Tuesday, February 07, 2012

While I Was Away...

While I was (mostly) away from the internet, I missed over a week of online excitement. These items are old news by now, but in case you've forgotten...

(1) NPR Morning Edition had a piece on acutely administered ketamine for the treatment of depression:
Could A Club Drug Offer 'Almost Immediate' Relief From Depression?

There's no quick fix for severe depression.

Although antidepressants like Prozac have been around since the 1970s, they usually take weeks to make a difference. And for up to 40 percent of patients, they simply don't work.

As a result, there are limited options when patients show up in an emergency room with suicidal depression.

The doctors and nurses at Ben Taub General Hospital in Houston say they see this problem every day.
More from NPR: 'I Wanted To Live': New Depression Drugs Offer Hope For Toughest Cases.

Other media outlets followed suit. ABC: Ketamine: Quick Fix for Severe Depression? CBS: Club drug ketamine cures depression instantly: How? But why the sudden interest in ketamine and its mechanism of action? Here's an NIMH press release from Tuesday, July 24, 2007:
Faster-Acting Antidepressants Closer to Becoming a Reality
Experimental medication ketamine relieves depression in just hours; points to targets for new medications
A visit to clinicaltrials.gov found 38 studies in a search for 'ketamine depression', starting with the NIMH study first posted in 2004. Twenty-two of these are still (or soon-to-be) recruiting patients, including Intranasal Ketamine In the Treatment of Pediatric Bipolar Disorder and the study covered by NPR, Optimization of IV Ketamine for Treatment Resistant Depression. Perhaps someone at Ben Taub Hospital knows someone at NPR (or vice versa)?

Not everyone thinks this dissociative anesthetic/club drug/animal tranquilizer is a great antidepressant. The Neurocritic covered both sides of the story in Ketamine for Depression: Yay or Neigh? as well as a questionable treatment regimen in Chronic Ketamine for Depression: An Unethical Case Study? On a mechanistic level, the mTOR (mammalian target of rapamycin) protein kinase pathway, which is rapidly activated by ketamine, may have its ups and downs. Although activation of mTOR leads to the beneficial effect of increased synaptogenesis in the medial prefrontal cortex (Li et al., 2010), it can also cause accelerated tumor growth, as recently noted by Yang et al., 2011 ("Be prudent of ketamine in treating resistant depression in patients with cancer").

What if you were depressed 10 yrs ago, tried ketamine but didn't know it was supposed to instantly "cure" your depression, and then ended up merely frightened by the K-hole and not better at all? Has that happened to anyone? The anti-ketamine bandwagon is being led by Gawker and its stable of experienced ketamine users:
Super Powerful Club Drug Cures Depression Instantly

Neuropsychiatric researchers say that although traditional antidepressants can take weeks to work, depressed patients who are given BANANAS 'PAUSE BUTTON ON YOUR BRAIN' K-HOLE-INDUCING CLUB DRUG KETAMINE A.K.A. SPECIAL K feel relief from their depression "almost instantly." But could huge shots of heroin combined with a baseball bat to the head be equally effective? Ketamine-receiving patients say [just stares at the wall].

Ketamine Is the World’s Dumbest Drug

. . .

The '90s were a lot of fun the first time around, and there were tons of great things about the decade. We even did a lot of wonderful, powerful, mind-altering substances... K was not one of them. K was a stupid mistake. Even a bigger mistake than Fat Boy Slim, P.L.U.R., and a strange affection for Ring Pops at the age of 20. It was one of the few things I look back on and think, "Man, that was really, really dumb. Why did we ever do that?" If the '90s are going to come back, take this lesson from someone who really enjoyed the first time around—leave the K for the cats.
Finally, I just have to say one thing about this clinical trial on Ketamine For Suicidal Ideation at Mount Sinai. The only primary and secondary outcome measures are at 24 hours post infusion? Really?? You're not following up the patients to see if they're still suicidal a week later, let's say? Is that so difficult?

(2) LiveScience declared that Family's Mental Disorders May Shape Your Interests, and Medical Xpress carried this understated story:
Survey suggests family history of psychiatric disorders shapes intellectual interests

A hallmark of the individual is the cultivation of personal interests, but for some people, their intellectual pursuits might actually be genetically predetermined. Survey results published by Princeton University researchers in the journal PLoS ONE suggest that a family history of psychiatric conditions such as autism and depression could influence the subjects a person finds engaging.
Genetically predetermined? Really? Eighteen year old Princeton freshman provide expert psychiatric diagnoses of their relatives, declare their intended majors, and somehow manage to confirm the 'tortured alcoholic artist' and 'autistic engineer' stereotypes (Campbell & Wang, 2012). Surprise!

But the basic premise of asking 18 yr olds for valid psychiatric diagnoses of family members might be flawed, you say? Neuroskeptic posted on this paper, but not skeptically enough, in my view. I would go directly to this comment by Professor Keith R Laws:
Obviously there are a few issues with such studies:
1) the ability of individuals to report accrurately - it seems for example that they viewed propsopagnosia as a memory disorder - so they are not identifying at all accurately (at least for some conditions)
2) there seem to be strong oddities in the incidence rates e.g. schizophrenia
3) in the latter case, there may be a strong social desirability effect
4) indeed, in relation to desirability, such individuals may be more prone to endorse stereotypes (of autism-geek etc)
5) comorbidities were not apparently evaluated e.g. about a third of all people with autism have a comorbid disorder; similarly with other disorders esp things such as OCD (with sz etc)
And it's really stretching it to say anything at all about genetics from a survey (Campbell & Wang, 2012):
Our results suggest that shared genetic (and perhaps environmental) factors may both predispose for heritable neuropsychiatric disorders and influence the development of intellectual interests.
Moving right along...

(3) Mail Online screamed that Every textbook on the brain is wrong - and our brains are more similar to monkeys than we thought. Did you know that Wernicke's area has moved? Wow, only 12 yrs after the pioneering PET/fMRI studies on speech perception by Scott et al. (2000) and Binder et al. (2000)? It seems to me that the authors of the paper in question (DeWitt & Rauschecker, 2012) were not at all shy about taking credit for this seemingly historical change in human neuroanatomy. Some choice quotes from the Mail Online article:
But, now, research that analyzed more than 100 imaging studies concludes that Wernicke's area is in the wrong location.

The site [not so] newly identified is about 3 centimeters closer to the front of the brain and on the other side of auditory cortex — miles away in terms of brain architecture and function.

The finding, published online this week in the Early Edition of the Proceedings of the National Academy of Sciences (PNAS), means that ‘textbooks will now have to be rewritten,’ says the study's senior author, Josef Rauschecker, Ph.D., a professor in the department of neuroscience at Georgetown University Medical Center (GUMC).

‘We gave old theories that have long hung - a knockout punch,’ says Rauschecker...

‘If you Google 'language organization in the brain,' probably every cartoon illustration out there is wrong,’ says lead author Iain DeWitt, a Ph.D. candidate in Georgetown's Interdisciplinary Program in Neuroscience.
This was all the more curious because the term "Wernicke's area" did not appear once in the original PNAS paper. I might get around to posting on this topic, but (even if I do) it's better to read Professor Sophie Scott's post, Wernicke's area: are we still looking for it? Was it ever lost.


Binder JR, Frost JA, Hammeke TA, Bellgowan PS, Springer JA, Kaufman JN, Possing ET. (2000). Human temporal lobe activation by speech and nonspeech sounds. Cereb Cortex 10:512-28.

Campbell BC, Wang SS (2012). Familial Linkage between Neuropsychiatric Disorders and Intellectual Interests. PLoS One 7(1):e30405.

Dewitt I, Rauschecker JP. (2012). Phoneme and word recognition in the auditory ventral stream. Proc Natl Acad Sci Feb 1. [Epub ahead of print]

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959-64.

Scott SK, Blank CC, Rosen S, Wise RJ. (2000). Identification of a pathway for intelligible speech in the left temporal lobe. Brain 123:2400-6.

Yang C, Zhou ZQ, Yang JJ. (2011). Be prudent of ketamine in treating resistant depression in patients with cancer. J Palliat Med. 14:537.

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At February 07, 2012 12:47 PM, Blogger Eric Charles said...

Great post.

Regarding 1) I didn't know what to make of the Ketamine reports when I started hearing them. Is that really the way pharmacology is going? If we are willing to put street drugs into people through an IV, why would ketamine be the first choice? I'll also bet that an injection of cocaine makes you less depressed. Probably quite a few hallucinogens as well. Odd stuff.

Regarding 2) Did you see how small the effect were in those articles? I'm amazed they had anything to conclude. Certainly there were no demonstrations of general trends.

Regarding 3) This was just silly. Every intro text book in every subject is wrong. The real question is whether they are wrong in a way that stunts the educational process. Seriously, who cares if a first year engineer in an intro psych class thinks Wernicke's area is three centimeters away from where it "really is". The only reason to be talking about that is because it is an example of brain-area specialization. All we want them to know is that brain areas are specialized to greater and lesser extents. Even if the critics are 100% right, it is still much ado about nothing.

At February 19, 2012 9:29 AM, Blogger Zigs said...

I totally agree regarding that study of suicidal patients treated with ketamine not having an adequate outcome measure. Another problem with studies of ketamine so far is that they have been administering the MADRS at 1 hour and 24 hours. This is meaningless as the MADRS is supposed to assess stability of symptoms of depression over 1 week.

While I too am surprised by the rating scale score in that case report, it is important to recognize that scores on rating scales do not always correlate well with intensity of suffering and functional impairment. For example, someone can have very intense dysphoria and suicidal ideation, but only mild somatic symptoms and obtain a low score. They are best used for giving an estimation of symptom severity and following response to treatment.

I have been using ketamine in our psychopharm research unit for select patients with a severe refractory depression who have failed many approved treatments. It works well and quickly for most people. It is much better tolerated than ECT and has not resulted in cognitive impairment (which we have been following in our patients). It does not give a "high" or euphoria the way that cocaine or heroin would. The experience is more of a "trip" which seems to be accompanied by a reduction in anxiety, tension, dysphoria and lassitude. Our limited experience indicates that it does not seem to be addictive in this population (though we have not given it to patients with a history of addiction). We tried a specially compounded nasal spray and got poor results compared to the IV treatment. The only long term side effect that we have seen is development of migraines, which stopped when the treatment was held for a few weeks.

Hopefully, the many research studies underway will help determine the best dosing schedule, long term risks, and which patients may benefit most.

At February 19, 2012 11:23 AM, Blogger The Neurocritic said...

Zigs - Thanks for your observations. What sort of dosing schedule are you using at present? I think it's important to report the increased risk of migraines. I found a few papers on the use of ketamine for the treatment of migraine (e.g., Nicolodi & Sicuteri, 1995), but not about new onset migraines caused by ketamine.

Eric Charles - A very belated thanks to you for your comments!

At February 19, 2012 12:28 PM, Blogger Zigs said...

We have been using 0.5 mg/kg IV over 35-40 minutes. Some patients do well with 1 treatment every 3 or so weeks. For others, the effect lasts only a few days.

I also saw that ketamine is used occasionally for migraines. Only 1 of the 8 people we have treated got migraines and it occurred after about 6 months of bi-weekly treatment. (This was a person with exceptionally treatment refractory depression and is not the norm in our clinic.) Again, the migraines stopped a couple of weeks after we held the ketamine treatment.

At February 19, 2012 11:15 PM, Blogger The Neurocritic said...

Thanks. That seems to be the standard dose. I asked because I recently came across this paper, Using ketamine to model semantic deficits in schizophrenia, which used a dose of 0.8 mg/kg per hour for 80 min. Glutamatergic theories of schizophrenia have been around for a while...

At February 20, 2012 3:46 PM, Blogger Zigs said...

Yes. We have also tried the 0.2 mg/kg bolus over 2 minutes. A few of the patients did not find it as effective as the infusion.

At February 28, 2012 12:54 PM, Anonymous Sam Wang said...

In regard to Eric Charles's comment, the odds ratios of our findings were between 2:1 and 3:1 for individual neuropsychiatric disorders, and over 20:1 for the compounded PRESUME score. These are large effects by any standard.

In regard to the remarks quoted by Neurocritic, the statements by Keith Laws contain a number of errors. We address these errors on the Neuroskeptic site.

Sam Wang
Princeton University.

At February 28, 2012 10:17 PM, Anonymous Anonymous said...

3) Some of the quotes are a little over the top but, the result is interesting. The original press release gives more context:

“Other researchers have found what we have, as well, which has caused a lot of controversy in the field as to where Wernicke’s area really is,” Rauschecker says. “This study provides a definitive, irrefutable answer.”
DeWitt agrees. “After the 1990s, the first decade of cognitive brain imaging, it was already clear to some researchers that the anterior portion of the superior temporal gyrus was a more likely site for word recognition. The majority of imagers, however, were reluctant to overturn a century of prior understanding on account of what was then a relatively new methodology,” he says. “The point of our paper is to force a reconciliation between the data and theory. It is no longer tenable to overlook or dismiss evidence supporting a central role for the anterior portion of the superior temporal gyrus in auditory word recognition.”


For comparison, look at this:

Program#/Poster#: 837.1
Title: Reassessing the pathway for intelligible speech
Location: Room 25A
Presentation Time: Wednesday, Nov 17, 2010, 1:00 PM - 1:15 PM
Authors: *G. S. HICKOK;
Univ. California, Irvine, CA
Abstract: Sophie Scott and colleagues published an influential series of papers in the last decade, which described functional imaging experiments that contrasted various forms of intelligible and unintelligible speech stimuli. The primary finding from this work was that a left anterior superior temporal region responded preferentially to intelligible speech. This led to the view that the pathway for intelligible speech projects anterior from primary auditory areas within the left hemisphere. Here I will reassess the evidence for this view both from the perspective of the neuropsychological literature and from two new functional imaging studies using the same intelligibility manipulations to those in the Scott et al. experiments. The new studies found a bilateral pattern of activation that includes posterior temporal regions as well as anterior regions. I conclude that the pathway for intelligible speech is bilaterally organized with posterior temporal regions supporting lexical-phonological processing and anterior regions supporting higher-order integrative functions.

At February 28, 2012 10:19 PM, Anonymous Anonymous said...

Also, check the Author Summary for the article, it mentions Wernicke's area.

At February 28, 2012 11:30 PM, Blogger The Neurocritic said...

Prof Wang - You didn't address one of the major criticisms of your study. How did you verify the accuracy of the "psychiatric diagnoses" given by 18 yr old undergrads?

At February 28, 2012 11:35 PM, Blogger The Neurocritic said...

Sam Wang's rebuttal to Keith Laws is reprinted below.

Keith Laws has made some factual errors here. Some replies, for the record.

(1) It is incorrect that respondents viewed prosopagnosia as a memory disorder. They were not asked to make this classification. It is true that trouble recognizing faces was a survey item that encompasses both prosopagnosia, dementia, and other problems.

(2) and (3) The reported prevalence of schizophrenia in the US population 7.2 per 1000. It is hard to know what to expect from students' relatives since they include both parents and siblings, the latter of whom are younger. But n=18 is not aberrant in any way.

(4) Laws has no basis for this statement.

(5) This is untrue. Comorbidities were implicitly included in the survey, which took the form of a checklist. Also, it is not clear what point is being made here.

At February 28, 2012 11:47 PM, Blogger The Neurocritic said...

Anonymous of February 28, 2012 10:19 PM - Clearly I missed the rollout of PNAS Plus and the introduction of the Author Summary. I only read the main article.

At March 30, 2012 9:49 AM, Blogger Vance Harrington said...

Many people don't consider marijuana and addictive drug! They should probably reconsider that idea after they become addicted and allow the devastating gateway drug open the doors to a horrible future full of failure and you disappointing your family. Do you know someone who needs help treating marijuana addiction?

At March 30, 2012 10:26 AM, Blogger The Neurocritic said...

Why thank you, "Vance Harrington," for that stern warning.

Forever Recovered, you really need to rethink your SEO strategy...

At March 30, 2012 11:16 AM, Blogger Neuroskeptic said...

I do love the rare spam comments that are so bad they become good. They're why I still read every single spam comment on Neuroskeptic (5-10 per day now). Once in a long while they're so good I let them stay.

At March 30, 2012 12:45 PM, Blogger The Neurocritic said...

Just got another one promoting the same spam url, on a different post. Many of these grammatically incorrect blog comments are from the Philippines these days. I hope the SEO sharks are paying the working spammers a decent wage, but I doubt it.


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