The enigma of mental illness: Why is it so hard to treat?

Every culture, in every period of history, has had professionals whose job it was to allay the fear of death and the uncertainties of life, even if their ability to do so chiefly consisted of sharing tales of hope and comfort. For thousands of years, the work of priests and physicians was not very different, and their effectiveness in eliminating specific ailments was very limited. Two centuries ago, however, the scientific method transformed the field of medicine. By identifying the microorganisms that caused lethal diseases such as smallpox or typhus, it became possible to fight them with hygiene, antibiotics or vaccines, and this saved millions of lives. And precise knowledge about physiological failings that cause conditions such as diabetes made it possible to diagnose them and successfully treat them.

But after decades of spectacular progress in many areas, modern medicine has run into more complicated obstacles than infectious diseases. Mental illness, according to the Organisation for Economic Co-operation and Development (OECD), are the leading cause of disability in Western nations. They represent 30% to 40% of long-term sick leaves, at a cost of 4% of GDP. Yet progress on this front is very limited.

After decades of research, Alzheimer’s still lacks an efficient treatment, for instance. And as for psychiatric disorders such as schizophrenia or depression, therapy options are few and their effectiveness limited. According to data collected by researchers of the Alicante Neuroscience Institute in Spain and published in Frontiers in Psychiatry, a study of people with major depression found that 31% felt well after 14 weeks of treatment with selective serotonin reuptake inhibitors, one of the more popular treatments. Among bipolar patients, only 24% were depression-free for eight straight weeks, a similar rate as the control group who did not get the medication.

Jorge Manzanares, a pharmacology professor at Miguel Hernández University in Alicante, Spain and lead author of the study, said that the success rate of psychiatric treatments depends on a lot of factors, from the severity of the case to the psychiatrist’s own abilities. “They’re a bit like the druids of mental disease. Unlike physicians, who can measure a factor related to a disease [such as high blood pressure or transaminase levels] and act accordingly, psychiatrists act in a very empirical, more artisanal manner,” he says. “They don’t have markers for genetic or anatomical alterations, or protein markers to help them make decisions, so success depends largely on the psychiatrist’s experience assessing patients and selecting a treatment, or deciding when to switch to a different one because another prescription drug is going to work better.”

Right now, diagnoses are made following guides and tests meant to identify all possible pathologies, but it is not possible to improve the assessment with a blood test or an MRI scan. This does not mean that nobody has flagged up biological and anatomical traits that might be associated with various mental conditions. ”If we compare a broad group of people with disorders such as autism, schizophrenia or bipolar disorder with a disease-free group, we can observe clear biological differences, from alterations to the structure and volume of some brain areas to a bigger or smaller presence of inflammatory markers,” notes Guillermo Lahera, a psychiatrist at Príncipe de Asturias University Hospital in Alcalá de Henares, Spain. “But right now, none of these biomarkers helps diagnose or predict the onset of disease,” he said.

If we compare a broad group of people with disorders such as autism, schizophrenia or bipolar disorder with a disease-free group, we can observe clear biological differences

Guillermo Lahera, a psychiatrist at Príncipe de Asturias University Hospital

“Most diseases are multifactorial and chief among these are psychiatric conditions,” adds Juan Carlos Leza, group coordinator at CIBERSAM Biomedical Health Center, a part of the Carlos III Health Institute Network. Leza notes that genetic factors are very relevant: a person whose parents are both schizophrenic has a 40% chance of suffering the disease as well. But the genes involved might be a few dozen or a few hundred. It might also take external factors to trigger the disease, such as sustained stress levels, a viral infection or exposure to toxic substances. And all of these circumstances play a larger role if they take place in the years when the brain is being formed, from gestation to the final teenage years.

Leza and his team are working to identify molecules related to uncontrolled inflammation in the brain as a response to all those factors, in order to find therapeutic targets. They are also looking for differences in the intestinal bacteria of people with depression, as this is also tied to the harmful inflammation.

Despite the size of the challenge and the scarce practical applications of the biology of psychiatric diseases, Lahera believes this “should not take us back to the obsolete idea that disorders of the mind have no underlying bodily factors.” And Manzanares underscores the economic and human cost of mental disease and addiction. “Although there are not very good solutions yet, we need to invest more, precisely because there are still a lot of unknowns,” he says.

Lahera believes that in the coming years, knowledge about mental disorders will be driven by advances in neuroscience, genetics and technology, but warns that there will be no simple answers of the switch on-switch off variety. “There is a direct and bidirectional influence between our environment and our biology,” he notes. That is why finding reliable biomarkers for mental disorders could help develop new drugs, but also help assess their effectiveness in combination with therapy.

Although there are not very good solutions yet, we need to invest more, precisely because there are still a lot of unknowns

Guillermo Lahera, a psychiatrist at Príncipe de Asturias University Hospital

The most important biomarkers will be those that predict the probability that a treatment will work, or offer clues to find new treatments. Just like with cancer, mental diseases have many subtypes and overlapping traits, and there are few tools for finding the right treatment.

These biomarkers could also help predict the risk of someone developing a disease before it happens. But Ignacio Morgado, an emeritus professor of psychobiology at the Autonomous University of Barcelona’s Neuroscience Institute, warns about the risks. “A biomarker that says you have a 60% chance of developing Alzheimer when there is no treatment could be useful for researchers, but it makes no sense for the patient,” he says. “The Roman emperor Marcus Aurelius used to say that what makes us suffer is not what happens to us but the way we look at it. A piece of news like that will scare you, and the fear and stress could trigger epigenetic factors that lead to disease.”

Still, the study of mental diseases has improved the lives of patients. Starting in the 1950s, the first anti-psychotic drugs allowed some people with schizophrenia to leave psychiatric hospitals and lead somewhat normal lives. The first efficient anti-depressants were developed. Progress has been slower since then, but psychedelic substances such as MDMA or psilocybin are showing some promising results with post-traumatic stress and depression. In 2019, the approval by drug regulation agencies of esketamine to treat severe depression was presented as a turning point, but in some countries like Spain, authorities are refusing to finance treatment because of a lack of evidence of its utility.