids getting one diagnosis, to give them another one? Should we really be creating diagnoses for more or less "strategic" purposes? When the time comes for DSM-VI, and the fashion for "pediatric bipolar" has receded, will TDDD get deleted as no longer necessary? What will happen to all the "TDDD" kids then?

Can't we just decide to diagnose people less? Apparently, that would be a rather too radical change...

Dope, Dope, Dopamine

When you smoke pot, you get stoned.
Simple. But it's not really, because stoned can involve many different effects, depending upon the user's mental state, the situation, the variety and strength of the marijuana, and so forth. It can be pleasurable, or unpleasant. It can lead to relaxed contentment, or anxiety and panic. And it can feature hallucinations and alterations of thinking, some of which resemble psychotic symptoms.

In Central nervous system effects of haloperidol on THC in healthy male volunteers, Liem-Moolenaar et al tested whether an antipsychotic drug would modify the psychoactive effects of Δ9-THC, the main active ingredient in marijuana. They took healthy male volunteers, who had moderate experience of smoking marijuana, and gave them inhaled THC. They were pretreated with 3 mg haloperidol, or placebo.

They found that haloperidol reduced the "psychosis-like" aspects of the marijuana intoxication. However, it didn't reverse the effects of THC of cognitive performance, the sedative effects, or the user's feelings of "being high".

This makes sense, if you agree with the theory that the psychosis-like effects of THC are related to dopamine. Like all antipsychotics, haloperidol blocks dopamine D2 receptors, and increased dopamine transmission has long been implicated in psychosis; some studies have found that THC causes increased dopamine release in humans (although others have not.)

Heavy marijuana use probably raises the risk of psychotic illnesses, like schizophrenia, although this is still a bit controversial, but it's accepted that some people do experience psychotic-type symptoms while stoned. So Liem-Moolenaar et al's conclusion that "psychotic-like effects induced by THC are mediated by dopaminergic systems" while the other aspects of being stoned are mediated by other brain systems, is not unreasonable, and this study is a nice example of the 'pharmacological dissection' of drug effects.

Still, like most papers of this kind, this leaves me wanting to know more about the subjective effects experienced by the volunteers. What did it feel like to get stoned on haloperidol? The paper tells us that

THC caused a significant increase of 2.5 points in positive PANSS, which was significantly reduced by 1.1 points after pre-treatment with haloperidol... Haloperidol completely reversed THC-induced increases in ‘delusions’ and ‘conceptual disorganization’ and almost halved the increase in ‘hallucinatory behaviour’. Although not statistically significant, haloperidol seemed to increase the items ‘conceptual disorganization’, ‘suspiciousness/persecution’ and ‘hostility’ compared with placebo.

The PANSS being a scale used to rate someone's "psychotic symptoms". On the other hand haloperidol had no significant effect on the users' self-rated Visual Analogue Scales (VAS) scores for things like "altered external perception" and "feeling high".

But surely the haloperidol must have changed what it felt like in some way. It must have changed how people thought, felt, perceived, heard, and so forth. These kinds of rating scales are useful for doing statistics with, but they can no more capture the full depth of human experience than a score out of 5 stars substitutes for a full Roger Ebert movie review.

This matters, because it's not clear whether haloperidol really reduced "psychosis-like experiences", or whether it just sedated people to the extent that they were less likely to talk about them. In other words, its not clear whether the scores on the rating scales changed in "specific" or a "non-specific" way. This is no criticism of Liem-Moolenaar, though, because it's a general problem in psychopharmacology. For example, a sleeping pill could reduce your score on most depression rating scales, even if it had no effect on your mood, because insomnia is a symptom of depression.

There are various ways to try to work around these issues, but ultimately I suspect that there's no substitute for personal experience, with direct observation of other people taking the drugs coming second, and rating scales a distant third. Of course, direct observation is unsystematic, and prone to bias, and few would say it was practical for psychopharmacologists to go around drugging themselves and each other... but life is more than a series of numbers.

Link: On Being Stoned (1971) by Charles Tart is a classic book which used a very detailed questionnaire to investigate what it's like to be stoned, although the methodology was hardly rigorous.

Liem-Moolenaar, M., Te Beek, E., de Kam, M., Franson, K., Kahn, R., Hijman, R., Touw, D., & van Gerven, J. (2010). Central nervous system effects of haloperidol on THC in healthy male volunteers Journal of Psychopharmacology DOI: 10.1177/0269881109358200

Neuroskeptic Embarrassed by Hand Pic

OK, I admit it, sometimes I write notes to help me remember what I'm going to blog about. Still, at least I'm in good company.

Are We All Homeopaths Now?

There are two kinds of Complementary and Alternative Medicine (CAM) - the ones that involve actually doing stuff, and the ones that don't.

Things like herbal medicine, chiropractic, and acupuncture could plausibly make someone better, as more than just a placebo, given what we know about physics and chemistry, because they involve physically acting on the body. I don't claim to know whether they do in fact work, but in theory, they could.

Other CAM techniques, however, are just magic. Homeopathy is the best example of this: it cannot work, except as a placebo, unless our understanding of nature is fundamentally wrong. The "active ingredient" in a homeopathic remedy is diluted in water to the point where not a single molecule of it remains (and then diluted more, for good measure). If some mystical "essence" or "energy" can somehow survive in water despite dilution then, logically, all water must contain the essence of pretty much everything. Homeopathy literally involves nothing beyond sugar pills and water

But there's one useful thing about homeopathy: it shines a light on the rest of modern medical science, or rather, it holds up a mirror to it. Unfortunately, the reflection is not as pretty as you'd hope.

These two graphs come from a paper by Shang et al, Are the clinical effects of homoeopathy placebo effects?, which was a major meta-analysis of 110 randomized, placebo-controlled trials (RCTs) of homeopathy. It was published in The Lancet in 2005.

Shang et al 2005 was bad news for homeopathy, because it concluded that "[the meta-analysis] is compatible with the notion that the clinical effects of homoeopathy are placebo effects." - i.e., homeopathy doesn't work. Since its publication the paper has been hotly criticized by homeopaths, and defended by skeptics, with the skeptics generally being right. But it was bad news for conventional medicine too.

These two graphs are funnel plots. Each dot represents a published RCT. Dots to the left of the vertical line are trials where the 'active treatment' did better than the placebo control; the further left, the better. The higher up the dot is, the more "precise" the results of the trial, i.e. the less variability there was in the results. They may not look like much, but they're terrifying.

The top funnel plot shows the 110 published RCTs of homeopathy for various illnesses. The bottom one shows 110 RCTs of "conventional" medical treatments that Shang et al picked out as comparisons. These trials were quasi-randomly selected from a list of over 300,000, such that each one was matched to a homeopathy trial for disease, and number of patients.

You'll notice that the two plots look rather similar - there's a lot of spread, but most of the dots are to the left of the vertical line, meaning that the treatments were better than the placebos. Quite a lot are very far to the left, meaning the treatment worked really well. Very few are on the right.

But homeopathic treatments, by definition, are placebos - they're literally sugar pills. So any trial of homeopathy should have an equal chance of finding it to be better than placebo, or worse. Placebos are placebos. It should be a coin toss, 50/50. In fact, Shang et al found only about 20 trials showing homeopathic placebos to be worse than placebo placebos, and 90 finding they were better.

How can this be? Either homeopathy works, in which case we need to rewrite physics and chemistry, or there is something very wrong with the published literature. I find it easier to believe the latter. But then how could the published literature be so wrong?

Almost certainly, a large part of the answer is publication bias, broadly speaking. If people do a trial and don't get the result they want, they generally either don't write it up for publication; or if they try to, it doesn't get published. Related to this is selective outcome bias: they pick out and write up only those results that do match what they wanted; or they pick out statistical techniques to get the result they wanted, etc.

The plot for homeopathy RCTs is what you get when people study a treatment that doesn't work, but that they believe does work, and publish their findings in a biased way. But the plot for "real" medicines looks disturbingly like that.

In other words, the whole clinical trial literature - all of those RCTs and meta-analyses, published in respectable journals, the ones we rely on to determine what treatment decisions doctors make - could be produced even if all of our treatments were no better than placebos. Like I said, terrifying.

I should stress that this doesn't mean that real medicines are no better than placebos. Shang et al's results are also what you'd see if there's no publication bias in conventional medicine, and the treatments work really well. (The evidence for positive effects in the "real medicine" trials was also somewhat stronger than in the homeopathy trials - the dots were further left - which is reassuring, but the difference was pretty small.) The problem though is that we can't tell - at least not on the basis of the clinical trial literature.

Luckily, there's an answer - mandatory registration of clinical trials. Medical journals or, ideally, governments, can require researchers to publicly announce the details of each trial, and how they plan to analyze the results, before the trial takes place, and require that the final results are made public. The USA has had such a system in place, backed by law, since 2007, and most major medical journals now demand registration.

Sadly, biases still seem to be happening in registered trials. But this doesn't mean the system doesn't work, it just means it should be more strictly enforced, and extended to other countries and, I'd argue, beyond just clinical trials. Either that, or we might as well take up homeopathy.

Shang, A., Huwiler-Müntener, K., Nartey, L., Jüni, P., Dörig, S., Sterne, J., Pewsner, D., & Egger, M. (2005). Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy The Lancet, 366 (9487), 726-732 DOI: 10.1016/S0140-6736(05)67177-2

Beware The Clam of Forgetfulness

Every day, PubCrawler emails to tell me about the latest papers that match various search terms. It means I never miss a relevant paper, but it also means I get told about an awful lot of irrelevant ones. Sometimes though, the title alone grabs my attention and demands a read. Such as yesterday's Risk assessment of the amnesic shellfish poison, domoic acid, on animals and humans. Shellfish causing amnesia?

It turns out that there's a neurotoxin, domoic acid, which can indeed cause brain damage including memory loss. It's produced by certain algae, and can accumulate inside shellfish, especially mussels.

Domoic acid is responsible for amnesic shellfish poisoning, which struck a cluster of over 100 people in Canada in 1987; 4 died, and several others suffered permanent neurological symptoms, including epilepsy and most notoriously, anterograde amnesia, the inability to form new memories.

Autopsies revealed prominent damage to the hippocampus and nearby temporal lobe areas. Domoic acid victims were therefore very similar to Henry Molaison (HM), the most famous amnesia sufferer, whose memory loss was caused by the surgical removal of the same areas.

Domoic acid is related to kainic acid, which neuroscientists will have heard of: it's widely used in epilepsy research to give animals seizures, amongst other things. Both are excitotoxins - they kill neurons by over-activating them, which opens ion channels allowing calcium to enter the cell and reach toxic levels. They're able to do this because of their chemical similarity to glutamate, the brain's most common neurotransmitter (and the one that the drug ketamine antagonizes).

Since 1987, there have been no further cases in humans, thanks to shellfish harvesting regulations. Marine animals and birds continue to suffer however, especially sea lions, although interestingly, sharks seem to be immune despite having the same glutamate receptors as mammals.

Overall, this is one more reason I'm glad to be a vegetarian. Although, that said, there are some equally nasty neurotoxins in plants...

Kumar KP, Kumar SP, & Nair GA (2009). Risk assessment of the amnesic shellfish poison, domoic acid, on animals and humans. Journal of environmental biology / Academy of Environmental Biology, India, 30 (3), 319-25 PMID: 20120452