Eric A. Storch, PhD

“Brain health conditions are a key contributor to the global burden of disease and disability. The devastating impact of these conditions is even more apparent as the world faces global challenges such as the COVID-19 pandemic, climate change, societal inequity, and more. To make progress, we need a fundamental shift in our approach. Convergence Brain Health deftly makes the case that a convergence approach is urgently needed to tackle the global brain health crisis and provides a roadmap for change.”

— Victor Dzau MD, President, National Academy of Medicine

Even before the COVID-19 pandemic, the world was in the midst of an escalating global brain health crisis with severe physical, social, and economic ramifications. According to a recent World Health Organization report, around 450 million individuals were suffering from mental health conditions, marking mental health disorders among the leading causes of ill-health and disability worldwide.

 The Organisation for Economic Co-operation and Development (OECD) estimates that the consequences of mental ill health cost up to 

Due to social and physical distancing, unemployment and underemployment, stress and other factors, there have been significant increases in issues such as depression, anxiety, social isolation, substance abuse, loneliness, and cognitive decline in older adults.

 In addition, as observed after the SARS pandemic, it is expected that COVID-19 survivors may endure long term cognitive and psychiatric consequences, including suicide, posttraumatic stress disorders, and depression.

 Furthermore, brain health is a prototypical 

 in that it is extremely complex and textured by innumerable variables from biology, sociology, genetics, psychology, and the natural environment to economics and beyond.

 Compounding these issues are challenges at all levels of innovation around brain health, listed in 

Table 1. Challenges and Opportunities for the Brain Health Field

Progress in the 21st century will be molded by our collective response to the global brain health crisis.

 Fortunately, beacons of hope are beginning to shine. Stigma has been reduced in high-income country settings, allowing individuals to overcome the barriers to seeking care.

 The COVID-19 pandemic has—in a positive sense—lowered the perceived and actual barriers to technology adoption, ushering in a new era of technology-driven brain health care. Some governments are beginning to increase spending on brain health, and venture capital funding for brain health start-ups has never been more in vogue. PitchBook data shows that 146 deals generated nearly $1.6 billion in venture capital investments as of December 10th, 2020. A decade ago, there were only 3 deals, worth $6.6 million, whereas last year saw a total of 

However, these advances on their own cannot solve the myriad global challenges posed by the brain health emergency. A paradigm shift is needed to address the unprecedented complexities associated with the current global brain health crisis—a crisis now inextricably linked to concurrent interacting crises surrounding discrimination and inequality, mass misinformation, environmental catastrophes, accelerated climate change, entrenched economic models, population displacements and immigrant status, and more.

 Governments, employers, and healthcare systems around the world need to acknowledge the scope of the problem and embrace solutions to empower consumers to take charge of their own brain health and to protect existing levels of health, well-being, and social inclusion.

In response to the evolving issues, convergence science integrates knowledge, tools, and thought strategies from diverse fields to address challenges that exist at the interface of 

 Convergence science not only recognizes the need to respond to apparent societal problems, but also emphasizes approaches which allow us to consider a myriad of the known unknowns and improves the odds of us quickly adapting to newly identified gaps.

 Acknowledging the serendipity of accidentally obtained knowledge permits 

 Taking these approaches when investigating solutions to brain health challenges permits greater flexibility and utility when unforeseen challenges are inevitably met.

Brains are the indispensable drivers of human progress. Why not invest more heavily in them? There are currently 

 allocated to Environment, Sustainability, and Governance investing around the world.

 If only a portion of this amount were invested in brain health, we could produce major improvements for our society.

 note that this present moment is a clarion call for the philanthropic community, which is uniquely positioned to lead an approach in 2 distinct ways. In the short term, the immediate mental health crisis can be mitigated by supporting interventions for the most vulnerable, the development and deployment of rapidly available mental health tools and technologies, and research to drive evidence-based responses to COVID-19-related mental health challenges. Much work is needed to address the long-term mental health impacts caused by the pandemic. There is an ongoing and urgent need for targeted investment in research to better understand and treat mental health conditions, build capacity and diversity within the mental health system, and advocate for social and policy solutions to improve the ecosystem of mental health care.

Given the critical need to nurture healthier, more resilient, and increasingly flexible brains worldwide, we have introduced the concept of Brain Capital—broadly defined as a form of capital which prioritizes brain skills and brain health.

The OECD Neuroscience-inspired Policy Initiative seeks to place Brain Capital at the center of a new narrative to fuel societal resilience in mitigating economic shocks, and to create preparedness should future societies fundamentally transform, for instance through irreversible damage to the environment. The OECD’s New Approaches to Economic Challenges Unit has created the Neuroscience-inspired Policy Initiative. This initiative seeks to reconceptualize and revitalize the economy, laying the groundwork to identify relevant metrics while building a transdisciplinary network of stakeholders. The initiative will rapidly refine and advance the concept of Brain Capital via a series of research projects, economic modelling, seminars, and clear policy analyses and recommendations.

In this context, our Brain Capital Grand Strategy supports the focus of the OECD initiative. The Grand Strategy has 3 main components: considering Brain Capital in all policies, developing a comprehensive investment plan to support Brain Capital, and generating a Brain Capital Index.

Brain health issues should be addressed in the context of improving performance within the fields of innovation and entrepreneurship. Because most 

 are created by firms less than 5 years old,

 creative and innovative entrepreneurs are needed to drive social and economic growth at the regional and national levels. In many ways, together with unprecedented government investment in many countries, entrepreneurs stand as a critical firewall against recession and deprivation. They serve as economic first responders when (exogenous) catastrophic events produce national and global economic shocks. 

In the United States, deaths due to suicide, opioid overdoses, and other addictions and poisonings (deaths of despair) are a barrier to complete economic recovery from COVID-19.

 Approximately 20% of prime-aged males who have dropped out of the labor force are 

 in these deaths, and many of them will not take up jobs even when available due to the severity of their addiction.

A senior economist at The Brookings Institution is leading an initiative to coordinate the many efforts to deal with this crisis. An important role for the task force would be to coordinate with the many burgeoning local level efforts to address addiction and despair, and these local organizations could greatly benefit from ties to a federal-level coordinating agency. Among other things, this agency could serve as an 

 Without addressing the linked issues of mental health and labor market drop-out simultaneously, it will be difficult to solve the tragic mental health crisis or achieve the goal of widely shared economic prosperity.

It is also essential that, given the complexity of the challenges being addressed, freedom to fail is offered liberally. Flat organizational structures, which are agile and empower individuals to make decisions in their specific areas and roles without need to constantly consult with managers at higher levels, are important. However, these decisions should be aligned with the mission and not deviate from the already traced goals and strategy. In 

, we provide examples of organizations and buildings which foster Convergence Brain Health activities.

Table 2. Infusing Convergence Brain Health Practices Into Various Levels of Innovation

Existing models of innovation are not adequate—suffering from siloing and a lack of speed. There are now a number of more contemporary models which may propel the brain health field forward more quickly and effectively. 

For example, The Davos Alzheimer Collaborative (DAC) is a public-private partnership committed to a collective global response against the challenges Alzheimer disease presents to millions of families around the world.

 The DAC aims to raise around USD $700 million for a 6-year plan to accelerate and diversify innovation in Alzheimer disease research. The 3 main components of DAC include a global cohort developed to identify new targets for potential treatments, a global clinical trial support platform to reduce the cost and time to bring new treatments to market, and a healthcare system prepared to get new treatments to patients. The DAC project will enable novel biomarker development, connect global researchers using the data platform provided by the Alzheimer Disease Data Initiative, and keep individuals with the lived experience of Alzheimer disease at the center of its efforts.

The first big data wave occurred over a decade ago, fueled by the reduced cost of -omics techniques (eg, genomics, transcriptomics), increased access to neuroimaging equipment, and the transition to electronic medical records. Insights from this data, however, have not translated into dramatically improved outcomes for patients. Diagnostic clarity is often elusive and treatment selection remains primarily trial-and-error. A second wave of big data proliferation is already underway with the increased implementation of mobile applications and wearable devices.

 Solutions are desperately needed to resolve current bottlenecks in transforming data into insights and action. 

Furthermore, according to economist Klaus Schwab, PhD, we are on the verge of the Fourth Industrial Revolution, which will see a rise in cyber-physical systems that blur “the lines between the physical, digital, and biological spheres.”

 Virtual reality environments, brain-computer interfaces, wearable or implantable devices, and mobile applications will continue to contribute to the current data explosion. Artificial intelligence integrates knowledge from a myriad of disciplines, including computer science, data science, mathematics, engineering, physics, statistics, linguistics, signal processing, ethics, and philosophy. Artificial intelligence is no longer a novelty, but a requisite set of convergence tools for navigating the future.

As psychological disorders are mediated by complex interactions between genetic and environmental factors it will be imperative to dedicate significant effort to understanding the modifiable risk factors emerging from the environment.

 Since the environment includes biological, psychosocial, and ecological components, it is likely to be more complex than the genes, proteins, and metabolites that are currently analyzed by a variety of tools. Therefore, within the framework of convergence brain health it will be necessary to develop highly powerful and complex tools that record, measure, and analyze the myriad environmental factors. This effort will be pursued as it has been with the omics technologies but with a much larger scope, ranging from psychophysiological data collected from millions of individual smartphones to satellite tracking of air pollution in big cities. Important ethical issues, however, will have to be addressed with some urgency.

Operationalizing a convergent clinical framework will require effective direction and utilization of the continuing data explosion.

 The role of digital clinical operating systems is therefore critical for allowing effective patient care, as well as ongoing research. These clinical operating systems house data from clinical encounters, imaging, pathology, personal medical devices, wearables, and finance. Analytics methods include the use of mathematical and algorithmic-based processing of data resources, including subfields of artificial intelligence, such as machine learning, natural language processing, and visual analytics to generate descriptive, predictive, and prescriptive models to analyze and derive insight from data. Machine learning has been utilized in predictive risk assessment, clinical decision support, home health monitoring, finance, and resource allocation.

Convergent approaches often require consideration of many different data types. Data harmonization involves creating a single consistent macro-data source from multiple, potentially disparate micro-datasets. Contributing datasets are structured to remove inconsistencies, creating harmony, such that the final dataset provides a cohesive view of a subject from many different perspectives. Machine learning enables automatization of this process, permitting integration of clinical, behavioral, -omic, imaging, neurosignals, and other datatypes for data mining and predictive modelling. Deep learning in combination with multidimensional biological data (eg, genomics, proteomics) enables examination of the impact of genetic variation or other system disturbances on transcription, translation, signaling, and resultant phenotypic variation. 

Perioperative brain health is an emerging example of the need for a convergence approach in brain health science. The average individual undergoes 9 surgical procedures in his or her lifetime, typically at an older age when the brain is more vulnerable to perioperative insults such as stress, illness, and immobility.

 As such, the perioperative period is a very high-risk period for older adults, and brain health impairments are abundant with considerable negative impacts. For example, the US National Health and Aging Trends Study found clinically significant depressive and anxiety symptoms in 39% and 24% older adults in rehabilitation facilities, respectively, in older adults recently in rehabilitation facilities (vs. 10% and 9% for older adults in the community).

Similarly, a study in the UK of postoperative Intensive Care Unit patients found rates of 40% and 46%, respectively.

 Depression and anxiety are connected to poor postoperative outcomes, including persistent pain, delirium, longer hospital stays, poor functional recovery, lower quality of life, and increased chance of both falls and rehospitalization.

A new field of perioperative mental health is responding to the need to integrate mental and cognitive healthcare with surgical and postsurgical care. The increasing number of older adults undergoing surgery creates high demand for this innovation, so that care can move beyond an emphasis only on surgical success and anesthetic safety, to a convergent brain health view of outcomes, such as improved functional recovery, reduced rehospitalization, and decreased long-term morbidity. These innovations are further driven by bundled care models, which include preoperative optimization, in-hospital care, and postoperative rehabilitation. With the recent genesis of the Center for Perioperative Mental Health, funded by the National Institute of Mental Health (P50MH122351), surgeons, anesthesiologists, nurses, physical and occupational therapists, and surgical patients will work together with psychiatrists in an accelerated laboratory for translating scientific advances to practical clinical care that improves the lives of older adults.

With the emergence of so many digital innovations, care providers are presented with more tools than ever. However, such a crowd of novel options adds complexity and uncertainty. To be clinically useful, such point solutions must first be vetted and then clustered into symphonies shown to play well together to optimize collective benefit for specific conditions. In the dementia field, for example, it is encouraging to see multidomain interventions being deployed.39 In the future, a therapeutic guidance system may make sense, similar to those used to advance precision medicine, such as oncology and neurosurgery.

To develop a workforce that can harness and deploy a convergence brain health framework, increased inclusion and empowerment of women and other traditionally under-represented populations is required. Building institutions that are both inclusive and meritocratic is health promoting in its own right. But more importantly, it is a powerful mechanism for producing the additional talent, fresh perspectives, and new ideas that are needed.

Meanwhile, certain behavioral characteristics among individual innovators should be cultivated. MacRae and Furnham

 articulated 3 dimensions of a high-potential individual suited to convergent teamwork building on Silzer and Church’s model of potential.

 There are 3 core dimensions: foundational, growth, and career dimensions. These dimensions explain how personality traits are foundational to potential because they represent fundamental and stable individual differences. Personality traits, especially conscientiousness and adjustment, contribute to success in nearly any type of work and have, “higher predictive ability of potential in roles that are more complex, challenging, and demanding such as that of the convergence practitioner.”

Career dimensions are the unique and specific skills, expertise, and occupational knowledge required for success in a specific career or role: “Convergence practice requires sublimating one’s own objectives into the vision and the objectives of the team.”

 MacRae and Furnham explain in detail how personality traits fit within a model of convergence practitioner potential and expand on 10 behaviors that are related to career dimensions of potential.

 These behavioral and workplace cultural characteristics allow us to formulate screening criteria for potential new entrants into convergent brain health work, identify those who are high potential convergence practitioners, as well as consider training approaches for those within our existing brain health structures.

Leaders must assume a critical role in optimizing transdisciplinary collaboration and facilitating the emergence of discoveries from these endeavors.

 Gray outlined 3 responsibilities of transdisciplinary leaders: cognitive leadership, structural leadership, and processual leadership:

. Effective cognitive leadership provides a vision that links and motivates transdisciplinary researchers to step beyond their disciplinary lens, relax old assumptions, and search for creative frame-breaking solutions.

. Effective structural leadership adds value by creating bridges and links among unconnected individuals, labs, groups, or departments.

- Processual Leadership: Effective processual leadership encourages trust and turns conflict into constructive interactions.

These leadership approaches should be kept in mind when fostering Convergence Brain Health within an organization. Other 

 of a convergence workplace include a flat organizational structure with minimal discipline silos, a culture of trust and mutual respect, and an open acceptance of the need to respectfully challenge entrenched ways of thinking.

 Teams should be humble in acknowledging that nobody has cracked the many complex problems to date, and likely never will due to unsolvable uncertainty. However, being open to novel and seemingly eccentric ideas may help navigate such problems and identify ways for their best possible management.

Teams in a convergence workplace must embrace the three somehow radical tenets outlined in Jim Dator, PhD’s 

: 1) The future cannot be predicted because the future does not exist; 2) Any useful idea about the future should appear to be ridiculous; and 3) We shape our tools and thereafter our tools shape us.

 An optimal convergence science environment should have a strong guiding vision, will be capable of identifying myriad possible alternative futures, and better guide the organization toward the desired future.

Convergence Brain Health provides direction for transformational change in how teams could work and how organizations need to be built and operated. As we embark on building the new normal of our post-COVID-19 world, Convergence Brain Health will play a key role in this rapidly unfolding change. Indeed, Convergence Brain Health provides an opportunity to grow global Brain Capital and enter a new era of innovation and progress, leading to greater health justice for all people and preparing for the unprecedented brain health challenges of the 21st century.

is cofounder of the PRODEO Institute, adjunct associate professor with IMPACT at Deakin University, instructor in brain health diplomacy at the Global Brain Health Institute, and co-lead of the OECD Neuroscience-inspired Policy Initiative.

is Director of Innovation at a major mental health association and expert in residence at Georgetown University, and the author of Wired This Way.

is an associate with the PRODEO Institute and Thiel Fellow at Stanford University.

is a professor of psychiatry at University of California in Los Angeles (UCLA).

is Distinguished and Emeritus Professor of Psychiatry, University of Pittsburgh, Pittsburgh, PA.

is the global head of Science for Minds at Johnson & Johnson.

is a health policy researcher at the Global Brain Health Institute.

is a social gerontologist at the Global Brain Health Institute.

is a research professor and Director of Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada, Las Vegas.

is a venture partner at Alsop Louie Partners.

is professor and vice chair of Psychiatry & Behavioral Services at Baylor College of Medicine.

is special advisor to the OECD secretary general and head of the OECD New Approaches to Economic Challenges Unit.

is the Wallace & Lucille Renard Professor of Psychiatry and the Director of the Healthy Mind Lab at Washington University School of Medicine in St. Louis, Missouri.

is head of strategic projects and alliances at Delix Therapeutics.

is a professor in the department of Integrative Structural and Computational Biology at Scripps Research Institute.

is Head Stakeholder Liaison Alzheimer disease at Biogen.

is a professor of Law and Health Sciences at the University of Surrey School of Law and adjunct assistant professor of Medicine at the David Geffen School of Medicine at UCLA.

is the founding director of the Center for Brain Health at UT Dallas.

is a T. Boone Pickens Distinguished Scientist at the Center for BrainHealth, a co- director at Global Brain Health Institute, professor emeritus at Trinity College Dublin, and founding director of its Institute of Neuroscience.

is the Leo Pasvolsky Senior Fellow at the Brookings Institution, a College Park Professor at the University of Maryland, and a Senior Scientist at Gallup.

is a postdoctoral researcher, Center for Precision Health School of Biomedical Informatics at the University of Texas Health Science Center at Houston.

is Researcher at the Department of Aquatic Sciences and Assessment; Section for Ecology and Biodiversity at the Sveriges lantbruksuniversitet.

is Assistant Clinical Professor of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine at UCLA and UCLA Olive View Medical Center. 

is a neuroscientist at the Global Brain Health Institute.

MB is supported by a NHMRC Senior Principal Research Fellowship (1156072). MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier – all unrelated to this work. HAE is an employee of PRODEO LLC. ES is an employee of PRODEO LLC. ASC is an official employee of Biogen Int and the VP of Euresearch. Her contribution to this work is based on her personal opinion and might not reflect the one of the organizations with whom she is affiliated. AI has received Grant/Research Support from ANID/FONDECYT Regular (1210195); FONCYT-PICT 2017-1820; ANID/FONDAP/15150012; Alzheimer’s Association GBHI ALZ UK-20-639295; Sistema General de Regalías [BPIN2018000100059] Universidad del Valle [CI 5316], and the Multi-Partner Consortium to Expand Dementia Research in Latin America [ReDLat, supported by National Institutes of Health, National Institutes of Aging (R01 AG057234), Alzheimer’s Association (SG-20-725707), Rainwater Charitable Foundation (Tau Consortium), and Global Brain Health Institute)]. EJL has received support from the NIH, Patient-Centered Outcomes Research Institute, Taylor Family Institute for Innovative Psychiatric Disorders, and Center for Brain Research in Mood Disorders at Washington University.

1. Eyre HA, Berk M, Lavretsky H, Reynolds III C, eds. 

Convergence Mental Health: A Transdisciplinary Approach to Innovation.

2. World Health Organization. The world health report 2001 - mental health: new understanding, new hope. 2001.

3. Organization for Economic Cooperation and Development. Health at a glance: Europe. Accessed May 6, 2021. 

https://www.oecd-ilibrary.org/social-issues-migration-health/health-at-a-glance-europe-2020_82129230-en

4. Holmes EA, O’Connor RC, Perry VH, et al. Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science. 

5. Blazer D. Social isolation and loneliness in older adults-A mental health/public health challenge. 

6. Vahia IV. COVID-19, aging, and mental health: Lessons from the first six months. 

7. Orben A, Tomova L, Blakemore SJ. The effects of social deprivation on adolescent development and mental health. 

8. Steenblock C, Todorov V, Kanczkowski W, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the neuroendocrine stress axis. 

9. Milner A, King TL, LaMontagne AD, et al. Underemployment and its impacts on mental health among those with disabilities: evidence from the HILDA cohort. 

10. Koralnik IJ, Tyler KL. COVID-19: a global threat to the nervous system. 

11. Varatharaj A, Thomas N, Ellul MA, et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

12. Mak IW, Chu CM, Pan PC, et al. Long-term psychiatric morbidities among SARS survivors. 

13. Taquet M, Geddes JR, Husain M, et al. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records

14. Stony Brook University. What’s a wicked problem

https://www.stonybrook.edu/commcms/wicked-problem/about/What-is-a-wicked-problem

Articles

How can we face the current pandemic while addressing the brain health crisis?  

Boosting Brain Health After COVID-19: A Convergence Solution 

A Case Built on Current Research Findings

Ketamine has caused quite a stir in psychiatric practice. Sub-anesthetic administrations of ketamine have been shown to markedly improve symptoms of depression and anxiety.

 While the growing off-label use of ketamine speaks to the need for novel approaches to psychiatric care and treatment-resistant illness, it also presents an ethical dilemma, wherein widespread adoption has once again leaped ahead of scientific understanding.

The current literature suggests that therapeutic effects of ketamine involve modulation of glutamate neurotransmission, Î±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor potentiation, downstream influences on neurotrophic signaling cascades and neuroplasticity, and functional changes in assorted neural networks. Additional work is necessary to clarify the importance and reliability of these biological findings.

Another arc to the ketamine story dates back to a decades-old era of psychedelic research and search for medications with transformative power. Indeed, although primarily conceptualized today as a dissociative anesthetic, ketamine has also been classified more broadly as a hallucinogen. Hallucinogens function by various pharmacological mechanisms of action but exhibit similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes.

Current biological theories involving ketamine’s antidepressant effect may be inseparable from these non-ordinary experiences of consciousness, but we can only know the answers to questions we ask. Here we examine findings from contemporary research that hint at the unexplored hallucinogenic potential of ketamine and considerations for future investigation.

There has been a resurgence of interest in hallucinogenic psychedelics (eg, psilocybin, lysergic acid diethylamide (LSD), mescaline, N,N-Dimethyltryptamine (DMT)) and entactogens (eg, 3, 4-methylenedioxymethamphetamine [MDMA]) in psychiatric research, which are hypothesized to achieve clinical benefit due to, in part, experiences of altered consciousness and fundamental shifts in mental frameworks.

These drugs have been associated with cognitive states of enduring personal importance and have been compared with mystical experiences that might emerge over the ordinary course of life and carry sacred or spiritual meaning. Furthermore, these experiences may powerfully influence existential concepts of self, including moral values, self-identity, and purpose. There is converging evidence that these psychedelic effects are mediated in part by activity at 5HT-2A receptors. Ketamine may induce alterations in consciousness and personal frameworks similar to those achieved by serotonergic psychedelics while also sharing a common glutamatergic pathway of drug effect.

 However, there has been little investigation into how such changes might mediate the therapeutic potential of ketamine.

Preliminary data suggest that ketamine produces meaningful, transformative experiences that may help patients accept healthier values, behaviors, and beliefs related to abstinence from drugs and alcohol.

 Other evidence suggests that dose-related mystical-type experiences mediate the effects of ketamine on motivation to quit in cocaine-dependent research volunteers.

 Few recent studies have examined whether ketamine’s hallucinogenic properties are implicated in antidepressant effects; however, psychiatric vulnerabilities to depression plausibly involve an existential dimension. This dimension includes depressive symptoms of hopelessness, guilt, and suicidality, which appear to be ketamine-sensitive.

Given the paucity of modern literature exploring the psychedelic and mystical properties of ketamine in depression, more widespread data on psychotomimetic and dissociative effects of ketamine provide some initial groundwork. Berman and collegeagues

 and Zarate and colleagues10 suggested that the antidepressant effects of ketamine (0.5 mg/kg over 40 min) were disconnected from ketamine-induced psychotomimetic symptoms. The antidepressant effects, measured by the Hamilton Depression Rating Scale (HDRS), were significant even after positive symptoms on the Brief Psychiatric Rating Scale (BPRS) returned to baseline. However, it was also noted that initial changes in BPRS positive symptom scales from baseline trended to predict a greater decrease in HDRS scores within a day of treatment with ketamine.

A small study further demonstrated a substantial relationship between psychotomimetic effects 30 minutes after ketamine administration (0.54mg/kg over 30 min) as measured by BPRS and antidepressant effects in the following week.

 A larger study involving 108 patients found that dissociation measured by the Clinician Administered Dissociative States Scale (CADDS) at 40 minutes was associated with HDRS score improvement at 230 minutes and 7 days after infusion.

 Although no relationship between initial BPRS positive subscale scores and antidepressant effect was found, a correlation between CADSS and BPRS scores was found at 40 minutes postinfusion.

In a small study by Valentine and colleagues,

 the proposed correlation between ketamine-induced dissociation and antidepressant efficacy was not observed. However, a larger analysis found that greater intra-infusion dissociation as measured by CADDS was one of the strongest predictors of extended antidepressant response.14 Both of these studies utilized a single 0.5 mg/kg ketamine infusion delivered over 40 minutes.

Further investigation is needed, but there is an emerging rationale for a connection between the psychotomimetic or dissociative effects of ketamine and its antidepressant efficacy. Perhaps the experience of these effects simply un-blinds patients as to whether they are receiving ketamine or placebo in randomized trials; it may also be that such symptoms are only a “side effect” of ketamine’s mechanism of action. However, it is also worth considering that the psychotomimetic or dissociative effects associated with ketamine treatment are markers or mediators of subjective experiences of potential therapeutic value seen with other hallucinogenic agents.

The recommended doses of ketamine for anesthetic induction are typically 1 to 4.5mg/kg IV and 6.5 to 13 mg/kg IM, with alternate, off-label recommendations for 0.5 to 2 mg/kg IV and 4 to 10 mg/kg IM, primarily in the context of adjuvant drug use. For use in depression, ketamine is most commonly administered at a sub-anesthetic dose of 0.5mg/kg IV across 40 minutes.

Interestingly, in a study of electroconvulsive therapy (ECT) and anesthetic induction with either a near-anesthetic dose of IV ketamine (0.8mg/kg) alone, sub-anesthetic ketamine (0.5mg/kg) plus propofol (0.8mg/kg), or propofol alone (0.8mg/kg), predicted a more rapid antidepressant effect and a higher remission rate than propofol use. The near-anesthetic dose of ketamine was associated with superior antidepressant effects than the mixed, sub-anesthetic dose.

In a study of ketamine alongside psychotherapy for heroin addiction, Krupitsky and colleagues

 compared the effects of 2 doses of ketamine (0.2 and 2.0 mg/kg IM) and found that only the higher dose was associated with a “full psychedelic experience” as measured by the Hallucinogen Rating Scale (HRS). The lower dose was considered a “sub-psychedelic” active placebo, but was nonetheless associated with some positive drug effects: patients were still affected by their experiences and considered them useful and therapeutic. The high dose group ultimately experienced higher rates of abstinence, greater effect on emotional attitudes related to abstinence, and lower rates of relapse and drug craving than the low dose group. Both doses resulted in post-treatment reductions in measures of depression and anxiety; there were no significant differences between the groups.

 compared the effects of 0.41 mg/kg and 0.71 mg/kg doses of IV ketamine given to cocaine-dependent patients. Dose-dependent mystical-type effects as measured by Hood’s Mysticism Scale (HMS) were seen as well as a relationship between HMS scores and the motivation to quit cocaine 24 hours post-infusion.

A different study involving a lower dose of intramuscular (IM) ketamine did not generate the same mystical-type phenomena.

 Perhaps these results highlight the importance of calibrating dosing and delivery. Clements and colleagues

 demonstrated that ketamine had reduced bioavailability with IM administration compared with IV administration. Taken together, these findings support the idea that positive treatment outcomes for ketamine may be dose-dependent and its psychoactive effects are based on delivery parameters.

One criticism of ketamine has been its short duration of antidepressant effect, with benefits peaking at 24 hours post-infusion and generally subsiding by 72 hours. The most promising approach to this challenge thus far seems to be the strategy of repeated-dose ketamine infusions, which have observed extended time-to-relapse and increased rates of antidepressant response.

If ketamine’s therapeutic effect is indeed mediated by psychoactive experience, it may be that repeated dosing of ketamine improves outcomes by increasing opportunities for personally meaningful events to occur. One caveat is that some studies have shown repeated dosing to be associated with fewer dissociative symptoms over time-at first glance this suggests that the antidepressant value of serial ketamine administration might be independent of hallucinogenic effects.

While this requires further investigation, it is also important to consider other interpretations of that evidence: that acclimation to altered states of consciousness may contribute to recall bias, that experimental protocols that frame dissociative symptoms as a “side effect” or “adverse event” may lead to underreporting if overall patient experiences of ketamine are positive, or even that the benefit of repeated dosing may be less related to cumulative drug effect than other factors, such as repeated interactions with care providers or increased opportunities for reflection and synthesis.

One study of repeated infusions demonstrated that antidepressant response very early in the course of treatment strongly predicted subsequent response; conversely, a lack of rapid response was a poor prognostic indicator for improvement after additional infusions. Whether positive early responses to ketamine are mediated by psychological factors, biological susceptibility, or both: it is necessary to clarify these factors in shaping sustainable strategies for treatment.

A cautious approach also seems imperative given evidence that ketamine demonstrates agonist activity at Î¼-opioid receptors and dopaminergic effects that may confer acute relief of depressive symptoms but also greater risk for positive drug reinforcement and dependence. With further insight into psychological responses mediated by ketamine, it may be that a therapy-based framework for ketamine administration optimizes treatment efficacy and sustainability, while also minimizing unnecessary drug exposure, adverse effects of chronic use, and dependency risk.

In one study, long-term abstinence in persons who were substance dependent was achieved with Ketamine Psychedelic Therapy (KPT), which incorporates 1 or 2 sessions of ketamine-facilitated existential reappraisal into an existential psychotherapy.

 Additional exploration would be needed to determine which therapeutic approaches most beneficially augment ketamine treatment and minimize risks for harm. Nevertheless, a more holistic approach to ketamine as a treatment modality may be better suited to recreate the marked, persistent effects of MDMA in patients with PTSD. For example, in one study sustained symptom reductions were achieved with 12 weeks of psychotherapy but with limited MDMA exposures of only three 8-hour sessions.

Another area that requires further investigation is how a patient’s past history might shape psychoactive responses. These personal and quite variable histories have been explored for some hallucinogenic agents but minimally for ketamine. The expectations and personal experiences of the individual user along with the external environment of use have been identified as critical factors in influencing subjective drug effects-coined “set” and “setting,” respectively-and are now considered well-established elements of human hallucinogen research.

Therapies aimed at the pharmacological production of a transformative experience may depend on factors such as patient personality structure, preparation for treatment, emotional activation before drug intake, treatment context, and perceived quality of the experience. Given the unique psychological risks of hallucinogen administration, it is recommended that clinicians screen for personal or family histories of psychotic or other severe psychiatric disorders prior to treatment. Clinicians are also encouraged to facilitate careful patient preparation for sessions, provide a safe physical environment for treatment administration, and allow for interpersonal support during sessions. These and other insights from hallucinogenic research might valuably inform treatment protocols for ketamine administration.

Ketamine is uniquely poised to make a tremendous impact on psychiatric care, even redefining boundaries for patients with variations in depressive disorders that were once thought to be “treatment resistant.” Our synthesis of this emerging and old literature points to the unexplored hallucinogenic potential of ketamine. By further understanding the desirable psychoactive effects of ketamine, clinicians can build on initial treatment successes and maximize patient successes.

  • Further investigating the relationship between ketamine-induced psychotomimetic and dissociative effects and treatment efficacy

  • Clarifying the connection between these effects and potentially desirable hallucinogenic experiences

  • Exploring the therapeutic value of such elicited experiences

  • Revisiting dosing strategies that account for existential phenomena and looking beyond dissociation as simply being an “adverse event”

  • Incorporating psychotherapy-based frameworks into ongoing investigation

  • Assessing set and setting factors that may shape treatment responses

Some answers and clues are likely to be found in the forgotten works of older psychedelic research. Agents like ketamine can exert their greatest therapeutic effect in the afterglow of profound alterations of consciousness, revealing a propensity for growth and healing that has not been evident to the suffering, depressed patient. Wherever the journey takes us, it is exactly the right time to bring together all the strands-brain and mind, old and new, caution and thrill-in assembling the unfinished story of ketamine.

Dr. Mathai is PGY 1 Psychiatry Resident, Dr. Mathew is Professor of Psychiatry, Dr. Storch is Professor of Psychiatry, and Dr. Kosten is Professor of Psychiatry, Baylor College of Medicine, Houston, TX.

 Feifel D. Breaking sad: unleashing the breakthrough potential of ketamine’s rapid antidepressant effects. 

 Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. 

 Perry EB, Cramer JA, Cho HS, et al. Psychiatric safety of ketamine in psychopharmacology research. 

 Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 

. Sarasota, FL: Multidisciplinary Association for Psychedelic Studies; 2001.

 Krupitsky E, Burakov A, Romanova T, et al. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. 

 Dakwar E, Levin F, Foltin RW, et al. The effects of sub-anesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine dependent research volunteers. 

 Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment-resistant unipolar depression: current evidence. 

 Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.

 Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. 

 Sos P, Kirova M, Novak T, et al. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. 

 Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? 

 Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. 

 Pennybaker SJ, Niciu MJ, Luckenbaugh DA, Zarate CA. Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion. 

 Zhong X, He H, Zhang C, et al. Mood and neuropsychological effects of different doses of ketamine in electroconvulsive therapy for treatment-resistant depression. 

 Lofwall MR, Griffiths RR, Mintzer MZ. Cognitive and subjective acute dose effects of intramuscular ketamine in healthy adults. 

 Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. 

 Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. 

 Mithoefer, M. C. et al. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. 

 Leary T, Litwin GH, Metzner R. Reactions to psilocybin administered in a supportive environment. 

An exploration of findings from contemporary research that hint at the unexplored hallucinogenic potential of ketamine and considerations for future investigation.

Eric A. Storch, PhD

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