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There is now evidence that, based on cytokine profiles, bipolar disorder (BD) is accompanied by simultaneous activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), and that both components may be associated with the staging of illness. Nevertheless, no BD studies have evaluated the IRS/CIRS ratio using CD (cluster of differentiation) molecules expressed by peripheral blood activated T effector (Teff) and T regulatory (Treg) subpopulations. This study examined Teff/Treg subsets both before and after ex vivo anti-CD3/CD28 stimulation using flow cytometric immunophenotyping in 25 symptomatic remitted BD patients and 21 healthy controls and assessed human cytomegalovirus (HCMV)-specific IgG antibodies. BD is associated with a significantly lowered frequency of unstimulated CD3 + CD8 + CD71+ and CD4 + CD25 + FOXP3 and increased CD4 + CD25 + FOXP3 + CD152+ frequencies and with lowered stimulated frequencies of CD3 + CD8 + CD71+, CD4 + CD25 + FOXP3 + CD152+, and CD4 + CD25 + FOXP3 + GARP cells and, consequently, by an increased stimulated Teff/Treg ratio. Moreover, the number of manic, but not hypomanic or depressive episodes, is significantly and negatively associated with the stimulated proportions of CD3 + CD4 + CD154+, and CD69+ and CD71+ expression on CD4+ and CD8+ cells, while duration of illness (≥ 10 years) is accompanied by a depleted frequency of stimulated CD152+ Treg, and CD154+ and CD71+ CD4+ T cells. BD and anti-human cytomegalovirus (HCMV) IgG levels significantly interact to decrease the expression of CD4 + CD25 + FOXP+GARP T phenotypes. In conclusion, in BD patients, immune injuries, staging, and HCMV seropositivity interact and cause CIRS dysfunctions and exaggerated IRS responses, which play a key role in parainflammation and neuroaffective toxicity. HCMV seropositivity contributes to an immune-risk phenotype in BD.

Psychotic disorders affect ~3% of the general population and are among the most severe forms of mental diseases. In early stages of psychosis, clinical aspects may be difficult to distinguish from one another. Undifferentiated psychopathology at the first-episode of psychosis (FEP) highlights the need for biomarkers that can improve and refine differential diagnosis. We investigated gene expression differences between patients with FEP-schizophrenia spectrum (SCZ; N=53) or FEP-Mania (BD; N=16) and healthy controls (N=73). We also verified whether gene expression was correlated to severity of psychotic, manic, depressive symptoms and/or functional impairment. All participants were antipsychotic-naive. After the psychiatric interview, blood samples were collected and the expression of 12 psychotic-disorder-related genes was evaluated by quantitative PCR. AKT1 and DICER1 expression levels were higher in BD patients compared with that in SCZ patients and healthy controls, suggesting that expression of these genes is associated more specifically to manic features. Furthermore, MBP and NDEL1 expression levels were higher in SCZ and BD patients than in healthy controls, indicating that these genes are psychosis related (independent of diagnosis). No correlation was found between gene expression and severity of symptoms or functional impairment. Our findings suggest that genes related to neurodevelopment are altered in psychotic disorders, and some might support the differential diagnosis between schizophrenia and bipolar disorder, with a potential impact on the treatment of these disorders.

Objectives: To describe the onset pattern, frequency, and severity of the signs and symptoms of the prodrome of the first hypomanic/manic episode and first depressive episode of bipolar disorder (BD) and to investigate the influence of a history of childhood maltreatment on the expression of prodromal symptoms., Methods: Using a semi-structured interview, the Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R), information regarding prodromal symptoms was assessed from patients with a DSM-IV diagnosis of BD. History of childhood maltreatment was evaluated using the Childhood Trauma Questionnaire (CTQ)., Results: Forty-three individuals with stable BD were included. On average, the prodrome of mania lasted 35.8 ± 68.7 months and was predominantly subacute or insidious, with rare acute presentations. The prodrome of depression lasted 16.6 ± 23.3 months and was also predominantly subacute or insidious, with few acute presentations. The prodromal symptoms most frequently reported prior to the first hypomanic or manic episode were mood lability, depressive mood, and impatience. A history of childhood abuse and neglect was reported by 81.4% of participants. Presence of childhood maltreatment was positively associated with prodromal symptoms, including social withdrawal, decreased functioning, and anhedonia., Conclusions: This study provides evidence of a long-lasting, symptomatic prodrome prior to first hypomanic/manic and depressive episode in BD and suggests that a history of childhood maltreatment influences the manifestations of this prodrome.

Bipolar disorder (BD) usually follows a neurobiological progression pathway, but a relatively long interval between the first symptoms of the disorder and the correct diagnosis and treatment takes place in most patients. Strategies used to recognize BD at an early stage and even prior to the first manic episode could help identify the risk and modifying factors that influence the onset and course of disease, and improve outcomes. Drawing on current research results, this article presents considerations on risk factors for the development of BD, including genetic/familial risk, endophenotypes and clinical characteristics. Taken together, this article provides a framework and tools for research on the BD prodrome, as well as for the early recognition and timely treatment of patients prior to and immediately after the emergence of BD.