Differential Diagnosis of Major Depressive Disorder and Bipolar Disorder: Genetic and Hormonal Assessment and the Influence of Early-Life Stress.

Few studies have assessed biomarkers for the differentiation of major depressive disorder (MDD) and bipolar disorder (BD). However, some elements of depression such as hormones and receptors of the renin-angiotensin-adrenal system (RAAS), the hypothalamus-pituitary-adrenal (HPA) axis, and history of early-life stress (ELS) could be considered for differential diagnosis. Therefore, this study aimed to assess aldosterone and cortisol levels, MR and GR gene polymorphisms, and ELS as potential biomarkers for differentiating MDD and BD. This study presents a case-control design. Groups comprised samples for genetic, cortisol, and aldosterone analysis: healthy control (HC; n = 113/97/103), MDD (n = 78/69/67) and BD (n = 82/68/65) subjects. Furthermore, all subjects were assessed for diagnostic screening, the severity of depression, and history of ELS by applying MINI-PLUS, GRID-HDRS, and CTQ, respectively. In addition, genotype and allelic frequencies of GR (N363S, R22/23K and BclI) and MR (MI180V and -2G/C) polymorphisms were evaluated via PCR. Our findings demonstrate that basal aldosterone levels may be a biomarker for differentiating BD and MDD. Furthermore, ELS affects the HPA axis in BD, cortisol may be considered a biomarker for distinguishing BD and MDD, but only in the absence of ELS, and, finally, history of ELS and MR-2G/C variant alleles are factors that contribute to the severity of depressive symptoms in MDD and BD.

Association of 11ß-hydroxysteroid dehydrogenase type1 (HSD11b1) gene polymorphisms with outcome of antidepressant therapy and suicide attempts.

The hypothalamic-pituitary-adrenal axis has been implicated in the pathophysiology of depressive disorders. HSD11B1 encodes 11ß-hydroxysteroid dehydrogenase type1 enzyme, responsible for converting cortisone to cortisol. Genetic polymorphisms in HSD11B1 may impact in depression outcome and risk of suicide. This study aimed to assess whether HSD11B1 genotypes and haplotypes are associated with depression risk, severity of symptoms and suicidal attempts, considering early-life stress as an environmental factor. Here, 142 depressive patients and 103 healthy controls were included. Patients were enrolled from the Affective Disorders ambulatory and day hospital units, both within the University General Hospital of Ribeirao Preto. All subjects were clinically assessed applying the Mini-PLUS International Neuropsychiatric Interview, followed by the 21-item GRID-Hamilton Depression Scale, Childhood Trauma Questionnaire and Beck Scale for Suicidal Ideation (BSI). All subjects underwent antecubital vein puncture to obtain blood for DNA extraction. Genotyping of rs11119328 and rs11811440 were performed using allele-specific oligonucleotide polymerase chain reaction. We found a significant association of rs11119328 variant genotypes with increased risk for at least one suicide attempt (OR: 7.10, p = 0.049) and an association of variant genotypes of rs11811440 with euthymic mood under optimized pharmacological treatment (OR: 0.05, P = 0.014). These tests included correction for confounding factors. The association of genetic markers with depression risk, GRID-HAM-D21 and BSI scores and the number of suicidal attempts were nonsignificant. Haplotypes combining both markers were not associated with the studied phenotypes. We conclude that HSD11B1 polymorphisms may be relevant biomarkers for detecting subjects genetically vulnerable to poorer antidepressant response and higher risk of suicide attempts.

Child Abuse and Neglect as Risk Factors for Comorbidity Between Depression and Chronic Pain in Adulthood.

It is estimated that comorbidity between depression and chronic pain reaches more than half of the depressed adult patients around the world. Evidence indicates that some stressors, such as early-life stress (ELS), mediate the co-occurrence of depression and chronic pain. This study aimed to assess whether ELS or any of its subtypes could be considered as risk factors for comorbidity between depression and chronic pain. For this purpose, 44 patients in depressive episode were evaluated, in which 22 were diagnosed with depression and chronic pain, and the other 22 patients were diagnosed with depression but without chronic pain. Results had shown that ELS occurrence is more significant among depressive patients with chronic pain compared with those without pain. When subtypes of ELS were evaluated, the group of depressive patients with pain showed significantly higher prevalence of emotional neglect than those depressive participants without pain. Data analysis has shown that severity of the depressive symptoms has a significant impact on the total score of childhood trauma, emotional abuse, physical abuse, emotional neglect, and physical neglect, and that emotional abuse, sexual abuse, and physical neglect have significant impact on the severity of depression. In conclusion, our findings indicate that ELS can be considered as a risk factor for the comorbidity between depression and chronic pain.

Genetic biomarkers for differential diagnosis of major depressive disorder and bipolar disorder: A systematic and critical review.

Depressive symptoms are present in the depressive mood state of bipolar disorder (BPD) and major depression disorder (MDD). Often, in clinical practice, BPD patients are misdiagnosed with MDD. Therefore, genetic biomarkers could contribute to the improvement of differential diagnosis between BPD and MDD. This systematic and critical review aimed to find in literature reliable genetic biomarkers that may show differences between BPD and MDD. This systematic review followed the PRISMA-P method. The terms used to search PubMed, Scopus, PsycINFO, and Web of Science were depress*, bipolar, diagnos*, genetic*, biomark*. After applying the selection criteria, N = 27 studies were selected, being n = 9 about biomarkers for BPD; n = 15, about MDD; and n = 3 for distinguishing MDD from BPD. A total of N = 3086 subjects were assessed in the selected studies (n = 486 in BPD group; n = 1212 in MDD group; and n = 1388, healthy control group). The articles were dated up to June 2017. Of the N = 27 studies, n = 16 assessed gene, n = 1 miRNA, n = 2 lcnRNA and n = 3 protein expressions, n = 4 methylation, and n = 4 polymorphisms. Some studies applied more than one of these genetic analyses. To find reliable genetic biomarkers we have taken into account the methodological care during the studies development and their validity. The genetic biomarkers selected are related to genes that play a fundamental role in synaptic plasticity, neurogenesis, mood control, brain ageing, immune-inflammatory processes and mitochondrial respiratory chain. BDNF gene expression was one of the genetic biomarkers that highlighted because of its capacity of distinguishing BPD and MDD groups, and being adequately reproduced by more than one selected study.

Emotional abuse in childhood is a differential factor for the development of depression in adults.

We evaluate the association between subtypes of early life stress (ELS; sexual abuse, physical abuse, emotional abuse, physical neglect, and emotional neglect) and psychiatric disorders in adults. The sample was composed of 81 adult psychiatric patients treated at the Day Hospital Unit in Brazil. The patients were assessed using the Mini International Neuropsychiatric Interview according to diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The presence of ELS was confirmed by the Childhood Trauma Questionnaire, which investigates abuse and neglect subtypes. The patients were also evaluated for the severity of psychiatric symptoms through self-report questionnaires. A total of 71.6% of the patients experienced some type of severe ELS compared with 28.4% of the patients without ELS. Of these, 55.5% reported having experienced emotional abuse; 48.1%, physical neglect; 45.7%, emotional neglect; 39.5%, physical abuse; and 27.2%, sexual abuse. Our data showed that, among the ELS subtypes, emotional abuse was positively associated with psychopathology in adults, particularly with mood disorders (p < 0.05). The patients with a history of emotional abuse had higher severity scores in all symptoms, such as depression, hopelessness, suicidal ideation, anxiety, and impulsivity. These data demonstrate the impact of ELS, especially in cases of emotional abuse, as a trigger for psychiatric disorders and indicate that the severity of ELS is associated with severity of psychiatric symptoms. Therefore, further studies are needed to assess the importance of emotional abuse as a risk factor of severe psychopathology in adults.

Assessment of the hypothalamic-pituitary-adrenal axis activity: glucocorticoid receptor and mineralocorticoid receptor function in depression with early life stress - a systematic review.

OBJECTIVE: The mechanisms involved in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, especially in the functioning of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in depressed patients, are not well elucidated. The objective of this study was to conduct a systematic review of articles that assess the HPA axis activity from GR and MR in depressed patients and healthy controls with or without early life stress. METHODS: We conducted a systematic review of articles in PubMed, SCOPUS and SciELO published between 2000 and 2011, using the following search terms: child abuse, depression, HPA axis, dexamethasone, prednisolone, fludrocortisone and spironolactone. Thirty-four papers were selected for this review. RESULTS: Most studies identified in this review used the dexamethasone/corticotropin-releasing hormone test and dexamethasone suppression test. In these studies, hypercortisolaemia was associated with depression. We identified three studies with the Prednisolone suppression test, only one study with the use of fludrocortisone and one with spironolactone. This review found nine studies that evaluated the HPA axis in individuals with early life stress. CONCLUSIONS: The majority of the studies assessed in this review show that early life stress leads to permanent changes in the HPA axis and may lead to development of depression in adults. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolaemia and reduced inhibitory feedback. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between GR and MR. Evidences have consistently showed that GR function is impaired in major depression, but few studies have assessed the activity of MR in depression and early life stress.