Reduced mitochondrial respiratory capacity in patients with acute episodes of bipolar disorder: Could bipolar disorder be a state-dependent mitochondrial disease?

BACKGROUND: Bipolar disorder (BD) is a chronic and recurrent disease characterized by acute mood episodes and periods of euthymia. The available literature postulates that a biphasic dysregulation of mitochondrial bioenergetics might underpin the neurobiology of BD. However, most studies focused on inter-subject differences rather than intra-subject variations between different mood states. To test this hypothesis, in this preliminary proof-of-concept study, we measured in vivo mitochondrial respiration in patients with BD during a mood episode and investigated differences compared to healthy controls (HC) and to the same patients upon clinical remission. METHODS: This longitudinal study recruited 20 patients with BD admitted to our acute psychiatric ward with a manic (n = 15) or depressive (n = 5) episode, and 10 matched HC. We assessed manic and depressive symptoms using standardized psychometric scales. Different mitochondrial oxygen consumption rates (OCRs: Routine, Leak, electron transport chain [ETC], Rox) were assessed during the acute episode (T0) and after clinical remission (T1) using high-resolution respirometry at 37°C by polarographic oxygen sensors in a two-chamber Oxygraph-2k system in one million of peripheral blood mononuclear cells (PMBC). Specific OCRs were expressed as mean ± SD in picomoles of oxygen per million cells. Significant results were adjusted for age, sex, and body mass index. RESULTS: The longitudinal analysis showed a significant increase in the maximal oxygen consumption capacity (ETC) in clinical remission (25.7 ± 16.7) compared to the acute episodes (19.1 ± 11.8, p = 0.025), and was observed separately for patients admitted with a manic episode (29.2 ± 18.9 in T1, 22.3 ± 11.9 in T0, p = 0.076), and at a trend-level for patients admitted with a depressive episode (15.4 ± 3.9 in T1 compared to 9.4 ± 3.2 in T0, p = 0.107). Compared to HC, significant differences were observed in ETC in patients with a bipolar mood episode (H = 11.7; p = 0.003). Individuals with bipolar depression showed lower ETC than those with a manic episode (t = -3.7, p = 0.001). Also, significant differences were observed in ETC rates between HC and bipolar depression (Z = 1.000, p = 0.005). CONCLUSIONS: Bioenergetic and mitochondrial dysregulation could be present in both manic and depressive phases in BD and, importantly, they may restore after clinical remission. These preliminary results suggest that mitochondrial respiratory capacity could be a biomarker of illness activity and clinical response in BD. Further studies with larger samples and similar approaches are needed to confirm these results and identify potential biomarkers in different phases of the disease.

Clinical, sociodemographic and environmental predicting factors for relapse in bipolar disorder: A systematic review.

INTRODUCTION: Bipolar disorder (BD) is a chronic and recurrent illness characterized by manic, mixed or depressive episodes, alternated with periods of euthymia. Several prognostic factors are associated with higher rates of relapse, which is crucial for the identification of high-risk individuals. This study aimed at systematically reviewing the existing literature regarding the impact of sociodemographic, clinical and environmental factors, in clinical relapses, recurrences and hospitalizations due to mood episodes in BD. METHODS: A systematic search of electronic databases (PubMed, Cochrane library and Web of Science) was conducted to integrate current evidence about the impact of specific risk factors in these outcomes. RESULTS: Fifty-eight articles met the inclusion criteria. Studies were grouped by the type of factors assessed. Family and personal psychiatric history, more severe previous episodes, earlier age of onset, and history of rapid cycling are associated with clinical relapses, along with lower global functioning and cognitive impairments. Unemployment, low educational status, poorer social adjustment and life events are also associated with higher frequency of episodes, and cannabis with a higher likelihood for rehospitalization. LIMITATIONS: Small sample sizes, absence of randomized clinical trials, diverse follow-up periods, lack of control for some confounding factors, heterogeneous study designs and diverse clinical outcomes. CONCLUSIONS: Although current evidence remains controversial, several factors have been associated with an impaired prognosis, which might allow clinicians to identify patients at higher risk for adverse clinical outcomes and find modifiable factors. Further research is needed to elucidate the impact of each risk factor in the mentioned outcomes.

Association between neutrophil to lymphocyte ratio and inflammatory biomarkers in patients with a first episode of psychosis.

Neutrophil to lymphocyte ratio (NLR) has been proposed as an emerging marker of the immune system alterations in psychotic disorders. However, it is not entirely clear whether NLR elevation is a characteristic of the psychotic disorder itself, which inflammatory pathways activation is detecting, or which possible confounding variables could alter its interpretation. We aimed to analyze the relationship of NLR values with a panel of inflammatory and oxidative/nitrosative stress biomarkers and main potential confounding factors in a well-characterized cohort of 97 patients with a first episode of psychosis (FEP) and 77 matched healthy controls (HC). In the FEP group, NLR values presented a moderate, positive correlation with the pro-inflammatory mediator Prostaglandin E2 levels (r = 0.36, p < 0.001) and a small but significant, positive correlation with cannabis use (r = 0.25, p = 0.017). After controlling for cannabis use, the association between NLR and PGE2 remained significant (beta = 0.31, p = 0.012). In the HC group, NLR values negatively correlated with body mass index (BMI, r = -0.24, p = 0.035) and positively correlated with tobacco use (r = 0.25, p = 0.031). These findings support a relationship between the elevation of NLR values and an elevated expression of proinflammatory pathways related to stress response in patients with a FEP. In addition, our study highlights the importance of considering variables such as cannabis or tobacco consumption, and BMI when interpreting the results of studies aimed to establish a clinical use of NLR. These considerations may help future research to use NLR as a reliable biomarker to determine immune system status in this population.

Manic episode in a patient with pancreatic adenocarcinoma: a case report.

Psychiatric comorbidity is common in cancer patients, emphasizing the need for comprehensive care. While depressive symptoms in pancreatic cancer have been studied, there is limited attention given to manic symptoms. This case report aims to contribute to the knowledge of pancreatic cancer psychiatric comorbidities by describing a case of a patient with stage IV pancreatic cancer who presented a sudden onset manic episode. The patient, a 61-year-old male with stage IV pancreatic cancer, presented at the Emergency Room with abrupt behavioural changes suggestive of a manic episode of 2 weeks of evolution. The patient had been undergoing chemotherapy and short 3-day cycles of corticosteroids for the past 9 months but had been off this treatment for 20 days when the episode began. Acute organic causes were ruled out. The patient was admitted to the psychiatric unit, where organic screening was expanded and treatment with antipsychotics and a mood stabiliser was initiated with subsequent remission of symptoms after 2 weeks. This case shows a manic episode as a rare psychiatric complication in pancreatic cancer. In the literature reviewed, four other similar cases have been observed. Further research is needed to elucidate the underlying pathophysiology and explore possible treatment strategies.