ATAI’s Chief Scientific Officer addresses the future of psychiatric drug development at ISAD19

(originally published on ATAI.life on November 23, 2019)

Last week, Srinivas Rao, Chief Scientific Officer of ATAI Life Sciences, spoke at the 10th Conference of the International Society for Affective Disorders (ISAD19), an important gathering of the European affective disorders expert community. This year’s programme addressed fundamental, clinical and translational issues in affective disorders, with experts from around the world travelling to London to share the latest scientific research developments.

Speaking to an audience of leading experts and academics in the field, Dr. Rao began by outlining the unique approach of ATAI’s biotech platform — which currently includes drugs with a diversity of pharmacology for the treatment of depression, anxiety and addiction — and describing how ATAI is bridging psychiatric drug development’s “Valley of Death”.

Psychiatric Drug Development’s “Valley of Death”

This area of insufficient funding and development arose for numerous reasons. Firstly, a reductionist approach (therapeutics with single targets) to mental healthcare poses intrinsic challenges as mental illnesses are complex and multifactorial. Secondly, there are significant translation issues in moving from animal to human models, and drugs that have shown efficacy in the former often fail to do so in the latter, discouraging investment from big pharma. By contrast, ATAI cultivates early stage polypharmacological drugs that have been de-risked (e.g. psilocybin, which boasts a long history of positive anecdotal evidence) and impact key mental health biomarkers.

Dr. Rao then went on to outline the underlying biology of depression, noting the functional brain changes that occur in depressed individuals. These include:

• Elevated activation of the ventral limbic affective network, leading to negative mood and anhedonia
• Decreased activation in frontal-striatal reward network, resulting in losses in motivation and interest in daily life
• Increased default mode network activity, which appears to be associated with rumination
• Diminished activation of dorsal cognitive control, thought to result in cognitive deficits, particularly in executive functioning and emotional regulation

Dr. Rao emphasized that these functional changes are associated with structural changes as well. Activation of the brain’s stress pathways leads to decreases in brain derived neurotrophic factor, in turn leading to structural atrophy, both as a result of cell loss (particularly in the hippocampus) and diminished neuropil density.

“Although the ATAI platform offers a diversity of pharmacology, there’s also an underlying link to how we think about what’s promising,” said Dr. Rao. “Any effective therapeutic will have to address not just individual targets, but the broader functional and structural changes associated with psychopathology.”

To this end, ATAI’s portfolio includes psilocybin and arketamine for treatment resistant depression, deuterated etifoxine for anxiety, and — most recently — EntheogeniX, a computational biophysics and artificial intelligence biotech working to design the next generation of psychedelics-inspired mental health drugs. Dr. Rao described the mechanisms and science underlying each with a focus on describing common mechanisms around neuroplasticity:

• Psilocybin is converted to psilocin by the liver, which then acts as a partial agonist for some types of serotonin receptors, particularly the type 2A receptor. Activation of the latter leads to profound mood and perceptual changes, but also appears to directly increase BDNF levels, thus increasing neuroplasticity. The combination of perceptual changes in the context of profoundly increased neuroplasticity may underlie the rapid and durable antidepressant effects seen with psilocybin.
• Ketamine’s stereoisomers bind to the NMDA receptor, although with different affinities. Esketamine has nearly 2–3 times greater affinity for the NMDA receptor than arketamine. However, while NMDA antagonist activity is thought to be important for ketamine’s antidepressant activity, arketamine appears to be more potent of an antidepressant than esketamine in animal models, suggesting other mechanisms may also play a role.
• Etifoxine appears to produce its anxiolytic effects through modulation of the mitochondrial translocator protein (TSPO), leading to increases in levels of endogenous neurosteroids, including allopregnanolone. Reduced levels of such compounds have been shown to occur in subsets of depression and anxiety, and levels are normalized in patients showing response to different forms of antidepressant therapies.
• EntheogeniX will initially focus on creating and developing next generation psychedelic and non-psychedelic rapid-acting agents, using an artificial intelligence-based platform to design and synthesize novel compounds from psychoactive seed molecules like psilocybin.

Dr. Rao concluded by noting that the stage has been set for significant changes in the way we develop mental health solutions: Regulatory momentum for psychedelic medicine in the United States has grown at the federal level; advances in neuroscience have transformed our understanding of the neural correlates of both mental illness and wellbeing; technology and artificial intelligence can streamline drug development to an unprecedented extent; and diminished stigma coupled with increased awareness of the current system’s failings have stoked public interest in alternatives.

“While there’s certainly work left to be done, the writing is on the wall,” said Dr. Rao in his closing statement. “We need a comprehensive response to the ever-growing mental health crisis, and a platform approach that combines psychedelics, non-psychedelics, and technology is the most promising route to deliver solutions to the millions of people who need it most.”

Other speakers at the event included James Rucker and Aster Daniel of King’s College London, as well as Robin Carhart-Harris and Taylor Lyons of Imperial College London, among others.

Learn more about ISAD19 here.

Srinivas Rao is the Chief Scientific Officer at ATAI Life Sciences AG. Dr. has over 19 years of professional experience in the pharmaceutical and biotechnology industries. Prior to ATAI, Dr. Rao has held the titles of Chief Scientific, Medical, or Executive Officer at companies ranging from venture backed startups to vertically-integrated, publicly traded pharmaceutical companies. Dr. Rao completed an internship in Internal Medicine at Yale-New Haven Hospital. He received his Ph.D. in neurobiology from Yale Graduate School and his M.D. from Yale School of Medicine. He holds both a Bachelor of Science and Master of Science degree in Electrical Engineering from Yale College and Yale Graduate School, respectively.