Why are there no approved treatments for cognitive impairment in schizophrenia?
Authors: Richard S.E. Keefe
Journal: World Psychiatry (2019)

The paper by Green et al1 details the evidence that cognitive impairment associated with schizophrenia (CIAS) remains a tremendous scourge on the lives of millions of people across the world. It is the aspect of the illness that most accounts for the social isolation and functional disability that plagues most people with schizophrenia for their entire lives. Yet, tragically, there are no pharmacological or behavioral treatments for CIAS approved by any regulatory agencies across the world. Advances in genetics, biology, pharmacology and technology have facilitated the development of targeted treatments across various areas of medicine, especially in oncology, cardiology and immunology. These advances have transformed some illnesses from devastating, life-threatening events to simple annoyances. Why have the tremendous advances in neuroscience, psychopharmacology and genetics not provided patients with CIAS similar relief? The most obvious consideration is the amount of investment that is being made in the development of treatments. The 2018 US National Institutes of Health (NIH) budget for research on schizophrenia was $258 million, but for heart disease it was 10 times as much, and for cancer 25 times as much2. This disparity is even greater in the pharmaceutical industry, where the overall research and development budget, which in 2017 was $71.5 billion3, dwarfs government efforts. There are over 1,000 ongoing clinical trials in cancer for every one in CIAS4 and, contrary to common belief, not because cancer drugs are a safer bet: the latest estimate that a treatment will successfully progress from phase 1 to the US Food and Drug Administration (FDA) approval is 5.1% for cancer indications, very similar to psychiatry at 6.2%5. Since many strategies will fail before a success is reached, a large number of attempts is required to find a treatment that is legitimately safe and effective. Further, serendipity flourishes greatest in the most active arenas. Unfortunately, the pharmaceutical industry has not presented nearly as many opportunities for success in CIAS as it has in other illnesses. Perhaps curing cancer is more personally tangible and may appear on the surface to be more morally compelling to investors than improving cognition in the people living in the darkness on the edges of town, and pharmaceutical companies are highly vulnerable to the whims of impressionistic shareholders. It is likely not a coincidence that the drug company listed on clinicaltrials.gov as having the greatest number of ongoing trials for the treatment of CIAS is privately owned. What may explain why the CIAS trials conducted thus far have not been successful? Are the outcome measures used to assess cognitive and functional change to blame? The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project developed a cognitive test battery, the MATRICS Consensus Cognitive Battery (MCCB), that was accepted as an FDA gold standard and has been used in most of the later phase trials. Several trials using the MCCB as the primary endpoint have been positive6, but the one phase 3 program using the MCCB to test the efficacy of an alpha-7 nicotinic agonist was negative and well-publicized. An FDA gold-standard measure is often one of the key components of a registration trial that drug companies are not able to alter, it is thus a natural scapegoat for a failed or negative trial. However, early notions – based on very small samples – that the MCCB had problematic psychometric characteristics were soundly refuted by a collaborative group pooling data on over 800 patients receiving placebo from 12 separate clinical trials7. Another important consideration for the negative trials to date is that almost all of them have targeted a chronic schizophrenia population with an average age around 40 years old. Has the opportunity to improve cognition passed at that age? Models of brain plasticity suggest that the propagative properties of neurons diminish over time, and it is reasonable that this aging process is accelerated in people with schizophrenia, who are more likely to have comorbid medical conditions, substance use and reduced physical and mental engagement with the environment. Some data have suggested that younger patients may be more responsive to CIAS treatments. The idea of treating CIAS in first episode patients has often been proposed, but completing these trials has been challenging. Several of us have urged for the remediation of cognitive impairment with highly safe treatments prior to the onset of psychosis in vulnerable populations8, 9, but again these trials are challenged by patient recruitment concerns and the length of time required to identify treatment response. Beyond these questions of study design and implementation are darker considerations. Do we need to wait for a greater understanding of how complex human neural systems operate before we can discover pharmacological and behavioral treatments that interact with them favorably? Or perhaps CIAS is so elemental to the genetic manifestation of a diseased brain that we will never be able to alter it once an infant is born? All of these pessimistic perspectives are possible. However, the history of medicine includes a steady stream of examples where scientists and clinicians whose ideas and compassion were too great to listen to the herd mentality of financial investors and fear mongers. Those with the courage and resources to pursue reasonable hypotheses based upon the limited data we have available now will perhaps be viewed by history as resolute prospectors who invested in the reduction of suffering.