Stratifying Risk for Renal Insufficiency Among Lithium-Treated Patients: An Electronic Health Record Study.

Although lithium preparations remain first-line treatment for bipolar disorder, risk for development of renal insufficiency may discourage their use. Estimating such risk could allow more informed decisions and facilitate development of prevention strategies. We utilized electronic health records from a large New England health-care system between 2006 and 2013 to identify patients aged 18 years or older with a lithium prescription. Renal insufficiency was identified using the presence of renal failure by ICD9 code or laboratory-confirmed glomerular filtration rate below 60 ml/min. Logistic regression was used to build a predictive model in a random two-thirds of the cohort, which was tested in the remaining one-third. Risks associated with aspects of pharmacotherapy were also examined in the full cohort. We identified 1445 adult lithium-treated patients with renal insufficiency, matched by risk set sampling 1 : 3 with 4306 lithium-exposed patients without renal insufficiency. In regression models, features associated with risk included older age, female sex, history of smoking, history of hypertension, overall burden of medical comorbidity, and diagnosis of schizophrenia or schizoaffective disorder (p<0.01 for all contrasts). The model yielded an area under the ROC curve exceeding 0.81 in an independent testing set, with 74% of renal insufficiency cases among the top two risk quintiles. Use of lithium more than once daily, lithium levels greater than 0.6 mEq/l, and use of first-generation antipsychotics were independently associated with risk. These results suggest the possibility of stratifying risk for renal failure among lithium-treated patients. Once-daily lithium dosing and maintaining lower lithium levels where possible may represent strategies for reducing risk.

Pharmacological approaches to the challenge of treatment-resistant depression.

Although monoaminergic antidepressants revolutionized the treatment of Major Depressive Disorder (MDD) over a half-century ago, approximately one third of depressed patients experience treatment-resistant depression (TRD). Such patients account for a disproportionately large burden of disease, as evidenced by increased disability, cost, human suffering, and suicide. This review addresses the definition, causes, evaluation, and treatment of unipolar TRD, as well as the major treatment strategies, including optimization, augmentation, combination, and switch therapies. Evidence for these options, as outlined in this review, is mainly focused on large-scale trials or meta-analyses. Finally, we briefly review emerging targets for antidepressant drug discovery and the novel effects of rapidly acting antidepressants, with a focus on ketamine.

Aunque hace más de medio siglo los antidepresivos monoaminérgicos revolucionaron el tratamiento del Trastorno Depresivo Mayor (TDM), alrededor de un tercio de los pacientes con este cuadro presentan una depresión resistente al tratamiento (DRT). Tales pacientes representan una parte desproportionadamente alta del costo de la enfermedad, lo que se evidencia en el aumento de la discapacidad, el sufrimiento humano y el suicidio. Esta revisión está orientada a la definición, causas, evaluación y tratamiento del TDM unipolar, así como a las principales estrategias terapéuticas, incluyendo la optimización, aumento, combinación y cambio de tratamientos. La evidencia para estas opciones, como se describe en esta revisión, está focalizada printipalmente en ensayos de gran escala o meta-análisis. Por último, se revisan brevemente los blancos que están emergiendo para el descubrimiento de antidepresivos y los nuevos efectos de los antidepresivos de acción rápida, con el foco en la ketamina.

Les antidépresseurs monoaminergiques ont révolutionné le traitement de l'épisode dépressif caractérisé (majeur) (EDM) il y a une cinquantaine d'années, mais environ un tiers des patients déprimés ont une dépression résistante au traitement (DRT). Ces patients représentent un fardeau important et disproportionné de la maladie, comme le prouve l'augmentation du handicap, des coûts, de la souffrance humaine et des suicides. Cet article s'intéresse à la définition, aux causes, à l'évaluation et au traitement de la DRT unipolaire, ainsi qu'aux principales stratégies thérapeutiques, dont les traitements d'optimisation, d'augmentation, d'association et de substitution. L'article souligne que ces solutions se fondent principalement sur des essais à grande échelle ou des métaanalyses. Enfin, nous revoyons brièvement la découverte de nouvelles cibles des médicaments antidépresseurs et les nouveaux effets des antidépresseurs d'action rapide, avec pour objectif principal la kétamine.

The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function.

BACKGROUND: Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function. METHODS: We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in healthy individuals. RESULTS: Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .046). The association appeared to be stronger when early-onset (age ≤ 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p = .0048). CONCLUSIONS: Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.

Risk factors for fatal and nonfatal repetition of suicide attempts: a literature review.

OBJECTIVES: This review aimed to identify the evidence for predictors of repetition of suicide attempts, and more specifically for subsequent completed suicide. METHODS: We conducted a literature search of PubMed and Embase between January 1, 1991 and December 31, 2009, and we excluded studies investigating only special populations (eg, male and female only, children and adolescents, elderly, a specific psychiatric disorder) and studies with sample size fewer than 50 patients. RESULTS: The strongest predictor of a repeated attempt is a previous attempt, followed by being a victim of sexual abuse, poor global functioning, having a psychiatric disorder, being on psychiatric treatment, depression, anxiety, and alcohol abuse or dependence. For other variables examined (Caucasian ethnicity, having a criminal record, having any mood disorders, bad family environment, and impulsivity) there are indications for a putative correlation as well. For completed suicide, the strongest predictors are older age, suicide ideation, and history of suicide attempt. Living alone, male sex, and alcohol abuse are weakly predictive with a positive correlation (but sustained by very scarce data) for poor impulsivity and a somatic diagnosis. CONCLUSION: It is difficult to find predictors for repetition of nonfatal suicide attempts, and even more difficult to identify predictors of completed suicide. Suicide ideation and alcohol or substance abuse/dependence, which are, along with depression, the most consistent predictors for initial nonfatal attempt and suicide, are not consistently reported to be very strong predictors for nonfatal repetition.

Psychopathology in adolescent offspring of parents with panic disorder, major depression, or both: a 10-year follow-up.

OBJECTIVE: The authors examined the specificity and course of psychiatric disorders from early childhood through adolescence in offspring of parents with confirmed panic disorder and major depressive disorder. METHOD: The authors examined rates of psychiatric disorders at 10-year-follow-up (mean age, 14 years) in four groups: offspring of referred parents with panic and depression (N=137), offspring of referred parents with panic without depression (N=26), offspring of referred parents with depression without panic (N=48), and offspring of nonreferred parents with neither disorder (N=80). Follow-up assessments relied on structured interviews with the adolescents and their mothers; diagnoses were rated present if endorsed by either. RESULTS: Parental panic disorder, independently of parental depression, predicted lifetime rates in offspring of multiple anxiety disorders, panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Parental depression independently predicted offspring bipolar, drug use, and disruptive behavior disorders. Parental panic and depression interacted to predict specific phobia and major depressive disorder. Phobias were elevated in all at-risk groups, and depression was elevated in both offspring groups of parents with depression (with or without panic disorder), with the highest rates in the offspring of parents with depression only. Parental depression independently predicted new onset of depression, parental panic disorder independently predicted new onset of social phobia, and the two interacted to predict new onset of specific phobia and generalized anxiety disorder. CONCLUSIONS: At-risk offspring continue to develop new disorders as they progress through adolescence. These results support the need to screen and monitor the offspring of adults presenting for treatment of panic disorder or major depressive disorder.

Cognitive behavioral therapy for 4- to 7-year-old children with anxiety disorders: a randomized clinical trial.

OBJECTIVE: To examine the efficacy of a developmentally appropriate parent-child cognitive behavioral therapy (CBT) protocol for anxiety disorders in children ages 4-7 years. DESIGN: Randomized wait-list controlled trial. Conduct: Sixty-four children (53% female, mean age 5.4 years, 80% European American) with anxiety disorders were randomized to a parent-child CBT intervention (n = 34) or a 6-month wait-list condition (n = 30). Children were assessed by interviewers blind to treatment assignment, using structured diagnostic interviews with parents, laboratory assessments of behavioral inhibition, and parent questionnaires. ANALYSIS: Chi-square analyses of outcome rates and linear and ordinal regression of repeated measures, examining time by intervention interactions. RESULTS: The response rate (much or very much improved on the Clinical Global Impression Scale for Anxiety) among 57 completers was 69% versus 32% (CBT vs. controls), p < .01; intent-to-treat: 59% vs. 30%, p = .016. Treated children showed a significantly greater decrease in anxiety disorders (effect size [ES] = .55) and increase in parent-rated coping (ES = .69) than controls, as well as significantly better CGI improvement on social phobia/avoidant disorder (ES = .95), separation anxiety disorder (ES = .82), and specific phobia (ES = .78), but not on generalized anxiety disorder. Results on the Child Behavior Checklist Internalizing scale were not significant and were limited by low return rates. Treatment response was unrelated to age or parental anxiety but was negatively predicted by behavioral inhibition. Gains were maintained at 1-year follow-up. CONCLUSIONS: Results suggest that developmentally modified parent-child CBT may show promise in 4- to 7-year-old children.

Risk factors for fatal and nonfatal repetition of suicide attempt: a critical appraisal.

PURPOSE OF REVIEW: To perform a critical appraisal of reports on suicide attempts published in 2009, looking for features and predictors of suicidal behavior. RECENT FINDINGS: We searched Psychinfo, Embase, and Pubmed in the period from 1 December 2008 to 31 December 2009 looking for papers on suicide attempt. Rates of suicide attempts are in line with previous data and confirm a north-south gradient in the suicide attempt rate. Previous attempts are the strongest risk factors for further attempt. Moreover, we point out the importance of mood disorders (in particular depression) and personality disorders, unemployment, and a medium age as risk factors. In adolescence, the repetition rate seems to overlap that of the adult population, though the samples are very small. Even in this case, the presence of a previous suicide attempt increases the risk for repeated suicide attempt. By contrast, the role of psychiatric and demographic variables is less clear. Studies on personality disorders confirm that having a personality disorder increases the risk for further attempt, but this correlation is significantly less strong for fatal repetition. In depressed patients, the presence of anxiety perhaps acts as a protective factor. SUMMARY: The risk for a suicide attempt is higher for people who had previously attempted. Having a psychiatric diagnosis and more specifically a mood disorder is also a strong predictor for both fatal and nonfatal suicide attempt.

Executive functioning in offspring at risk for depression and anxiety.

BACKGROUND: Executive functioning deficits (EFDs) have been found in adults with major depression and some anxiety disorders, yet it is unknown whether these deficits predate onset of disorder, or whether they reflect acute symptoms. Studies of at-risk offspring can shed light on this question by examining whether EFDs characterize children at high risk for depression and anxiety who are not yet symptomatic. METHODS: This study examined neuropsychological functioning in a sample of 147 children, ages 6-17 years (M age=9.16, SD=1.82), of parents with major depression (MDD) and/or panic disorder (PD) and of controls with neither disorder. Children were assessed via structured diagnostic interviews and neuropsychological measures. RESULTS: Although parental MDD and PD were not associated with neuropsychological impairments, presence of current offspring MDD was associated with poorer performance on several executive functioning and processing speed measures. Children with current generalized anxiety showed poorer verbal memory, whereas children with social phobia had more omissions on a continuous performance task. CONCLUSIONS: Findings suggest that EFDs do not serve as trait markers for developing anxiety or depression but appear to be symptomatic of current disorder.

Association of a polymorphism near CREB1 with differential aversion processing in the insula of healthy participants.

CONTEXT: Previous functional neuroimaging studies have identified a network of brain regions that process aversive stimuli, including anger. A polymorphism near the cyclic adenosine monophosphate response element binding protein gene (CREB1) has recently been associated with greater self-reported effort at anger control as well as risk for antidepressant treatment-emergent suicidality in men with major depressive disorder, but its functional effects have not been studied. OBJECTIVE: To determine whether this genetic variant is associated with altered brain processing of and behavioral avoidance responses to angry facial expressions. DESIGN AND PARTICIPANTS: A total of 28 white participants (mean age, 29.2 years; 13 women) were screened using the Structured Clinical Interview for DSM-IV to exclude any lifetime Axis I psychiatric disorder and were genotyped for rs4675690, a single-nucleotide polymorphism near CREB1. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent signal by functional magnetic resonance imaging in the amygdala, insula, anterior cingulate, and orbitofrontal cortex during passive viewing of photographs of faces with emotional expressions. To measure approach and avoidance responses to anger, an off-line key-press task that traded effort for viewing time assessed valuation of angry faces compared with other expressions. RESULTS: The CREB1-linked single-nucleotide polymorphism was associated with significant differential activation in an extended neural network responding to angry and other facial expressions. The CREB1-associated insular activation was coincident with activation associated with behavioral avoidance of angry faces. CONCLUSIONS: A polymorphism near CREB1 is associated with responsiveness to angry faces in a brain network implicated in processing aversion. Coincident activation in the left insula is further associated with behavioral avoidance of these stimuli.

Disruptive behavior disorders in offspring of parents with major depression: associations with parental behavior disorders.

OBJECTIVE: Although the offspring of parents with major depressive disorder (MDD) are at increased risk to develop disruptive behavior disorders (DBD) in addition to MDD, it remains unclear whether this heightened risk is due to MDD or to comorbid DBD in the parents. METHOD: In a secondary analysis of longitudinal data from offspring at risk for MDD and panic disorder and comparison children, we stratified 169 children of parents who had been treated for MDD based upon presence (n=50) or absence (n=119) of parental history of DBD (ADHD, oppositional disorder, and conduct disorder) and contrasted them with children of parents with DBD but without MDD (n=19) and children whose parents had neither MDD nor DBD (n=106). The children had been assessed in middle childhood using structured diagnostic interviews. RESULTS: Offspring of parents with MDD + DBD had significantly higher rates of MDD, DBD in general, and ADHD in particular, compared with offspring of parents with MDD alone. Offspring of parents with MDD + DBD also had higher rates of mania than controls. Both parental MDD and DBD conferred independent risk for MDD and DBD in the offspring. However, only parental DBD conferred independent risk for conduct disorder and ADHD and only parental MDD conferred independent risk for oppositional defiant disorder. CONCLUSION: Elevated rates of DBD in the offspring of parents with MDD appear to be due in part to the presence of DBD in the parents. Further studies of samples not selected on the basis of parental panic disorder are needed to confirm these results.

Influence of RGS2 on anxiety-related temperament, personality, and brain function.

CONTEXT: Although anxiety disorders are heritable, their genetic and phenotypic complexity has made the identification of susceptibility genes difficult. Well-validated animal models and intermediate phenotypes provide crucial tools for genetic dissection of anxiety. The gene encoding regulator of G protein signaling 2 (Rgs2) is a quantitative trait gene that influences mouse anxiety behavior, making its human ortholog (RGS2) a compelling candidate gene for human anxiety phenotypes. OBJECTIVE: To examine whether variation in RGS2 is associated with intermediate phenotypes for human anxiety disorders. DESIGN: Family-based and case-control association analysis of single-nucleotide polymorphisms at the RGS2 locus in 3 independent samples. SETTING: Massachusetts General Hospital, University of California, San Diego, and San Diego State University. PARTICIPANTS: Study participants included a family-based sample (n = 119 families) of children who underwent laboratory-based assessments of temperament (behavioral inhibition), a sample of 744 unrelated adults who completed assessments of extraversion and introversion, and 55 unrelated adults who underwent functional magnetic resonance imaging measures of response to emotional faces. MAIN OUTCOME MEASURES: Laboratory-based behavioral measures of childhood temperament, self-report measure of personality, and functional magnetic resonance imaging response to emotion processing. RESULTS: Markers spanning RGS2 were associated with childhood behavioral inhibition, a temperamental precursor of social anxiety disorder (haplotype P = 3 x 10(-5); odds ratio, 2.99 in complete trios). In independent samples, RGS2 markers, including rs4606, which has previously been associated with RGS2 expression, were also associated with introversion (a core personality trait in social anxiety disorder) and with increased limbic activation (insular cortex and amygdala) during emotion processing (brain phenotypes correlated with social anxiety). The genotype at rs4606 explained 10% to 15% of the variance in amygdala and insular cortex activation to emotional faces. CONCLUSIONS: These results provide the first evidence that a gene that influences anxiety in mice is associated with intermediate phenotypes for human anxiety disorders across multiple levels of assessment, including childhood temperament, adult personality, and brain function. This translational research suggests that some genetic influences on anxiety are evolutionarily conserved and that pharmacologic modulation of RGS2 function may provide a novel therapeutic approach for anxiety disorders.