1 Boring Old Man

So what pollen does to the brain is make things fuzzy and they get lost in the sulcus-scape. This is a thread I lost three weeks ago that I wanted to follow up on – an article by Dr. Steven Hyman, former Director of the NIMH [see Psychiatric Drug Development: Diagnosing a Crisis, whither the crisis…, notwithstanding…, the biggest point…, Walk the Walk]. Like so many of his colleagues, he was talking about the crisis in the development of psychiatric drugs. In the article, he seems to be blaming the "forced swim test," an animal model used to evaluate drugs for antidepressant properties, for some of the lack of progress. A reminder:

Psychiatric Drug Development: Diagnosing a Crisis
The Dana Foundation: Cerebrum
By Steven E. Hyman
April 02, 2013

^{The antidepressant drug imipramine prolongs the period during which the rat attempts to swim. This forced swim assay was rationalized with anthropomorphic terms such as “behavioral despair,” but it was never shown to model human depression… Despite some degree of surface plausibility — the forced swim result seemed to mimic learned helplessness, a putative model of depression — the mechanism by which imipramine causes continued swimming is still not known. Moreover, imipramine increases the duration of swimming with a single dose, whereas depressed human beings generally require several weeks of treatment before therapeutic effects emerge… From the very beginning, however, astute scientists predicted that this approach to drug development would result in the identification of only “me too” drugs. Unfortunately, during the last 50 years that concern has been fully borne out…}

This was not a new point for Dr. Hyman. He’d made it in a review article with Eric Nester in 2010 and had mentioned it in a variety of recent presentations:

Animal models of neuropsychiatric disorders.
^{by Nestler EJ and Hyman SE.}
Nature Neuroscience. 2010 13(10):1161-9.

^{Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.}

^{As stated earlier, the targets of the major classes of drugs that treat neuropsychiatric disorders were identified post hoc by studying the mechanism of action of drugs identified by serendipity. To discover new drugs, several behavioral screens were developed that used the animal nervous system as a black box, with behavior as its readout, to detect drugs that act in similar fashion to existing reference compounds. These screens were not developed as mechanistic models of drug action, nor have they been shown to reflect either the pathophysiological processes of human disease or the therapeutic mechanism of action of the reference compounds. These screens also may not detect potential efficacy of compounds that interact with distinct molecular targets. A frequent failing of the literature is the use of such screens as if they were based on validated pathophysiological models…}

The comment stuck with me for an odd reason. I had talked to a friend a few weeks back who has been pretty depressed for a while, and there’s an obvious situational component – one that’s genuinely unresolvable. She wanted to try an antidepressant, and had started on an SSRI. At about three weeks, she spontaneously told me, "It’s helping." I asked her how she knew. She’d been shopping and picked out a bunch of things, obsessed about whether they were the right things, then she thought, "Oh it doesn’t matter anyway" and went home empty-handed. At this point I’m wondering how this story is about the medication helping. Then she said, "But then I got in the car and went right back and got them! That’s what I do when I’m depressed – I give up." It was a story that stuck with me since then – giving up. That is what depressed people do in reactive depressions, they give up [sometimes before they even get started], and become immobile. Obsessing like that has always been her M.O., but she could tell that the medication was helping her overcome it like she was used to doing – more her normal. And in the weeks that have followed, her overall improvement has been visible to all of us. If it’s a placebo effect, viva placebo! But I don’t think so. And it made me think of the Porsolt Test [the forced swim test] that had probably been used to screen her antidepressant back in its infancy:

Behavioural despair in rats: a new model sensitive to antidepressant treatments
^{by R.D. PORSOLT, G. ANTON, N. BLAVET and M. JALFRE
Centre de Recherche Delalande, Rueil-Malmaison, France}
European Journal of Pharmacology. 1978 47:379-391.
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^{Abstract: Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.}

^{"The test is based on the observation that rats when forced to swim in a restricted space from which they cannot escape will eventually cease apparent attempts to escape and become immobile apart from the small movements necessary to keep their heads above water. We suggested that this characteristic and readily identifiable behavioural immobility reflects a state of despair in the rat and showed that immobility was reduced by a variety of agents which are therapeutically effective in depression"…}

^{"The experiments reported below expand these original findings and show that reduction of immobility by antidepressant treatments can be clearly dissociated from mere stimulant effects on locomotor activity. Further findings indicate that the depressive behaviour measured in this test is also alleviated by non-pharmacological treatments such as electroconvulsive shock, deprivation of REM sleep, and exposure to an "enriched" environment"…}

Open-space forced swim model of depression for mice.
^{by Stone EA and Lin Y}
Current Protocols in Neuroscience. 2011 Jan;Chapter 9:Unit9.36.
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^{This protocol describes a simplified method for inducing a chronic depression-like state in mice that is based on the repeated open-space forced swim method originally developed for rats. The method consists of mice swimming daily in lukewarm water in rat tub cages, for 15 min/day for 4 days, and thereafter once per week. This procedure produces a progressive decrease in distance swum and a concomitant increase in immobility [floating] in ∼70% of the mice, both of which persist unaltered for weeks. The model has predictive, face, and construct validity and has a number of advantages over previous methods in that it utilizes very mild stress, is short in duration, and is easily standardized. Moreover, since it utilizes a greater swimming area than the traditional [Porsolt] method it can be used to study interactions of depressive behavior with behavioral flexibility and perseveration…}

^{"A number of animal models of depression are currently available. In general, these can be divided into those producing acute and chronic depression. Examples of the acute kind are the forced swim and tail suspension tests; while of the chronic type are chronic mild stress, learned helplessness, and prolonged subordination stress. The acute models are induced rapidly in one or two sessions and can respond to acute or subchronic antidepressant drug administration. In contrast, the chronic models are induced either over a period of weeks and/or require exposure to traumatic stress and only respond to prolonged treatment with antidepressants. Because depressed patients also only respond to chronic treatment, the chronic depression models are deemed to possess greater face validity than the acute ones with respect to human depression. However, the long induction periods or severe stress requirement of the chronic models have represented significant drawbacks. Consequently, there has been a need to develop more rapid and milder methods for the induction of chronic depression. To meet this need Sun and Alkon developed the repeated open-space forced swim model for rats in which the animals are subjected to short daily swims for three days. They found that this procedure produces a long lasting syndrome of passive, inactive water behavior which has high predictive validity in terms of its responsiveness to chronic and not acute antidepressants and lack of responsiveness to non-antidepressants"…}

^{"While it has been claimed that learned passive responses are as adaptive as learned active responses, passive responding has been found to be aversive and associated with negative mood and physiological signs of stress in humans and animals. In support of these latter findings, we have shown with Fos immunohistochemistry that the open space swim procedure produces an activation of the paraventricular nucleus of the hypothalamus and one that shows minimal habituation with repeated swims… It is reasonable to conclude therefore that the repeated forced passivity in the presence of a stressful stimulus of the present model is sufficient to induce a depressive-like state in rodents"…}

^{Perhaps the greatest disappointment with existing animal models of neuropsychiatric disorders is that they have failed, over several decades, to predict treatment efficacy in humans for previously unknown mechanisms of action. Of course, such failures also reflect the current state of clinical knowledge with a lack of objective diagnostic tests and validated biomarkers of these highly heterogeneous illnesses. Our hope is that clinical advances driven by progress in genetics, which may await full sequencing of the genomes of large numbers of affected individuals, combined with human experimental neurobiology ranging from neuroimaging to deep brain stimulation will facilitate the development of better validated and more useful animal models…}

Certainly no one would choose me as an advocate for the current drugs or the forced swim test used to screen candidate neurochemicals. But reading through the literature on that test and its evolution, I was impressed that a lot of people had put a good deal of solid scientific work into it. In his criticism, Dr. Hyman actually ignored the advances with the model in simulating chronicity and the expected lag time for a therapeutic effect from antidepressants. He characterized it as a mere neurobiological tool rather than a disease model [I think my friend might disagree with him]. He points us towards the future for more human·depression-like animal models informed by [you guessed it] genomics, neuroimaging, and deep brain stimulation. It feels like he’s looking for a scape·goat [scape·rat?] to me.

My reaction to Dr. Hyman is the same as it has been to Dr. Insel.  For the last several years, they and an army of others have been critical of the previous approaches to drug development, the current drugs, and neuropsychiatric research. They have a cornucopia of reasons things haven’t gone better and suggestions for future directions. But back in those days they now criticize, they were in charge! it was their show! It was Hyman’s NIMH [and much of what he did was initiate an era of NIMH Drug Trials: STAR*D, CATIE, etc]. Why wasn’t he pushing for better animal models then? As late as 2007, he was advocating for integrating neurobiology into the DSM-V. Then from 2002, Insel was the Elmer Gantry of neuroscience, speaking of recent advances at every opportunity and laying out his 2005 timetable aiming for clinical neuroscience nirvana [Psychiatry as a Clinical Neuroscience Discipline]. Where have his drug development initiatives been? They both have been champions for translational science without generating anything much to translate.

^{"As long as we guard against renewed self-deception about what constitutes meaningful advances, there is good reason to feel optimistic about the long-term future of translational psychiatry—despite its palpable scientific challenges. My optimism is based partly on the extraordinary vitality of neuroscience and perhaps, even more important, on the emergence of remarkable new tools and technologies to identify the genetic risk factors for psychiatric disorders, to investigate the circuitry of the human brain, and to replace current animal models that have failed to predict efficacious new drugs that act by novel mechanisms in the brain. New ideas are, of course, central to scientific progress, but new tools can open up unexpected worlds and thus undergird the formulation of truly novel hypotheses. As brilliant as Galileo was, without advances in optics, he would not have observed the four moons of Jupiter that undergirded new models of the solar system"…}