Clear Thinking About Addictions

      The drive for life achievement can be subverted by addictions. Addictions can be viewed as actions (state) and behaviors (trait) that you do or allow to happen that make you in the short term feel good and give you an illusion of life achievements  without achievement of real objectives. In addition, addictions have one or more of the following three characteristics (as for example in the case of drug abuse and dependence):  1. they have detrimental health consequences, 2. they lead to missed opportunities in life, by taking up attention, energy, time and money that could be used instead for productive pursuits, and 3. they create social and legal problems. As such, addictions impinge upon and thwart real life achievements. While in thrall of the addictive product, the addicts are happy about their life, despite where they are in their life, and hopeful for the future as they know they can become happy again with the next addictive product dose. However, when not under the influence of the addictive product, the addicts realize what a mess their life might in fact be, and how hopeless their future might become, day by day. In vulnerable people, such a state can lead to depression and suicidal thoughts. That is why addicts become physiologically and psychologically dependent, and seek their next addictive product dose- to avoid this withdrawal discomfort/pain/aversion, and to get pleasure again. 

      It is to be noted however, that the majority of dependencies are positive, enhance your life, and are not addictions. You are dependent on things necessary to live, such as oxygen, water, food, clothing and shelter, and so no. It is only the dependencies on addictive products, which diminish your life, that are pernicious.

       1 in 3 people with an addiction may relapse after a period of sobriety. That can be prevented by bio-psycho-social treatments, in essence making people's live's better.

The Signal, the History, and the Context

      What a signal does/means depends on the context.  A hormone or biomarker level in the blood is not as informative as knowing the longitudinal history of levels and  their contexts. What is the   % change of the current level- is the marker increasing or decreasing, and how fast is that occurring? Has the marker in the past been this high or higher, and then it went down?  What made it go down? What was the maximal level attained in the past? What was the maximal % change? A specific driver is having  a personal and/or family history of having illnesses related to that marker. A first layer of context is if they have other signs of illness.  A second layer of context is  provided by information about living in an environment or having been subjected to events  relevant to the illness. Context, while non-specific, may give rise to or enable the illness manifesting, if the specific driver is in place to channel it into disease.  

      For exemplification, think PSA levels and prostate cancer. While absolute PSA levels provide some information, the slope of increasing PSA is more informative.  Have they had in the past high levels like this, which then went down?  What made them go down? What were the maximal levels attained in the past? What was the maximum slope?  A driver is a personal history or a family history of prostate illness.  A first layer of context is a physical exam or imaging test revealing an enlarged prostate. A second layer of context is provided by age, ethnicity, and environmental factors such as high fat diet. Context, while non-specific,  may  give rise to or  enable disease, if the specific driver/mutations are in place to channel it into disease .

      Another example, this time from psychiatry, is that of suicidal ideation.  While absolute levels of suicidal ideation intensity provide some information, the slope of increasing suicidal ideation may be more informative regarding risk of committing suicide.  Have they had in the past high suicidal ideation comparable to this or higher, that then resolved?  What made it resolve?  What was the maximum suicidality (ideation, attempts) they had in the past? What was the maximum slope? A specific driver of behavior is a personal history or a family history of suicidal behavior, or knowing somebody who attempted or committed suicide.  A first  layer of context is a mental status exam or test revealing increased anxiety, low mood, or distorted thinking.   A second layer of context is provided by gender, age, ethnicity, and environmental factors such as stressful life events and addictions. Context, while non-specific, may  give rise to or  enable suicide, if the specific driver is in place channel it into to suicidal ideation and action. 

Alexander B. Niculescu, III, MD, PhD

A brief proposal for improving drug discovery

       We need to move from the primacy of therapeutics to the primacy of diagnostics, from “companion diagnostics” to “companion therapeutics”. Drug discovery greatly benefits from being based on correcting biological markers of disease.  Once you have such markers, you can identify drugs that modulate them individually, or modulate the biological pathways they are in, or modulate in opposite direction the gene/phene expression signature of a panel of top markers.

         The later approach is probably the best, as most diseases are complex, and by modulating a biosignature you are more likely to be more efficacious as well as more specific for the disease. For example, using a gene expression biomarkers signature, “dry lab” approaches such as connectivity map, or “wet lab” approaches such as de novo screening of compounds in cells or model organisms, may yield useful compounds. Using several low dose combinations of such compounds in subsequent clinical trials may synergize their abilities and minimize their liabilities, resulting in a broad-spectrum therapeutic with favorable side effect profile.  The biomarker signature can be monitored as a primary measure of response to treatment, providing real-time feedback.

      After the clinical trials are successfully completed, in subsequent actual clinical practice, tailoring the compounds in the combinations and their dosages based on the profile of biomarkers in a particular patient may yield additional benefit. Again, the biomarker signature can be used to monitor not only the efficacy and make any needed adjustment in dosages, but also as a way of gaining additional insights about stratification in a wider context, taking into account gender, possible subtype of disease, age, ethnicity, and, importantly, environmental factors.

Alexander B. Niculescu, III, MD, PhD

Suicidality: from phenomenology to treatment

      Suicidality can be viewed as whole-organism apoptosis (self-poptosis). First, suicide might have evolved to occur adaptively due to life factors, to minimize detrimental impact and burden on the extended kin when the present is perceived as bleak and unsuccessful for the individual, and there is little hope for future improvement and successes, with the individual perceiving it is irreversibly damaged, not needed by family, extended kin, peer group, or society at large. Suicidality is a decision and choice leading to self-harming actions and behaviors driven by feelings and thoughts of pain or fear, hopelessness or anger, despondency or perceived uselessness. Conversely, a life that is perceived to be successful and meaningful is protective. Second, suicide often occurs maladaptively, due to mind abnormalities, with the individual who commits suicide being vulnerable due to a psychiatric illness, misperceiving circumstances and/or overreacting in an impulsive fashion. Related to that, suicide can be an attempt to assuage perceived guilt, or an attempt to harm (through social opprobrium or guilt) the individual(s) perceived to be the source of the lack of success of the suicidal person. Conversely, a well-balanced and functioning mind is protective. Third, body health abnormalities. Having severe health problems or pain may make an individual more prone to suicide. Conversely, a healthy, strong and resilient body is protective. Fourth, environmental factors. Environmental stressors, such as a hostile environment and loss of social connections and status can make individuals more prone to suicide. Conversely, a pleasant environment and good social standing are protective. Fifth, addictions. Addictions may destroy an individual’s life, mind and body, making them more prone to suicide. Conversely, being free from and immune to addictions is protective. Sixth, cultural factors. Cultural enablers (a personal or family history of suicidality, or being part of an environment or culture where suicide is an option) also come into play. Conversely, cultural and religious beliefs that make suicide not be an option are protective.

      Suicidality is a combination of increased risk factors/drivers (increased reasons why to do it) and decreased protective factors/brakes (decreased reasons not to do it). Younger people, older people, and males are more at risk for it. The evolutionary rationale in the young is primarily to avoid transmitting damaging combinations of genes. In the old, it is primarily to avoid being a burden. In males, it may be a price paid for increased testosterone-related drive and impulsivity.

      Discrepancies between where you are in your life vs. your standards and goals (where you would have liked to be in life) can lead to suicidality. Treatment and prevention need to involve reducing this perceived gap, in addition to improving hope for the future, and improving the mind (feelings and thoughts) that can color how life is perceived, improving body health, improving environment, improving any addictions, and improving cultural factors.


 Alexander B. Niculescu, III, MD, PhD

Neuroscience and Heisenberg Uncertainty

The current sources of data for neuroscience research are naturalistic data (where there is no intervention and the subjects do not know they are being observed), and experimental data (where there is an intervention, and/or the subjects know they are being observed). Any naturalistic data may suffer from the fact that it was not specifically designed apriori to answer a particular question. Any experimental data may suffer from the Heisenberg uncertainty principle, where the intervention/observer modifies to some extent what is being observed. That holds true from induced pluripotent stem cells to testing of patients in clinical trials. What is the solution to circumvent these limitations and transform them into strengths? We believe that a convergent combination of naturalistic data with experimental data has the best yield, and should be programmatically pursued at all levels of neuroscience. For example, in developing tools to predict psychiatric disease outcomes such as suicide, a combination of naturalistic medical records and other life records mining with experimental neuropsychological and laboratory tests will yield the best outcome. Similar arguments can be made for drug development, and so on.

Less is more: the secrets of success in human (psychiatric) genetic and biomarker studies

1. Phenotype

- Study discrete quantitative phenotypes ("phenes"), not broad diagnostic categories.
- Study these phenes (for example,  mood, hallucinations, suicidality ) in high –risk populations ( bipolar schizophrenia), which provide an enriched pool.
- Study these phenes longitudinally, over time. Wireless devices and mobile health applications are crucial.

2. Cohorts

- When enrolling subjects, for reliability of phene measures use an longitudinal within-subject design whenever possible.
- Validate phene measures by the convergence of internal feelings and thoughts ( as measured by self-report scales) and of external actions and behaviors ( as measured by external raters).
- Separate cohorts by gender and by ethnicity, as this homogeneity leads to a reduction in noise.

3. Gene expression (biomarker discovery) is much more powerful than genetics (mutations discovery)
- One expressed gene may integrate the effects of up to  ~ 10³ SNPs, epigenetic changes, as well as the current effects of the environment.
- Focus on discovering  first state biomarkers, correlated with phenes measured at the time of biomarker testing, not trait biomarkers, unless you have good longitudinal phene data. State over time is trait.

4. Study design 
- A within -subject design is the best, as it factors out genetic variability. You can do aggregates of n of 1 studies. You may need n~10¹ for gene expression studies, and n~ 10⁴ for family based genetic studies (the closest you can come to “within-subject” in genetics).
- A case-case design is second best, as it factors out some disease related variability. You may need n~10² for gene expression studies, and n~ 10⁵ for genetic studies.
- A case-control design is the least powerful, due to heterogeneity and noise that is not factored out, i.e. many of the differences do not have something to do directly with the phenotype you are studying. You may need n ~10³ for gene expression studies, and n~ 10⁶ for genetic studies.

5. Convergent Functional Genomics (CFG) at a gene level

- ~ 10² more reproducibility at a gene level than at a SNP level.
- Reproducibility in independent cohorts  is more important than strength of signal in the discovery cohort, as that could be a fit-to-cohort effect.

- CFG is like a magnet that finds the biomarker “needle” in the genetic or blood gene expression “haystack”. It  uses in a Bayesian way the whole prior body of work in the field to identify,  prioritize and give credence to disease-related genes from the long lists of differentially tagged genes in genetic association studies ( GWAS), and from differentially expressed genes in the brain or blood.

-Moreover, the genes and biomarkers prioritized by CFG are fit-to-disease, not fit to cohort. Because of that, they travel well, reproduce and are predictive in independent cohorts, which is the ultimate litmus test for any genetic or biomarker finding.  

How to prevent suicide     

 

      Suicidal behavior can occur due to a combination of existential reasons, biological vulnerabilities, and environmental factors. The existential reasons include lack of satisfaction with current life (health, finances, social importance), lack of hope for the future, and not being/feeling needed (especially by progeny and family). The biological vulnerabilities include mental health issues and addictions, including a genetic vulnerability to suicide as reflected in a family history of suicides among biological relatives. The environmental factors include increased stress and pain (physical and psychological), as well as cues that enable this behavior (previous attempts, knowing examples of other people who have done it, living in an environment and (sub-) culture where suicide is an option, seems attractive, and the means are available). 

      The opposites of each of the above items are protective. Individuals can have a mixture of risk factors and protective factors.

      A simple checklist of all these factors, tabulating risk factors and protective factors, along with improved objective biomarkers, should lead to very high levels of identification of individuals at risk, combining specificity with sensitivity of detection. This would permit preemptive intervention- changing and saving lives.

 

      We are working on that.

Trend of the Year 2013:

Genomics out, biochemistry in, for curing diseases?

Genomic variation and complexity are such that the genetic basis of most  human diseases is  going to require another decade or more to unravel completely, and even then it will be only partially explanatory, due to the profound role of the environment and of developmental history. Even when driver mutations are found and are targeted by a drug, the disease process may not be completely blocked, and alternative biological pathways may be recruited by the disease, as is the case in cancers.

However, diseases have key "vulnerabilities" at a metabolic and biochemical level that can be therapeutically attacked much sooner than that. Such metabolic targets are the result of the combinatoric integration of myriad mutations and environmental effects. For example, in psychiatry, the use of DHA (an omega-3 fatty acid), may correct membrane, signalling and inflammatory abnormalities that are responsible for vulnerability to stress, anxiety, mood and cognitive symptoms.

Genomics will still be important for scientific understanding in the long run, and for risk stratification and diagnostics in the short run.


Alexander B. Niculescu, III, MD, PhD

Science(-fiction) musings on how to achieve longevity and immortality

Prevention:

1. Store regenerative material at a younger age (umbilical cord, sperm/oocytes, iPS).

2. Live a healthy lifestyle to minimize damage. Avoid toxins, build resilience.


Treatment:

1. Treat early on and aggressively any abnormality.

2. Replace body-parts as need be with (self-) regenerative medicine or bionic prostheses.


Transcendence:

3. Create a legacy through your progeny, your life’s work, and through educating/influencing others.

4. “Download” your mind to a cloud computer website/app when your body eventually fails beyond repair, like a car with too many miles. Put all your legacy of knowledge and wisdom online. Your mind computer app will continue to interact with and advise your progeny, kin, and the world at large.

 

Reasons for the increased incidence of autism (and other brain disorders)

The reasons for the increased incidence of autism and other disorders are two-fold: on the one hand we have increased awareness and diagnosis, on the other hand we have a genuine increase in the incidence of disease.

The genuine increased incidence of disease is due to three factors: age, quantity and fit. Age refers to older parents, in which there is increased incidence of DNA mutations in spermatocytes and oocytes. Over 80% of the genes in the genome are involved in brain function, providing plenty of targets in which random mutations can occur that may affect brain function. Quantity refers to increased environmental exposure to factors that affect brain development and growth, including for autism possible chemicals in the environment and nutritional factors that promote a diabetes-like state in mother and fetus. Fit refers to the fact that there is an increased preservation and selection in the population of gene variants involved in mental functions, which are the same gene variants that, if you have too many of them, in the wrong combination and in the wrong environment, can lead to psychiatric disorders such as autism, schizophrenia or bipolar disorder (what we call in our group the 4C x E model of disease- contextual cumulative combinatorics of common gene variants and environment).

Our best estimate so far, is that autism is a disease of connectivity, based on the body of evidence in the field, and comparative genomics of schizophrenia and autism (see for example Ayalew, Le-Niculescu et al. Molecular Psychiatry 2012 In Press). We think that autism is a disease of localized increased connectivity in the brain (abnormal or supra-normal), and overall decreased connectivity to the environment, hence the occasional very high levels of performance on specific tasks but overall social problems. Schizophrenia may have localized abnormal increased connectivity in certain brain circuits (leading to hallucinations, delusions and paranoia), but overall is characterized by much more decreased connectivity in the brain and with the environment, hence the occasional increased creativity but overall poor social functioning if left untreated.

The solution for both disorders is to modulate the age, quantity and fit factors. Parents should conceive at an earlier age or at least store their germinal cells in youth for later conception. Environmental factors that affect brain development and growth should be identified ( stress, inflammation, infections, head trauma, drugs, nutritional factors, chemical pollution), avoided and mitigated against with early preventative treatments. The continued increased selection and enrichment of genes involved in increased mental performance is unavoidable in our current information-driven era (where the brain is our main tool and reason for professional success), but genetic testing for possible early intervention, coupled with brain exercises and better treatments to minimize the deficits, and a greater appreciation and tolerance for diversity and specific skill sets, should make most individuals into content and productive members of society!



Alexander B. Niculescu, MD, PhD

Trend of the Year 2012: Living in truth- from science to society

2012 will be the year when some of the previous visionary advances become reality through better execution, and others are revealed to be empty hope and fall by the wayside. The contextual cumulative combinatorics and integration of existing methodologies and knowledge from disparate domains will lead to major advances in scientific understanding, diagnostics, and pharmaceutical drug development. The work necessary for such advances will be precise and tedious, but the results will be spectacular.

Discovery-based non-hypothesis driven science carried out in well established laboratories, primarily in developed countries, will lead to real advances, as opposed to the mass of more hypothesis-driven science (and clinical trials) of dubious reproducibility carried out by career-driven less established researchers, primarily in ( and from) developing nations. The issue of ethics and not cutting corners will become as prominent in biomedical sciences and pharma industry as it has been in the last few years in business and finance.

All in all, a solid year ahead.


Alexander B. Niculescu, MD, PhD

The color blue for promoting mental health initiatives

The breast cancer community has done a terrific job of decreasing stigma, raising funds for research and treatment, and increasing awareness using the color pink in marketing and promotional campaigns. We should learn from them.

Mental health is as important an issue for women -and men, but less well publicized. I would propose we use blue as a color for mental health in marketing and promotional campaigns, for exactly the same reasons as in breast cancer- to decrease stigma, raise funds and increase awareness.

In popular culture, blue has already been associated with depression (“having the blues”), or it’s opposite (“blue sky thinking”). It is a soothing color that may decrease anxiety and increase cognition. So the full triad of major mental health domains (anxiety, mood and cognition) can be linked to blue and be well represented by it. There is some research supporting its use as well: http://www.guardian.co.uk/education/2008/jun/24/highereducation.improbableresearch

Who wants to help promote this? Email us and spread the word.


Alexander B. Niculescu, MD, PhD

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

Treating Addictions: The Way of The Fist and The Palm

Addictions -and allergies- of any type can be treated by removing the stimuli (drug) and changing the receptivity of the person. As when a "kung-fu" salute ends, the fist and the palm must come apart and turn away from each other. The fist is the stimuli, and the palm is the person’s receptivity to it. “Pull the fist, turn the palm” is sage-like advice that works.

1. External trigger (The Fist): avoiding environmental exposure

1.1. Psychosocial:

Avoiding environmental/ informational/memory cues

1.2. Biological:

Avoiding slippery slope use of drug


2. Internal receptivity (The Palm): decreasing relapse risk

2.1. Psychosocial:

Increasing fear of adverse outcomes if drugs are used

Increasing support/self-esteem/importance if abstinence is practiced

Increasing desire to do good/ spirituality

2.2. Biological:

Treating withdrawal, blocking the effects of the drug

Treating other predisposing disorders (Axis I/II in psychiatry)

Increasing biological resilience: exercise, diet, meditation



 by Alexander B. Niculescu, III, MD, PhD