of mice and men…

Posted on Friday 26 April 2013

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.
And from the text of the review:
    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
Centre de Recherche Delalande, Rueil-Malmaison, France
European Journal of Pharmacology. 1978 47:379-391.
[commentary on-line]

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.
I heard about the forced-swim test long ago, but I admit that I have spent zero time pondering its mysteries. And I doubt that reading about it the other week would have registered with me had it not been for the serendipitous comments of my friend ["That’s what I do when I’m depressed – I give up."]. But I found myself looking up Porsolt’s original description:
    "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"…
They seemed to have done their homework – testing all known therapies for depression and ruling out non-specific drug effects like stimulation or sedation:
    "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"…
There has been a remarkable amount of research done on various versions of the Porsolt Test [best strains, dose schedules, timing, etc.], and as Hyman says, it has been used to screen compounds for antidepressant properties for thirty·five years. In the classic scenario, on day one, they give the rat an impossible task – escaping the inescapable water-filled beaker. The next day, the rat tries a bit, then just floats [accepting fate?]. But when treated with antidepressants, he keeps trying longer. And as time has marched on, there have been variations and refinements in the model:
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.
[full text on-line]

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…
I picked this second article because it has a summary description of the rodent models for chronic depression requiring longer treatments with antidepressants for a response mimicking what happens in humans [also this group developed their model with mice, so I can entitle the blog "Of Mice and Men"]:
    "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"…
Thinking about this from the rat’s perspective, whatever the antidepressant does for the rat, it’s a treatment for a psychological issue. It’s a sure bet that the antidepressant doesn’t treat some basic Disorder, correct some chemical imbalance or a brain circuitry problem, nor are epigenetic inheritance or neurogenesis likely in the picture. I guess those rats get something more like a depressive neurosis. But whatever its doing, the rats don’t give up so quickly when treated with antidepressants. Then, in the chronic models [open-space forced swim], the mice apparently develop changes in the brain and behavior that convinced their handlers that they are indeed depressed:
    "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"…
In their 2010 piece, Nester and Hyman concluded:
    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.

The upper layers of academic, research, and organized psychiatry have spent the decades talking eruditely about the psychopharmacology that has been generated by the scientists of the pharmaceutical industry. But they’ve contributed very little science of their own. They can’t seem to figure out what to do with industry’s bench scientists and funding leaving, except to criticize the past [that they were an integral part of], and to create fantasies about a vague future. Says Hyman:
    "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"…
I reread this article, and the ending reminded me of something – of Alan Greenspan around the time he retired, explaining about his faith in the vitality of the market to weather the collapse of the housing industry. At least he had the good sense to get out of the way. And I thought of Porsolt’s rats having the good sense to know when to give up and stop swimming…
    Jack Friday
    April 27, 2013 | 1:01 AM

    Nice job as always Mickey. Made me think. This time lag effect with ssri ‘s in some, but not all patients. See


    “Within 2 days”!

    A recent serendipitous step forward in depression also made me wonder:


    Why might there be a sub group of depressed people who respond differently (faster) to treatments?

    April 27, 2013 | 4:38 AM

    Theoretically an ssri can have an impact on anxiety in approx 4 hours.

    see: http://bjp.rcpsych.org/content/194/6/535

    see a MNT article here: http://www.medicalnewstoday .com/articles/192750.php

    I noticed a feeling very much like taking a xanax at roughly 4 hours after I took an SSRI. But it gave me unblinking insomnia, so I stopped taking it. Also, my experience of xanax was that, while it was great to learn what the feeling of not being anxious was like, the rebound anxiety was about 3 times worse and took about 2 days to mostly dissipate. (What I mean is I think it made me a bit leery of continuing the drug.)

    April 27, 2013 | 4:59 AM

    Oh, and my bet is that I am an unexpected shocks rat and (thus) a socially isolated (via my own avoidant behavior) rat.

    April 27, 2013 | 8:24 AM

    The “giving up” or “learned helplessness” response in depression is why Behavioral Activation has proven to be such an effective treatment.

    April 27, 2013 | 2:29 PM

    Have ya’ll seen the rat laughing while being tickled?


    Perhaps rats are sentient enough to also feel despair in the face of human cruelty. Rats are cheaper than monkeys who are more like humans than rats are, but such cruelty would also be more obvious when applied to primates.

    In this world, sometimes we do need and benefit from a drug that will keep us swimming in a situation that is hopeless or in which we feel hopeless until someone or something plucks us from it; but I see no long-term benefit from simply labeling that despair “depression” and prescribing a drug for it for a population while telling the patient that they have a life-long medical condition.

    Regardless of what your friend was suffering from, to treat a large population as if they have a medical condition with drugs that were first tested by torturing rats, is a little maddening to me.

    April 27, 2013 | 7:28 PM

    To paraphrase ‘The Treasure of Sierra Madre’ –

    We ain’t got no science.
    We don’t need no science.
    We don’t have to show you no stinkin’ science!



    April 27, 2013 | 7:47 PM

    Science –



    April 30, 2013 | 9:01 PM

    I’m sorry, I cannot accept that scientists can truly read the minds of rats and ascertain they are suffering from a human emotion. This is projection of the most self-serving sort.

    As for why antidepressants sometimes take a while to take effect: They tend to be stimulating, and they tend to disrupt normal autonomic homeostasis (cf sleep disruption, dizziness, palpitations, etc.). For some people, it takes some time for a new homeostasis to incorporate the influence of the drug. For others, the stimulating effect is felt sooner.

    I recently discussed the difference between cardiologists and a psychiatrists with a doctor friend. Our conclusion: Cardiologists know the autonomic nervous system exists. We had a good laugh over that.

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