A number of influences have converged that make this Special Theme Issue timely: “A New Direction: Considering Developmentally Sensitive Targets for Very Early Intervention in Schizophrenia”. These factors include: 1. the substantial knowledge about premorbid developmental vulnerabilities to psychosis, especially regarding schizophrenia; 2. the promising results emerging from interventions during the clinical high-risk (CHR) phase of psychosis and; 3. the recognition that the CHR period is a relatively late phase of developmental derailment. These factors have together led to a perspective that even earlier intervention is warranted. This paper briefly summarizes the articles comprising the Special Theme including new data on early neurocognitive development, proposed potential targets for psychosocial and psychopharmacological interventions during the premorbid period as early as pregnancy, and ethical challenges. These thought experiments must be empirically tested, and the ethical challenges overcome as posed by the various interventions, which range from relatively low risk, supportive, psychosocial to higher risk, experimental, pharmacological interventions. All of the interventions proposed require careful study of ethics, safety, potential stigma, feasibility, efficacy and tolerability, and the meaning to the people involved.
Perinatal pharmacological intervention with choline
“Ross and Freedman suggest a novel approach toward identifying underlying mechanisms of risk for psychosis through the measurement of endophenotypes during the perinatal period. This is innovative because schizophrenia is a neurodevelopmental disorder, whose onset is the end result of brain changes that begin prenatally, but most endophenotype studies have evaluated adolescents or adults who have entered or passed through the age of risk for the disorder. They suggest a treatment approach that targets a well-known schizophrenia endophenotype, P50 sensory gating. They based a randomized control trial in 76 healthy pregnant women on the hypothesis that perinatal choline supplementation would increase activation of alpha7 nicotinic receptors and normalize developmental defects associated with receptor deficiencies, including deficits in P50 sensory gating. Infants whose mothers had received prenatal choline demonstrated improved infant P50 sensory gating, compared to those whose mothers received placebo. There was an interaction between choline supplementation with infant genotype on CHRNA7 SNP re3087454 on P50 suppression ratio that increased plausibility. At 40 months follow-up, the children had significantly improved attention, which is often impaired in children who later develop schizophrenia. This preliminary work is promising, and if safe, could be considered for a neurobiologically informed primary prevention intervention for pregnant mothers with schizophrenia. Nevertheless, the idea that choline can prevent schizophrenia is quite speculative, and there are many steps needed to confirm this approach including whether improving P50 or accelerating the maturation of P50 can change the vulnerability to schizophrenia.”
Animal studies involving choline supplementation in prenatal/perinatal [1, 2] and adolescent  developmental periods have shown various benefits. A procholine supplement has improved sensory gating and executive function in healthy adults 
Targeting oxidative stress, neuroinflammation, NMDAR hypofunction
[researchers] “…suggest that drugs that target the “hub” of oxidative stress and related dysfunctions (neuroinflammation and NMDAR hypofunction) would be candidates for repairing these developmental anomalies, including Omega 3, sulforaphane and N-acetylcysteine (NAC)”
- supplementation with the correct amount of vitamin D in early life could decrease the risk of schizophrenia
- supplementation of omega-3 fatty acids in the form of fish oils could decrease the onset of psychosis for high-risk subjects
- supplementation with d-serine during juvenile and preadolescent stages could prevent the onset of psychosis at the adult stage. A natural conclusion would be that supplementation with the endogenous, and therefore safe d-serine, could protect adolescents and young adults at high-risk of developing psychosis.
- Sulforaphane (SFN) conferred antipsychotic benefits in rodent models of schizophrenia. Interestingly, we found that supplementation with SFN during juvenile stages could prevent the onset of cognitive impairment in the preclinical PCP model of schizophrenia. Therefore, supplementation with SFN-rich broccoli sprout extract during childhood and pre-adolescence may prevent the onset of psychosis in adulthood, assisted by the fact that this extract is widely available as a supplement.
- The antioxidant N-acetylcysteine (NAC) has the potential to prevent psychosis
“These findings suggest that early intervention with safe supplements could improve cognitive impairment in adolescents and young adults, and possibly prevent the onset of schizophrenia. Finally, we would like to propose a hypothesis that nutrition in childhood and preadolescent stages could have a high impact on subsequent mental health at adolescent and adult stages, particularly the adequate intake of omega-3 fatty acid-rich fish and vegetables (e.g., SFN-rich broccoli sprout), and possibly prevent the onset of psychiatric diseases.”