Ketamine cystitis following ketamine therapy for treatment-resistant depression - case report.

BACKGROUND: Ketamine is a novel and exciting putative antidepressant medication for patients with treatment-resistant depression. A complication commonly seen in frequent and heavy recreational use of ketamine is ulcerative cystitis, which presents with lower urinary tract symptoms (LUTS) and upper renal tract damage and can be seen in over 25% of regular users. Although Ketamine-induced cystitis (KIC) is a recognised complication in recreational use of ketamine, its occurrence in therapeutic use of ketamine in depression has so far not been reported. The exact pathogenesis of KIC is currently unknown, making treatment and prevention advice much more difficult. Early diagnosis of KIC and immediate cessation of ketamine has been shown to improve adverse urinary tract symptoms and prevent further damage. CASE PRESENTATION: We present a case of a 28-year-old female who was started on ketamine treatment for depression, and who then developed symptoms of KIC, which was confirmed by urine microscopy, culture and analysis. CONCLUSIONS: To our knowledge, this is the first reported case of KIC in a patient receiving treatment-dose ketamine as part of their antidepressant therapy.

Posttraumatic stress disorder (PTSD) and depression severity in sexually assaulted women: hypothalamic-pituitary-adrenal (HPA) axis alterations.

BACKGROUND: Sexual assault is implicated in several adverse psychological and physical health outcomes, including posttraumatic stress disorder (PTSD) and depression. Neurobiological research has shown variations related to the hypothalamic-pituitary-adrenal (HPA) axis, immune alterations, metabolic function, and brain circuitry. Although these mechanisms have been extensively studied, the results have demonstrated different outcomes in PTSD. METHODS: We compared the plasma adrenocorticotropin (ACTH) and salivary cortisol levels of fifty-eight women with PTSD developed after sexual assault to those of forty-four female controls with no history of trauma. We also evaluated the psychiatric diagnosis and symptom severity of PTSD and depression. The participants' clinical conditions were associated with their hormonal levels to assess whether symptom severity was related to hormonal imbalance. RESULTS: A large percentage of sexually assaulted women had PTSD and comorbid depression. The ACTH levels were higher in the PTSD group than the control group and increased as PTSD severity increased, considering depressive symptoms, measured by the Beck Depression Inventory (BDI) (p < 0.0001), as well as PTSD symptoms, measured by subscale D of the Clinician-Administered PTSD Scale (CAPS-5) (p = 0.045) and the CAPS-5 total scale (p = 0.026). Cortisol levels measured at 10 pm were higher for the PTSD group than the control group (p = 0.045, p = 0.037, respectively), and the cortisol awakening response showed elevated cortisol levels for the PTSD group. CONCLUSIONS: These results show a correlation between symptom severity and HPA axis imbalance in patients with PTSD. Elevated ACTH and an elevated cortisol response in patients with comorbid depressive symptoms were the opposite of the expected response for patients with PTSD only. This association leads to the hypothesis that the neurobiological alterations of PTSD are related to the type of symptoms presented and their severity. These manifestations likely influence the disease course, prognosis and response to treatment. These outcomes highlight the need to discuss particular neurobiological alterations in patients with PTSD developed after sexual assault, mainly those with severe depressive symptoms.

International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic).

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

Vagus nerve stimulation as adjunctive therapy in patients with difficult-to-treat depression (RESTORE-LIFE): study protocol design and rationale of a real-world post-market study.

BACKGROUND: Depressive illness is associated with significant adverse consequences for patients and their families, and for society. Clinical challenges are encountered in the management of patients suffering from depression whether they are designated difficult-to-treat or treatment-resistant. Prospective serial depression treatment trials have shown that less than 40% of patients with major depressive disorder remit with an initial pharmacotherapy trial, and a progressively smaller proportion of patients remit with each subsequent trial. For patients who suffer from difficult-to-treat depression (DTD), treatments should focus on patient-centred symptom control, patient functioning, and improving patient quality of life. Among the treatment options for patients with DTD is Vagus Nerve Stimulation (VNS) Therapy. VNS Therapy involves intermittent electrical stimulation of the left cervical vagus nerve and has been shown to be efficacious for long-term management of patients with DTD. METHODS: RESTORE-LIFE is a prospective, observational, multi-site, global post-market study intended to assess short-, mid-, and long-term effectiveness and efficiency outcomes in a 'real-world' setting among patients with DTD treated with adjunctive VNS Therapy. A minimum of 500 patients will be implanted with a VNS Therapy System at up to 80 global sites. Eligible patients will participate in a baseline visit between 1 and 6 weeks before device implant and will be followed for a minimum of 36 months and a maximum of 60 months. The diagnosis of depression and comorbid disorders will be determined using the Mini-International Neuropsychiatric Interview (MINI). The primary endpoint is response rate, defined as a decrease of ≥50% in Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to 12 months post-implant. DISCUSSION: A standardized approach in the management of DTD may not be appropriate for the treatment of such a complex heterogenous patient population. This study has been designed to evaluate whether VNS Therapy meaningfully improves and sustains clinical and depressive symptom outcomes in patients with DTD. This study will investigate the durability of VNS response in DTD and utility of VNS for long-term disease management of DTD. In addition, the study results will potentially clarify clinical, functional, and health economic questions in a real-world patient population with DTD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03320304. Registered 25 October 2017.

The Role of Early Life Stress in HPA Axis and Anxiety.

Substantial evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology. The most recent studies reviewed here suggest that early life stressors are associated with an increased risk for anxiety disorders in adulthood. Early life stress predisposes individuals to develop a number of psychiatric syndromes, particularly affective disorders, including anxiety disorders, and is therefore a significant health problem.This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and generalized anxiety disorder (GAD), panic disorder, and phobias and the role of early life stress as an important risk factor for HPA axis dysfunction.The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. In addition to melancholic depression, a spectrum of other conditions may be associated with increased and prolonged activation of the HPA axis, including panic, GAD, phobias and anxiety. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the anxiety syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysfunction of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in anxiety disorders. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. Early stressful life events may provoke alterations of the stress response and thus of the HPA axis that can endure during adulthood, predisposing individuals to develop psychopathology.

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.

Early-life stress and HPA axis trigger recurrent adulthood depression.

It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual. During acute stress, adaptive physiological responses occur, which include hyperactivity of the HPA axis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behavior, and they influence the process of adaptation or 'allostasis'. It is correct to state that at the same time that our experiences change our brain and thoughts, namely, changing our mind, we are changing our neurobiology. Increased adrenocortical secretion of hormones, primarily cortisol in major depression, is one of the most consistent findings in neuropsychiatry. A significant percentage of patients with major depression have been shown to exhibit increased concentrations of cortisol, an exaggerated cortisol response to adrenocorticotropic hormone, and an enlargement of both the pituitary and adrenal glands. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of hypothalamic-pituitary-adrenal (HPA) hormones through binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Evidence indicates that early-life stress can induce persistent changes in the ability of the HPA axis to respond to stress in adulthood. These abnormalities appear to be related to changes in the ability of hormones to bind to GR and MR receptors. First episodes may begin with an environmental stressor, but if the cycles continue or occur unchecked, the brain becomes kindled or sensitized, and future episodes of depression, hypomania, or mania will occur independently of an outside stimulus, with greater frequency and intensity. Generally, HPA axis changes appear in chronic depressive and more severe episodes. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA dysfunction has been associated with higher rates of relapse and chronicity.

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.

Effect of childhood emotional abuse on depression and anxiety in adulthood is partially mediated by neuroticism: Evidence from a large online sample.

Childhood trauma is widely recognized as a potential risk factor for psychiatric illness in adulthood, yet the precise mechanisms underlying this relationship remain incompletely understood. One proposed mechanism involves the impact of childhood trauma on personality development, particularly in relation to neuroticism, which may subsequently heighten susceptibility to psychiatric disorders. In this study, we aimed to investigate this hypothesis through an online survey involving 1116 participants (232 male, 21 %). Participants completed the Childhood Trauma Questionnaire (CTQ), assessing emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect, along with the Trait Self-Description Inventory (TSDI) for personality assessment and the PHQ-9 and GAD-7 clinical questionnaires for depression and anxiety symptoms evaluation, respectively. Our analyses revealed significant positive correlations between all facets of childhood trauma and neuroticism (all p < .01). Linear regression analysis demonstrated that emotional abuse significantly contributed to neuroticism (ß = 0.267, p < .05), openness (ß = 0.142, p < .05), and agreeableness (ß = 0.089, p < .05), while sexual abuse was associated with agreeableness (ß = 0.137, p < .01) Emotional neglect was negatively correlated with conscientiousness (ß = -0.090, p < .01), extroversion (ß = -0.109, p < .01) and agreeableness (ß = -0.154, p < .01). Furthermore, linear regression analysis revealed that emotional abuse was positively and significantly correlated with PHQ-9 and GAD-7 scores (r = 0.330, p < .01 and r = 0.327, p < .01, respectively). Mediation analysis supported a significant mediating role of neuroticism in the association between childhood emotional abuse and both depression (PHQ-9) (z = 8.681, p < .01) and anxiety (GAD-7) (z = 9.206, p < .01). Notably, the correlation between childhood emotional abuse and psychiatric symptoms was attenuated but not eliminated after controlling for neuroticism, suggesting partial mediation. While our cross-sectional design precludes causal inference, our findings support the notion that childhood emotional abuse may contribute to increased neuroticism, thereby elevating vulnerability to affective disorders in adulthood. These results underscore the importance of considering personality factors in understanding the long-term consequences of childhood trauma on mental health outcomes.

Early life stress unravels epistatic genetic associations of cortisol pathway genes with depression.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of the most consistent pathophysiological findings in depressive disorders. Cortisol signaling is affected by proteins that mediate its cellular responses or alters its availability to mineralocorticoid and glucocorticoid receptors. In our study, we evaluated candidate genes that may influence the risk for depression and suicide due to its involvement in cortisol signaling. The aim of the study was to assess whether the genotypes of these genes are associated with the risk for depression, severity of depressive symptoms, suicidal ideation, and suicide attempts. And whether there is interaction between genes and early-life stress. In this study, 100 healthy controls and 140 individuals with depression were included. The subjects were clinically assessed using the 21-item GRID-Hamilton questionnaires (GRID-HAMD-21), Beck Scale for Suicidal Ideation (BSI), and the Childhood Trauma Questionnaire (CTQ). A robust multifactorial dimensionality reduction analysis was used to characterize the interactions between the genes HSD11B1, NR3C1, NR3C2, and MDR1 and early-life stress. It was found a significant association of the heterozygous genotype of the MDR1 gene rs1128503 polymorphism with reduced risk of at least one suicide attempt (OR: 0.08, p = 0.003*) and a reduction in the number of suicide attempts (ß = -0.79, p = 0.006*). Furthermore, it was found that the MDR1 rs1228503 and NR3C2 rs2070951 genes interact with early-life stress resulting in a strong association with depression (p = 0.001). Our findings suggest that polymorphisms in the MDR1 and NR3C2 genes and their interaction with childhood trauma may be important biomarkers for depression and suicidal behaviors.

A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study.

(1) Background Pharmacological treatment for psychiatric disorders has shown to only be effective in about one-third of patients, as it is associated with frequent treatment failure, often because of side effects, and a long process of trial-and-error pharmacotherapy until an effective and tolerable treatment is found. This notion emphasizes the urgency for a personalized medicine approach in psychiatry. (2) Methods This prospective patient- and rater-blinded, randomized, controlled study will investigate the effect of dose-adjustment of antidepressants escitalopram and sertraline or antipsychotics risperidone and aripiprazole according to the latest state-of-the-art international dosing recommendations for CYP2C19 and CYP2D6 metabolizer status in patients with mood, anxiety, and psychotic disorders. A total sample of N = 2500 will be recruited at nine sites in seven countries (expected drop-out rate of 30%). Patients will be randomized to a pharmacogenetic group or a dosing-as-usual group and treated over a 24-week period with four study visits. The primary outcome is personal recovery using the Recovery Assessment Scale as assessed by the patient (RAS-DS), with secondary outcomes including clinical effects (response or symptomatic remission), side effects, general well-being, digital phenotyping, and psychosocial functioning. (3) Conclusions This is, to our knowledge, the first international, multi-center, non-industry-sponsored randomized controlled trial (RCT) that may provide insights into the effectiveness and utility of implementing pharmacogenetic-guided treatment of psychiatric disorders, and as such, results will be incorporated in already available dosing guidelines.

The role of early life stress in adult psychiatric disorders: a systematic review according to childhood trauma subtypes.

Early life stress (ELS; sexual abuse, physical abuse, emotional abuse, physical neglect, and emotional neglect) has been the focus of numerous studies. It has been associated with the onset and the severity of psychiatric disorders in adults. The objective of this study was to review the literature on ELS associated with psychiatric disorders in adulthood, seeking to identify whether there are independent effects between subtypes of early stress in triggering psychopathology in adults. We reviewed articles from 2001 to 2011 in four databases (PubMed, SciELO, LILACS, and PsycINFO), with the following key words: child abuse, maltreatment, early life stress, psychiatric disorders, mental disease, and psychopathology. Forty-four articles were selected, and most of these articles demonstrate that the subtypes of ELS are associated with several psychiatric disorders, more specifically: physical abuse, sexual abuse, and unspecified neglect with mood disorders and anxiety disorders; emotional abuse with personality disorders and schizophrenia; and physical neglect with personality disorders. Physical neglect had the weakest association between the subtypes. ELS subtypes in childhood and adolescence can predict the development of psychopathology in adults. Scientific evidence shows that ELS triggers, aggravates, maintains, and increases the recurrence of psychiatric disorders. These results demonstrate the importance of a deeper understanding about the unique effects of ELS subtypes, especially for mental health professionals.

Effectiveness of psychoeducation for depression: a systematic review.

OBJECTIVE: Pharmacological treatment is considered indispensable to major depressive disorder. In spite of this, a significant number of patients do not respond adequately to treatment based only on medication, presenting high relapse and recurrence rates. Therefore, psychosocial interventions, such as psychoeducation, have been increasingly recognized as an essential component in the treatment of depression, associated with pharmacological strategies. Thus, the aim of the present systematic review was to evaluate the effectiveness of psychoeducation for patients with unipolar depression, analyzing the evidence from the literature. METHOD: Searches were undertaken from April to October 2012 in LILACS, PsycINFO, PubMed, SCOPUS and ISI Web of Knowledge with keywords including 'psychoeducation', 'psychoeducational intervention' and 'depression', with no restriction regarding publishing dates. RESULTS: Fifteen studies were included in the review, 13 of which evaluated the effectiveness of psychoeducation for patients with depression: 10 papers evaluated in-person psychoeducation approaches and three papers evaluated long-distance approaches. In addition to these 13 papers, one evaluated psychoeducational interventions for patients' families and patients' responses and another evaluated psychoeducational interventions for patients' families and families' responses. Findings suggest that increased knowledge about depression and its treatment is associated with better prognosis in depression, as well as with the reduction of the psychosocial burden for the family. CONCLUSIONS: Psychoeducation is a psychosocial treatment that has been well documented as an adjunct to pharmacological therapy. However, there are only a few studies regarding its effectiveness on adult patients with major depressive disorder. Although the publications in this area are still very limited, the articles selected in this review suggest that psychoeducation is effective in improving the clinical course, treatment adherence, and psychosocial functioning of depressive patients.

Early life stress, depression and epigenetics.

Different factors are essential in increasing the vulnerability to psychiatric disorders, such as genetics. Among these factors, early life stress (ELS), including sexual, physical, emotional abuse, and emotional and physical neglect, enhances the odds of having menial conditions throughout life. Exhaustive research has shown that ELS leads to physiological changes, such as alteration in the HPA axis. During the most critical development period (childhood and adolescence), these changes increase the risk of having child-onset psychiatric disorders. Furthermore, research has suggested a relationship between early life stress and depression, particularly more prolonged episodes of depression with treatment-resistant outcomes. Molecular studies indicate that, in general, the hereditary character of psychiatric disorders is polygenic, multifactorial and highly complex, with innumerable low-effect genetic variants interacting with each other. However, whether there are independent effects among subtypes of ELS remains unclear. This article provides an overview of the interplay of epigenetics, the HPA axis, early life stress and the development of depression. Advances in our knowledge of epigenetics in the context of early life stress and depression provide a new understanding of the genetic influence on psychopathology. Furthermore, they could lead to identifying new targets for clinical intervention.

Early Clinical Experiences of Esketamine Nasal Spray in the UK in Adults with Treatment-Resistant Major Depressive Disorder: Advisory Panel Recommendations.

Purpose: Treatment-resistant depression (TRD) is associated with profound morbidity for patients, placing a significant burden on those affected, the health service and wider society. Despite this, TRD remains chronically underserved in terms of viable treatment options. To address this gap, an advisory panel of psychiatrists and clinical researchers with experience in managing TRD convened to develop best practice statements on the use of esketamine nasal spray, one of the first TRD treatments to be licensed in 30 years. Methods: During a virtual meeting held on 12th November 2020, the advisory panel shared their experiences of using esketamine nasal spray in their clinical practice. The meeting focused on developing and refining recommendations for setting up and running an efficient esketamine nasal spray clinic for patients living with TRD. At the conclusion of the meeting, agreement was reached on all recommendation statements. Results: In setting up an esketamine nasal spray clinic, it is important to consider the logistical requirements involved and put measures in place to ensure it runs as efficiently as possible. Educating patients about the treatment and maintaining their well-being is paramount for preventing discontinuation. Putting in place checklists can be a useful strategy for ensuring treatment appointments run smoothly and safely. Conclusion: Providing additional treatment options for the management of TRD, such as esketamine nasal spray, is likely to be key to improving the long-term outcomes of this underserved patient population.

Biological rhythms are correlated with Na+, K+-ATPase and oxidative stress biomarkers: A translational study on bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a chronic, severe, and multifactorial psychiatric disorder. Although biological rhythms alterations, sodium potassium pump (Na+, K+-ATPase) changes, and oxidative stress appear to play a critical role in the etiology and pathophysiology of BD, the inter-connection between them has not been described. Therefore this study evaluated the association between biological rhythms, Na+, K+-ATPase, and oxidative stress parameters in BD patients and the preclinical paradoxical sleep deprivation model (PSD). METHODS: A translational study was conducted, including a case-control protocol with 36 BD and 46 healthy controls (HC). Subjects completed the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). In addition, Erythrocyte Na+, K+-ATPase activity, and oxidative and nitrosative stress markers were assessed (4-hydroxynonenal [4-HNE], 8-isoprostane [8-ISO], thiobarbituric acid reactive substances [TBARS], carbonyl, 3-nitrotyrosine [3-nitro]). In the preclinical protocol, the same biomarkers were evaluated in the frontal cortex, hippocampus, and striatum from mice submitted to the PSD. RESULTS: BD patients had a significantly higher total score of BRIAN versus HCs. Additionally, individuals with BD showed decreased Na+, K+-ATPase activity and increased oxidative stress parameters compared to HC without psychiatric disorders. This difference was driven by actively depressed BD subjects. The mice submitted to the PSD also demonstrated decreased Na+, K+-ATPase activity and increased oxidative stress parameters. LIMITATIONS: BRIAN biological underpinning is less well characterized; We did not control for medication status; Sample size is limited; PSD it is not a true model of BD. CONCLUSIONS: The present study found a significant correlation between Na+, K+-ATPase and oxidative stress with changes in biological rhythms, reinforcing the importance of these parameters to BD.

Identifying the neuropsychiatric health effects of low-dose lithium interventions: A systematic review.

BACKGROUND: Lithium is widely evidenced for its neuropsychiatric benefits. Advantages of 'sub-therapeutic' doses are increasingly being reported, which is apposite given enduring concerns around adverse effects of 'therapeutic' doses. We aimed to synthesise all available evidence from interventional studies investigating low-dose lithium (LDL) across neuropsychiatric outcomes. METHODS: Electronic databases were systematically searched to include studies where a group of adult humans were treated with LDL (∼serum level ≤0.6 mmol/L), where data describing a neuropsychiatric outcome were reported either before and after treatment, and/or between lithium and a comparator. RESULTS: 18 articles were examined and grouped according to outcome domain (cognition, depression, mania, and related constructs e.g., suicidality). Significant benefits (versus placebo) were identified for attenuating cognitive decline, and potentially as an adjunctive therapy for people with depression/mania. Across studies, LDL was reported to be safe. CONCLUSIONS: Despite the paucity and heterogeneity of studies, LDL's apparent pro-cognitive effects and positive safety profile open promising avenues in the fields of neurodegeneration, and augmentation in affective disorders. We urge future examinations of LDL's potential to prevent cognitive/affective syndromes.

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.