The latest American
Journal of Psychiatry features a strange series of four drawings
made by a 15 year old girl during an episode of the disease, which presented as psychotic symptoms but later progressed to severe insomnia and epilepsy before it was diagnosed and treated.
"As she gradually recovered we asked her to draw something. She did not know what to draw, so we suggested an animal, such as a dog, but she did not know how to start. When we told her that a dog has four legs, a tail, two ears, two eyes, and a mouth, she drew an abstract figure that consisted of a head with four legs (A). Her next drawing, of a cat, looked exactly the same, apparently since they share the same basic features. Two weeks later the dog now looked more recognizable but like a human, standing upright, with two arms and four legs...All body parts were listed beneath the figure in the same color as they were drawn (B). Two months after the patient was transferred to a local rehabilitation center, the cat was catlike for the first time; it had four legs, was normally proportioned, and was correctly positioned. Colors were used adequately. However, this drawing still looked like one by a primary school child instead of a 15- year-old girl (C). Finally, after 5 months of rehabilitation her drawing had a normal composition. She still had the urge to write down what she drew, she did not encircle the figures anymore (D)."
Esseveld MM, van de Riet EH, Cuypers L, and Schieveld JN (2013). Drawings During Neuropsychiatric Recovery From Anti-NMDA Receptor Encephalitis. The American journal of psychiatry, 170 (1), 21-2 PMID: 23288386
There's a theory that 'psychiatric diseases' like depression and schizophrenia aren't diseases because they're not diagnosed on the basis of any kind of biological abnormality, but purely on symptoms - unlike 'real' diseases like cancer and AIDS.
Now, in my view there's quite a bit of truth in that - but there's also a serious flaw in the argument. Sometimes, disorders diagnosed on the basis of psychiatric symptoms do turn out to have had a clear biological cause. So the original diagnosis of a psychiatric disease was correct: there was indeed a disease.
This is happening more and more often now because of biomedical advances.
A group of German neurologists and psychiatrists recently wrote about a case of a man diagnosed with bipolar disorder:
In February 2009, a 28-year-old presented to our clinic with a first episode of depression. He reported depressed mood, anhedonia, decreased drive, reduced alertness and concentration. The symptoms responded well to quetiapine 100 mg.
Fourteen months later, a first manic episode with logorrhea [excessive speech], aggressive and disinhibited behavior occurred... it completely remitted after treatment with quetiapine 1000mg. A diagnosis of bipolar I disorder was made.
Two months later, the patient presented with another depressive episode... Despite treatment with quetiapine, aripiprazole, lithium, valproate and escitalopram, the patient did not improve...
So far, seems like a fairly typical case of bipolar. However, it turned out that...
Neurological examination was remarkable for extrapyramidal symptoms with left-sided rigor and bradykinesia [slowed movements]. On initial and concurrent magnetic resonance imaging (MRI), numerous subcortical lesions in the frontal lobes were detected... Screening for autoimmune antibodies detected NMDAR antibodies.
It turned out the guy had autoimmune encephalitis: his body was generating antibodies that blocked the brain's key NMDA receptors; the drug ketamine does that too. Treatment with immunosuppressant drugs was started and he recovered fairly quickly. For a first-hand account of the disease, in which it was also diagnosed as a psychiatric disorder initially, see the recent book Brain On Fire.
Now, let's imagine that this had happened in 1960. What would the guy's story have been then?
He'd have been seen by a psychiatrist and diagnosed with bipolar, just as he was today. Depending on how severe the depression was, and whether or not he had any more episodes, he might well have ended up in a psychiatric hospital.
But he probably wouldn't have been diagnosed with a neurological disorder. He'd have tested negative for all the neurological diseases known at the time. No-one tested for NMDA antibodies back then, because NMDA receptors weren't even discovered until 1981.
It's true that his neurological exam showed a movement disorder (left-sided
rigor and bradykinesia) but this might well have been
written off as a side effect of the high dose antipsychotics he was
taking, which cause similar movement disorders.
50 years ago this guy, and many others like him, could well have ended up committed to an asylum. 100 years ago, I think it would have been almost certain he'd have been deemed 'insane' and locked up at some point.
If so, some of the people in psychiatric hospitals 50 or 100 years ago will have had this disease - or others. And if we didn't know about anti-NMDA encephalitis until recently, who's to say what we'll discover next?
Choe CU, Karamatskos E, Schattling B, Leypoldt F, Liuzzi G, Gerloff C, Friese MA, and Mulert C (2012). A clinical and neurobiological case of IgM NMDA receptor antibody associated encephalitis mimicking bipolar disorder. Psychiatry research PMID: 23246244
There's a lot of interest in the idea that ketamine provides unparalleled rapid, powerful antidepressant effects, even in people who haven't responded to conventional antidepressants.
Earlier this year, I asked:
Ketamine - Magic Antidepressant, or Expensive Illusion? There have now been several studies finding dramatic antidepressant effects of ketamine, the "club drug" aka "horse-tranquilizer". Great news? If you believe it. But hold your, er, horses... there's a problem.
My concern was that although depressed patients certainly do report feeling better after an injection of ketamine, compared to people given placebo, that doesn't prove that the drug is actually an antidepressant.
Rather, patients might be experiencing an enhanced, 'active' placebo effect, because ketamine causes subjectively powerful hallucinogenic experiences. So the placebo-controlled trials weren't really blinded.
To settle the question, I suggested a three-way trial comparing it both to an inert placebo, and to some other hallucinogen; if ketamine has a specific antidepressant effect, it should produce more improvement than the comparison drug.
Zarate et al tried a novel drug, AZD6765 in depressed people. AZD6765 works much like ketamine in that it blocks brain NMDA receptors. But it is a less powerful trapping blocker than ketamine, meaning that AZD6765 causes less dramatic effects on the target receptors, in some respects.
In practice, this makes AZD6765, much less hallucinogenic than ketamine.
So it's interesting that, compared to placebo, the new drug only produced small benefits. On the MADRS depression symptom scale, patients felt a little better on AZD6765, but the boost only lasted a few hours.
The effect was far smaller than in an earlier ketamine trial as my crudely-mashed-up graph shows (although note that the patient populations were somewhat different, one bipolar and one unipolar depression, although their baseline severity was the same.)
While on ketamine people experienced significant subjective effects, with AZD6765 they didn't, and couldn't tell whether they got drug or placebo. Is that why they got a smaller benefit?
This is what we'd see if NMDA blockers do have a modest antidepressant effect but the dramatic improvements seen on ketamine are largely active placebo phenomena. Then again, it's also consistent with ketamine being a powerful antidepressant and AZD6765 just being less effective because it's a milder blocker of NMDA - effectively, a low dose of ketamine.
To tell the difference, we need... an active placebo controlled trial, like I've been banging on about for ages. But I wasn't the first one to suggest it - that was none other than Carlos Zarate et al in 2006.
Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, and Luckenbaugh DA (2012). A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression. Biological psychiatry PMID: 23206319
A few weeks back I blogged about an error-ridden paper from pharmaceutical company Janssen. It reported on the failure of a candidate antidepressant, JNJ-18038683. But it was rubbish: the Abstract contradicted the results of the study, wrongly claiming that the drug did statistically significantly better than placebo in a particular analysis, when it didn't. And they repeatedly mixed up the names of two other antidepressants.
I posted on May 17th. On May 23rd, a new version of the offending article quietly appeared on the journal's website: here it is. But the old version is still up, although I'm not sure it's intended to be, because the link is gone, so I think the only way to find it is from this blog.
Interestingly, the new manuscript corrects those two issues I noted. As far as I can see those are the only changes. Coincidence?
The original paper was a "Fast Forward" online accelerated publication manuscript, and it's common for these to be corrected in minor ways when they're officially published (i.e. when they appear in print), but that's not what happened here, because the new version is still a Fast Forward. This kind of revision is unusual.
So it seems that someone at Janssen is reading this blog!
If so: Hey. Believe it or not, I'm on your side, I want you to succeed. I suffer from depression, and I've love it if you came up with an actually good new antidepressant. But your industry hasn't released one in at least 10 years (be honest), and you're not fooling anyone with clever statistical tricks.
Forget that, and invest in some proper science. For example, ketamine is clearly the most exciting potential antidepressant right now, and glutamate could be the next serotonin. But because no-one has tested it against an active placebo, no-one, including you, knows whether it's really working. Run a really serious trial of ketamine, if it does work, then that's your next generation of antidepressants right there. If not, better to know that now than later when you've sunk billions into the idea.
Not one but two new papers have appeared from the Carlos Zarate group at NIMH reporting that a single injection of the drug ketamine has rapid, powerful antidepressant effects.
One placebo-controlled study found a benefit in depressed bipolar patients who were already on mood stabilizers. The other found benefits in treatment-resistant major depression, though ketamine wasn't compared to placebo that time. Here's the bipolar trial:
There have now been several studies finding dramatic antidepressant effects of ketamine, a compound that all journalists seem contractually bound to call either a or a "club drug" or a "horse-tranquilizer". Great news?
In theory, the trial was double blind - neither the
patients nor the doctors knew whether they were getting ketamine or placebo. But you'll know when
you've been injected with 0.5mg/kg ketamine. You get high. That's why
people take it [recreationally]. The study can't really be called double blind.
To
their credit, Zarate et al did acknowledge this, and suggested that in
future ketamine could be compared to another drug which produces
noticeable effects. But they really should have done that to begin with.
It's now 2012, and there have still not been any published studies comparing ketamine to an active comparator i.e. a different drug that produces noticable psychoactive effects, to avoid unblinding. This means it's 12 years since the initial pilot report on ketamine in depression, and 6 years since the first large trial appeared.
The authors of the 2006 paper themselves wrote that "limitations in preserving study blind may have biased patient reporting... One potential study design in future studies with ketamine might be to include an active comparator" and suggested amphetamine for the big role.
Good idea. But six years later, we're still waiting. Which is really a bit silly. There have been dozens of papers written about the possible antidepressant effects of ketamine, from human trials to mouse work. That's a lot of research dollars (and dead mice) on something that might just be an active placebo.
Looking at the registered ketamine research on clinicaltrials.gov, I found that four active-comparator ketamine trials are in the pipeline (1,2,3,4), plus one cancelled (5). Only one is for depression though. The others being for OCD, cocaine dependence and suicidal ideation.
In all of these trials a benzodiazepine is the active comparator. Is that a good idea? Well, it's certainly better than nothing, but I wonder.
An active comparator has to "make an impression" on the patient equal to that produced by the real drug. The null hypothesis, remember, is that ketamine has no specific antidepressant effect. That means it produces improvement through a combination of a) the placebo effect (expectation) and b) non-specific psychoactive changes.
More on that second one: any psychoactive drug might relieve depression by "taking your mind off it" and a change in mental state, as provided by a drug, also provides a demonstration that "I won't always feel this way". By showing that states of consciousness are products of brain chemistry, almost any drug could therefore offer a "glimmer of hope" to the depressed. If all this sounds very subjective, it is, but that's the point. Psychiatry is.
Would a benzo make as big an impression as 0.5 mg/kg ketamine IV? It's impossible to predict, really; so we'd need to ask people about the subjective strength of the drug effect. Personally, I worry that a lot of people just get sleepy on benzos and don't really feel much, so I'd prefer they used something a bit more hard-hitting like amphetamine, but maybe that's just me.
There's a deeper problem though. Suppose our ketamine-benzo trial finds no difference between ketamine and benzo. A critic could say, ah, but maybe it was just a "failed trial", so it doesn't overturn the positive studies. The patients weren't properly diagnosed, or weren't depressed enough, or were too depressed, etc.
Nitpicking such differences between studies is a well-practiced art.
Critics could complain in other ways if the study did find a benefit of ketamine. As I see it, the only way to settle this once and for all is to do a three-way randomized controlled trial- inactive placebo vs. active comparator vs. ketamine.
That way, if it's a failed trial, we'd know: there'd be no difference between ketamine and the inactiveplacebo. If there was a difference, but the active comparator was just as good as ketamine, that means it was all about nonspecific effets. Finally, if ketamine was better than the other two conditions, we could be pretty confident it was really working.
Also important is the question of volunteer expertise; subjects shouldn't be able to tell what drug they're on, but people who'd taken ketamine and/or the comparator drug before might be able to do that, so you'd want naive volunteers.
In conclusion:It's possible that ketamine has no specific antidepressant effects. To find out we ideally need a three-way trial, with both active and inactive comparators, careful monitoring of subjective drug effects and patient knowledge and expectations. Until that happens, I will be skeptical of ketamine in depression.
This is not because I just think it's impossible. Ketamine profoundly affects the brain in ways that we don't understand. I've suffered depression and I know it can come and go in a matter of minutes. So I think it's entirely possible that it works - but it's also possible that it's a nonspecific effect.
Look. I really want to know the answer to this. Both as a neuroscientist, and as a depression sufferer, this is very important to me. That's why we urgently need a good trial.
Link: See also the discussion and the comments over at The Neurocritic and this Scientific American piece which is pretty good except that it doesn't cover the active placebo issue. Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, and Luckenbaugh DA (2012). Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial. Biological psychiatry PMID: 22297150
Ibrahim, L., et al. (2012). Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week, Double-Blind, Placebo-Controlled Study Neuropsychopharmacology DOI: 10.1038/npp.2011.338
Generally, when the list of the authors' conflicts of interest (550 words) is nearly as long as the text of the paper (740 words), it's not a good sign, but this one isn't bad. Perlis et al remind us that if you do a double-blind placebo controlled trial:
The blind may be compromised in a variety of ways, however, beginning with differences in medication taste or smell. Of particular concern may be the emergence of adverse effects, particularly when those adverse effects are known to be associated with a specific medication ... Indeed, when the degree of unblinding is assessed in antidepressant trials, multiple reports suggest that it is extensive: at least three-quarters of patients are typically able to correctly guess at their treatment assignment.
The point of a placebo-controlled trial is that neither the patients nor their doctors know whether they're getting the placebo or the real drug. Hence the strength of the placebo effect should be the same in each group, allowing the "real" drug effect to be measured.
But if the drug causes side effects, as pretty much all do, then people could work out which group they're in by noticing whether they're feeling side effects or not. This might enhance the placebo effect in the drug group, and make the drug seem to work better than it really does. Or it might not. But the possibility that it might is worrying.
This is called the active placebo effect. It's why I'm skeptical of claims that scopolamine and ketamine have rapid-acting but short lived antidepressant effects. I may be wrong, but while both of these drugs have been shown to work better than placebo, bothhave very pronounced subjective effects, so there's no chance the blind will have been intact.
Whether the active placebo effect also underlies the efficacy of established antidepressants like Prozac is very controversial. There have been 9 trials comparing antidepressants to active placebos, i.e. drugs that have similar side effects to antidepressants and that should therefore help to preserve the blind. (The active placebos were all atropine which is basically the same as scopolamine.)
The trials were reviewed by antidepressant critic Joanna Moncrieff et al who found that the overall effect size of antidepressants vs. active placebos was d = 0.39. That's not very high, although it's not too bad, and ironically it's actually higher than the effect that Moncrieff's friend and fellow Prozac-baiter Irving Kirsch found in his famous 2008 antidepressant vs. sugar pill placebo meta-analysis, d=0.32. So if you take that seriously, the active placebo effect plays no part in antidepressant efficacy. However the active placebo trials are mostly small and old, so to be honest, we don't really know.
*
A point that's often overlooked is that a drug could have an active placebo effect via having a "real" psychoactive treatment effect. Diazepam (Valium), for example, has basically no peripheral side effects at all: unlike scopolamine it doesn't cause dry mouth, nausea, etc. But it is a tranquillizer; it causes calmness and, at higher doses, sleep. They're pretty noticeable. So if you were to give a depressed person Valium and tell them that it's not only a tranquillizer, it's an antidepressant, then the active placebo problem would arise.
In fact, any active drug will also produce active placebo effects - almost by definition, if you think about it. These may be hard to disentangle from the "real" effects. Say you're anxious about giving a speech so you take some diazepam hoping to feel calmer. A short while later you feel the lovely warm tranquillizing feeling setting in. Phew, you're calm now, anxiety's gone, the speech will be no worry. That thought might well be tranquillizing in itself. In other words the anti-anxiety effects of diazepam are partially driven by active placebo responses due to... the anti-anxiety effects of diazepam.
*
This leads onto another point. Suppose a drug has a genuine effect which improves some of the symptoms of a disease. Does that drug "treat" that disease? In a weak sense, yes, and it might be a helpful drug, but it's not a specific treatment. Morphine's very helpful in cancer, because it treats pain, but it doesn't cure cancer. Likewise insomnia is a symptom of depression, but we feel that in order to qualify as an antidepressant a drug has to treat the core symptoms: mood, anxiety, etc. rather than just being a sleeping pill.
But suppose someone suffered from low mood and you gave them a treatment which stopped them feeling any moods or emotions. That solves their low mood problem: no mood, no problem. But is that a specific treatment for depression? It's a bit of a grey area, but many would say no.
Many people say that this is exactly what SSRI antidepressants do: they blunt your emotions. That doesn't mean they're not helpful in depression: a lot of people find them very useful. I did. But then are they really "antidepressants", or just anti-mood? SSRIs are the drugs of choice not just for depression but also most anxiety disorders, and obsessive-compulsive disorder, etc. In fact they work better in OCD than they do in depression, relative to placebo. So are SSRIs actually antiobsessives that happen to be helpful in some cases of depression? Good question.
Here's Chris Rock on the issue of non-specific effects...
*
Perhaps an ideal clinical trial of a drug for a psychiatric condition should have 4 groups: the drug you're studying, another psychotropic with non-specific effects (e.g. Valium, or caffeine if you want a stimulant), an active placebo with purely peripheral side effects, and sugar pills. But even then, if the active drug performed better than the other 3 groups, a die-hard skeptic could say that maybe it's just more effectively causingnon-specific sedation, or blunting, or whatever, than the Valium. Ultimately, a randomized controlled trial can never prove that a psychotropic drug has a specific as opposed to a non-specific effect.
So where do we stand? Does that mean we don't know what drugs do? No - unless we're some cloistered soul who only reads papers as opposed to talking to people, reading subjective reports, or taking drugs themselves. I know what alcohol does, not because I've read papers about it, but because I've drunk it. I've also been depressed and taken antidepressants, and for what it's worth, in my experience, some of the drugs currently marketed as antidepressants do have a specific anti-depression effect, although others don't. Overall, though, my view is that we know surprisingly little about what antidepressants actually do.
Perlis RH, Ostacher M, Fava M, Nierenberg AA, Sachs GS, & Rosenbaum JF (2010). Assuring that double-blind is blind. The American journal of psychiatry, 167 (3), 250-2 PMID: 20194487
Moncrieff J, Wessely S, & Hardy R (2004). Active placebos versus antidepressants for depression. Cochrane database of systematic reviews (Online) (1) PMID: 14974002
Esseveld MM, van de Riet EH, Cuypers L, and Schieveld JN (2013). Drawings During Neuropsychiatric Recovery From Anti-NMDA Receptor Encephalitis. The American journal of psychiatry, 170 (1), 21-2 PMID: 23288386
