Husseini K. Manji, MD

Since the 1980s, shareholder-value ideology (boosting profits above all other considerations) has led to a pattern of corporate behavior with troubling consequences. It has created employment instability, undermined productivity and innovation, exacerbated income inequality, and compromised the environment. The erosion of middle-class jobs has created enormous mental stress and uncertainty. Structural changes in employment help account for this, including the fissuring of the workplace, the end of the norm of a career with one company, and offshoring of employment to low-wage nations (driven by globalization and technological change).

Corporations have implemented these practices purely for financial gain, pursuing strategies to maximize returns to shareholders and high-level executives. This has encouraged an excessive focus on short-term returns and a decline in long-term investment. It has not sufficiently taken into account the human cost of such strategies. As an alternative, there are a number of efforts to advance stakeholder capitalism. Stakeholder capitalism would ensure that the broader interests of workers, local communities, and society are represented on corporate boards. The stakeholder value model thus builds a multi-bottom line approach, which goes beyond shareholder value creation to include a broader array of economic and societal values.

The Economic Burden of Brain Health Disorders

 emotional, behavioral, and cognitive health across the lifespan. In this context, compromised brain health greatly increases the risk of disorders (for example, depression, anxiety, substance misuse, dementias, neurodevelopmental disorders, and neurocognitive disorders).

 In total, brain health disorders cost the global economy more than $3 trillion per year in lost productivity.

In particular, mental health has been a growing concern among workers as the pandemic has worn on. According to data from the Society for Human Resource Management (SHRM), roughly 41% of employees feel burnt out, drained, or exhausted from their work.

 In addition, nearly 1 in 4 employees report frequently feeling down, depressed, or hopeless—yet more than 1 in 3 employees reported having done nothing to cope with these feelings.

 Having a significant proportion of the workforce reporting such symptoms is particularly concerning, as depression is associated with acute changes in cognitive capacity that can persist as residual symptoms after pharmacological treatment.

 These changes in cognitive capacity can have a detrimental impact on problem solving, memory recall, and motivation.

 Given the implications of these effects on workforce productivity and overall well-being, mental health should be among companies most pressing concerns.

Looking beyond mood and psychiatric illness, companies should also consider the implications of dementia and Alzheimer disease. According to a study conducted in Spain, the costs related to loss of labor productivity due to informal caregiving for people with dementia amounted to $5370 per individual per year.

 These informal caregivers experienced partial absenteeism and burdens that disabled them from maximizing productivity. Furthermore, research shows that 23% of individuals who will eventually be diagnosed with Alzheimer disease show accelerated cognitive decline around 5 years before an official diagnosis.

 This accelerated cognitive decline can be clinically referred to as mild cognitive impairment, but it is critical to note that the deterioration in brain health is progressive. Prior to mild cognitive impairment, individuals likely experience a period of undiagnosed mild cognitive decline 6 to 7 years prior, though they may be able to remain in the workforce during this time. 

Notably, issues of mental health and cognitive health are often considered separately, although they are inextricably linked. Brain Capital provides a mechanism to consider these in a more integrated way. 

Brain Capital is a novel form of capital that puts a premium on brain health and brain skills.

 Brain skills are critical in a digitized economy and include self-control, emotional intelligence, creativity, compassion, altruism, systems thinking, collective intelligence, and cognitive flexibility. Brain health must be optimized to support the necessary brain skills to thrive.

We refer to a digitized economy that places a premium on cerebral rather than manual skills as a Brain Economy. Brain Capital is clearly critical in an already digitized economy, especially as automation replaces traditional jobs that relied on manual skill.

 In a Brain Economy, innovation is a tangible and increasingly pivotal measure of employee productivity, and innovation is channeled through employee thoughts, ideas, and creativity.

Innovative Approaches to Promoting Brain Capital in the Workplace

Several approaches can promote Brain Capital in the workplace. These range from multiorganization workplace initiatives (

), to novel accounting frameworks, to social impact investing, to venture capital investing, to novel indices for tracking and measuring issues over time.

Table 1. Examples of multi-organizational workplace initiatives in action

One example is emotional flexibility training for private sector knowledge workers. In 1 pilot study conducted to explore the effects of such a program, emotional flexibility advancement was found to be a highly effective treatment in clinical settings for depression, anxiety, and chronic pain.

 This approach—which had not previously been empirically explored with private sector, high-paced, high-demanding, and highly educated knowledge workers—demonstrated broad improvements in self-efficacy for those in the treatment group versus the control group. These results suggest that emotional flexibility boosts both well-being and performance.

Human capital can be a company’s greatest asset; it can make or break the business strategy and is a key differentiator. A company’s intangible assets, including human capital and culture, are now estimated to comprise on average 52% of a company’s market value.

 To date, given the intangible nature of strong corporate culture, stakeholder leadership, and employee well-being, companies have struggled to quantify the contribution of their human capital assets. But the principles of the Human Capital Accounting Framework, recently published by the World Economic Forum and Willis Towers Watson, could help firms measure Brain Capital effectively.

 A Human Capital Accounting Framework couldenable a company to monitor and assess the return on its investments in its employees in the same way that it measures returns on financial and intellectual capital.

The Global Reporting Initiative (GRI), in partnership with the Robert Wood Johnson Foundation, has developed health metrics that include social impact in current sustainability indexes.

 Encouraged by the added measure of certainty and transparency surrounding their activities, investors large and small would allocate more capital to financing positive initiatives, and entrepreneurs would devise business models whose ambition and growth potential match investor and market demand. Continued refinement of these taxation and accounting practices that prioritize Brain Capital may support improved workplace and societal well-being.

Venture capital companies have recently made record-breaking investments in mental health, with $637 million invested in more than 60 different mental health companies, almost 23 times the investment observed in 2013.

 Lyra Health was just valued at more than $1 billion, making it the first unicorn in mental health.

 The company, which provides mental health benefits for large employers, offers an array of in-person and remote behavioral therapy that helps remove access barriers to high-quality mental health care. The demand for teletherapy services is soaring, particularly as employers look to support workers during the 

. The company has added more than 800,000 new members since the start of the pandemic.

Novel Indices for Tracking and Investing in Brain Capital

 The central components of Brain Capital need to be formalized and developed into an investment plan. Since one cannot manage what one does not measure, developing a Brain Capital Index (BCI) to track the progress of this approach is critical.

Such an index could help track the Brain Capital impacts of companies and governments. The index could also track the value of investments in this area. If such an index were investable—as is the case for mutual funds or exchange-traded fund—it would encourage investment in the entire space by opening it to the passive investor. Index-tracking funds have recently passed the $10 trillion mark of assets under management globally, surpassing assets under active management for the first time. Attracting even a small fraction of global passive investment using a BCI would transform the Brain Economy as a whole. Consequently, creating a well-defined and easily computed index is a key part of investing in a Brain Economy.

The BCI could be associated with a range of potential components. Health-related metrics could include incidence and prevalence metrics, access to care, and relapse rates. In particular, access to mental health care for child and youth populations is of paramount importance, so coverage for families and employees should be prioritized. As of September 9, 2020, the National Council for Behavioral Health stated on its website that the demand for mental healthcare is at an all-time high; however, the ratio of professionals to patients is incredibly low, suggesting it should be tracked. To improve access, more efforts toward training and incentivizing providers need to be made. A BCI could also track purpose at work, as it has been shown to have a range of brain health benefits, including reducing the likelihood of dementia and stroke.

 Created in partnership between Thrive Global, SAP SuccessFactors, Qualtrics, and Fortune, the Thrive XM Index aims to assess and quantify individual experiences to gauge how employee well-being is directly connected to business outcomes. According to the Thrive Global website, the Index will combine employee-reported experience information, HR-reported performance insights, and business performance data, allowing companies to receive a comprehensive view of the way experience metrics (X-data™) and HR metrics (O-data™) can collectively serve as leading indicators for business performance.

Refining the Return on Investment Analysis

An emphasis on returns on investment (ROI) is critical for tracking and investing in Brain Capital. According to a recent report by Deloitte Canada, a pioneering research initiative determined that positive ROI for workplace mental health initiatives are within reach for Canadian businesses.

 Companies with mental health programs in place for 1 year had a median annual ROI of $1.62 for every dollar invested, and the median annual ROI more than doubled for companies with programs in place for 3 or more years, valued at $2.18 for every dollar spent.

 Components of the research included determining and tracking key performance indicators, assessing the effectiveness of interventions with employees, and regularly calculating ROI. Though often overlooked, these elements are essential to demonstrating the financial and nonfinancial benefits of mental health programs. Robust performance measurement enables organizations to “achieve desired program impact, improve adoption rates, and enhance decision-making.”

 Deloitte’s work helps build a framework for determining the ROI of workplace mental health initiatives. However, for optimal, far-reaching impact, the framework must be expanded to include a wider span of issues that Brain Capital encapsulates, such as brain skill issues and aging brain health conditions.

Recommendations for Building Brain Capital at Work

To propel this field forward in the coming years, clear recommendations are required for all stakeholders. These stakeholders include human resource managers, employee benefit managers, social impact investors, and beyond. Recommendations are outlined in 

Table 2. Recommendations for stakeholders

Brain and mind issues must play a central role in measuring the sustainability and societal impact of investment in a workforce. A Brain Capital perspective needs to be integrated into existing frameworks, programs, and investment models to prevent or mitigate the profound effects and economic toll brain health disorders have on the workplace and society.

is a pre-medical human biology student at Stanford University.

is an MD candidate at David Geffen School of Medicine at UCLA.

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

is head of the OECD New Approaches to Economic Challenges Unit and Senior Advisor to the OECD Secretary General.

is a neuroscientist and senior director at the Milken Institute Center for Strategic Philanthropy.

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 global head of Science for Minds at Johnson & Johnson.

is president of the Euro-Mediterranean Economists Association.

is a co-founder of the PRODEO Institute, adjunct associate professor with the Institute for Mental and Physical Health and Clinical Trials (IMPACT) at Deakin University, and an instructor with the Global Brain Health Institute.

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Brain health INnovation diplomacy: a model binding diverse disciplines to manage the promise and perils of technological innovation

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Articles

Brain health disorders cost the global economy more than $3 trillion per year in lost productivity. What can we do about it?

Smart Growth: the Case for Measuring Brain Capital

Although several antimanic agents are available to treat individuals with bipolar disorder (BD), many patients have a less than satisfactory response or experience adverse effects.

 With the exception of lithium, all of the current antimanic agents are either anticonvulsant or antipsychotic drugs. It is remarkable that no drug has been developed specifically for BD, especially because this illness was conceptualized more than a century ago. The lack of available therapeutics with a novel mechanism of action results in large part from our modest understanding of the relevant molecular and cellular substrates of this complex emotional, behavioral, and activity disorder.

Different strategies have been proposed for the development of better compounds for patients with psychiatric disorders. It has been argued that the ultimate goal of drug development should be to reduce the prevalence of psychiatric disorders through cure therapeutics and strategic preventive measures. Insel and Scolnick

 have suggested that drug development for mental disorders over the past 50 years has been significantly stalled compared with other areas of medicine and that drastically different approaches are in order.

It is our firm opinion that we are entering an era in which we will be able to develop markedly improved treatments for severe mood disorders. A growing body of data suggests that mood disorders arise from abnormalities in synaptic and neuronal plasticity cascades, leading to aberrant information processing in critical synapses and circuits.

Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters. In this article, we discuss current approaches to drug development in mood disorders at the Mood and Anxiety Disorders Program of the Intramural Research Program at the National Institute of Mental Health and provide an example of one such approach.




At the Mood and Anxiety Disorders Program, the model of drug development that we are pursuing is based on 2 highly integrated preclinical-clinical pathways:

1. 

Understanding the long-term, therapeutically relevant targets of the medications currently in use.

 For example, in the case of SSRIs, instead of studying the initial increases in intrasynaptic serotonin, the goal would be to study the long-term changes in synaptic and neural plasticity that likely underlie their delayed therapeutic effects. Such knowledge can then be used to design new drugs directed at the target(s).

2. 

Understanding the pathophysiology of the illness and using that knowledge to design therapeutics to attenuate or prevent pathological processes.

 These may be envisioned as true disease-modifying strategies rather than simply as symptom control.

Because of space limitations, this article focuses on the first approach. For there to be substantial progress in generating novel compounds, susceptibility genes involved in illness need to be identified. However, this alone is insufficient to provide the knowledge necessary to expand our current therapeutic armamentarium. Fundamentally, we need information about the intracellular signaling cascades that are disrupted within the complex set of interacting neuronal networks and the specific changes that occur within these systems as a result of the effective treatments administered in a therapeutically relevant paradigm and in a time sensitive manner.

For example, much could be learned by gathering information at the precise point when there is a change in mood episode poles (switch from depression to mania) in BD or when an effective treatment intervention takes place. The advent of methodologies such as subtractive hybridization, messenger RNA differential display, and microarrays has illustrated the importance of hypothesis-generating by mimicking the conditions of illness or examining when effective treatments act (eg, in an animal model of mania and lithium treatment); this is particularly true when dealing with disorders whose pathophysiology remains elusive.



Thus, it may be very useful to develop drugs that are based on pertinent intracellular signaling molecular targets of current mood stabilizers; these later could be adapted to optimize efficacy, specificity, and/or adverse-effect profiles. In addition, all current medications have a considerable onset lag before their full therapeutic properties are activated (implying changes in gene expression, protein function, and-more generally-plasticity). Thus, identification of targets after prolonged treatments in cell- and animal-based models may be a useful approach in the development of novel therapeutics.

This approach may increase the likelihood of identifying relevant downstream targets with potentially more potent and rapid actions. Ultimately, novel agents identified in this manner also may benefit patients who are treatment-resistant, because alterations in the intracellular pathways (ie, defects) could simply be bypassed to the end-stage molecular targets that are ultimately relevant to the therapeutic effects. The use of this strategy could provide clues on how to bypass the defect in a number of ways. There is no shortage of targets, and the task of determining the ones that are most therapeutically relevant is challenging.

Our work attempts to focus on those target proteins and pathways with the most evidence for involvement in mood disorders, the greatest relevance to current disease models, or where other medications with the same or similar actions have been developed and could be used for proof-of-concept trials.



An example of drug development for BD: identification of a novel molecular target


The recent identification of biochemical targets of effective treatments has been facilitated by gene and protein expression profiling, which has led to the identification of several hitherto unexpected targets. It is important to note that these methodologies are only a screening technique, and the results need independent validation. More information on understanding the molecular mechanisms presumably involved in mood stabilization through genome-wide gene expression profiling is reviewed elsewhere.

 

Because target validation for complex psychiatric disorders is so challenging, the following criteria for selecting mood stabilizers for further study were put forth: (1) corroboration of a target at the protein and functional level; (2) observation with chemically dissimilar but clinically effective agents; (3) occurrence at a dose/plasma level 

 time frame consistent with clinical therapeutic effect; (4) localization to brain regions implicated in the neurobiology of the disorder under consideration; (5) when known, relevance to pathophysiology; and (6) when possible, tethered to human genetic findings. Application of these stringent criteria led a number of independent groups

 to recognize protein kinase C (PKC) as a promising direct biochemical target for developing therapeutics to treat BD.

The mood stabilizers that meet the aforementioned criteria for further testing are lithium (a monovalent cation) and valproate (an 8-carbon, branched fatty acid). Lithium and valproate are structurally dissimilar, but researchers have postulated that their similar therapeutic effects take place in the critical circuits of brain regions implicated in the pathophysiology of BD. The therapeutic effects are specific to these agents and occur at drug concentrations in vivo. The resultant biochemical changes occur only after long-term-but not short-term-administration in a time frame consistent with improvement of symptoms of the illness.

Both lithium and valproate were found to bring about markedly analogous effects on the PKC signaling cascade, actions that appear to be most pertinent to their antimanic profile. The PKC example we will now describe is one of the few instances in which a drug is being developed specifically to treat BD based on an identified molecular target. Indeed, such development has gone from identifying a direct molecular target in 1990 to a positive, proof-of-concept clinical study with a modulator of the relevant target in humans in 2007.




PKC is a family of 12 closely and structurally related isozyme subspecies with a heterogeneous distribution throughout the body that depends on isoforms.

 In the brain, PKC has a varied distribution and plays a significant role in regulating synaptic facets of neurotransmission. A number of additional functions for PKC have been described, including regulation of neuronal excitability, neurotransmitter release, long-term alterations in gene expression and plasticity, and mediation of intracellular signaling pathways.


Biochemical data support the possible connection between PKC and the pathophysiology and treatment of BD. Friedman and colleagues

 studied PKC activity and PKC translocation in response to serotonin in platelets collected from patients with BD before and during lithium treatment. They found that the ratios of platelets membrane-bound to cyto- solic PKC activity were increased in participants during a manic episode.

 found increased PKC activity and translocation in the brains of patients with BD compared with controls.

Studies have also shown that PKC signaling pathways are altered after treatment with lithium or valproate.

 Long-term treatment with lithium in rats resulted in a significantly decreased PKC stimulation-induced release with phorbol esters in the cortex, hypothalamus, and hippocampus. PKC isozymes a and e were reduced in the frontal cortex and hippocampus following lithium administration.

 Similarly, valproate was also found to cause an isozyme-specific decrease in PKC a and e.



Furthermore, studies have shown that stimulants, such as amphetamine, which are capable of triggering manic episodes in susceptible individuals and which induce manic-like behaviors in rodents,

 activate PKC and growth-associated protein (GAP)-43 phosphorylation (implicated in neurotransmitter release).

 Given the compelling biochemical data, a number of behavioral studies have been undertaken to validate the role of PKC in mania-related behaviors. 

In rodents, the PKC inhibitor tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity, and it normalized amphetamine-induced increases in visits to the center of an open field (representing risk-taking behavior); tamoxifen also attenuated amphetamine-induced phosphorylation of GAP-43.

 PKC activity is increased in the prefrontal cortex following exposure, and the ability of the prefrontal cortex to regulate emotion, thought, and action is markedly impaired by overactivity of PKC sig- naling.

 the evidence suggests that pharmacological or stress-induced activation of PKC in animals results in many of the behavioral changes seen in mania, such as hyperactivity, risk-taking behavior, and increased hedonic drive. Its inhibition attenuates these same behavioral changes in a manner similar to that of mood stabilizers on acute mania.

These data strongly suggested that further study of PKC inhibitors in humans with BD was indicated. When the decision was made to further validate this target in humans, tamoxifen was the only relatively selective PKC inhibitor available to test. Tamoxifen, a synthetic antiestrogen widely used in the treatment of breast cancer, has a favorable adverse-effect profile compared with other chemotherapeutic agents

; considerable data exist on its safety profile and ability to cross the blood-brain barrier.

Finally, the exciting recent identification of a bipolar susceptibility gene that is an upstream regulator of PKC has strengthened the potential role of PKC signaling pathway in the pathophysiology of BD. For example, 2 recent, independent genome-wide association studies identified diacylglycerol (DAG) kinase e (DGKH) as a gene associated with higher risk of BD.

 DGKH is a major regulator of DAG, which activates all known classic and novel isoforms of PKC.



PKC inhibitors: novel therapeutics for acute mania?


Based on the data generated since the 1990s, researchers embarked on proof-of-concept studies with tamoxifen for acute mania. The first study included 7 patients (5 male and 2 female) with acute bipolar mania.

 Participants were inpatients or outpatients aged 18 to 65 years with a diagnosis of bipolar mood disorder manic episode based on a 

 structured clinical interview. Tamoxifen resulted in a significant decrease in manic symptoms as rated by the Young Mania Rating Scale (YMRS), with a mean decrease of 10 points. In addition, 71% of patients met response criteria (ie, a 50% decrease in the YMRS score from baseline).

In a double-blind, placebo-controlled monotherapy pilot trial in patients with bipolar mania, tamoxifen was found to have significant antimanic effects as early as day 5 and throughout the 3 weeks of the trial.

 Very recently, these studies were replicated in a larger placebo-controlled study.

 These studies confirm the hypothesis that directly inhibiting PKC improves manic symptoms. It is important to emphasize that while these findings are encouraging, the results are preliminary and based on fairly small sample sizes; the results need to be confirmed in larger studies involving several hundred participants and with more selective PKC inhibitors.

Nonetheless, this strategy illustrates that it is possible to develop a drug to treat a specific disorder; in this case, the illness was BD, for which no novel mechanism of action had ever been identified and proved in clinical studies.

The evidence to date on multiple levels (ie, preclinical, clinical) supports further study of PKC inhibitors in BD. Other selective PKC inhibitors are currently in phases 1 through 3 of development for treatment of a variety of conditions (eg, diabetic complications) and are possible candidates to test in BD.

 Naturally, issues regarding PKC isoform selectivity, brain penetrance, and short- and long-term tolerability will need to be examined.

Finally, a point that merits further discussion is our need to integrate current technologies with the drug evaluation process in proof-of-concept studies. The importance of identifying endophenotypes in complex neuropsychiatric disorders has been reviewed elsewhere.

 Briefly, endophenotypes can be conceptualized as quantifiable components along the pathway between phenotype of disease and distal genotype. An endophenotype may be biochemical, neuropsychological, endocrinological, neuroanatomical, cognitive, or neurophysiological (eg, seen in magnetic encephalography, polysomnography) in nature. 

These new investigational tools are beyond the scope of this review. We note them, however, because they may have considerable utility in predicting phenomena such as time to response, remission, and degree of improvement. Given our current inability to predict who will respond to which medication and within what time frame, the evaluation of characteristics observed using valuable new technologies may provide a better understanding of the neurobiological basis involved in symptom improvement, and it also may allow for the identification of surrogate outcomes and molecular targets for the next generation of treatments. Indeed, such strategies are being increasingly used in our study of complex neuro-behavioral medical illnesses.




Thus, there is now strong evidence to support the view that targeting intracellular signaling cascades is a useful strategy in drug development for BD. The use of modulators of ubiquitous kinases in the CNS, however, is met with some trepidation because of possible problems in specificity, tolerability, and safety. At present, many kinases are in the early stages of drug development for diverse medical illnesses.

 It should be emphasized that while appropriate concerns regarding these compounds are in order, lithium is a drug that targets multiple signaling cascade molecules, has been found to be generally safe, and has been a primary therapeutic used for BD for more than half a century. This latter point illustrates that it may, indeed, be possible to develop safe and effective signaling system modulators for CNS illnesses.

We believe that the strategy of drug development research we have described here will, in due course, result in noticeably improved therapeutics for psychiatric illnesses.

 

 Gitlin M. Treatment-resistant bipolar disorder. 

 Insel TR, Scolnick EM. Cure therapeutics and strategic prevention: raising the bar for mental health research. 

 Zhou R, Zarate CA, Manji HK. Identification of molecular mechanisms underlying mood stabilization through genome-wide gene expression profiling. 

 Chen G, Manji HK, Hawver DB, et al. Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. 

 Jope RS. Anti-bipolar therapy: mechanism of action of lithium. 

 Casabona G. Intracellular signal modulation: a pivotal role for protein kinase C. 

Prog Neuropsychopharmacol Biol Psychiatry.

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 Manji HK, Chen G. PKC, MAP kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers.

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 Manji HK, Etcheberrigaray R, Chen G, et al. Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the alpha isozyme. 

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 Giambalvo CT. Protein kinase C and dopamine transport--2: effects of amphetamine in vitro. 

 Gnegy ME, Hong P, Ferrell ST. Phosphorylation of neuromodulin in rat striatum after acute and repeated, intermittent amphetamine. 

 Iwata S, Hewlett GH, Gnegy ME. Amphetamine increases the phosphorylation of neuromodulin and synapse I in rat striatal synaptosomes. 

 Iwata SI, Hewlett GH, Ferrell ST, et al. Enhanced dopamine release and phosphorylation of synapsin I and neuromodulin in striatal synaptosomes after repeated amphetamine. 

 Birnbaum SG, Yuan PX, Wang M, et al. Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. 

 Jordan VC. Molecular mechanisms of antiestrogen action in breast cancer. 

 Baum AE, Akula N, Cabanero M, et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. 

 Bebchuk JM, Arfken CL, Dolan-Manji S, et al. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. 

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Although several antimanic agents are available to treat individuals with bipolar disorder (BD), many patients have a less than satisfactory response or experience adverse effects.1 With the exception of lithium, all of the current antimanic agents are either anticonvulsant or antipsychotic drugs. It is remarkable that no drug has been developed specifically for BD, especially because this illness was conceptualized more than a century ago.

Husseini K. Manji, MD

Articles

Smart Growth: the Case for Measuring Brain Capital

Focus on Bipolar Disorder