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Psychiatry's Past is Failing its Future to Develop Drugs Targeting Inflammation

Co written by Prof. Andrew H. Miller and Dr. Charles L. Raison


Despite substantial research showing that inflammation plays a role in multiple psychiatric disorders, the development of anti-inflammatory drugs to treat psychiatric illnesses is in peril.


Inflammation is a function of the immune system — inflammatory cells are triggered in response to bacteria and germs typically, however research shows that some people may have higher levels of inflammation even in the absense of bacteria and germs. There is evidence of this for some people who have psychiatric disorders.


Results of clinical trials using anti-inflammatory drugs to treat diseases ranging from depression to schizophrenia have routinely disappointed, leading to the conclusion that blocking inflammation to treat psychiatric disease is a dead end. This to the detriment of the vast number of patients who are intolerant or resistant to the conventional drugs (such as antidepressant medications) currently used in psychiatry.


The impending death of anti-inflammatories is only the most recent example of a drug discovery engine in psychiatry that is failing the field. Almost unnoticed, a similar fate befell drugs targeting the hypothalamic-pituitary-adrenal (HPA) axis in the 90s. These drugs also disappointed and ultimately died, a loss totaling many billions of dollars in research and development funds. The sad truth is that the drugs are not at fault; it is the way psychiatry conducts its clinical trials. Clinical trials in psychiatry are based on outdated, overinclusive diagnoses, poorly defined outcomes, and the misguided notion that “one size fits all”.


I am a psychiatrist at Emory University School of Medicine in Atlanta Georgia, and I am passionate about developing new treatments for psychiatric disorders. My research has focused on the role of inflammation in depression. I am writing this article because I want to voice my concerns about missed opportunities in psychiatry to develop therapies that are targeted at specific biological processes like inflammation and thereby support the development of more personalized treatments. I have co-written this piece with Dr. Charles L. Raison, Professor of Psychiatry at the University of Wisconsin Madison.


In a recent paper entitled “Burning Down the House: Reinventing Drug Discovery in Psychiatry for the Development of Targeted Therapies,” Chuck and I highlight ongoing mistakes in psychiatric drug development by comparing mental health treatments with those developed to treat cancer.


Both fields began their path to drug discovery through serendipitous observations of the efficacy of drugs that are effective for many disorders but nominally specific for any one disorder, chemotherapy in oncology and antidepressants, mood stabilizers and antipsychotics in psychiatry. But while advances in oncology mean that cancer is far more treatable than it was several decades ago, in that same period of time, no similar advances have been made in psychiatric pharmacology.


Sadly, patients in psychiatry today are still treated with some combination of the same or similar drugs that have been available for over 50 years, and we still don’t know how they work. Even newly popular treatments such as psychedelics and ketamine, while effective in some patients, have been around for years and work in ways that are even more opaque than conventional medications. Aside from some improvements in safety and side effect profiles, this is not progress.



Psychiatric research and drug development have missed opportunities to embark on a similar course as oncology, being stuck in the past with a misguided commitment to developing non-specific treatments for highly heterogenous (diverse), symptom-based conditions that lack consistent underlying pathological causes. This misguided approach is costly. More than 20% of Americans will experience a psychiatric diagnosis on a yearly basis, and the average cost of developing a new psychiatric drug ranges between 1 and 2 billion dollars. Yet far too many of these drugs are prematurely dismissed as ineffective because they don’t work for everyone in the overly inclusive diagnostic group being studied, even though they may have been effective for a subgroup of patients with an abnormality in the biological system targeted by the drug.


In contrast, oncology has made striking advances as a result of realizing that conventionally recognized types of cancer are not one-size-fits-all entities. Instead of starting with a type of cancer and searching for a treatment, oncology has identified specific mechanisms by which different cancers grow and spread and has developed treatments to identify and target those mechanisms.


This has led to the realization that tumors which appear similar may require very different pharmacological treatments, and tumors that appear different may share underlying biological mechanisms amenable to a similar pharmacological treatment approach.


We contend that pharmacological treatments in psychiatry will only advance when a similar strategy is embraced. Although psychiatry continues to search for one-size-fits-all type treatments for conditions such as depression or schizophrenia, more progress will be made when the diverse biological causes that drive symptom development are identified and addressed with treatments that specifically target these causes.


For us, this mechanism-pathway approach emerged from our work with inflammation. In a 2013 study, we tested a powerful anti-inflammatory agent as a new treatment, based on the assumption that, because inflammation can cause depression, then major depression is wholly a disorder of inflammation. Instead, the findings were more nuanced: For those with increased inflammation, infusions of the anti-inflammatory drug worked significantly better than a placebo. But for those who reported depression symptoms but did not have increased inflammation, the anti-inflammatory treatment was no better than placebo (“dummy”) infusions of salt water. Thus, inflammation can be a mechanism that causes depression in some patients, but not everyone who is depressed has increased inflammation.



So, we began to see that our labels of depression masked a whole variety of different and more specific biological mechanisms. Studies on anti-inflammatory drugs should therefore focus on patients with increased inflammation; otherwise, the drugs will fail. Unfortunately, most studies to date have lacked this focus, and therefore the disappointing results are not surprising.


But there still is hope. In our paper, we offer a radically different approach for the future of psychiatry with specific recommendations including funding translational research that realigns findings from the clinician’s office with findings from the research bench, an openness to identifying patients by specific pathologies rather than traditional diagnoses and an approach to research funding that prioritizes truly transdiagnostic studies.


We acknowledge there will be hesitance for these recommendations — especially from a pharmaceutical industry and insurance billing system built on the existing diagnostic categories used in psychiatry (i.e., those in the Diagnostic and Statistical Manual of Mental Disorders). We also recognize that targeting more specific mechanisms of pathologies may cost market share in some disorders, being limited to subgroups of patients with a given diagnosis. Nevertheless, enhanced specificity means pharmaceutical companies are likely to ultimately gain market share by targeting mechanisms that are transdiagnostic and therefore relevant to multiple psychiatric disorders. Such mechanism-based specificity will also greatly benefit patients with treatments that are ideally suited to their specific disease processes.


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 drugs that treat those symptoms — regardless of the diagnosis in which those symptoms occur.



 


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