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Prominent researchers call for critical overhaul of psychiatric drug development and new approaches to anti-inflammatory treatments
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Many studies have found that inflammation contributes to several psychiatric disorders but developing drugs that target inflammation as a treatment for these conditions is proving to be difficult. Clinical trials using anti-inflammatory drugs to treat depression and schizophrenia for example have had limited success, and there is great risk that these drugs will be abandoned altogether. This is a problem because many patients are intolerant or resistant to conventional drugs used in psychiatry, and there is a lack of new treatments being developed. Similar to anti-inflammatory drugs, drugs that targeted the hypothalamic-pituitary-adrenal (HPA) axis also failed in clinical trials, resulting in a waste of billions of dollars in research and development funds. Unfortunately, the issue may not be with the drugs, but with the way clinical trials are conducted in psychiatry, which are based on outdated and poorly defined diagnoses and outcomes, and the belief that when it comes to drug development, one size fits all.

A recent perspective published in the journal Molecular Psychiatry points out that drug development in psychiatry has been facing ongoing challenges. The authors, Andrew H. Miller, MD, professor of psychiatry and behavioral sciences at Emory University and Charles L. Raison, professor of psychiatry at the University of Wisconsin Madison compare the development of drugs in psychiatry with that of cancer treatment. Both fields started their drug development journey by chance observations of drugs that worked effectively but not necessarily specifically. For example, chemotherapy in cancer and antidepressants, mood stabilizers, and antipsychotics in psychiatry.

However, while significant progress has been made in oncology drug development, there has been little advancement in psychiatric pharmacology over the past 50 years. Patients with mental health issues are being treated with similar drugs that have been around for years and there is still limited understanding of how these drugs work. Even newer treatments such as psychedelics and ketamine, which have been effective in some patients, are not yet understood. This lack of progress is concerning to Miller and Raison.

In their perspective piece, the authors address how the field of mental health research and drug development has not followed the same path as the field of cancer treatment. Instead of focusing on finding specific causes of mental health conditions, many treatments have been developed to address the symptoms. This is different from how cancer treatment has evolved. Cancer treatment has improved by identifying the specific ways in which different cancers grow and spread, and then creating treatments to target those mechanisms. This has shown that even if cancers look similar, they may need different treatments. Likewise, cancers that appear different may share the same underlying biological mechanisms and benefit from similar treatments. 

Miller and Raison believe the field of psychiatry can improve its medications if it uses a method similar to that used in cancer treatment. Instead of looking for a single treatment that works for everyone with depression or schizophrenia, they suggest that we need to identify and address the many different biological reasons behind these conditions. By developing treatments and clinical trials that target these specific causes, we can make progress in treating mental health issues more effectively. 

The two researchers have long studied inflammation and its relationship to depression. In a 2013 study, they tested a new way to treat depression by using a powerful anti-inflammatory drug. At the time, they believed that depression was an inflammatory disorder because of the link between inflammation and depression. In the study, they were surprised to find the anti-inflammatory drug was only effective for people who had increased inflammation. The drug did not work better than a placebo for those who had depression symptoms but did not have increased inflammation. Their findings showed that depression is not necessarily an inflammatory disorder, and the relationship between inflammation and depression is more complex than previously thought. 

“Inflammation can be a mechanism that causes depression in some patients, but not everyone who is depressed has increased inflammation,” explains Miller, “So we began to see that our labels of depression masked a whole variety of different and more specific biological subtypes.”  

Miller says research on anti-inflammatory drugs should be concentrated on patients who have a high level of inflammation, otherwise the drugs are unlikely to be effective. However, most clinical trials conducted on anti-inflammatory drugs have not specifically focused on patients with high levels of inflammation, which is why the results have not been very successful.

Miller and Raison also argue in the perspective article that the current method of developing psychiatric drugs can be very costly. Every year, over 20 percent of Americans receive a diagnosis related to mental health and creating a new drug to treat these disorders costs around 1 to 2 billion dollars on average. However, many drugs are dismissed as ineffective because they may work for a smaller group of people who have a specific abnormality that the drug targets but don't work for everyone in the larger diagnostic group being studied.

“Psychiatry runs the risks of throwing out good stuff for people with specific biological issues because we insist that the cure needs to work for a disorder writ large,” says Raison.

Miller and Raison propose a new way of approaching psychiatry in the future. They suggest that research should focus on connecting what is learned in the lab with how it can be used to help patients in the clinic. They recommend that doctors move away from using the traditional diagnostic system (based on the Diagnostic and Statistical Manual - DSM) and instead use more specific diagnoses based on each patient's unique condition. Finally, they suggest that studies should focus on treating mechanisms that may affect multiple diagnoses rather than just one.

The researchers recognize there may be resistance to their recommendations, especially from the pharmaceutical industry and insurance billing systems that currently rely on the DSM diagnoses. However, if they focus on identifying more specific causes of symptoms that operate across different mental health disorders, while this may reduce market share for a single disorder like depression, it may also increase market share by targeting mechanisms that are transdiagnostic and therefore relevant to multiple psychiatric disorders. 

“Lives can be meaningfully transformed. Real progress can be made, but only when we identify and test specific biological mechanisms known to affect symptoms – and then develop and appropriately test drugs that treat those symptoms – regardless of the diagnosis in which those symptoms occur,” Miller says.

Miller is the William P. Timmie Professor of Psychiatry and Behavioral Sciences in the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine. Miller also is the Director of the Behavioral Immunology Program of Emory University.

Raison is the Mary Sue and Mike Shannon Distinguished Chair for Health Minds, Children and Families in the School of Human Ecology and a Professor of Psychiatry in the School of Medicine and Public Health at the University of Wisconsin – Madison.

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