The 1950s and 1960s were the golden age of psychiatry. At that time, reliable options were being discovered that curbed the shadows of the mind and regulated emotional pain. Antipsychotics that blocked the reception of dopamine and antidepressants that acted on the reuptake of serotonin were chanced upon. It was a radical development that emerged from a vacuum and led to drugs that muted the voices of schizophrenia or threw a lifeline to sufferers of depression.
With the commercialization of Valium (diazepam) in 1963, benzodiazepines — which boosts the neurotransmitter GABA — allowed risky barbiturates to be removed from anxiety treatment. Within the space of 15 years and after a lot of laboratory work and a couple of strokes of luck, psychiatrists had a small but solid arsenal of remedies to offer their patients.
Little has changed since then, argues the controversial Imperial College professor David Nutt in a recent article published in The Lancet. The author of works such as Drugs Without the Hot Air, Nutt believes the last 50 years have been, with few exceptions, a slew of variations on the same theme. Science, he argues, has limited itself to increasing the tolerability and galvanizing the efficacy of three mechanisms of action. His review is relentless: half a century with hardly any new findings.
“We have failed many times, and yet we keep making the same mistakes,” says Nutt via videoconference. According to Nutt, stumbling over the same stone is due to excessive regulatory zeal and methodological rigidity, two obstacles that stifle ingenuity and provoke timorous attitudes when investigating mental pathologies.
Not everyone sees a five-decade wasteland when looking back. Eduard Vieta, head of psychiatry at the Hospital Clinic in Barcelona, agrees that the drugs that have emerged since the late 1960s are, as a rule, closely related to the earlier ones, but he insists there has been a lot of finetuning regarding side effects. “Things have improved tremendously. Before, you used to see terrible cases of dystonia [involuntary movements], catatonia and even death,” he points out.
Although he says that a boom like that of the post-war years is not on the cards, Vieta considers that we are living in a silver age of psychiatry. And he justifies his enthusiasm with two recently approved advances. These are muscarinic, which has enabled the development of Cobenfy — a new antipsychotic, for now only available in the U.S. — and glutamatergic, which enables esketamine to work in some patients suffering from resistant depression.
With varying degrees of optimism, experts agree that there are intrinsic pitfalls in psychiatric research. “The brain is the most complex organ and we are far from understanding it,” says Leyre Urigüen, a neurobiologist and researcher at the University of the Basque Country.
Not only are researchers dealing with the absence of precise biomarkers essential for the analysis of purely physical diseases, they also have the subjective component in diagnoses and evaluations to contend with.
“We question people who often do not understand themselves,” says Juan Carlos Leza, who heads a molecular neuropsychopharmacology group at the Complutense University. “We have to measure thoughts and emotions, and there is no totally objective way to do that,” Vieta adds.
The inherently human nature of psychiatric disorders also limits the use of animal experimentation. Leza explains: “You can’t ask a mouse if it is sad or if it has considered taking its own life.” Utigüen adds: “It’s easy to replicate cancer in a rodent, but not depression.”
Utigüen, is, however, hopeful about the potential of research being carried out with organoids — miniature recreations of human organs created from stem cells. Nutt is less optimistic. “Organoids may be useful for investigating brain growth factors, but I don’t think they will help us develop new medicines. Even if we can get them to have the subjective qualities of a depression, it would be unethical to go that way. If a brain organoid started thinking like a human, it would no longer be an organoid.”
From a social point of view, so-called anti-psychiatry — a concept that emerged at the end of the 1960s — has put another brake on the development of new drugs. “There is a current of opinion that claims that mental illness does not exist, that everything would be solved by tackling the underlying social problems,” Leza points out.
According to Nutt, these ideas have permeated the circles of power and have marginalized the need to alleviate the suffering of the psyche. “In the United Kingdom, public funds are allocated to the fight against cancer, but not schizophrenia, and that is a political decision,” he says.
Nutt proposes to turn research regarding mental illness on its head. He advocates giving up on the methodological zeal that places randomized controlled trials (RCTs) on a pedestal. “There is an illusion that they are the only ones that provide scientific certainty, but experience tells us that, apart from being very expensive, in psychiatry they tend to be highly ineffective,” he says.
Nutt points out that, in 2007, Michael Rawlins, then head of the British drug regulatory body, said that “RCTs were not the pinnacle of clinical trials, but just another tool.” His words fell on deaf ears. “Perhaps people are scared of change,” says Nutt who advocates a return to the spirit of the 1950s and 1960s, when there was more focus on symptoms and researchers were more experimental and exposed to lucky breakthroughs.
After decades of restrictions, Vieta is excited about the recent openness to test and, if necessary, introduce psychedelic substances into the arsenal available to psychiatrists. He himself is doing research with psilocybin — a substance found in hallucinogenic mushrooms — and dimethyltryptamine, which is found in various plants such as ayahuasca. “They are very potent serotonergic agonists, with a mechanism of action that, we suspect, could reset the brain, perhaps correcting depression and anxiety.” According to Vieta, they are currently producing “impressive results in people with bipolar disorder and severe depression.”
Nutt is skeptical. “Regulatory overreach is likely to destroy the hope placed in psychedelics,” he says. He believes that their use on an extensive scale would mean turning iron-clad regulations and practices on their head. Taking these substances requires consultations with psychiatrists and/or psychologists who need to be around to ground the experience. Nutt fears that, “because it’s not just a drug, but drug plus therapy, regulators will argue that they can’t approve it.” Moreover, with pharmaceutical companies out of the picture, there is no sizable profit to be made. “It would mean changing the model that has been in place for 70 years: a company obtains a patent on a molecule and does business with it.”
Despite his mistrust, Nutt says change is possible. In Australia, regulators already allow Mind Medicine, a non-profit organization, to administer psilocybin and MDMA (ecstasy) in controlled settings. “They have decided that there is sufficient evidence of therapeutic benefit and that it is time to move beyond the kind of innovation that only seeks financial gain,” he says. Cautiously, Nutt allows his pessimistic vision to be punctured by a psychedelic ray of light that may well help overcome 50 years of stagnation.
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