Monday, September 27, 2010

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

Tuesday, September 21, 2010

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