The Scripps Research Institute in La Jolla, CA is one of the premier centers for brain research in the country, and so when the Institute announced in late December that its scientists had discovered a “brain cell malfunction in schizophrenia,” one might assume that it would be careful work. The published article would detail how the researchers accounted for the deceased patients’ exposure to neuroleptics and other psychiatric drugs, which is an obvious confounding factor.
But this research, funded by the National Institute of Health, doesn’t pass that simple test. As a result, we now have yet another research study funded by American taxpayers, that, in my opinion, is essentially worthless, or even worse than worthless. By assigning the abnormality to the disease, without having assessed whether it may in fact be due to the drug exposure, the study may be presenting a “finding” that is fundamentally misleading.
And so I offer a modest proposal: I think it is time for federally funded brain research in psychiatry to move in a new direction.
First, let’s look at this particular study. The researchers studied 82 “postmortem human brain samples.” Thirty-four were from “normal subjects,” 32 were from schizophrenia subjects, and 16 from subjects with bipolar disorder. The investigators did report that none of the subjects had a record of treatment with valproic acid. They did so because this is a drug thought to be protective against the deficiency in gene expression they were going to be assessing. However, the researchers didn’t report on other medication use by the schizophrenia and bipolar subjects, and obviously most of those diagnosed with schizophrenia would have spent years taking neuroleptics.
In the December issue of Translational Psychiatry, the researchers announced that, based on their study of the 82 brain samples, DNA “stays too tightly wound” in the brain cells of schizophrenia subjects. This can lead to certain genes in the cells being “turned off,” and thus the cells won’t manufacture proteins essential to normal functioning. In a press release, Scripps’ neuroscientist Elizabeth Thomas said that her group was “excited by the findings,” which could lead to the development of new drugs to treat schizophrenia.
That is the usual concluding pronouncement from such studies. An abnormality is discovered, it is attributed to the disease and not the medications used to treat the disease, and then the researchers say this could lead to new drug development.
Now let’s turn to a 1996 paper by Steve Hyman titled “Initiation and Adaptation: A Paradigm for Understanding Psychotropic Drug Action.” A neuroscientist, Hyman was director of the NIMH when he authored that paper. He told of how psychotropic drugs perturb neurotransmitter function, and how in response to that perturbation, the brain goes through a series of compensatory adaptations in order to maintain its normal functioning. However, after a time these compensatory adaptations break down, and the “chronic administration” of the drugs causes “substantial and long-lasting alterations in neural function,” Hyman wrote. As part of this adaptive process, there are changes in intracellular pathways and “gene expression.”
Focus on those last words. The drugs alter gene expression in brain cells. And what is this finding by Elizabeth Thomas and the Scripps’ scientists? There is evidence of abnormal gene expression in the brain cells of schizophrenia patients.
That begs an obvious question: If DNA is too “tightly wound” in the brain cells of schizophrenia patients, is that due to the “disease” or the drugs?
There is a fairly easy way to at least partly investigate that question. The Scripps’ researchers could have administered neuroleptics to healthy rats for an extended period of time, at clinically relevant dosages, and assessed whether the same “brain cell malfunction” showed up in the rats. But their paper does not tell of that simple step having being done.
This study is emblematic of the many problems with the brain research literature in psychiatry. The confounding factor of drug exposure is often ignored. While there have been a number of first-episode studies, or studies in “medication naïve” patients, that seemingly avoid this problem, those studies—upon closer examination—are often not what they seem. Many of the subjects—even in the “medication naive” studies—may in fact have been exposed to psychiatric drugs, at least for a short period of time (with the researchers then discounting this exposure because of its relative short duration.) Another problem with this literature is that the studies regularly present “composite” findings. The researchers use MRIs or some other technology to put together a picture of the “schizophrenic” brain in comparison to a “normal” brain, and while that composite comparison may lead to an identified “abnormality” in the schizophrenia group, many individuals in the schizophrenia group don’t actually exhibit the identified abnormality, while some in the “normal” group do. When this overlap happens, it is a bit of a leap to conclude that you have identified a pathology that is a defining characteristic of a disease, and yet that is how the findings are often presented to the public.
But even more to the point, decades of such brain research has not produced any notable therapeutic payoff. As is now clear, the second-generation psychiatric drugs are no more effective than the first-generation psychiatric drugs. Nor is there a promising “third-generation” of psychiatric drugs coming down the pipeline. In fact, new drug development in psychiatry is stymied precisely because decades of brain research has failed to provide pharmaceutical companies with promising new molecular targets.
Thus, a modest proposal: Rather than continue putting so much money into a line of inquiry that has proven rather futile, the NIMH should concentrate on funding research into the effects of psychiatric drugs on brain morphology and brain function The purpose of this research would be to flesh out the many possible harmful effects of psychiatric drugs, a pursuit, it should be noted, that is consistent with the Hippocratic Oath to “Do No Harm.” It is also one certain to be therapeutically useful. It would provide both physicians and the general public with information needed to better evaluate a drug’s risks and benefits, particularly over the long term.
I can think of many questions that desperately need to be investigated. In the U.S. today, one is six babies is born to a mother who took a psychiatric drug during her pregnancy. How might that in-utero drug exposure affect brain development? The organizing of cell structures in the brain? And how will any brain abnormality arising from that in-utero exposure affect the child over the long-term? There is research in rats that suggests in-utero exposure to an SSRI leads to a clumsy adult rat; is the same thing occurring in humans?
Next, we are prescribing stimulants, antidepressants, antipsychotics and mood stabilizers to our children today on a regular basis. This has often been described as one big “experiment.” The kids are the guinea pigs in this experiment, and so shouldn’t we at least try to answer a few fundamental questions? What effect do the various drugs have on brain development? The maturation of the frontal lobes? Hormonal systems? Sexual development? Cognitive function? Metabolic function? Physical skills? Will the drugs cause lasting changes in gene expression? Will neuroleptics cause the teenage brain to shrink? And so on. The daily taking of a psychiatric drug modifies the child’s brain, and I would think that both parent and child would like to see such questions answered.
With adults, many of the same questions apply. NIMH-funded studies could investigate a drug’s long-term effect on brain morphology, gene expression, the functioning of neurotransmitter pathways, cognition, behavior, and physical health.
Finally, here is the one pressing question that I am regularly asked when I give a talk about Anatomy of an Epidemic. In response to a psychiatric drug, the brain goes through a series of compensatory adaptations. If you then withdraw from the drug, does the brain return to its normal functioning? For instance, in response to an SSRI, which blocks the normal reuptake of serotonin from the synaptic cleft, the postsynaptic neurons decrease the density of their serotonergic receptors. Upon withdrawal from the SSRI, will the density of serotonergic receptors return to normal?
Unfortunately, nobody knows the answer to that question.
This is why I think it is time for the NIMH to reallocate its research dollars. We have had decades of research seeking to discover the biological causes of mental disorders, but that research has failed to produce any notable therapeutic benefit. The NIMH should alter its focus, or at least expand it, and provide financial support to brain research of a kind that is certain to benefit society. It should fund animal and human studies that would give us a better understanding of what we are doing to our newborns, our children, and our adult selves when we take these medications on a regular basis.