First Aid for Mental Health

December 15, 2012

Almost by definition there is something wrong with the mental health of mass shooters like the Aurora cinema guy, the Sikh Temple shooter and the one who just killed 20 elementary school children, 6 staff members, his own mother and ultimately himself.

In parallel with the calls for better gun control in the US we experience calls for improved health care for the brain. But the failing is not the provision of care so much as it is the detection of mental health problems that might lead to mass shootings.

We will never get to a one to one prediction of who is about to become the next news cycle. But then, we don’t know who will heal eventually from a given infection, who will recover from stroke without a given intervention…or who will get heart attack save for the cholesterol meds, statins and what not.

So we go with the odds.

And we detect problems with broad screening (annual checkups), acute responses (minor cardiac event perhaps)…and crowdsourcing.

If someone were bleeding in front of you, chances are decent that you would know whether to get a bandaid (even a 5 year old knows to add the antibiotic cream) or stick a finger on the vein while yelling for help. In a crowd? Someone would know CPR if a person stops breathing…in a pinch you’d have a go based only on what you remember from teevee shows.

What about when someone shows signs of a mental health problem? How does the crowd and pre-FirstResponse do with those situations?

I have only recently been made aware of Mental Health First Aid.

It intrigues me.

Advertisements

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?
___
*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

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.
__
*such as it is

The Monitoring the Future study has added the synthetic marijuana products (see here, here, here for additional) to their annual survey. Data on annual use rates are now available for the 12th grader segment. I have taken the liberty of graphing the annual use rates for a selection of the more common drugs in this 2011 dataset.
What you can see (click on the graph to see a bigger version) is that these products are more popular than a host of drugs that have a considerably longer history. These packets of plant material spritzed with one or more full endocannabinoid CB1 receptor agonists (see dr leigh here, here for details) only really appeared on the US market in 2010 in broad availability.

Not too shabby to already be beating these other drugs, eh?

Unfortunately the full monographs aren’t available yet and the update tables for “lifetime” and “30 day” do not appear to include the synthetic marijuana category yet. Nevertheless, it’s a good thing that this drug category has been added to the survey. As we go forward it will be interesting to see if popularity continues or if this was a brief flash in the pan related to broad quasi-licit availability of these products.

These data will also provide a nice comparison to more limited investigations such as this one. Hu et al (2011) report 8% cannabimimetic use in a sample of 852 college students collected in September of 2010.
__
The Annual Prevalence table is here.

MtF 2011 update page

To the Maximus Foundation (@FakeWeed)

HR 1254 (pdf) has passed the House.

This Act would criminalize possession of a range of compounds which activate the endogenous cannabinoid CB1 receptor. The language covers several structural classes as well as an extended list of, e.g. the JWH-xxx compounds. In essence this is another attempt on the analog front in which the DEA is not able to move quickly enough on specific new drugs that emerge within a general neuropharmacological class.

The bill also doubles the amount of time the DEA has to generate the support for a final rule, once an emergency action has been invoked.

The House Resolution next addresses 17 compounds in the likely stimulant/empathogen class, with most of them being cathinone derivatives. Readers of this blog will be familiar with the well known 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxypyrovalerone (MDPV) on this list.

One assumes that Chuck Schumer will be leading the charge on this in the Senate and that it will pass in short order…opposition to this sort of legislation is not usually robust among elected politicians.

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.
__
Swinney, D., & Anthony, J. (2011). How were new medicines discovered? Nature Reviews Drug Discovery, 10 (7), 507-519 DOI: 10.1038/nrd3480