Some things take a moment to digest. This next bit from the story of anti-depressant drug development seems at first like something being made up, but that’s not the case. It’s called the behavioral despair test, the Porsolt, or the forced-swimming test [1977]:Animals are subjected to two trials during which they are forced to swim in an acrylic glass cylinder filled with water, and from which they cannot escape. The first trial lasts 15 minutes. Then, after 24-hours, a second trial is performed that lasts 5 minutes. The time that the test animal spends without moving in the second trial is measured. This immobility time is decreased by antidepressants.
Says Dr. Hyman [see whither the crisis…]:
Lacking molecular tools, pharmacologists working in psychiatry developed assays, mostly in laboratory rats, based on the effects of prototype drugs such as chlorpromazine, imipramine, and chlordiazepoxide [Librium] on animal behavior. For example, a rat placed in a beaker of cold water will swim for a time, but it will eventually stop swimming and begin to float. 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 association of helplessness with depression has been around for a long time. Freud had seen anxiety as a biological signal of danger. Psychiatrist Edward Bibring extended that idea to depression which he saw as a signal of helplessness [1953]. Psychologist Martin Seligman came up with the idea of learned helplessness in the 1960s, popularized in a number of widely read books. Here’s an example set of results from the forced swimming test:
Since the 1950s, scientists have worked to go beyond these assays and to create animal models of human depression, bipolar disorder, schizophrenia, and other psychiatric disorders. Relying mostly on laboratory rodents, they have used a range of tools from environmental stressors to the insertion of human disease risk genes into the brains or germ lines of mice. If we are to be clear-eyed about the results to date, we would have to conclude that none of these models have proven adequate…
Like the psychiatric literature, the research hopes are infused with future·think and waiting for new technologies, new assays, new something that’s not here yet:
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…
Animal models are central to biological and pharmaceutical research. And it’s easy to see why they have such a hard time in psychiatric research – they really don’t yet have much to work with. Their hopes for the future seem to rest on psychiatric disorders that are genetically determined and as yet undiscovered innovative assay techniques:
Our best hope is that the genetics will unfold over the next several years, due to the efforts of large international consortia that have formed to recruit and to study patients. As genetic clues accumulate, scientists are devising new ways to investigate their neurobiological functions and dysfunctions. One interesting development is to use stem cell technologies to complement the use of laboratory animals with human neurons engineered from skin cells of healthy subjects and from patients. The leading approach is to take a small skin biopsy from the arms of volunteers and to transform skin fibroblasts into neural progenitors and into neurons. Genetic engineering can then be used to add risk-causing mutations to “healthy” neurons and to reverse risk mutations in patients’ neurons. But it is still early in this new field, and it is not yet possible to engineer the specific kinds of neurons implicated in schizophrenia by postmortem studies.
On one hand, I found Dr. Hyman’s article to be a fairly interesting tour through the state of the art in psychiatric drug development. It’s easy to see how his NIMH flowed into Insel’s NIMH – both dominated by a focus on finding ways to study drug treatment for psychiatric disorders – Translational Medicine, moving to bedside. It’s also easy to see the difficulty of their task. But on the other hand, I found it painfully monocular. First, it’s obvious that for him the central problem is the "retreat" of the pharmaceutical industry. At the risk of my being accused of being melodramatic, it has the feel of a piece written after being jilted by a lover. "How could he leave me? We were so good together. I need him!":
This retreat has occurred despite the fact that mental disorders are not only common worldwide, but also increasingly recognized by healthcare systems. There is, moreover, vast unmet medical need, meaning that many individuals with mental disorders remain symptomatic and often disabled despite existing treatments. For example, people suffering with the depressed phase of bipolar disorder often continue to experience severe symptoms even when they take multiple medications with serious side effects. For some significantly disabling conditions, such as the core social deficits of autism and the cognitive impairments of schizophrenia, there simply are no effective treatments. Because mental disorders are highly prevalent and our ability to treat them remains limited, these illnesses cause enormous societal burden. In aggregate, they are the world’s leading cause of disability.
In addition, this retreat has happened despite the fact that different classes of psychiatric drugs have been among the industry’s most profitable products during the last several decades—and despite the fact that, according to Medco Health Solutions, one in five American adults now takes at least one psychiatric drug. Among the earliest commercial successes were the Valium-like benzodiazepines, used both as tranquilizers and as sleeping pills. These were followed by the Prozac-like selective serotonin reuptake inhibitor [SSRI] antidepressants. Most recently, “second-generation” antipsychotic drugs have been among the global revenue leaders for the pharmaceutical industry, serious side effects notwithstanding. That’s why it’s surprising that almost all industry research dollars are invested in cancer, metabolism, autoimmunity, and other disease areas…
"We gave him everything he wanted. How can he leave at a time like this?" The blurring of boundaries between academia and pharma and their goals couldn’t be more obvious – painfully obvious. And the second thing is that Dr. Hyman tells his story with no mention of the magnitude of corruption and deceit that this relationship has generated, or the epidemic of wrongful-doing pharma suits settled, or the entrepreneurialism among the academic KOLs. Do they think if they don’t talk about that stuff, it just won’t be there?
And this is really hard to hear him say, "… second-generation antipsychotic drugs have been among the global revenue leaders for the pharmaceutical industry, serious side effects notwithstanding." There’s nothing about the minimized, ignored, or even denied serious side effects that fits with "notwithstanding"! I might add hidden from both patients and practicing doctors. If I were a patient who had those serious side effects reading this, I’d have trouble containing my rage, "You knew about those serious side effects! and didn’t tell us!"
There’s a disconnect here that’s hard to resolve. A lot of people are standing on their heads to right the wrongs of the past and to make sure they don’t happen again, and yet Drs. Insel, Hyman, and plenty of others are willing to stand on their heads to lure pharma back into the game, and seem willing to do almost anything to facilitate their return. For this latter group, the crisis is that pharma is pulling out, instead of the crisis of integrity that’s so painfully clear. Perhaps holding up the academic end of this bargain along the way, including not signing on to papers from the spirit world, might have averted this crisis all together…
So if a human being is pulled under then swept far away from the shore, they may, after struggling in the deep for hours with no help in sight, begin to feel helpless; which means that they are depressed. While doing everything in their power to survive in the open sea, it might become apparent to that lost soul that they were probably genetically inclined to be feeling that way and should have taken medication to prevent it.
Where’s a psychiatrist when you need one?
Another portion of the discussion. Don’t know that I agree, but of interest perhaps:
http://neuroself.com/2011/05/09/what-are-the-units-of-the-mind/
“However a more fundamental reason for adopting units by which to measure the mind is that this will allow the detection of unconscious processes, long the dream but never the reality of field. Indeed it often escapes the attention of practitioners that as presently constituted, psychiatry can postulate but not detect unconscious contributions to mental life.
There is abundant clinical evidence that most patients are unaware of maladaptive motivational processes that damage their wellbeing, even as their friends and family gossip easily about how they “don’t want to grow up,” or “are afraid of success,” or “always sabotage their relationships by falling in love with unavailable women.” Most psychotherapists spend the majority of their time attempting to make patients aware, years into treatment, of problems the therapist noticed in the first few sessions; clinically the unconscious is patently obvious.
Further, there is overwhelming neuroscientific evidence that that vast majority of neural processing is unconscious, that suboptimal processing can occur in these unconscious regions, and finally that this suboptimality can lead to psychiatric illness. Prudence would appear to dictate a means by which to understand the informational content of unconscious processing, which moving forward we will call the informational correlates of neurons (ICN). It is worth noting how entirely unradical and frankly conventional this emphasis on neuroscience’s potential to discover unconscious causes of mental illness is. In fact it is so conventional that for decades the overwhelming majority of neuroscience articles have simply assumed that it is the job of neuroscience to observe the physical correlates of unconscious mental processes: they attempt to analyze the informational implications of neural processes and structures that, as when in lower animals, clearly lack conscious correlates. In academic psychiatry, the movement to predict the development of psychiatric illness by measuring cortical thickness, white matter connectivity, and subcortical activity is an index of the field’s impulse to look beyond what consciousness can tell us about the human experience”
Again, don’t know that I agree, but perhaps of interest.
Those animal models in psychiatry are inherently ridiculous. Who knows what the rat is thinking? Maybe it’s plotting revenge. Experimenters’ projections about the rats’ inner lives tell more about the scientists than the rats. (New Yorker cartoonists have long had a field day interpreting lab rat psychology — see http://www.youtube.com/watch?v=aRY6dl4P0xM )
Perhaps someone should explain to Dr. Hyman what “market saturation” means. With 20% of Americans on psychiatric drugs, drug companies no doubt saw greener pastures in market growth elsewhere.
When 20% of the population is captured as customers, that doesn’t mean 80% is left — it means each additional customer will cost more for less profit. The market is tapped out. Time to mine other diseases that anyone might be suffering from, such as aging or Alzheimer’s.
I’m reading Loving to Survive: Sexual Terror, Male violence, and Women’s Lives by Dee L. R. Graham. The book deals with “Generalized Stockholm Syndrome” that applies to all peoples who are essentially being held hostage by threats of violence, death, or psychological destruction.
Generalized Stockholm Syndrome involves survival strategies that resemble what psychiatrists refer to as Borderline Personality Characteristics, reflecting psychiatry’s tendency to pathologize victim’s survival responses to unhealthy interpersonal environments.
The relationship between this and the lab rats seems pretty obvious to me. The psychiatrists/researchers could have “cured” the rats by not making them tread water helplessly, treating them kindly, and stopping the abuse. Isn’t that radical?
A lot of psychiatric patients who are in compliance with a lifelong regimen of neuroleptics and other dangerous drugs and treatments that aren’t really changing the fabric of their lives or psyches in a positive way may be suffering from Generalized Stockholm Syndrome— especially those who live with the threat of forced medication, forced electroshock, and the forced captivity of non-voluntary commitment.
As long as the field of psychiatry is not examining it’s own bias toward women/minorities/children/the poor and working class; it is lacking insight. As it stands right now, psychiatry is trying to “fix” people who act as if they weren’t privileged enough not to be overwhelmed by the social oppression that most of the KOLs don’t even think about suffering.