Psychiatric genetics: contextual cumulative combinatorics of gene variants and environment

Classic genetics research in psychiatric disorders has provided an abundance of data but a paucity of insight. Things will only get worse in terms of this ratio, as massive sequencing of genomes becomes routine.

The reasons are four-fold. First, psychiatric disorders are genetically complex, with many (hundreds, if not thousands) genes involved. We first proposed that over a decade ago, based on our pioneering gene expression work cross-matched with human genetic data (Convergent Functional Genomics). Second, psychiatric disorders are genetically heterogeneous, with different mutations in the same gene present in different individuals. Many of these mutations are in fact common variants present in non-psychiatrically ill individuals as well. Third, psychiatric disorders as currently defined by DSM are overlapping and interdependent, with genes and biological pathways shared among disorders. Fourth, the environment plays a major role in modulating gene expression and the development or not of illness.

The key to progress is to acknowledge reality in the four areas mentioned above. Illness or lack of illness are the result of cumulative combinatorics of common gene variants and environmental stressors (or favorable factors). Genetic context and environmental context are important to whether a mutation contributes or not to the illness.  Gene expression studies are more informative than classic genetics, as they reflect the actual results of the interaction between genes and environment, and underlie the subsequent patho-physiological outcomes. Biological pathways and mechanistic-level analyses will show more commonality and reproducibility across individuals, and from study to study. A dimensional approach to psychiatric profiling of individuals will eliminate the confusion and overlap of DSM, as well as permit a better mapping and tracking of biological reality. Our group has provided comprehensive proof and solutions over the years in all these areas, and we will continue to do our bit.

 
Alexander B. Niculescu, III, MD, PhD

Clock Genes and Mood

"There can be no transforming of darkness into light and of apathy into movement without emotion"
      - Carl Jung     

      After more than a decade of work on understanding mood, using the magnifying glass of severe mood dysregulation disorders such as bipolar disorder, our group has proposed and provided evidence for mood being related to levels of activity, energy and growth, in response to internal and external environment cues. When the environment is favorable, levels of activity and growth are (or should be) high. When the environment is unfavorable, levels of activity are (or should be) low. When there is a discongruence between levels of activity of the organism and the environment, we are dealing with a mood disorder, manifested as depression or (hypo)mania.

      Following early hypotheses from W. Bunney and R. Lennox, our group has provided over the last decade cumulative empirical evidence that supports a model where circadian clock genes are the core mechanism of mood regulation and dysregulation. They serve as a thermostat, increasing or decreasing the level of activity of cells, brain and of the whole organism. Some key circadian clock genes we have identified and provided evidence for involvement in mood are ARNTL, RORB, and DBP. DBP, first identified by us as a candidate gene for bipolar disorder over a decade ago, has provided a basis for us developing the first broad-spectrum genetic mouse model of bipolar disorder, which mimics both phases of the illness, depression and mania, as well as mimics the sensitivity to stress and the propensity to substance abuse.

      Due to the genetic overlap and biological interdependence between mood, anxiety and cognition, circadian clock genes have also appeared in screens conducted by us and others for genes involved in other disorders, such as anxiety disorders and schizophrenia. It is understandable how levels of energy (mood) can influence signal transduction reactivity (anxiety) or brain connectivity (cognition).

      Clock genes are present in every cell in the body, regulating the expression of thousands of other genes. They are likely going to become key targets for therapeutic intervention and new drug development, and provide a biological rationale for circadian medicine, circadian psychiatry, and other subspecialties of the future.

Alexander B. Niculescu, III, MD, PhD

The Biomarkers Solution: How to Improve Pharma Drug Discovery

The drug discovery process is currently flawed at both pre-clinical and clinical levels. Biomarkers are an emerging “bridge over troubled waters” between these two areas, and a solution for their respective ills.

Preclinically, gene expression networks, not single gene products, need to be targeted for comprehensive and successful treatment of diseases. Combinations of drugs need to be developed and used from the beginning for broad impact. Profiling baseline gene expression and response to drugs in animal models using biomarkers can ensure the right combinations of drugs are selected and advanced towards clinical testing.

Clinically, one size does not fit all. The blockbusters of the future will not be blockbusters in terms of patient population sizes treated, but rather due to precision and efficacy, commanding a deserved premium price that way. Some of the same biomarkers derived from discovery work and pre-clinical studies can be used in clinical studies, providing solutions for their current limitations: better diagnosis and patient stratification, objective monitoring of response to treatment, and a handle on the placebo effect. Early biomarker information from clinical trials will provide in an iterative fashion intelligence for improved selection criteria and outcomes in later clinical trials, leading to an enhanced rate of successfully approved medications, albeit for more narrow indications.


Alexander B. Niculescu, III, MD, PhD

Trend of the Year in 2011: Social connections, lower stress

Isolation is a powerful stressor-in people, animals, and probably all the way to single cells. It is associated with higher anxiety, lower mood and lower cognition, and myriad health problems. Isolation leads to uncertainty about safety, ability to thrive and ability to influence events. It is becoming more prevalent in modern societies, where social, familial and intergenerational bonds are frayed by geographic relocations/dislocations. On the dark side, social isolation has also been used as a way of punishing and/or coercing individuals.

Real or perceived social connections, from online connections such as Facebook to the local pub, exert a powerful soothing effect, and people are willing to pay for that with their attention, time and money, despite less than nourishing offerings (flimsy online friends, grubby pub fare).

As in the popular old TV series “Friends”, “Seinfeld” and “Cheers”, people go to these places (coffeehouses, corner deli, bars) as much for the actual fare served as for the fact that there (hopefully) “everybody knows your name, and they’re always glad you came”.

More positively, the health promoting effects of church attendance have been well documented. Proactive ways of social integration- from reconnecting with families, friends to joining social groups with a cause in a contributory fashion, will improve individual health and the health of society as a whole. Fads and companies come and go, but the importance of social connections is a perennial lesson that bears learning and relearning.

Alexander B. Niculescu, III, MD, PhD

Increasing resilience to disease by increasing genomic resilience through nutritional supplementation

It is becoming clear that DNA mutations, epigenetic changes, and gene expression modulation are involved in medical disorders in general, and psychiatric disorders in particular. In addition to avoiding the offending environmental agents, what else can be done? A powerful approach in medicine is to increase resilience/immunity as a way to prevent/treat diseases.

De novo DNA mutations (micro- single nucleotide mutations , SNPs, or macro- copy-number variants, CNVs) in germinal cells may be responsible for the increased paternal and maternal age effects seen in most psychiatric disorders where modern genetic studies have been carried out to date. These parental age effects may turn out to be a widespread phenomena for psychiatric disorders and non-psychiatric disorders alike. Besides parental transmission, de novo mutations may arise in somatic cells, including neurons. Free radicals may be involved in mutation mechanisms. Free radical quenchers such as the antioxidant vitamins C, E and Selenium have a favorable risk/benefit ratio for preventive purposes. We also suggest it is of interest for the future to study their role in anxiety regulation processes.

Epigenetic changes (such as the addition or removal of methyl groups from DNA) may mediate the depressogenic effects of environmental stress and trauma on the genome. B vitamins, in addition to helping with energy metabolism, may reduce epigenetic changes and thus have an antidepressant role. We suggest it is of interest for the future to study their role in mood regulation processes.

Lastly, gene expression modulation by adverse environments and inflammation could be counteracted by omega-3 fatty acids and vitamin D3. We suggest it is of interest for the future to study their role in cognitive regulation processes.

In conclusion, at the risk of sounding like a supermarket tabloid, here are some of our biologically informed practical applications. First do no harm, so one should not exceed manufacturer and/or FDA recommended doses. It is the cumulative combination of different vitamins taken over time that may provide inter-related benefits on anxiety, mood and cognitive disorders, rather than massive acute doses of any single one of them. The earlier they are started, the better the preventative effects. A multivitamin/multimineral pill is a good starting point, along with a diverse diet rich in (organic) fruits and vegetables, and along with overall calorie restriction.

Alexander B. Niculescu, III, MD, PhD

Suicidality: a form of transient psychosis

Suicidality in a broad sense can be viewed as a self-deletion (apoptosis) of the organism due to a perception of suffering, being damaged, hopelessly/irreversibly so, and a burden to its extended kin. While there is an evolutionary rationale for such a mechanism and behavior to exist and persist in the population at large, in most cases an affective and cognitive distortion occurs, leading to psychotic thinking in the perisuicidal period- either manic/positive symptoms (delusions, paranoia), or depressed/negative symptoms (avolition, lack of interest in living). The former can be labeled as “hot” suicide (impulsive, externalizing), the later as “cold” suicide (planned, internalizing).

 Particular, psychologically and culturally influenced, forms of suicidality are: 1. passive-aggressive suicide, when the act is meant to distress or induce guilt in somebody else, 2. copycat suicides, where precedents in the environment demystify and lower the fear of committing the act in people who were vacillating, and 3. atonement suicide, prompted by overwhelming guilt at something one has done and possible ostracism consequences. The passive-aggressive suicide is more towards the psychotic side of the spectrum, whereas the atonement suicide is more towards the evolutionarily normal side of the spectrum, with copycat suicides somewhere in between.

 Identification of people at risk for hot or cold suicide due to psychiatric and medical illnesses, chronic and acute social stressors, and alcohol/drug use, can be enhanced by developing blood tests. More subtle factors such as existential crises and isolation, like for single cells, tip the balance to apoptosis. They should be probed for and included in any risk prediction score and algorithm.

Treatment should be individualized and multifaceted, based on reversing the panel of causes and risk factors each individual has. The opposites of the risk factors for suicide are protective factors for suicide, in a yin-yang fashion, and should be enhanced. For example, a strong sense of spirituality and social support may compensate for and overcome other risk factors. Medications like lithium and clozapine, that prevent cellular apoptosis by increasing BCL-2, have also been shown to prevent organismal apoptosis, i.e. suicide. Other anti-apoptotic and neurotrophic medications should be considered and studied for suicidality treatment, perhaps distinguishing between the two broad categories- hot and cold.
 
Alexander B. Niculescu, III, MD, PhD

Alzheimer (and schizophrenia) are the result of stress, plasticity and fragility

Our speculative but data-informed view: Alzheimer disease is a result of the cumulative combination of stresses on the brain in people who have increased neuronal plasticity, and reach a tipping point of neuronal fragility leading to apoptosis.

In this view, amyloid, as well as tau, are symptoms, not causes of the neuronal deterioration. In fact, they may slow down and try to mitigate neuronal apoptosis, so their therapeutic targeting is not indicated.

ApoE is involved in the increased neuronal plasticity, disconnection, remodeling and adaptation in response to stress, useful in young people with robust neurons, but detrimental in older people with fragile neurons. Free radical damage and decreased growth factor levels make neurons more fragile with age.

Evolutionarily, populations that have been subjected over the centuries to harsh and stressful environments (in Africa or other continents-genocides, pogroms, persecution) may be more susceptible to Alzheimer in old age- if they reach that age, as they do in more modern and safer societies. Individually, people with a history of exposure to major stress and who have PTSD may be at higher risk of Alzheimer in old age, even more so if accompanied by traumatic brain injury. This should become a major area or research and intervention in combat veterans, and contact-sport athletes.

How to treat Alzheimer? Target neuronal apoptosis, specifically enough that you do not increase the opposite elsewhere, which is cancer. GSK3beta and its connected biological pathways are worth exploring.

How to prevent Alzheimer? In a Mindscape fashion, addressing the three dimensions: anxiety, mood and cognition. Reduce cumulative exposure to stress (or use an anti-anxiety medication such as an SSRI), modulate neuronal plasticity through cognitive-behavioral therapy (or use a mood stabilizing medication such as lithium), decrease neuronal fragility through rich nutrients and a rich environment (or use a cognitive enhancing medication). Infection and inflammation are major stressors on the brain, so limiting them helps prevent Alzheimer. For a “primum non nocere” strategy: physical exercise, omega-3 fatty acids, antioxidants and a stimulating life. These may be our best bets- in combination.

Last but not least, in our view schizophrenia is just an accelerated early form of this whole process- indeed dementia praecox, as Emil Kraepelin has suggested. The stresses occurs earlier on, including in utero, and the neurons are more plastic and more fragile due to multiple genetic vulnerability factors. Prevention and treatment: the same, but a need to intervene very early on, in childhood,  to prevent full blown illness from developing in young adults.

Alexander B. Niculescu, III, MD, PhD