Effects of lithium on oxidative stress parameters in healthy subjects

Increased neuronal oxidative stress (OxS) induces deleterious effects on signal transduction, structural plasticity and cellular resilience, mainly by inducing lipid peroxidation in membranes, proteins and genes. Major markers of OxS levels include the thiobarbituric acid reactive substances (TBARS) and the enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase. Lithium has been shown to prevent and/or reverse DNA damage, free-radical formation and lipid peroxidation in diverse models. This study evaluates OxS parameters in healthy volunteers prior to and following lithium treatment. Healthy volunteers were treated with lithium in therapeutic doses for 2-4 weeks. Treatment with lithium in healthy volunteers selectively altered SOD levels in all subjects. Furthermore, a significant decrease in the SOD/CAT ratio was observed following lithium treatment, wich was associated with decreased OxS by lowering hydrogen peroxide levels. This reduction in the SOD/CAT ratio may lead to lower OxS, indicated primarily by a decrease in the concentration of cell hydrogen peroxide. Overall, the present findings indicate a potential role for the antioxidant effects of lithium in healthy subjects, supporting its neuroprotective profile in bipolar disorder (BD) and, possibly, in neurodegenerative processes.

Stigma and higher rates of psychiatric re-hospitalization: Sao Paulo public mental health system

Objective: The aim of this study was to assess re-hospitalization rates of individuals with psychosis and bipolar disorder and to study determinants of readmission. Methods: Prospective observational study, conducted in Sao Paulo, Brazil. One hundred-sixty-nine individuals with bipolar and psychotic disorder in need of hospitalization in the public mental health system were followed for 12 months after discharge. Their families were contacted by telephone and interviews were conducted at 1, 2, 6 and 12 months post-discharge to evaluate readmission rates and factors related. Results: One-year re-hospitalization rate was of 42.6%. Physical restraint during hospital stay was a risk factor (OR = 5.4-10.5) for readmission in most models. Not attending consultations after discharge was related to the 12-month point readmission (OR = 8.5, 95% CI 2.3-31.2) and to the survival model (OR = 3.2, 95% CI 1.5-7.2). Number of previous admissions was a risk factor for the survival model (OR = 6.6-11.9). Family's agreement with permanent hospitalization of individuals with mental illness was the predictor associated to readmission in all models (OR = 3.5-10.9) and resulted in shorter survival time to readmission; those readmitted were stereotyped as dangerous and unhealthy. Conclusions: Family's stigma towards mental illness might contribute to the increase in readmission rates of their relatives with psychiatric disorders. More studies should be conducted to depict mechanisms by which stigma increases re-hospitalization rates.

Early improvement of psychotic symptoms with lithium monotherapy as a predictor of later response in mania

Although lithium has been the first line agent in the treatment of bipolar disorder (BD), few studies have evaluated lithium's efficacy in mania with psychosis and its association with later response. Furthermore, given the widespread concern about antipsychotic side effects, answering a question about whether lithium alone can manage to treat both psychotic and non-psychotic mania seems a very relevant one. The present study addresses the antipsychotic efficacy of lithium monotherapy in acute mania and early improvement of psychotic symptoms as a predictor of later response of manic symptoms. Forty-six patients presenting a manic episode (32 with psychotic features and 14 subjects without psychotic features) were treated for 4 weeks with lithium monotherapy and evaluated weekly using the Young Mania Rating Scale (YMRS). Subjects with rapid cycling, substance abuse/dependence, or mixed episodes were excluded. The overall antimanic efficacy of lithium in psychosis vs. non-psychosis groups was evaluated. In addition, early improvement of psychotic symptoms and its prediction of subsequent response (>50% decrease in total YMRS scores) or remission were evaluated. Lithium showed a similar efficacy in both psychosis and non-psychosis mania. Early improvement of psychotic symptoms was associated with clinical response and remission at endpoint. (C) 2012 Elsevier Ltd. All rights reserved.

Gene expression of peripheral blood lymphocytes may discriminate patients with schizophrenia from controls

To identify a classifier in schizophrenia, blood gene expression profiling was applied to patients with schizophrenia under different treatments and to controls. Expression of six genes discriminated patients with sensitivity of 89.3% and specificity of 90%, supporting the use of peripheral blood as biological material for diagnosis in schizophrenia. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Stigma and higher rates of psychiatric re-hospitalization: São Paulo public mental health system

OBJECTIVE: The aim of this study was to assess re-hospitalization rates of individuals with psychosis and bipolar disorder and to study determinants of readmission. METHODS: Prospective observational study, conducted in São Paulo, Brazil. One hundred-sixty-nine individuals with bipolar and psychotic disorder in need of hospitalization in the public mental health system were followed for 12 months after discharge. Their families were contacted by telephone and interviews were conducted at 1, 2, 6 and 12 months post-discharge to evaluate readmission rates and factors related. RESULTSOne-year re-hospitalization rate was of 42.6%. Physical restraint during hospital stay was a risk factor (OR = 5.4-10.5) for readmission in most models. Not attending consultations after discharge was related to the 12-month point readmission (OR = 8.5, 95%CI 2.3-31.2) and to the survival model (OR = 3.2, 95%CI 1.5-7.2). Number of previous admissions was a risk factor for the survival model (OR = 6.6-11.9). Family's agreement with permanent hospitalization of individuals with mental illness was the predictor associated to readmission in all models (OR = 3.5-10.9) and resulted in shorter survival time to readmission; those readmitted were stereotyped as dangerous and unhealthy. CONCLUSIONS: Family's stigma towards mental illness might contribute to the increase in readmission rates of their relatives with psychiatric disorders. More studies should be conducted to depict mechanisms by which stigma increases re-hospitalization rates.

Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function

The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation.

The International ADHD in Substance Use Disorders Prevalence (IASP) study: background, methods and study population

Attention deficit/hyperactivity disorder (ADHD) is an increasingly recognized comorbid condition in subjects with substance use disorders (SUDs). This paper describes the methods and study population of the International ADHD in Substance Use Disorders Prevalence (IASP) study. Objectives of the IASP are to determine the prevalence of ADHD in adult treatment seeking patients with SUD in different countries and SUD populations, determine the reliability and validity of the Adult ADHD Self-report Scale V 1.1 (ASRS) as ADHD screening instrument in SUD populations, investigate the comorbidity profile of SUD patients with and without ADHD, compare risk factors and protective factors in SUD patients with and without a comorbid diagnosis of ADHD, and increase our knowledge about the relationship between ADHD and the onset and course of SUD. In this cross-sectional, multi-centre two stage study, subjects were screened for ADHD with the ASRS, diagnosed with the Conner's Adult ADHD Diagnostic Interview for DSM-IV (CAADID), and evaluated for SUD, major depression, bipolar disorder, anti social personality disorder and borderline personality disorder. Three thousand five hundred and fifty-eight subjects from 10 countries were included. Of these 40.9% screened positive for ADHD. This is the largest international study on this population evaluating ADHD and comorbid disorders.

Physician perceptions of risk regarding mood disorders and pharmacological management during pregnancy: What is current practice?

Mood disorders are the most common form of mental illness and one of the leading causes of morbidity worldwide. Major depressive disorder and bipolar disorder have a lifetime prevalence of 16.2% and 4.4%, respectively. Women comprise a substantial proportion of this population, and an estimated 500,000 pregnancies each year involve women with a psychiatric condition. Management with psychotropic medications is considered standard of care for most patients with mood disorders. However, many of these medications are known human teratogens. Because pregnant women with mood disorders face a high risk of relapse if unmanaged, the obstetrician faces a unique challenge in providing the best care to both mother and baby. It has been suggested that many obstetricians overestimate the teratogenic risks associated with psychotropic medications, while concurrently underestimating the risks associated with unmanaged mood disorders. This may be due a knowledge gap regarding the most current teratogen information, and lack of official management guidelines. Therefore, the purpose of this study is to determine the current knowledge base of obstetricians regarding the teratogenic effects of common psychotropic medications, as wells as to capture current management practices for pregnant women with mood disorders. A total of 117 Texas obstetricians responded to a survey regarding teratogen knowledge and management practice. It was common for respondents to encounter women who disclose both having a mood disorder and taking a psychotropic medication during pregnancy. Many respondents did not utilize up-to-date drug counseling resources, and were unaware of or over-estimated the teratogenic risks of common medications used to treat mood disorders. Finally, many respondents reported wanting to refer pregnant patients with mood disorders to psychiatrists for co-management, but are reportedly restricted in doing so due to accessibility or insurance issues. This study demonstrates that there is a knowledge gap among obstetricians regarding the teratogenicity of common psychotropic medications utilized to manage a patient population they frequently encounter. Further, obstetricians have vastly different risk perceptions of these medications, resulting in various management approaches and recommendations. Future research should focus on establishing standard practice guidelines, as well as better accessibility to psychiatric services for pregnant women.

Limbic white matter microstructure plasticity reflects recovery from depression

BACKGROUND White matter microstructure alterations of limbic and reward pathways have been reported repeatedly for depressive episodes in major depressive disorder (MDD) and bipolar disorder (BD). However, findings during remission are equivocal. It was the aim of this study to investigate if white matter microstructure changes during the time course of clinical remission. METHODS Fifteen depressed patients (11 MDD, 4 BD) underwent diffusion-weighted MRI both during depression, and during remission following successful antidepressive treatment (average time interval between scans=6 months). Fractional anisotropy (FA) was sampled along reconstructions of the supero-lateral medial forebrain bundle (slMFB), the cingulum bundle (CB), the uncinate fasciculus (UF), the parahippocampal cingulum (PHC) and the fornix. Repeated measures ANCOVAs controlling for the effect of age were calculated for each tract. RESULTS There was a significant main effect of time (inter-scan interval) for mean-FA for the right CB and for the left PHC. For both pathways there was a significant time×age interaction. In the right CB, FA increased in younger patients, while FA decreased in older patients. In the left PHC, a reverse pattern was seen. FA changes in the right CB correlated positively with symptom reductions. Mean-FA of UF, slMFB and fornix did not change between the two time points. LIMITATIONS All patients were medicated, sample size, and lack of control group. CONCLUSIONS Right CB and left PHC undergo age-dependent plastic changes during the course of remission and may serve as a state marker in depression. UF, slMFB and FO microstructure remains stable.

Stimulant medication and psychotic symptoms in offspring of parents with mental illness

BACKGROUND: Stimulants, such as methylphenidate, are among the most commonly used medications in children and adolescents. Psychotic symptoms have been reported as rare adverse reactions to stimulants but have not been systematically inquired about in most previous studies. Family history of mental illness may increase the vulnerability to drug-induced psychotic symptoms. We examined the association between stimulant use and psychotic symptoms in sons and daughters of parents with major mood and psychotic disorders. METHODS: We assessed psychotic symptoms, psychotic-like experiences, and basic symptoms in 141 children and youth (mean ± SD age: 11.8 ± 4.0 years; range: 6–21 years), who had 1 or both parents with major depressive disorder, bipolar disorder, or schizophrenia, and of whom 24 (17.0%) had taken stimulant medication. RESULTS: Psychotic symptoms were present in 62.5% of youth who had taken stimulants compared with 27.4% of participants who had never taken stimulants. The association between stimulant use and psychotic experiences remained significant after adjustment for potential confounders (odds ratio: 4.41; 95% confidence interval: 1.82–10.69; P = .001) and was driven by hallucinations occurring during the use of stimulant medication. A temporal relationship between use of stimulants and psychotic symptoms was supported by an association between current stimulant use and current psychotic symptoms and co-occurrence in cases that were assessed on and off stimulants. CONCLUSIONS: Psychotic symptoms should be monitored during the use of stimulants in children and adolescents. Family history of mood and psychotic disorders may need to be taken into account when considering the prescription of stimulants.

Trapped in the Bell Jar: Mental Illness in College Students

This is a magazine article that explores the rising problem of mental health in college students, focusing on Connecticut. It explores the experiences of three college students dealing with depression and bipolar disorder, a family who lost a child to suicide, and the measures taken by colleges in Connecticut to curb the problem.

A full pedigree based method for the statistical assessment of genetic anticipation

Genetic anticipation is defined as a decrease in age of onset or increase in severity as the disorder is transmitted through subsequent generations. Anticipation has been noted in the literature for over a century. Recently, anticipation in several diseases including Huntington's Disease, Myotonic Dystrophy and Fragile X Syndrome were shown to be caused by expansion of triplet repeats. Anticipation effects have also been observed in numerous mental disorders (e.g. Schizophrenia, Bipolar Disorder), cancers (Li-Fraumeni Syndrome, Leukemia) and other complex diseases. ^ Several statistical methods have been applied to determine whether anticipation is a true phenomenon in a particular disorder, including standard statistical tests and newly developed affected parent/affected child pair methods. These methods have been shown to be inappropriate for assessing anticipation for a variety of reasons, including familial correlation and low power. Therefore, we have developed family-based likelihood modeling approaches to model the underlying transmission of the disease gene and penetrance function and hence detect anticipation. These methods can be applied in extended families, thus improving the power to detect anticipation compared with existing methods based only upon parents and children. The first method we have proposed is based on the regressive logistic hazard model. This approach models anticipation by a generational covariate. The second method allows alleles to mutate as they are transmitted from parents to offspring and is appropriate for modeling the known triplet repeat diseases in which the disease alleles can become more deleterious as they are transmitted across generations. ^ To evaluate the new methods, we performed extensive simulation studies for data simulated under different conditions to evaluate the effectiveness of the algorithms to detect genetic anticipation. Results from analysis by the first method yielded empirical power greater than 87% based on the 5% type I error critical value identified in each simulation depending on the method of data generation and current age criteria. Analysis by the second method was not possible due to the current formulation of the software. The application of this method to Huntington's Disease and Li-Fraumeni Syndrome data sets revealed evidence for a generation effect in both cases. ^

An integrated molecular biology and computational approach to CYP1A1 expression in human brain

The cytochromes P450 comprise a superfamily of heme-containing mono-oxygenases. These enzymes metabolize numerous xenobiotics, but also play a role in metabolism of endogenous compounds. The P450 1A1 enzyme generally metabolizes polycyclic aromatic hydrocarbons, and its expression can be induced by aryl hydrocarbon receptor (AhR) activation. CYP1A1 is an exception to the generality that the majority of CYPs demonstrate highest expression in liver; CYP1Al is present in numerous extrahepatic tissues, including brain. This P450 has been observed in two forms, wildtype (WT) and brain variant (BV), arising from alternatively spliced mRNA transcripts. The CYP1A1 BV mRNA presented an exon deletion and was detected in human brain but not liver tissue of the same individuals. ^ Quantitative PCR analyses were performed to determine CYP1A1 WT and BV transcript expression levels in normal, bipolar disorder or schizophrenic groups. In our samples, we show that CYP1A1 BV mRNA, when present, is found alongside the full-length form. Furthermore, we demonstrate a significant decrease in expression of CYP1A1 in patients with bipolar disorder or schizophrenia. The expression level was not influenced by post-mortem interval, tissue pH, age, tobacco use, or lifetime antipsychotic medication load. ^ There is no indication of increased brain CYP1A1 expression in normal smokers versus non-smokers in these samples. We observed slightly increased CYP1A1 expression only in bipolar and schizophrenic smokers versus non-smokers. This may be indicative of complex interactions between neuronal chemical environments and AhR-mediated CYP1A1 induction in brain. ^ Structural homology modeling demonstrated that P450 1A1 BV has several alterations to positions/orientations of substrate recognition site residues compared to the WT isoform. Automated substrate docking was employed to investigate the potential binding of neurological signaling molecules and neurotropic drugs, as well as to differentiate specificities of the two P450 1A1 isoforms. We consistently observed that the BV isoform produced energetically favorable substrate dockings in orientations not observed for the same substrate in the WT isoform. These results demonstrated that structural differences, namely an expanded substrate access channel and active site, confer greater capacity for unique compound docking positions suggesting a metabolic profile distinct from the wildtype form for these test compounds. ^

The illness experiences of African Americans residing in an inner city community, Houston, Texas

This dissertation documents health and illness in the context of daily life circumstances and structural conditions faced by African American families living in Clover Heights (pseudonym), an inner city public housing project in the Third Ward, Houston, Texas. Drawing from Kleinman's (1980) model of culturally defined health care systems and using the holistic-content approach to narrative analysis (Lieblich, Tuval- Mashiach, & Zilber, 1998) the purpose of this research was to explore the ways in which social and health policy, economic mobility, the inner city environment, and cultural beliefs intertwined with African American families' health related ideas, behaviors, and practices. I recruited six families using a convenience sampling method (Schensul, Schensul, & LeCompte, 1999) and followed them for fourteen months (2010–2011). Family was defined as a household unit, or those living in the same residence, short or long-term. Single, African American women ranging in age from 29–80 years headed all families. All but one family included children or grandchildren 18 years of age and younger, or children or other relative 18 years of age and older. I also recruited six residents with who I became acquainted over the course of the project. I collected data using traditional ethnographic methods including participant-observation, archive review, field notes, mapping, free-listing, in-depth interviews, and life history interviews. ^ Doing ethnography afforded the families who participated in this project the freedom to construct their own experiences of health and illness. My role centered on listening to, learning from, and interpreting participants' narratives, exploring similarities and differences within and across families' experiences. As the research progressed, a pattern concerning diagnosis and pharmacotherapy for children's behavioral and emotional problems, particularly attention-deficit hyperactivity disorder (ADHD) and pediatric bipolar disorder (PBD), emerged from my formal interactions with participants and my informal interactions with residents. The findings presented in this dissertation document this pattern, focusing on how mothers and families interpreted, organized, and ascribed meaning to their experiences of ADHD and PBD. ^ In the first manuscript presented here, I documented three mothers' narrative constructions of a child's diagnosis with and pharmacotherapy for ADHD or PBD. Using Gergen's (1997) relational perspective I argued that mothers' knowledge and experiences of ADHD and PBD were not individually constructed, but were linguistically and discursively constituted through various social interactions and relationships, including family, spirituality and faith, community norms, and expert systems of knowledge. Mothers' narratives revealed the complexity of children's behavioral and emotional problems, the daily trials of living through these problems, how they coped with adversity and developed survival strategies, and how they interacted with various institutional authorities involved in evaluating, diagnosing, and encouraging pharmaceutical intervention for children's behavior. The findings highlight the ways in which mothers' social interactions and relationships introduced a scientific language and discourse for explaining children's behavior as mental illness, the discordances between expert systems of knowledge and mothers' understandings, and how discordances reflected mothers' ‘microsources of power’ for producing their own stories and experiences. ^ In the second manuscript presented here, I documented the ways in which structural factors, including gender, race/ethnicity, and socioeconomic status, coupled with a unique cultural and social standpoint (Collins, 1990/2009) influenced the strategies this group of African American mothers employed to understand and respond to ADHD or PBD. The most salient themes related to mother-child relationships coalesced around mothers' beliefs about the etiology of ADHD and PBD, ‘conceptualizing responsibility,’ and ‘protection-survival.’ The findings suggest that even though mothers' strategies varied, they were in pursuit of a common goal. Mothers' challenged the status quo, addressing children's behavioral and emotional problems in the ways that made the most sense to them, specifically protecting their children from further marginalization in society more so than believing these were the best options for their children.^

El mito de la bipolaridad en la infancia

El artículo cuestiona la validez del mal llamado Trastorno Bipolar en la Infancia tomando material publicado en medios masivos y también de la propia clínica.