Reflections on "Schizophrenia"

As a professor of neuropsychopharmacology for 20 years at NYU, at times Columbia University and other city universities, I was intrigued when researchers at Columbia University discovered the neurochemical issue in “schizophrenia” and related “psychoses” was not in the dopaminergic mesolimbic pathways (there are 4, some say 3, dopaminergic pathways in the brain), rather in the dopaminergic striatum, more precisely, an excess of dopamine synthesis and release in the striatum “Antipsychotic” medications work downstream from the identified alteration. Researchers have demonstrated an increase in dopamine release in the ventral striatum in persons with a history of social adversity and early life stress. (e.g., Dopamine Release in Response to a Psychological Stress in Humans and Its Relationship to Early Life Maternal Care: A Positron Emission Tomography Study Using [11C]Raclopride
Jens C. Pruessner, Frances Champagne, Michael J. Meaney and Alain Dagher
Journal of Neuroscience 17 March 2004, 24 (11) 2825-2831).

It is important, in order to achieve a truly scientific model and theory which studies the whole person and not just reductionistic aspects, that one must try one’s best to integrate findings across alient domains, including, but not limited to: DNA, the epigenome (modified by the social, chemical, psychological and nutritional environments), first person subjective/phenomenological experience, the meanings given to what is experienced, developmental traumatology, geographic/neighborhood characteristics, history of social catastophes and upheavals experienced across generations (possibly affecting epigenetic regulation of gene expression)-the importance of the “Big History,” the “History Beyond Trauma” described so well by Francoise Davoine and Jean-Max Gaudillere., etc.

It is also helpful to have a good understanding of neuroanatomy and neurochemistry. One must see how neural regions dialogue and interact—how the DNA in neurons speak to each other across regions. The ventral striatum is part of the five nuclei of the basal ganglia. This structure receives massive inputs from the amygdala and the hippocampus, mesial-temporal areas subserving threat detection and learning/contextual memory/stress regulation, etc. The pathways, neuronal circuits, to the neocortex tunes it to emotional events. Therefore, via the ventral striatum, emotion (limbic structures) can be translated into movements (basal ganglia), and with hippocampal input, the final motor motor output is finely primed to reflect past experiences, emotional states, and present environmental input from sensory pathways. Parenthetically, the latter have been demonstrated by Martin Teicher’s lab, a psychiatrist and developmental traumatologist at Harvard Medical School, to be involved with the kinds of neural changes specific to the type of maltreatment, e.g., sexual abuse and molestation resulting in thinning out (atrophy) of neural tissue in the somatosensory parietal regions which subserve gential regions and touch. In other words, the excess synthesis of dopamine in “schizophrenia,” a neuromodulator, can be induced through recollections and predictions of traumatic experiences and the correlative adaptive responses.

The human brain is the most complex organ that we currently know of-with its approximately 87 billion neurons each synapsing with hundred to thousands of other neurons (trillions of synapses) and more numerous glial cells performing many vital functions besides neuronal support (e.g., myelination of axons creating white matter-the “information highways of our brains, neurotransmission, signal trsnsduction, etc.). If the brain were simple enough to understand, we would be too simple to understand it. There is so much we do not know.

Another area of concern is the “heritability gap” observed in the difference between family studies (e.g., concordance rates between monozygotic twins compared with dyzygotic twins) and the actual molecular biological studies using such tools as genome-wide association studies (GWAS) using polygenic risk scores (as well as whole exome and next generation sequencing strategies). The latter explain much less of the genetic variance than family studies, mostly revealing multiple risk variants (i.e., single nucleotide polymorphisms, SNPs) which have low Odds Ratios and low penetrance/impact. The human genome did not evolve with the intention of reifying ICD/DSM categories. The genome allows the possible, the environment parses out the actual.

So before falling back on simple physico-chemical explanations, in which vital knowledge can be lost, and invoking such terms as “brain disease” in regard to the persons with “schizophrenia”-one must have an in-depth understanding of how integrated brain regions are through the connectome, and importantly, how you cannot understand the brain apart from the body and social environment (across generations), and how what we call “symptoms” can work through the brain but not because of it.

After 43 years of psychotherapy experience with persons diagnosed with “schizophrenia” (it is time this term is dropped), in state and city hospitals and private practice, I have seen the following: histories of maltreatment, early life stress, possible severe prenatal stress, invalidation, social adversity, poverty, expressed emotion, peer rejection and bullying, urban birth/living, social exclusion/isolation and stigma, low self-esteem (as HS Sullivan pointed out from reflected appraisals of significant others), feelings of hopelessness and despair, feeling that one had no right to be born, beliefs that one had a destructive impact on others including caregivers, not having one’s loving actions recognized and validated, being exposed to such social pathologies as racism/homophobia/sexism/ableism/ transphobia, etc. All of these can potentially impact (or not, as recent MRI studies have shown) on a multiplicity of genetic/epigenetic, cellular, neural, immunological processes as well as impacting various body organs and systems.

We now know that chronic stress can have detrimental impacts on various neurodegenerative disorders including Alzheimers, Parkinsons, MS, etc., as well as some cancers, e.g., Chronic Lymphocytic Leukemia (CLL). It can prematurely age cells (measured by lengths of cell telomeres and telomerase), decrease neurogenesis and synaptogenesis, impact on myelination, change gene expression, reduce neurotrophic factors like BDNF (brain-derived neurotrophic factors), and atropy multiple neural regions (potentially hypertrophy, increasing dendritic branching, in the amygdala which subserves threat detection).

High ACE scores (adverse childhood experiences) are associated with later diagnosis of major depression, borderline personality disorder, suicidality, substance use disorders, bipolar disorder, “schizophrenia,” anxiety disorders, etc., as well as multiple medical disorders including pulmonary, cardiac, autoimmune, some cancers, etc.

I still believe, based on ongoing research, that many if not most, of the neurobiological, neurochemical and immunological findings in what we unfortunately call the “schizophrenias,” can be explained, when they are present (often they are not), as the result of chronic stress arising from many different social-environmental (even transgenerational) sources. I first proposed this at an ISPS conference in London in 1997 and in many conferences since then.

However, all of this is only one possible part of the picture. We need to pay more attention to the processes of post-traumatic growth and incredible resilience, etc., including at the genetic level (the differential susceptibility hypothesis which shows that the same genes potentially associated with “disorder” also confer adaptability, health and resourcefulness). I often feel that I could not have survived the adverse situations many of the persons I see have experienced. I am forever grateful for what these persons have given to me, especially in terms of human connection, vulnerability and honesty.