Burning down the house: reinventing drug discovery in psychiatry for the development of targeted therapies

Abstract

Despite advances in neuroscience, limited progress has been made in developing new and better medications for psychiatric disorders. Available treatments in psychiatry rely on a few classes of drugs that have a broad spectrum of activity across disorders with limited understanding of mechanism of action. While the added value of more targeted therapies is apparent, a dearth of pathophysiologic mechanisms exists to support targeted treatments, and where mechanisms have been identified and drugs developed, results have been disappointing. Based on serendipity and early successes that led to the current drug armamentarium, a haunting legacy endures that new drugs should align with outdated and overinclusive diagnostic categories, consistent with the idea that "one size fits all". This legacy has fostered clinical trial designs focused on heterogenous populations of patients with a single diagnosis and non-specific outcome variables. Disturbingly, this approach likely contributed to missed opportunities for drugs targeting the hypothalamic-pituitary-adrenal axis and now inflammation. Indeed, cause-and-effect data support the role of inflammatory processes in neurotransmitter alterations that disrupt specific neurocircuits and related behaviors. This pathway to pathology occurs across disorders and warrants clinical trial designs that enrich for patients with increased inflammation and use primary outcome variables associated with specific effects of inflammation on brain and behavior. Nevertheless, such trial designs have not been routinely employed, and results of anti-inflammatory treatments have been underwhelming. Thus, to accelerate development of targeted therapeutics including in the area of inflammation, regulatory agencies and the pharmaceutical industry must embrace treatments and trials focused on pathophysiologic pathways that impact specific symptom domains in subsets of patients, agnostic to diagnosis. Moreover, closer collaboration among basic and clinical investigators is needed to apply neuroscience knowledge to reveal disease mechanisms that drive psychiatric symptoms. Together, these efforts will support targeted treatments, ultimately leading to new and better therapeutics in psychiatry.

Fig. 1. Representative targets for treatment, verification of target engagement and primary outcomes in inflammation-induced behavioral change.

Stimulation of immune cells by microbial or danger-associated molecular patterns activate nuclear factor kappa B and inflammasome signaling pathways that drive the inflammatory response and are associated with metabolic shifts from energy efficient oxidative phosphorylation (OXPHOS) to energy expedient glycolysis. Metabolic reprogramming is also accompanied by increased fatty acid (FA) and amino acid (AA) synthesis that further supports rapid growth and proliferation of relevant immune cells. The peripheral inflammatory response including the release of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6 as well as the acute phase reactant C-reactive protein (CRP) along with immune cell trafficking to the brain can in turn transmit inflammatory signals to the brain, ultimately influencing neurotransmitter metabolism, brain circuitry and behavior. Neurotransmitter systems implicated in the effects of inflammation on the brain include dopamine and glutamate. Primary neurocircuits that are engaged include those involving the basal ganglia and its connectivity to the ventromedial prefrontal cortex (vmPFC) and subgenual anterior cingulate cortex (sgACC) as well as the supplementary motor area (SMA), leading to behavioral changes including deficits in motivation and psychomotor activity. Brain regions including the insula, dorsal ACC (dACC), hippocampus and amygdala are also affected with resultant increased threat sensitivity, increased sensitivity to loss and ultimately hypervigilance and anxiety.