Alfredo Bellon

A consistent postmortem finding in schizophrenia (SCZ) is reduction in dendrites’ size. However, neurons with larger dendritic trees have also been encountered. In vitro experiments with neurons and neuronal-like cells coming directly from patients with SCZ showed similar results, evidencing at times more extensions and at others less arborizations. The process of extending and retracting neuronal outgrowths depends on microtubules polymerization and depolymerization. The possibility that microtubule polymerization/depolymerization is related to defects in the neuronal structure comes from several microtubular anomalies reported in SCZ such as its abnormal distribution in the cytoplasm, irregular shape of microtubules and even absence of these cytoskeletal components in dendrites. Moreover, microtubules in olfactory neuroepithelial cells from patients with SCZ were resistant to depolymerization. But whether deficits in microtubules are associated with abnormalities in the neuronal structure has never been investigated in living cells coming directly from patients. Therefore, we studied dynamic neurostructural changes in Monocyte-Derived-Neuronal-like cells (MDNCs) from 12 controls and 13 patients with SCZ. First, we showed that human neuroprogenitor cells and MDNCs have comparable neurostructural plasticity. Then, we investigated whether colchicine, a microtubular stabilizing and depolymerizing agent, disrupts dynamic neurostructural changes. The lowest concentration of colchicine tested, stopped dynamic neurostructural changes in MDNCs from controls, while cells from patients with SCZ continued to extend and retract neuronal outgrowths. Following, we investigated if antipsychotics impact dynamic structural changes, but our results were inconclusive. Our data indicate that, under certain circumstances, neuronal-like cells from patients with SCZ evidenced hyperdynamic microtubule-based neurostructural changes and consequently, link deficits in microtubules with anomalies in the neuronal shape. While other potential confounders are unlikely to have influenced our results, the effects of medications cannot be excluded.

Over the past two decades, suicide has consistently ranked among the leading causes of death in the United States. While suicide deaths are closely associated with uicidal ideation and attempts, these are not good predictors of future suicide deaths. Establishing who is at risk of suicide remains a challenge that is mostly hampered by the lack of understanding of its pathophysiology. Nonetheless, evidence continues to accumulate suggesting that suicide is driven by a complex and dynamic interaction between environmental factors and genetics. The identification of genes that place people at risk of suicide remains elusive, but data are rapidly evolving. In this narrative review, we describe how Tryptophan hydroxylase (TPH) genes, particularly TPH1 and TPH2, have been associated with suicide in various publications. There is also replicated evidence linking the brain-derived neurotrophic factor gene to suicide, with its most consistent results originating from epigenetic studies. Not surprisingly, many genes involved in the hypothalamic–pituitary–adrenal axis have been connected with suicide, but these data require replication. Finally, among the inflammatory genes studied in suicide, only specific polymorphisms in TNF-alpha and IL-6 may increase susceptibility to suicidal behavior. In conclusion, significant work remains to be performed as inconsistencies undermine the reliability of genetic results in suicide. Potential avenues for future research are proposed.

The inaccessibility of neurons coming directly from patients has hindered our understanding of mental illnesses at the cellular level. To overcome this obstacle, six different cellular approaches that carry the genetic vulnerability to psychiatric disorders are currently available: Olfactory Neuroepithelial Cells, Mesenchymal Stem Cells, Pluripotent Monocytes, Induced Pluripotent Stem Cells, Induced Neuronal cells and more recently Brain Organoids. Here we contrast advantages and disadvantages of each of these six cell-based methodologies. Neuronal-like cells derived from pluripotent monocytes are presented in more detail as this technique was recently used in psychiatry for the first time. Among the parameters used for comparison are; accessibility, need for reprograming, time to deliver differentiated cells, differentiation efficiency, reproducibility of results and cost. We provide a timeline on the discovery of these cell-based methodologies, but, our main goal is to assist researchers selecting which cellular approach is best suited for any given project. This manuscript also aims to help readers better interpret results from the published literature. With this goal in mind, we end our work with a discussion about the differences and similarities between cell-based techniques and postmortem research, the only currently available tools that allow the study of mental illness in neurons or neuronal-like cells coming directly from patients.

Despite the benefits of antipsychotic medications, there are known and severe side effects. The cardiometabolic side effects have been well-studied, and there are practice guidelines directing their management (1). In contrast, while most antipsychotics are known to increase prolactin levels, routine monitoring of serum prolactin has not yet been adopted as standard practice. The Clinical Guidelines of The Endocrine Society recommend monitoring of prolactin in symptomatic patients, and in certain pathologic states, however, they do not comment on how to proceed when patients are prescribed medications that are known to increase prolactin levels (2). Given the negative consequences of hyperprolactinemia (3), and the possibility for reasonable modifications to antipsychotic regimens (4, 5), we suggest routine monitoring of prolactin in patients who are prescribed antipsychotics. The current standard in psychiatric practice is not to measure serum prolactin unless the patient becomes symptomatic, but hyperprolactinemia may be asymptomatic in the short term, and in the long term, there is potential for serious sequelae. In men and women, undetected hyperprolactinemia over time may cause decreased energy, reduced muscle mass, infertility, osteopenia, and bone fractures (6, 7). Differences between prolactin effects among antipsychotics have been well-studied, with Amisulpride and Risperidone causing the greatest increase in serum prolactin, and Aripiprazole decreasing prolactin levels. The adverse effects are generally dose-dependent, and differential effects are thought to be mostly due to varying degrees of dopamine-2receptor antagonism (8). Given the serious side-effects of hyperprolactinemia and the possibilities for changing management by lowering dosage or switching to a different antipsychotic, we propose routinely monitoring prolactin levels in patients who are prescribed antipsychotics. A baseline prolactin level should be drawn prior to initiation of antipsychotics, and a followup level after titration is completed. While this may add to the cost of healthcare (9), we believe that the benefits to patients outweighs the financial burden. Just as we monitor

Cardiovascular disease (CVD), including heart disease and stroke, continues to be the leading cause of death worldwide. Patients with mental health disorders, including schizophrenia (SCZ) are known to have an increased risk for CVD. Given the association with metabolic syndrome, patients with SCZ are often prescribed metformin and statins but its impact remains unsatisfactory. The use of aspirin (ASA) to decrease cardiovascular risk in the general population has been thoroughly investigated and clear guidelines are currently in place. Since adjuvant treatment with ASA could possibly decrease CVD risk and mortality in SCZ, we conducted a systematic review of the literature to determine the state of the current literature on this subject. Our systematic review points to gaps in the literature on CVD prevention in SCZ and illustrates an obvious need for further research. Although several studies have shown increased CVD risk in SCZ, to date, no research has been conducted on the utilization of CVD preventative treatment such as ASA for SCZ.

The long lapse between the presumptive origin of schizophrenia (SCZ) during early development and its diagnosis in late adolescence has hindered the study of crucial neurodevelopmental processes directly in living patients. Dopamine, a neurotransmitter consistently associated with the pathophysiology of SCZ, participates in several aspects of brain development including pruning of neuronal extensions. Excessive pruning is considered the cause of the most consistent finding in SCZ, namely decreased brain volume. It is therefore possible that patients with SCZ carry an increased susceptibility to dopamine’s pruning effects and that this susceptibility would be more obvious in the early stages of neuronal development when dopamine pruning effects appear to be more prominent. Obtaining developing neurons from living patients is not feasible. Instead, we used Monocyte-Derived-Neuronal-like Cells (MDNCs) as these cells can be generated in only 20 days and deliver reproducible results. In this study, we expanded the number of individuals in whom we tested the reproducibility of MDNCs. We also deepened the characterization of MDNCs by comparing its neurostructure to that of human developing neurons. Moreover, we studied MDNCs from 12 controls and 13 patients with SCZ. Patients’ cells differentiate more efficiently, extend longer secondary neurites and grow more primary neurites. In addition, MDNCs from medicated patients expresses less D1R and prune more primary neurites when exposed to dopamine. Haloperidol did not influence our results but the role of other antipsychotics was not examined and thus, needs to be considered as a confounder.

The long lapse between the presumptive origin of schizophrenia (SCZ) during early development and its diagnosis in late adolescence has hindered the study of crucial neurodevelopmental processes directly in living patients. Dopamine, a neurotransmitter consistently associated with the pathophysiology of SCZ, participates in several aspects of brain development including pruning of neuronal extensions. Excessive pruning is considered the cause of the most consistent finding in SCZ, namely decreased brain volume. It is therefore possible that patients with SCZ carry an increased susceptibility to dopamine’s pruning effects and that this susceptibility would be more obvious in the early stages of neuronal development when dopamine pruning effects appear to be more prominent. Obtaining developing neurons from living patients is not feasible. Instead, we used Monocyte-Derived-Neuronal-like Cells (MDNCs) as these cells can be generated in only 20 days and deliver reproducible results. In this study, we expanded the number of individuals in whom we tested the reproducibility of MDNCs and deepened the neurostructural comparison between human developing neurons and these neuronal-like cells. Moreover, we studied MDNCs from 12 controls and 13 patients with SCZ. Patients’ cells differentiate more efficiently, extend longer secondary neurites and grow more primary neurites. In addition, MDNCs from a subset of patients expresses less D1R and prune more primary neurites when exposed to dopamine. Haloperidol did not influence our results but the role of other antipsychotics was not examined.