|
|
|
|
|
|
|
Medical Pharmacology Chapter 16: Pharmacology of Antipsychotics Drugs
|
|
|
|
|
|
|
Risk Factors for Psychosis and Schizophrenia
Schizophrenia and psychotic disorders are best understood through a stress-diathesis model: a neurobiological vulnerability likely genetic in origin which is necessary but not sufficient requiring interaction with environmental risk factors at critical developmental periods.7
No single gene, no single environmental insult, and no single neurobiological lesion is responsible.
The etiology appears polygenic, multi-environmental, and interactive.
The heritability of schizophrenia is estimated at approximately 65–80%, among the highest of any medical disorder.
The concordance rate in monozygotic twins is approximately 40–50%, and in dizygotic twins 10–15% which confirms a strong genetic influence while demonstrating that predisposition alone is insufficient.4,7 (concordance https://en.wikipedia.org/wiki/Concordance_(genetics))
First-degree relatives have a 10-fold increased risk.
Genome-Wide Association Study (GWAS) have identified hundreds of common Single Nucleotide Polymorphism (SNPs) of small individual effect. (https://www.genome.gov/genetics-glossary/Genome-Wide-Association-Studies-GWAS); (https://en.wikipedia.org/wiki/Single-nucleotide_polymorphism)
The C4A gene, which appears involved in synaptic pruning via the complement cascade during adolescence, as a possible site accounting for some of the genetic risk.3,4
Rare copy number variants (CNVs), including deletions at sites 22q11.2 (velocardiofacial syndrome), 1q21.1,and 15q11-13, confer notably elevated individual risk, and findings support the suggestions of shared genetic architecture across schizophrenia, bipolar disorder, autism spectrum disorder, and major depressive disorder.
Prenatal and Obstetric Risk Factors
Prenatal exposure to maternal influenza infection, particularly during the second trimester,was among the earliest identified risk factors, with the 1957 Helsinki birth cohort providing foundational evidence.
Maternal immune activation through Toxoplasma gondii and herpes simplex virus type 2 also conveys risk through immune-mediated disruption of fetal neurodevelopment.
Severe maternal nutritional deficiency, as documented in studies of the 1944 Dutch Hunger Winter, doubles the risk of schizophrenia in offspring, implicating nutritional epigenetic mechanisms.7
Obstetric complications such as hypoxia, preeclampsia, fetal distress, and low birth weight contribute through hypoxic-ischemic injury to developing dopaminergic and glutamatergic circuits.
Advanced paternal age at conception is an independent risk factor, operating through de novo mutations accumulating in the paternal germline.
Evidence from multiple longitudinal population-based studies suggests that cannabis use approximately doubles the risk of schizophrenia, with dose-response, frequency-response, and potency-response relationships.
Daily users of high-THC-potency cannabis have up to a five-fold increased risk.9
Cannabis also accelerates the age of onset of psychosis by two to five years in vulnerable individuals.
Neurobiological mechanism centers on THC action on CB1 receptors in the prefrontal cortex and limbic system, increasing striatal dopamine release.
Genetic variation, particularly in the AKT1 and COMT genes, moderates individual susceptibility.9,10
Other substances associated with psychosis include methamphetamine, cocaine, LSD, phencyclidine (PCP), and (in withdrawal) alcohol and benzodiazepines.
Psychosocial and Environmental Risk Factors
The 'social defeat hypothesis' proposes that chronic social exclusion, experienced disproportionately by ethnic minorities, migrants, and individuals in socially fragmented urban environments dysregulates the mesolimbic dopamine system through chronic stress sensitization, lowering the threshold for psychotic decompensation.
This assessment the elevated rates of schizophrenia in first- and second-generation migrants and the gradient of urbanicity itself.
A foundational meta-analysis by Varese et al. (2012), encompassing 36 independent studies, found childhood adversity to be strongly associated with psychosis with a population attributable risk of 33%.15
A subsequent dose-response meta-analysis of 21 studies comprising nearly 60,000 participants found that the odds ratio for psychosis increased from 1.76 (95% CI: 1.39–2.22) for a single exposure to 6.46 (95% CI: 4.37–9.53) for five or more exposures. These data provide evidence for a nonlinear, accelerating dose-response relationship.16
Auditory hallucinations in psychosis frequently have content related to past traumatic experiences, and trauma-informed care is important in treating psychotic disorders.17
Season of Birth, Immune, and Neurodevelopmental Factors
Epidemiological studies have consistently documented a modest but replicable excess of schizophrenia births in late winter and early spring in the Northern Hemisphere, thought to reflect prenatal viral exposure during the second trimester.7
The neurodevelopmental hypothesis which is now the dominant etiological paradigm proposes that schizophrenia is fundamentally a disorder of aberrant brain development initiated in utero or during early childhood, manifesting clinically only when the prefrontal cortex reaches full maturation in late adolescence.4,7
The apparent late onset is therefore not the beginning of the pathological process but its long-delayed clinical expression, following decades of aberrant synaptic pruning, neuronal connectivity abnormalities, and compensatory mechanisms that ultimately fail under the neurobiological demands of the mature brain.
The 'two-hit' model,an early priming insult in a genetically predisposed individual followed by an environmental second hit, remains a useful framework for analyzing etiology.7
|
|
|
|
|
|
 |
|
DISCLAIMER
|
