Despite recent successes in the development of new therapeutics for psychiatric disorders, many questions remain unanswered, said Steven Paul. He suggested that a more sophisticated knowledge of chemical neurotransmission and synaptic biology or an increased understanding of etiology and pathophysiology may lead to the identification of new and better drug targets. This increased understanding may also yield predictive biomarkers that will allow the stratification of patients for more precise treatments. Farchione noted that several research programs, including the Accelerating Medicines Partnership for Schizophrenia (AMP-Schizophrenia)1 and the Foundation for the National Institutes of Health (FNIH) Autism Biomarkers Consortium for Clinical Trials2 (ABC-CT), are working to identify biomarkers and more accurately define the pathophysiology of disorders. She expressed optimism about the future of psychiatric treatments, not only because of the identification of new targets, drugs, and treatment paradigms, but also because new companies are entering this space.
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1 To learn more about AMP Schizophrenia, see https://www.nih.gov/research-training/accelerating-medicines-partnership-amp/schizophrenia (accessed August 7, 2021).
2 To learn more about the FNIH Autism Biomarkers Consortium for Clinical Trials, see https://fnih.org/our-programs/biomarkers-consortium/autism-biomarkers (accessed August 7, 2021).
Paul agreed that new clinical paradigms, such as small sample size proof-of-principle trials, are needed to test novel compounds as antidepressants and antipsychotics. Venkatesha Murthy noted that high placebo responses in clinical studies for mood disorders, schizophrenia, and other psychotic disorders had limited the ability to translate innovative mechanisms into promising treatments. He suggested that shared placebo data and/or comparator trials against the standard of care rather than a placebo may help mitigate this problem.
NOVEL APPROACHES NEEDED TO ADDRESS UNANSWERED QUESTIONS
In certain areas of medicine, unanticipated approaches have proven to be instrumental in changing the field, and these types of “black swan” approaches may be on the horizon in psychiatry, said Paul. He suggested that such strategies may involve boosting resiliency to pathogenic processes as well as the use of optogenetics and chemogenetics, invasive and noninvasive neuromodulation, and combinations of drugs and devices. Black swan approaches require an entirely different way of thinking, he said. For example, he posited that psychiatric disorders may represent dysrhythmias of brain neurocircuits and may require novel treatment approaches similar to the way cardiac arrhythmias are treated with multiple drugs, procedures, and devices.
Taking a Systems Perspective
One poorly understood aspect of psychiatric disorders is treatment refractoriness, said Samantha Meltzer-Brody, who spoke about the clinical effects of brexanolone in PPD patients in Chapter 4. In the case of PPD, for example, she said, it is not uncommon for patients to report that they are suffering from this condition even many years after the birth of their child. Brexanolone can be given for up to 1 year postpartum, she said, but there has not been sufficient research to know how to treat these women appropriately with precise and targeted therapies.
Meltzer-Brody suggested that a systems perspective is needed to design polytherapeutic and precision medicine approaches. In precision psychiatry, treatments are refined based on the underlying pathophysiology and the molecular genetic profile of an individual patient. She noted that the results of a very large genetic study are coming out soon. These may provide biomarkers that can help guide treatment.
Magali Haas, chair, chief executive officer, and president of Cohen Veterans Bioscience, also advocated for a systems perspective. In stark contrast to other fields where the classification of diseases is defined by dis-
ease mechanism, neuropsychiatry continues to diagnose disorders based on emergent behavioral outcomes, she said. She argued that the field needs to come together as a community to craft an integrated view of the evidence. Using computational methods to simulate what is known experimentally across different pathways, circuits, and systems could enable the creation of in silico models to predict complex biological effects and test those assumptions, thus informing and improving understanding of disease mechanisms, said Haas. The challenge, however, is that large, deep, and rich phenotypic datasets with biomarker data collected longitudinally across populations and mapped to a common data model are currently unavailable. A systems perspective such as the one Haas envisions could enable the identification of novel molecular targets, then use that information to inform rational approaches to polytherapies that could integrate drug treatments with device and digital solutions.
Multidisciplinary approaches to therapeutic development for mental health conditions that go beyond a sole focus on neurons may also fuel progress, said Stuart Hoffman, senior health science officer for traumatic brain injury (TBI) for the Office of Research and Development at the Department of Veterans Affairs. He noted that TBI often leaves people with neurobehavioral conditions such as depression, anxiety, PTSD, and impulsivity. Given that TBI is also often associated with both acute and chronic inflammation, that neurons themselves express receptors for cytokines and other inflammatory mediators, and that lymphocytes have neurotransmitter receptors, Hoffman suggested that the mechanisms underlying the effects of some of the therapeutics discussed at this workshop may involve non-neuronal networks.
Cognitive Training to Improve Function in Schizophrenia
Brandon Staglin, president of One Mind, spoke about his experience living with schizophrenia, in particular how a turning point in his recovery came about in 1998 when he took part in a clinical trial of cognitive training led by Sophia Vinogradov at the University of California, San Francisco. The trial used computer-based exercises designed to strengthen specific neural pathways in the brain and improve cognition and function. Staglin believes this approach helped not only by inducing neuroplasticity in his brain, but also because the training gave him a sense of purpose. Vinogradov and others went on to show that auditory training improves auditory cognition as well as executive function, working memory, and behavioral organization by strengthening specific circuits in the prefrontal cortex, said Staglin. By addressing the primary symptoms of schizophrenia that contribute to disorganized thinking, Staglin said the approach improved his occupational functioning and ability to work.
A second turning point for Staglin came when he began taking aripiprazole, a partial D2 receptor agonist, which he believes also improved his cognition and motivation. He suggested that digital, pharmaceutical, and psychosocial treatments may work synergistically to help patients in a broad and deep way, helping them renew their sense of purpose and live fulfilling lives.
FINAL THOUGHTS ON THE FUTURE OF THERAPY FOR PSYCHIATRIC DISORDERS
For decades there was no light at the end of the tunnel in terms of new drugs for schizophrenia and depression, said Bryan Roth. Data presented at this workshop, however, suggest that “we have almost an embarrassment of riches,” he said. These include xanomeline and NV5138, two new drugs that appear to lack the metabolic and motoric side effects of all known antipsychotic drugs, as well as several new antidepressants, including brexanolone, with robust and sustained effects.
Rupert McShane, however, noted that the history of psychiatry is littered with potent interventions that have been overused, leading to backlash and stigma. Careful stewardship of these new valuable medicines will be necessary to avoid this fate again, he said. Specifically, he worried that the slow acceptance of ketamine as a treatment tool might lead to a societal response that is excessively restrictive regarding its therapeutic use. This may exacerbate poor access, increase costs, drive up instances of self-treatment, and foster stigma. Alternatively, he said, the vision that Paul Appelbaum espoused may be realized, where trials continue with fewer restrictions, broader inclusion criteria so that problems are identified early, and longer term follow-up. To achieve this, he said, will require collaboration with patients in the collection of large datasets that enable establishing outcomes and safety.
Greg Simon, an investigator at Kaiser Permanente Washington Health Research Institute and psychiatrist in Kaiser Permanente’s Behavioral Health Service, argued that the push in psychiatry for greater precision and more refined therapeutic targets has been stymied by increasing diffusion across the taxonomies of disorders and therapeutics. Comorbidity has become the norm, he said, with people often receiving multiple diagnoses across the domains of anxiety, mood, and psychotic disorders, while at the same time polypharmacy is becoming more common. Reduced specificity across diagnostic categories and in the selection of pharmacological therapies, he said, has resulted in treatments with mediocre effectiveness across multiple categories. Moreover, he suggested that these unclear taxonomies and non-specific outcome measures may hinder the discovery of better therapeutics. To emerge from this “morass,” he suggested following the path taken in the cancer space, where new targets and new therapeutics
remade the taxonomy, which led to the discovery of more new targets and new therapeutics in a self-reinforcing positive cycle.
Simon acknowledged, however, that more complex scenarios are likely to pose unexpected challenges. Using the analogy of a door with multiple locks, Simon suggested that each lock may need to be engaged by a different key, with the relative importance of each key varying from door to door. Even more complexity could arise if efficacy requires each key to engage its lock in a particular order, he said.
Meeting what she called the pandemic’s “mental health tsunami” has been a challenge, said Meltzer-Brody, but it is also an opportunity for the field to come together with a singularity of purpose to do the important work necessary to address the huge rates of anxiety, depression, PTSD, and other mental health consequences of the pandemic.
