Maternal and offspring pools of osteocalcin influence brain development and functions.

The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain, and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression, and favors learning and memory independently of its metabolic functions. In addition to these postnatal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result, the severity of the neuroanatomical defects and learning and memory deficits of Osteocalcin(-/-) mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin(-/-) mothers rescues these abnormalities in their Osteocalcin(-/-) progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development.

Brain cytochrome-c-oxidase as a marker of mitochondrial function: A pilot study in major depression using NIRS.

BACKGROUND: Brain mitochondrial dysfunction is implicated in the pathophysiology of mood disorders. Brain cytochrome-c-oxidase (COX) activity is associated with the mitochondrial function. Near-infrared spectroscopy (NIRS) noninvasively measures oxidized COX (oxCOX) and tissue oxygenation index (TOI) reflecting cerebral blood flow and oxygenation. METHODS: oxCOX and TOI were assessed in prefrontal cortex (Fp1/2, Brodmann area 10) in patients in a major depressive episode (N = 13) with major depressive disorder (MDD; N = 7) and bipolar disorder (BD; N = 6) compared with the controls (N = 10). One patient with MDD and all the patients with BD were taking medications. Computational modeling estimated oxCOX and TOI related indices of mitochondrial function and cerebral blood flow, respectively. RESULTS: oxCOX was lower in patients than controls (p = .014) correlating inversely with depression severity (r = -.72; p = .006), driven primarily by lower oxCOX in BD compared with the controls. Computationally modeled mitochondrial parameters of the electron transport chain, such as the nicotinamide adenine dinucleotide ratio (NAD+ /NADH; p = .001) and the proton leak rate across the inner mitochondrial membrane (klk2 ; p = .008), were also lower in patients and correlated inversely with depression severity. No such effects were found for TOI. CONCLUSIONS: In this pilot study, oxCOX and related mitochondrial parameters assessed by NIRS indicate an abnormal cerebral metabolic state in mood disorders proportional to depression severity, potentially providing a biomarker of antidepressant effect. Because the effect was driven by the medicated BD group, findings need to be evaluated in a larger, medication-free population.

A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder.

Gamma-amino butyric acid (GABA) and glutamate are the major inhibitory and excitatory neurotransmitters in the mammalian central nervous system, respectively, and have been associated with suicidal behavior and major depressive disorder (MDD). We examined the relationship between genotype, brain transcriptome, and MDD/suicide for 24 genes involved in GABAergic and glutamatergic signaling. In part 1 of the study, 119 candidate SNPs in 24 genes (4 transporters, 4 enzymes, and 16 receptors) were tested for associations with MDD and suicidal behavior in 276 live participants (86 nonfatal suicide attempters with MDD and 190 non-attempters of whom 70% had MDD) and 209 postmortem cases (121 suicide deaths of whom 62% had MDD and 88 sudden death from other causes of whom 11% had MDD) using logistic regression adjusting for sex and age. In part 2, RNA-seq was used to assay isoform-level expression in dorsolateral prefrontal cortex of 59 postmortem samples (21 with MDD and suicide, 9 MDD without suicide, and 29 sudden death non-suicides and no psychiatric illness) using robust regression adjusting for sex, age, and RIN score. In part 3, SNPs with subthreshold (uncorrected) significance levels below 0.05 for an association with suicidal behavior and/or MDD in part 1 were tested for eQTL effects in prefrontal cortex using the Brain eQTL Almanac (www.braineac.org). No SNPs or transcripts were significant after adjustment for multiple comparisons. However, a protein coding transcript (ENST00000414552) of the GABA A receptor, gamma 2 (GABRG2) had lower brain expression postmortem in suicide (P = 0.01) and evidence for association with suicide death (P = 0.03) in a SNP that may be an eQTL in prefrontal cortex (rs424740, P = 0.02). These preliminary results implicate GABRG2 in suicide and warrant further investigation and replication in larger samples.

Sex differences in the familial transmission of mood disorders.

BACKGROUND: Mood disorders exhibit familial transmission due to both environmental and genetic risk factors. Mood disorders are more common in women, yet the role of gender in the familial transmission of mood disorders is unclear. This study examines rates of mood disorder transmission to offspring based on the sex of affected parent, sex of offspring and role of clinical factors, such as childhood abuse history, comorbid psychiatric disorders, and traits of aggression and impulsivity. METHODS: Risk of transmission of mood disorder to offspring from females and males was compared in a sample of 272 probands with a major mood disorder using generalized estimating equations (GEE). Demographic and clinical characteristics of all male and female probands were compared. Characteristics that differed in probands were entered into the model to obtain an unbiased test of gender differences in transmission rate. Multivariate GEE models, one for male probands and one for female probands, were used to test for risk factors in transmission of mood disorder. RESULTS: Familial transmission rate of mood disorders from female probands was almost double that of males. There was no difference in transmission to male or female offspring. For male probands, offspring mood disorder was independently associated with earlier age of proband mood disorder onset, greater number of proband years ill, and proband history of childhood abuse. For female probands, offspring mood disorder was associated with higher aggression scores in probands. LIMITATIONS: We did not directly interview offspring and also had limited data on psychopathology in co-parents. This is a cross-sectional study and cannot account for emergence of illness in offspring in the future. CONCLUSIONS: The two-fold higher rate of maternal transmission of mood disorder may reflect differences in regulation of maternal and paternal transmission of mood disorder. Future studies need to determine the relative contribution of genetic and non-genetic factors and identify the factors responsible for higher rates of transmission of mood disorders by females with a mood disorder.

Immobilization stress elevates tryptophan hydroxylase mRNA and protein in the rat raphe nuclei.

BACKGROUND: Stress triggers adaptive and maladaptive changes in the central nervous system, including activation of the hypothalamic-pituitary-adrenal axis, and can trigger mood disorders and posttraumatic stress disorder. We examined the effect of immobilization stress (IMO) on gene expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, and the role of cortisol in that response. METHODS: Regular and adrenalectomized Sprague-Dawley rats were exposed to various repetitions of IMO. Tryptophan hydroxylase messenger ribonucleic acid (mRNA) was determined by competitive reverse transcriptase polymerase chain reaction, and TPH protein was examined by immunoblot and immunocytochemistry. RESULTS: Elevation of TPH mRNA by IMO was tissue-specific and dose-dependent. A single IMO elicited a threefold rise in TPH mRNA in median raphe nucleus (MRN), but repeated (3x) IMOs were needed for similar response in dorsal raphe nucleus (DRN). Repeated daily IMO, up to 7 days, triggered a robust induction (6-10-fold) in TPH mRNA, accompanied by corresponding rise in TPH protein levels in raphe nuclei but not in the pineal gland. The rise in TPH immunoreactivity was widespread throughout the DRN and MRN. Bilateral adrenalectomy did not prevent the IMO-triggered increase in TPH immunoreactive protein in the raphe nuclei. CONCLUSIONS: This study reveals adrenal glucocorticoid-independent induction of TPH gene expression in raphe nuclei in response to immobilization stress.

A randomized comparison of high-charge right unilateral electroconvulsive therapy and bilateral electroconvulsive therapy in older depressed patients who failed to respond to 5 to 8 moderate-charge right unilateral treatments.

BACKGROUND: Electroconvulsive therapy (ECT) is the treatment of choice in some older patients with severe depression. When compared with younger depressed patients, older patients have been shown to be as likely to respond to ECT but more likely to develop cognitive impairment. This study addresses whether adults aged 50 years and over who have already failed to respond to at least 5 moderate-charge right unilateral (RUL) ECT treatments (150% above seizure threshold) are more likely to benefit from a switch to high-charge RUL ECT (450% above threshold) or to bilateral (BL) ECT. METHOD: Twenty-four patients who were treated with 5 to 8 moderate-charge RUL ECT treatments and who failed to improve sufficiently were randomly assigned to receive either BL ECT (N = 11) or high-charge RUL ECT (N = 13). Depressive (24-item Hamilton Rating Scale for Depression) and cognitive scores (Mini-Mental State Examination [MMSE]) were compared under double-blind conditions at 3 phases of treatment. RESULTS: Patients in the BL ECT group exhibited significantly greater cognitive impairment (mean MMSE score decrease of 1.13) than those receiving high-charge RUL ECT (mean MMSE increase of 1.71). There were no statistically significant differences in clinical response to BL or high-charge RUL ECT (63.6% and 61.5%, respectively) or in depressive symptom remission (18.1% and 46.2%). CONCLUSION: These results suggest that older patients who fail to respond to moderate-charge RUL ECT may benefit from a switch to high-charge RUL ECT rather than BL ECT. Larger future studies will be needed to compare clinical response in patients switched from moderate-dose RUL ECT to higher-dose RUL or to BL ECT.

Effect of exposure to suicidal behavior on suicide attempt in a high-risk sample of offspring of depressed parents.

OBJECTIVE: Exposure to suicidal behavior in peers and relatives is thought to increase risk for suicidal behavior in vulnerable individuals, possibly as a result of imitation or modeling. This study examines exposure to suicidal behavior and likelihood of suicide attempt in a high-risk cohort of offspring of a depressed parent. METHOD: A total of 449 offspring of 255 probands with a mood disorder were enrolled in a family study. Probands and offspring were assessed for psychopathology and suicide attempt history, and offspring for suicide exposure. Generalized estimating equations (GEE) and generalized least squares models were used to compare suicide attempt history in exposed and nonexposed offspring as well as characteristics of exposure in exposed offspring suicide attempters and exposed nonattempters. GEE was used to compare exposure occurring before first attempt in attempter offspring and exposure occurring before the same age in matched nonattempter offspring. RESULTS: Offspring reporting exposure to suicidal behavior were four times more likely to report a lifetime suicide attempt compared with unexposed offspring, controlling for age. Suicide attempt status was not associated with age at first exposure, total number or degree (attempt or threat) of exposures, or relationship. Analysis of exposure occurring before age at first suicide attempt found no association between exposure and suicide attempt. CONCLUSIONS: Offspring exposed to suicidal behavior are more likely to report a lifetime suicide attempt than nonexposed offspring. However, when examining the temporal sequence of exposure and attempt, the association is no longer significant, suggesting that imitation is not sufficient explanation.

Parental care moderates the influence of MAOA-uVNTR genotype and childhood stressors on trait impulsivity and aggression in adult women.

OBJECTIVES: Adverse childhood experiences are associated with poor mental health outcomes, including vulnerability to mood disorders and/or antisocial behavior. A functional polymorphism in the regulatory region of the monoamine oxidase A gene (monoamine oxidase A untranslated variable nucleotide tandem repeat, MAOA-uVNTR) may moderate the degree of risk conferred by early trauma. Experiential factors may mitigate or exacerbate the effects of trauma on individuals at genetic risk. We examined the association among MAOA-uVNTR genotype, early stress (family death, family separation, parents' divorce, physical and/or sexual abuse), quality of parental care, and disadvantageous outcomes (trait impulsivity/aggression and depression severity) in adult women. METHODS: Diagnostic assessments were completed for 159 female participants. All were either healthy or were diagnosed with major depressive disorder or bipolar disorder. Participants were assessed for lifetime trait aggression and impulsiveness and current severity of depression, and were genotyped for the MAOA-uVNTR polymorphism. Participants rated the level of parental care they experienced, and were asked to report specific childhood stressors and abuse. RESULTS: High perceived parental care mitigated the effect of a childhood stressor on impulsivity scores in low-expressing MAOA-uVNTR allele carriers, but level of perceived care had no effect in the group homozygous for the high-expressing MAOA-uVNTR allele. Gene-environment interactions did not influence depression severity in the mood disorder group, indicating that the effects of parenting we observed in our participants were independent of depression status. CONCLUSION: These results suggest that gene-environment interactions influence not only disadvantageous outcomes, but also sensitivity to features of the environment that could alleviate these outcomes.

The history and current state of antidepressant clinical trial design: a call to action for proof-of-concept studies.

BACKGROUND: The development of new antidepressant drugs has reached a plateau. There is an unmet need for faster, better, and safer medications, but as placebo-response rates rise, effect sizes shrink, and more studies fail or are negative, pharmaceutical companies are increasingly reluctant to invest in new drug development because of the risk of failure. In the absence of an identifiable human pathophysiology that can be modeled in preclinical studies, the principal point of leverage to move beyond the present dilemma may be improving the information gleaned from well-designed proof-of-concept (POC) studies of new antidepressant drugs with novel central nervous system effects. With this in mind, a group of experts was convened under the auspices of the University of Arizona Department of Psychiatry and Best Practice Project Management, Inc. PARTICIPANTS: Forty-five experts in the study of antidepressant drugs from academia, government (U.S. Food and Drug Administration and National Institute of Mental Health), and industry participated. EVIDENCE/CONSENSUS PROCESS: In order to define the state of clinical trials methodology in the antidepressant area, and to chart a way forward, a 2-day consensus conference was held June 21-22, 2007, in Bethesda, Md., at which careful reviews of the literature were presented for discussion. Following the presentations, participants were divided into 3 workgroups and asked to address a series of separate questions related to methodology in POC studies. The goals were to review the history of antidepressant drug trials, discuss ways to improve study design and data analysis, and plan more informative POC studies. CONCLUSIONS: The participants concluded that the federal government, academic centers, and the pharmaceutical industry need to collaborate on establishing a network of sites at which small, POC studies can be conducted and resulting data can be shared. New technologies to analyze and measure the major affective, cognitive, and behavioral components of depression in relationship to potential biomarkers of response should be incorporated. Standard assessment instruments should be employed across studies to allow for future meta-analyses, but new instruments should be developed to differentiate subtypes and symptom clusters within the disorder that might respond differently to treatment. Better early-stage POC studies are needed and should be able to amplify the signal strength of drug efficacy and enhance the quality of information in clinical trials of new medications with novel pharmacologic profiles.

Using the gene ontology for microarray data mining: a comparison of methods and application to age effects in human prefrontal cortex.

One of the challenges in the analysis of gene expression data is placing the results in the context of other data available about genes and their relationships to each other. Here, we approach this problem in the study of gene expression changes associated with age in two areas of the human prefrontal cortex, comparing two computational methods. The first method, "overrepresentation analysis" (ORA), is based on statistically evaluating the fraction of genes in a particular gene ontology class found among the set of genes showing age-related changes in expression. The second method, "functional class scoring" (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step. We find that FCS yields more consistent results than ORA, and the results of ORA depended strongly on the gene selection threshold. Our findings highlight the utility of functional class scoring for the analysis of complex expression data sets and emphasize the advantage of considering all available genomic information rather than sets of genes that pass a predetermined "threshold of significance."