JeanKing Dr. Jean A. King [webpage] is Vice-Chair of Research and Professor in the Department of Psychiatry at the University of Massachusetts Medical School [PubMed; CV]. She completed her PhD in 1988 at NYU in Neurophysiology and conducted postdoctoral training at Emory. Dr. King’s research record is diverse but can be characterized as focusing on neuroendocrine systems, stress, aggression, fear and substance abuse. Her work has also focused on advancing noninvasive imaging techniques in animal models using magnetic resonance imaging, in addition to the papers she has credit on three patents for neuroimaging advances. Professor King is the Director of the Center for Comparative Neuroimaging within the UMass Medical School. A recent paper from her laboratory (open access) applies imaging techniques to investigate white matter structural integrity in the brains of nicotine addicted human subjects that are associated with measures of physical dependence.

Over the years Dr. King’s work has been funded by the National Science Foundation and the National Institutes of Health (a RePORTER search illustrates her NIH funding history as a Principal Investigator).

As you would expect for a scientist of this caliber, her expertise has been sought by an array of journals to provide peer review of manuscripts and by the NIH to serve on many grant review panels. I can confirm that Professor King is an excellent and insightful reviewer of grant applications with a persuasive and often humorous demeanor. Her comments were invariable informative, particularly for noob-ish grant reviewers (ahem). Similarly, Dr. King has supervised numerous trainees, participated on many service committees for her University, for the NIH and for multiple academic societies or entities. She has additional service in nonacademic settings. In this record there is a strong addition of service on issues important to women in science and in careers, generally.

I thank you, Professor Jean A King, for your long commitment to advancing our understanding of the brain and of affective disorder.

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Disclaimer: I am professionally acquainted with Dr. King.

picture borrowed from http://www.umassmed.edu/Content.aspx?id=96786

Series Note: The Diversity in Science Blog Carnival was created by D.N. Lee of the Urban Science Adventures! blog. In early 2009 she issued a call for a new blog carnival celebrating diversity in science and hosted the inaugural edition. The Diversity in Science Carnival #2 was hosted at Thus Spake Zuska under the theme Women Achievers in STEM – Past and Present. Prior entries from me have focused on Laura O’Dell, Carl Hart, Chana Akins, Percy Julian, Jean Lud Cadet,  and Yasmin Hurd.

An email from current president of the Society for Neuroscience announced the intent of the society to launch a new Open Access journal. They are seeking an Editor in Chief, so if you know any likely candidates nominate them.

The Society for Neuroscience Council has appointed a Search Committee to recommend candidates to serve as editors-in-chief for two Society-published journals:

The Editor-in-Chief of The Journal of Neuroscience, to be appointed for a 5-year term beginning Jan. 1, 2015, after a period of transition with the current editor; and
The first Editor-in-Chief of a new online, open access neuroscience journal, expected to launch in late 2014, and temporarily referred to herein as “New Journal.” Please see the announcement here for more information about New Journal. This 5-year appointment will commence in the spring of 2014, to allow the new editor to be involved in decisions connected with the start-up of New Journal and the organizing of an initial editorial board.

The members of the Search Committee are: Moses Chao, Chair; Holly Cline; Barry Everitt; David Fitzpatrick; and Eve Marder.

The list of evaluation criteria may help you to think about who you should nominate.

In evaluating candidates for the editor-in-chief positions, the Search Committee will consider the following criteria:

  • previous editorial experience

  • adequate time flexibility to take on the responsibilities of editor-in-chief

  • a distinguished record of research in neuroscience

  • familiarity with online submission, peer review and manuscript tracking systems

  • ideas about novel approaches and receptivity to innovation during a time of great change in the scientific publishing field

  • service to and leadership in the neuroscience community (e.g., SfN committees)

  • evidence of good management skills and the ability to lead colleagues on an editorial board

  • for New Journal: the capacity to proactively engage on a start-up venture, and to innovate and lead in the creation of a high quality open access neuroscience journal, and guide it on a path to success

  • for The Journal of Neuroscience: the capacity to build on an established record of success, while continuing to evolve a leading journal in the field and take it to the next level

Interesting next step for the SfN. Obviously reflects some thinking that they may be left behind (even further, see diminishing reputation after the launch of Nature Neuroscience and Neuron) in the glorious New World Order of Open Access publication. Might just be a recognition that Open Access fees for a new journal when all the infrastructure is already there is going to be a cash cow for the Society from the beginning.

What I will be fascinated to see is where they pitch the New Journal* in terms of impact. Are they just trying to match JNeuro? Will they deliberately go a little lower down the feeding chain to avoid undercutting the flagship journal?

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*my suggestion of Penfield must have been too esoteric a reference…..

BRAIN Initiative

May 7, 2013

I just watched part of a live stream [current link] of some meeting to brainstorm about what the $100M BRAIN Initiative should be.

What at a disaster.

Bunch of reinforcement that this is all about a bunch of senior dudes (mostly male dewds too) in neuron-recording neuroscience who used to make out like bandits from NIMH support. Now that we’ve undergone a long slide in funding levels and Insel’s push to translational-ize the NIMH portfolio has gained the upper hand…these folks are struggling to get grants. JUST. LIKE. THE. REST. OF. US.

and they can’t come up with anything amazing by themselves so they need $100M cash money to build some new recording tools to….you guessed it, record some more neurons.

Outside of the regular grant process because they find it hard to compete these days. JUST. LIKE. THE. REST. OF. US.

I have a proposal. Let’s throw down, what, maybe $1M to record symposia and meetings of these people for the next year. Maybe have a few more of these summits. And after all that, if they’ve come up with some thing that is ACTUALLY NEW AND INTERESTING then and only then do we give them the $99M.

UPDATE: Permalink

Failure to Replicate

March 20, 2013

I should have put that in quotes because it actually appears in the title of this new paper published in Neuropsychopharmacology:

Hart AB, de Wit H, Palmer AA. Candidate gene studies of a promising intermediate phenotype: failure to replicate. Neuropsychopharmacology. 2013 Apr;38(5):802-16. doi: 10.1038/npp.2012.245. Epub 2012 Dec 3. [PubMed]

ResearchBlogging.orgfrom the Abstract alone you can get a sense

We previously conducted a series of 12 candidate gene analyses of acute subjective and physiological responses to amphetamine in 99-162 healthy human volunteers (ADORA2A, SLC6A3, BDNF, SLC6A4, CSNK1E, SLC6A2, DRD2, FAAH, COMT, OPRM1). Here, we report our attempt to replicate these findings in over 200 additional participants ascertained using identical methodology. We were unable to replicate any of our previous findings.

The team, with de Wit’s lab expert on the human phenotyping and drug-response side and Palmer’s lab expert on the genetics, has been after genetic differences that mediate differential response to amphetamine for some time. There’s a human end and a mouse end to the overall program which has been fairly prolific.

In terms of human results, they have previously reported effects as varied as:
-association of an adenosine receptor gene polymorphism with degree of anxiety in response to amphetamine
-association of a dopamine transporter gene promotor polymorphism with feeling the drug effect and diastolic blood pressure
-association of casein-kinase I epsilon gene polymophisms with feeling the drug effect
-association with fatty acid amide hydrolase (FAAH) with Arousal and Fatigue responses to amphetamine
-association of mu 1 opioid receptor gene polymorphisms with Amphetamine scale subjective report in response to amphetamine

There were a dozen in total and for the most part the replication attempt with a new group of subjects failed to confirm the prior observation. The Discussion is almost plaintive at the start:

This study is striking because we were attempting to replicate apparently robust findings related to well-studied candidate genes. We used a relatively large number of new participants for the replication, and their data were collected and analyzed using identical procedures. Thus, our study did not suffer from the heterogeneity in phenotyping procedures implicated in previous failures to replicate other candidate gene studies (Ho et al, 2010; Mathieson et al, 2012). The failure of our associations to replicate suggests that most or all of our original results were false positives.

The authors then go on to discuss a number of obvious issues that may have led to the prior “false positives”.

-variation in the ethnic makeup of various samples- one reanalysis using ancestry as covariate didn’t change their prior results.

-power in Genome-Wide association studies is low because effect sizes / contribution to variance by rare alleles is small. they point out that candidate gene studies continue to report large effect sizes that are probably very unlikely in the broad scheme of things…and therefore comparatively likely to be false positives.

-multiple comparisons. They point out that not even all of their prior papers applied multiple comparisons corrections against the inflation of alpha (the false positive rate, in essence) and certainly they did no such thing for the 12 findings that were reported in a number of independent publications. As they note, the adjusted p value for the “322 primary tests performed in this study” (i.e., the same number included in the several papers which they were trying to replicate) would be 0.00015.

-publication bias. This discussion covers the usual (ignoring all the negative outcomes) but the interesting thing is the confession on something many of us (yes me) do that isn’t really addressed in the formal correction procedures for multiple comparisons.

Similarly, we sometimes considered several alternative methods for calculating phenotypes (eg, peak change score summarization vs area under the curve, which tend to be highly but incompletely correlated). It seems very likely that the candidate gene literature frequently reflects this sort of publication bias, which represents a special case of uncorrected multiple testing.

This is a fascinating read. The authors make no bones about the fact that they’ve found that no less than 12 papers that they have published were the result of false positives. Not wrong…not fraudulent. Let us be clear. We must assume they were published with peer review, analysis techniques and samples sizes that were (and are?) standard for the field.

But they are not true.

The authors offer up solutions of larger sample sizes, better corrections for multiple comparisons and a need for replication. Of these, the last one seems the best and most likely solution. Like it or not, research funding is limited and there will always be a sliding scale. At first we have pilot experiments or even anecdotal observations to put us on the track. We do one study, limited by the available resources. Positive outcomes justify throwing more resources at the question. Interesting findings can stimulate other labs to join the party. Over time, the essential features of the original observation or finding are either confirmed or consigned to the bin of “likely false alarm”.

This is how science progresses. So while we can use experiences like this to define what is a target sample size and scope for a real experiment, I’m not sure that we can ever overcome the problems of publication bias and cherry picking results from amongst multiple analyses of a dataset. At first, anyway. The way to overcome it is for the lab or field to hold a result in mind as tentatively true and then proceed to replicate it in different ways.

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UPDATE: I originally forgot to put in my standard disclaimer that I’m professionally acquainted with one or more of the authors of this work.

Hart, A., de Wit, H., & Palmer, A. (2012). Candidate Gene Studies of a Promising Intermediate Phenotype: Failure to Replicate Neuropsychopharmacology, 38 (5), 802-816 DOI: 10.1038/npp.2012.245

Go Team!!!!!

February 3, 2013

I’ve decided I am rooting for neuronal survival during the NFL SuperBowl today.

Go #teamneuron!

Hard on the heels of something I just learned about at a recent conference, the NIMH issued a Press Release for a new clinical trial they funded.

A drug that works through the same brain mechanism as the fast-acting antidepressant ketamine briefly improved treatment-resistant patients’ depression symptoms in minutes, with minimal untoward side effects, in a clinical trial conducted by the National Institutes of Health. The experimental agent, called AZD6765, acts through the brain’s glutamate chemical messenger system.

Interesting. The background is that prior studies* have shown that the dissociative anesthetic ketamine is capable of the rapid (within hours) amelioration of depressive symptoms. Yes, ketamine. The recreational drug known as Special K and the veterinary anesthetic they’ve used on your pet cat or dog. Same ketamine that is approved for human use in pediatric anesthesia, emergency medicine in some cases and for tricky clinical situations.

The same ketamine that has been widely used for decades in humans and nonhuman animals. It has established efficacy, mechanism of action and a huge therapeutic index. A big distance between effective doses and the dose that will kill you. Whether effect is recreational, medical or veterinary. Meaning it is safe.

So why are the studies (cited below*) of effect in depression so exciting? Because traditional drug therapy for depression takes weeks to have effect. Weeks of daily dosing. Selective Serotonin Reuptake Inhibitors (SSRIs) like Prozac are broadly familiar to most of my Readers, I would assume. Efficacy with these front-line meds takes up to three weeks to see effect on depressive symptoms. Trouble is, some cases of depression are acutely suicidal–they may just kill themselves before any SSRI has a chance to make them feel better. And hell, who wants to wait three weeks if another med could make you feel better by tomorrow? Prior to the ketamine work, the only other thing that seemed to have such a rapid effect was ECT. Yeah, ElectroConvulsive Therapy. Which has come a loooooong way from the One Flew Over the Cuckoo’s Nest era….but still. A single ketamine dosing seems quite preferable.

So…..on to the me-too drug development! Woot!
Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, Luckenbaugh DA. A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression. Biol Psychiatry. 2012 Nov 30. pii: S0006-3223(12)00941-9. doi: 10.1016/j.biopsych.2012.10.019. [Epub ahead of print][Publisher, PubMed]

This AZD6765 compound is, as you might deduce from the letters, property of AstraZeneca Pharmaceuticals and indeed one of the authors lists this as his affiliation. The rest of the folks are from the NIMH intramural program which, presumably, provided the majority of the funding for the study.

The conclusions appear to be that this novel compounds, with a similar mechanism of action as ketamine worked but less well. From the Presser:

About 32 percent of 22 treatment-resistant depressed patients infused with ASD6765 showed a clinically meaningful antidepressant response at 80 minutes after infusion that lasted for about half an hour – with residual antidepressant effects lasting two days for some. By contrast, 52 percent of patients receiving ketamine show a comparable response, with effects still detectable at seven days. So a single infusion of ketamine produces more robust and sustained improvement, but most patients continue to experience some symptoms with both drugs.

However, depression rating scores were significantly better among patients who received AZD6765 than in those who received placebos. The researchers deemed this noteworthy, since, on average, these patients had failed to improve in seven past antidepressant trials, and nearly half failed to respond to electroconvulsive therapy (ECT).

So this is good. Anything that shows promise as a rapid-alleviator of depression is good by my lights.

But why is NIMH spending taxpayer dollars to develop me-too drugs? Look, I recognize that drugs within a class of pharmacological mechanism, like the SSRIs, may be differentially effective for different patients. And it is a good thing if we have more options to tailor medication to the individual patient. ADHD is another situation where an array of monoamine transporter inhibitors, including methylphenidate and amphetamine, are used with success and failure. One drug works for one patient, another works for a different patient….and they might describe the other medication as even worse than not being treated. So…great.

But make no mistake. The central feature driving me-too drug development is profit. Drug companies decide they can take a big enough slice of the market away from the market-leader to make it worth their while. Perhaps they had development in parallel and had sunk enough cost in by the time their competitor gained FDA approval that there was no turning back. Whatever. Point being that they are in it for the money and not for some noble cause of serving that subset of patients that do not gain relief from their competitor’s drug.

Over the past few years the side-chatter about the ketamine effect on depression has frequently been a lament about the lack of financial motive for companies to push forward with ketamine. Push forward with specific clinical trials to gain on-label approval for the indication of depression. Push forward with marketing campaigns. Push forward with physician education and stroking like they do with their proprietary stuff.

The Zarate paper took a stab at claiming the reason for developing something else was an attempt to avoid the adverse effects of ketamine. The dissociative type effects can be unpleasant and recovery doesn’t look fun. So there’s some toehold there to claim one is motivated to find a “perfect” drug which somehow produces the therapeutic effect with nothing else. Color me skeptical, given what I know about existing NMDA channel blockers like ketamine (and PCP, did I mention that? Yeah, angel dust might work for depression….).

So I smell profit motive in this effort.

What I don’t understand is why NIMH is involved with this. Why not just pursue the evidence body for ketamine?
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*References pulled out of the paper
R.M. Berman, A. Cappiello, A. Anand, D.A. Oren, G.R. Heninger, D.S. Charney et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry, 47 (2000), pp. 351–354

N. Diazgranados, L. Ibrahim, N.E. Brutsche, A. Newberg, P. Kronstein, S. Khalife et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry, 67 (2010), pp. 793–802

C.A. Zarate Jr, N.E. Brutsche, L. Ibrahim, J. Franco-Chaves, N. Diazgranados, A. Cravchik et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial Biol Psychiatry, 71 (2012), pp. 939–946

G.W. Valentine, G.F. Mason, R. Gomez, M. Fasula, J. Watzl, B. Pittman et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS Psychiatry Res, 191 (2011), pp. 122–127

M. aan het Rot, K.A. Collins, J.W. Murrough, A.M. Perez, D.L. Reich, D.S. Charney et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression Biol Psychiatry, 67 (2010), pp. 139–145

There are two new pharmacological investigations on the substituted cathinone drugs that have been discussed here on occasion.

Each of

Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW.Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products. Neuropsychopharmacology. 2012 Oct 17. doi: 10.1038/npp.2012.204.

and

Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME.Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol. 2012 Aug 17. doi: 10.1111/j.1476-5381.2012.02145.x.

report very similar findings for MDPV, the cathinone that appears most frequently in US newspaper reports.

As a very general rule, the amphetamine class stimulants do a couple of things to enhance the neuron-to-neuron chemical communication that occurs in the brain. The most common and significant effects tend to involve the transporter mechanisms that remove dopamine, norepinephrine and / or serotonin from the synapse, the gap between two neurons. These transporter molecules are an integral part of terminating a signalling event which has been caused by the release of one of these three monoamines from one of the neurons in question. Interfere with the operation of these transporters and a drug can potentiate the magnitude or duration of a given signalling event (i.e., release of one of the dopamine (DA), norepinephrine (NE) or serotonin neurotransmitters).

The amphetamine class stimulants have these properties. As does cocaine. As do therapeutic drugs such as methylphenidate (Ritalin) and Prozac. The term selective serotonin re-uptake inhibitor, SSRI, for Prozac-class antidepressant drugs refers to the transporter, obviously, and also indicates a key thing with the term “selective”. Drugs which have the ability to interact with one of the monoamine transporters tend to interact with the other ones as well. Substantial differences in effect can be associated with differences in the relative ability a specific molecule has to attach to the DAT versus the NET versus the SERotonin transporter (SERT). As one clear example, methamphetamine and MDMA differ in their relative ability to inhibit the SERT….this property of MDMA is associated with many of it’s stimulant-atypical properties relative to other amphetamine-class drugs.

The new studies both show that MDPV blocks all three transporters with much more potent effects at the DAT and NET relative to SERT. As Baumann and colleagues note, MDPV is 50 and 10 times more potent than cocaine (not an amphetamine, we’ll come to this) at DAT and NET respectively. Simmler and colleagues similarly indicate that MDPV is much more potent at DAT than cocaine or methamphetamine which did not qualitatively differ from each other.

So to this point, MDPV looks like a high-potency traditional stimulant. Most effective at the DAT, fairly effective at the NET and with less ability to block the SERT.

Cocaine and the amphetamines diverge at this point because the amphetamines act as a substrate at the transporters. Instead of only interfering and blocking them from doing anything, the amphetamines actually substitute for the neurotransmitter in question and are taken up into the cell. In so doing, they also cause an exchange to happen whereby the transporter moves some neurotransmitter from inside the cell back into the synapse. This transporter mediated efflux contributes to any “regular” release of neurotransmitter mediated through the merging of intracellular sacs (called vesicles) with the cell membrane.

The two papers agree in finding that MDPV has no ability to cause transporter-mediated efflux of dopamine and is therefore best categorized neuropharmacologically as a “pure” blocker (like cocaine) rather than an amphetamine-like transporter substrate.

The Simmler paper adds an in vitro model of blood/brain barrier penetration…in very simple terms the degree to which a molecule is fat-liking versus water-liking can alter the speed at which it can cross cell membranes and get into the brain. This paper used an in vitro preparation of human capillary endothelial cells (that form the blood-brain barrier) to show that MDPV is likely to cross the blood-brain barrier very rapidly, consistent with high lipophilicity predicted from its structure.

The upshot of the two papers is that MDPV shows pharmacological properties consistent with classical stimulants. It shows relatively high selectivity for DAT over SERT and high potency relative to drugs such as methamphetamine or cocaine. In vivo neurochemistry in the Baumann paper confirm that MDPV has potent effects on dopamine levels in the nucleus accumbens, a hallmark of drugs (beyond the stimulants even) which have substantial risk for compulsive use. The only somewhat discordant note for the structure-activity nerds is that MDPV looks so much like the rest of the amphetamines and cathinones that it will be interesting to discover why it doesn’t act as a transporter substrate (Simmler et al included a number of other cathinones and showed that many of them do act as transporter substrates.)

Together these papers suggest that MDPV has high abuse liability with a use pattern characterized by frequent re-dosing much like one sees with cocaine. This is consistent with many self-reports that are emerging from people who use MDPV and therefore, despite the relatively brief time on the “market”, we can predict a cocaine-like dependence problem to emerge for MDPV in the near future.

I have been awaiting this paper since I saw the poster a few meetings back, Dear Reader. It contributes to an ongoing theme of posts on MDMA (Ecstasy) that I have neglected for some time. Some of you may recall the topic of my third blog post which noted the current attempts to get MDMA approved as adjunctive treatment during PTSD psychotherapy. I have been somewhat critical of their approach, mostly because of my understanding of the MDMA-associated neurotoxicity literature in animal species.

To overview, very briefly, if you administer MDMA twice per day at approximately 6-12 hr intervals for four days to rats, monkeys and a few other species, you produce lasting decrements in many markers for serotonin neurons / serotonin function in the brain. Lasting as in, as long as 7 years in a monkey (Hatzidimitriou, 1999). There is a parallel literature identifying lasting affective and cognitive alterations in human consumers of MDMA / Ecstasy and some imaging evidence of similar serotonergic changes.

It is tempting to associate at least the affective disruptions with the lasting serotonergic alterations. (Three monkey studies failed to connect these serotonergic patterns to substantial changes in cognitive behavior so that one is a little more tenuous…you can find some hints in the rat literature and some mother’s eye stuff in the monkey studies but the gun ain’t smoking very much.) However, as you are aware DearReader, the human studies of drug users are fraught with complications. One doesn’t know anything about pre-existing differences (depressives more likely to use MDMA?), the precise dose and pattern folks exposed themselves to, the environmental conditions, co-administered psychoactive substances and even the identity of the drugs being consumed as “Ecstasy”.

This cycles the discussion back to the controlled animal models. The MDMA enthusiast is frequently found to contest the relevance of the animal models, primarily on the grounds of the dose. The typical animal model features 10-20 mg/kg of MDMA per injection in rats and 5-10 mg/kg in monkeys. Again, these are repeated twice daily for four days. In addition, the route of administration is typically intraperitoneal (rat) and either intramuscular or subcutaneous in monkeys. Naturally, the majority of human use is oral which Pharm101 tells us should reduce the peak brain exposure as well as the rapidity with which peak levels are attained compared with the injected routes. So there has been vigorous debate, including between animal-research and human-research scientists, as to whether the animal data should be taken as relevant to the human condition.

As I blogged before, there is another concept from Pharm101 that relates to this discussion, i.e., that of species-scaling of drug doses. The short version is that you need higher per-kilogram-of-bodyweight doses in smaller species to produce similar outcome on parameters such as peak plasma levels, Area Under the Curve as well as toxic outcomes for various body systems including the brain. That prior post lays out data which show that a 1.6 mg/kg oral MDMA dose in a human produces peak plasma levels similar to 2.8 mg/kg in a squirrel monkey but an AUC similar to 5.7 mg/kg in a squirrel monkey (with a higher peak, obviously).

All well and good but the evidence of lasting serotonin changes on the low-end of the dosing spectrum has not been all that good. There was an old Ricaurte paper from the early days that found serotonergic changes in a handful of brain regions after a single oral dose of 5 mg/kg MDMA in squirrel monkeys. The trouble is, it was never replicated by any other papers and it was only in 3 subjects. So…not quite as convincing as the data on the higher-dose, injected, repeated models which come from multiple labs, in several species of laboratory animals and in many (total) animals per species.

A new paper from the Ricaurte group,

Mueller M, Yuan J, McCann UD, Hatzidimitriou G, Ricaurte GA. Single oral doses of (±) 3,4-methylenedioxymethamphetamine (‘Ecstasy’) produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations. Int J Neuropsychopharmacol. 2012 Jul 24:1-11. [Epub ahead of print] [PubMed]

provides a long-past-due update on their prior report (Ricaurte et al, 1988; PubMed).

The study tested single oral doses of 5.7 (N=8), 10.0 (N=6) and 14.3 (N=4) mg/kg MDMA and the brains were collected one week later for analysis. As with prior studies, significant reductions in brain content of serotonin and its major metabolite 5-HIAA were observed in multiple brain regions including frontal, temporal, parietal and occipital cortex, the hippocampus, caudate nucleus, putamen and thalamus. Importantly, these reductions were dose-dependent in magnitude with some differences from the vehicle control group (N=8) failing to reach statistical significance. The lowest dose, however, did produce significant reductions of serotonin in frontal and temporal cortex, hippocampus and caudate.

This last is the most critical contribution because it replicates the prior study in a larger sample.

The one oddest thing about the design was the collection of brains at one week instead of two. For the vast majority of studies in this area, two weeks seems to be the modal time for brain harvest. I think the choice of one week here is going to muddy the waters because there will be those that claim this is reflective of acute depletion of serotonin stores rather than the classic neurotoxicity profile. Concerns are partially alleviated by some serotonin transporter binding data provided suggesting reduced expression, but only a single brain slice per treatment group was shown. It would have been nicer if this had been a completed study with quantification from all animals. They authors have left some daylight for their critics and it is not really clear why they would have done this.

In the discussion, the authors continue their thesis that 5.7 mg/kg is equivalent to 1.6 mg/kg for a human. Therefore, they conclude that they have shown that lasting serotonergic deficits can be produced at doses that are unarguable “typical human doses” of MDMA. I have previously argued that this is a dose range that is being used in the clinical protocols even if you leave off notions of species scaling. So overall, yes I would say I agree with their basic contention that they have shown the expected serotonergic effects with MDMA exposure that is 1) oral, 2) single-dose and 3) within the range of expected human single-use episodes.

This study should further convince those who have previously argued that the animal data has no relevance because of dosing issues. This shows that there is no magic threshold of protection that happens to coincide with notions of “typical human use”.

A recent blogpost from NIMH Director (and Acting NCATS Director) Tom Insel details the grim future for private sector development of drugs for the brain and behavior disorders.

But change is coming from another direction as well, especially for psychiatric medications. Over the past year, several companies, including Astra Zeneca, Glaxo-Smith-Kline, Sanofi Aventis, and recently Novartis, have announced either a reduction or a re-direction of their programs in psychiatric medication R&D. Some of these companies (such as Novartis) are shifting from clinical trials to focus more on the early phases of medication development where they feel they can identify better targets for treating mental disorders. Others are shifting from psychiatry to oncology and immunology, which are viewed by some as lower risk.

There are multiple explanations for these changes. For instance, many of the blockbuster psychiatric medications are now available in inexpensive generic form. In addition, there are few validated new molecular targets (like the dopamine receptor) for mental disorders. Moreover, new compounds have been more likely to fail in psychiatry compared to other areas of medicine. Studying the brain and the mind has proven to be much more difficult than the liver and the heart. Most experts feel the science of mental disorders lags behind other areas of medicine. The absence of biomarkers, the lack of valid diagnostic categories, and our limited understanding of the biology of these illnesses make targeted medication development especially difficult for mental disorders.

As I may have mentioned already, this sort of change in the development “system*” gives me a better reason to agree with the creation of NCATS and the earlier noises about the NIH taking a more active role in therapy development. There are lots of indications that don’t receive enough attention because there is no route to sufficient profit. Drug abuse is one of those indications. Part of the reason we aren’t more advanced in pharmacotherapy for substance abuse is on us, the basic science folks. Sure. But a big part is also on private industry which never saw where the paycheck was going to come from. So there was never much enthusiasm for pursuing anti-substance abuse programs. No program, no drugs. Remember, estimates run some 10-20,000 compounds evaluated in a drug development pipeline to arrive at each approved medication.

I don’t believe the NIH can improve this by being smarter, that is a foolish conceit of many. But not having to seek blockbuster returns does change the calculus for what indications are worthy of serious drug development effort.

And that would be a GoodThing.
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*such as it is

The Backyard Brains folks are at it again.

Presentation 22.17SU/YY91 will be on display Saturday 1:00 p.m. – Sunday 5:00 p.m. with their presentation time scheduled for Sunday. It is entitled:

The blue light special: a portable, low-cost optogenetics kit for the classroom

The abstract reads:

Optogenetics is an innovative technology for studying brain circuits, but to date the lay public has had little exposure to its potential and limited access to low-cost tools to do experiments. What if you have an interest in cutting-edge neuroscience but you aren’t near a university? What if you prefer to do science in your garage, in a truck-bed, or on a plane on a boat? What if you are a high school biology teacher who wants to keep your students abreast of the most current neurotechnology but the latest millage did not pass? We can help you! We have designed a low-cost, easy-to-build, and portable electrophysiology rig for simple optogenetics demonstrations. The rig consists of a extracellular amplifier (our SpikerBox), a 3D-printed 3-axis micromanipulator, an off-the-shelf monocular 30X microscope, a high intensity blue LED (light-emitting diode), and an LED control circuit that can be precisely controlled with a tailor-made iPhone application or simple tone generator. We have successfully used our first clunky prototype to record blue light-evoked electromyograms from channelrhodopsin-2 expressing Drosophila larvae. We plan to spend the summer refining our prototype (making it more stable, improving control of light emission) and genetic tools. We plan to begin demonstrations in high school classrooms by Fall 2011. We also have other low-cost neurotechnology inventions to show you, so come by our poster to participate in real-time peer review!

Right? RIGHT? You know you think this is cool. Go see their presentation folks, they always amuse, entertain and educate.

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Update for additional reading on Backyard Brains and Marzullo and Gage
The $100 Spike
The $100 SpikerBox v1.0
Backyard Brains

ResearchBlogging.orgA link from writedit pointed me to a review of drugs that were approved in the US with an eye to how they were identified. Swinney and Anthony (2011) identified 259 agents that were approved by the US FDA between 1999 and 2008. They then identified 75 which were “first in class”, i.e., not just me-too drugs or new formulations of existing drugs or whatnot. There were 20 imaging agents, not further discussed, and 164 “follower” drugs.

The review also focused mostly on small molecule drugs instead of “biologics” because of an assumption that the latter are all exclusively “target based” discoveries. The main interest was in determining if the remaining small molecule drugs were discovered the smart way or the dumb way. That’s my formulation of what the authors term “target based screening” (which may include “molecular mechanism of action”) discovery and “phenotypic screening” type of discovery. As they put it:

The strengths of the target-based approach include the ability to apply molecular and chemical knowledge to investigate specific molecular hypotheses, and the ability to apply both small-molecule screening strategies (which can often be achieved using high-throughput formats) and biologic-based approaches, such as identifying monoclonal antibodies. A disadvantage of the target-based approach is that the solution to the specific molecular hypotheses may not be relevant to the disease pathogenesis or provide a sufficient therapeutic index.

A strength of the phenotypic approach is that the assays do not require prior understanding of the molecular mechanism of action (MMOA), and activity in such assays might be translated into therapeutic impact in a given disease state more effectively than in target-based assays, which are often more artificial. A disadvantage of phenotypic screening approaches is the challenge of optimizing the molecular properties of candidate drugs without the design parameters provided by prior knowledge of the MMOA.

You will note that this is related to some comments I made previously about mouse models of depression.

The authors found that 28 of the first-in-class new molecular entities (NMEs) were discovered via phenotypic screening, 17 via target based approaches and 5 via making synthetic mimics of existing natural compounds. To give you a flavor of what phenotypic screening means:

For example, the oxazolidinone antibiotics (such as linezolid) were initially discovered as inhibitors of Gram-positive bacteria but were subsequently shown to be protein synthesis inhibitors that target an early step in the binding of N-formylmethionyl-tRNA to the ribosome

and for target based approaches:

A computer-assisted drug design strategy that was based on the crystal structure of the influenza viral neuraminidase led to the identification of zanamivir

The authors even ventured to distinguish discovery approaches by disease area:

Evaluation of the discovery strategy by disease area showed that a phenotypic approach was the most successful for central nervous system disorders and infectious diseases, whereas target-based approaches were most successful in cancer, infectious diseases and metabolic diseases

Unsurprising of course, given that our state of understanding of nervous system disorders is, to most viewers, considerably less complete in comparison with some other health conditions. You would expect that if there are multiple targets or targets are essentially unknown, all you are left with are the predictive phenotypic models.

Of the follower drugs 51% were identified by target based discovery and 18% by phenotypic screening. This is perhaps slightly surprising given that in the cases of the me-too drugs, you would think target-based would be more heavily dominant. Perhaps we can think of a drug which initially looked to have property X that dominated but then in the phenotypic screening, it looked more like a property Y type of drug.

The authors take on this is that it is slightly surprising how poorly target-based discovery performed within a context of what they describe as a period in which there was a lot of effort and faith placed behind the target-based approaches. I suspect this is going to be in the eye of the beholder but I certainly agree. I can’t really go into the details but there are areas where my professional career is…affected, let us say…by the smart/dumb axis of drug discovery. It should be obvious to my longer term readers that I align most closely with animal models of various things related to health and neurobiology and so therefore you may safely conclude that I have a bias for phenotypic screening. And even in the case of the target-based discovery:

at least three hypotheses that must be correct to result in a new drug. The first hypothesis, which also applies to other discovery approaches, is that activity in the preclinical screens that are used to select a drug candidate will translate effectively into clinically meaningful activity in patients. The other two hypotheses are that the target that is selected is important in human disease and that the MMOA of drug candidates at the target in question is one that is capable of achieving the desired biological response.

Right. You still need good phenotypic models and ultimately you are going to have to pass human clinical trials. The authors further worry that this higher burden, especially knowing the MMoA is going to lead to some misses.

in the case of phenotypic-based screening approaches, assuming that a screening assay that translates effectively to human disease is available or can be identified, a potential key advantage of this approach over target-based approaches is that there is no preconceived idea of the MMOA and target hypothesis.

Ultimately I think this review argues quite effectively for an “all hands on deck” approach to drug discovery but it can’t help but come off as a strong caution to the folks that think that “smarter” (aka, “rational drug design”) is the only solution. Yes, this points the finger at Francis Collins’ big thrust for a new translational IC at the NIH but also at the BigPharma companies that seem to be shedding their traditional models-based, phenotypic discover research units as fast as they can. No matter which side you come down on, this is a great read with lots to think about for those of us who are interested in the discovery of new medicines.
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Swinney, D., & Anthony, J. (2011). How were new medicines discovered? Nature Reviews Drug Discovery, 10 (7), 507-519 DOI: 10.1038/nrd3480

I admit I got a little excited when I saw a Twitt RT’d earlier today from Noah Gray.

Soon to be in press: Strong evidence supporting the neurogenesis-depression hypothesis, from @jsnsndr: http://j.mp/qn6fyD

I’m sort of vaguely aware and following a literature that is trying to establish a causal link between depression and alterations in hippocampal neurogenesis, proliferation and general plasticity based on creating new, functioning cells.

This is generally a non-human literature, typically in mouse models and….highly correlative.

With respect to this latter, the state of the art for a long time has been to treat markers of neurogenesis (there are many stages and concepts here which I’ll glomp under one heading. Follow the link in the tweet to the Functional Neurogenesis blog for all your background reading) as dependent variables to be reported. Not manipulated. This is, perhaps obviously, the case for any post-mortem human brain analysis but also for many animal models to date. In essence, you do some thing to the animal and then look at the markers afterward. Then you report whether neurogenesis is up, down or unchanged. So far so good. But this approach doesn’t quite get at the question of causality which is important if we think that altering the effects on neurogenesis (say by a drug or behavioral therapy*) would have a beneficial effect on the affective disorder itself. It could, after all, be a result of depression with no causal role.

There is also a question of whether a given animal model is a valid representation of a human affective disorder. Here we can think about issues of predictability- does it matter, for example, what the mouse model looks like if the ability to predict what anti-depression, anti-anxiety or anti-mania drugs will work (ultimately) in the clinic is high? Of course not…if your goal is drug development.

If you goal is understanding the neurobiological underpinnings of the human disease, well, you want to be careful.

My take on the current state of the nonhuman models of depression is that we are not yet at the point where we have high confidence in calling any model “depression”. They are models, they have various points of high correspondence to human illness but they also have limitations. They are, in cases, highly predictive of drugs which will ultimately prove useful in the clinical setting.

So I confess that when I see a scientist (Noah Gray is, after all, a scientist by training even if he currently inhabits an Editor job) tweet “strong evidence”, well, I’m looking for some coolio stuff.

Following the link to the post on Functional Neurogenesis, I found the post title to include the word “confirmed”! yay, let’s read!!!!

So I’m excited to say that we will soon be publishing what (I think) is the best evidence that impaired adult neurogenesis actually causes depressive symptoms (in mice).

“in mice”. Fuck.

Okay, so let’s scratch the “strong evidence” and the “neurogenesis-depression hypothesis confirmed stuff” for now.

Pretty cool paper, by the sounds of it. Again, from my distinctly nonspecialist position, this is the next step. Manipulations of the neurogenesis processes as independent variables to provide stronger evidence that there is a causal relationship. Between these processes and a behavioral or physiological phenotype. I can’t really say where this all fits into the “first demonstration” or “best demonstration” or “critical demonstration” picture so as to give you a valance for exactly how cool it is. But I do recognize that these approaches are the next place the field needs to go to better establish that the neurogenesis-depression hypothesis could be “confirmed”.

Me, until the state of animal models are better and more convincingly established, I want to see data in human subjects before I am willing to concede either “confirmation” or “strong evidence”.

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ps. Do take a read over the Functional Neurogenesis blog. It is really quite good and this area of neuroscience is fun. Many of you may still labor under the old belief that the adult brain doesn’t grow new neurons and can’t repair itself. It’s no liver, but the brain does have some capacity to generate new neurons.

The Society for Neuroscience is accepting applications, due May 20, for the Neuroscience Scholars Program. The fellowships are to pay for attending the Annual Meeting of the SfN, membership dues and some unspecified stipend for local activities.
The part that contributes to one of our off-again, on-again conversations around these parts is the specification of Eligibility for the program.

Individuals from racial and ethnic groups that have been shown by the National Science Foundation to be underrepresented in health-related sciences on a national basis.

Okay, standard “minority” stuff here. Light the torches, my affirmative action antagonists, light the torches.

Read the rest of this entry »

The Society for Neuroscience is accepting applications, due May 20, for the Neuroscience Scholars Program. The fellowships are to pay for attending the Annual Meeting of the SfN, membership dues and some unspecified stipend for local activities.

The part that contributes to one of our off-again, on-again conversations around these parts is the specification of Eligibility for the program.

Individuals from racial and ethnic groups that have been shown by the National Science Foundation to be underrepresented in health-related sciences on a national basis.

Okay, standard “minority” stuff here. Light the torches, my affirmative action antagonists, light the torches.

Oh, wait….

Individuals who come from a family with an annual income below established low-income thresholds. These thresholds are based on family size; published by the U.S. Bureau of the Census; adjusted annually for changes in the Consumer Price Index; and adjusted by the Secretary for use in all health professions programs.

OR

Individuals who come from a social, cultural, or educational environment such as that found in certain rural or inner-city environments that have demonstrably and recently directly inhibited the individual from obtaining the knowledge, skills, and abilities necessary to develop and participate in a research career. This is most applicable to undergraduate candidates.

So let us review. A special opportunity for those that are underrepresented in the Neurosciences to get a small helping hand up.


[ UPDATE: The cartoon is from Barry Deutsch ]

Eligibility is based on underrepresentation, not skin tone.

In particular, the socio-economic and impoverished schooling/environment criteria are totally and completely applicable to men and women alike who self-identify as “white”.

So anyone who complains on and on that lower-class, socioeconomically disadvantaged whites are ignored or disenfranchised by affirmative action efforts are, yet again, falsified.

Given this, their motivations for continually and loudly opposing affirmative action efforts on the alleged basis of this principle are a little suspect, are they not?

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Illustration grabbed from The Hermitage

This one is for some folks I’ve been engaging with on the Twitts about Uncle Siggy…

Link to Youtube

Don’t forget DrZen’s comment:

Freud was a comparative neuroanatomist who made significant discoveries: http://bit.ly/vf3qK