A 'sticky' interhemispheric switch in bipolar disorder?

Despite years of research into bipolar disorder (manic depression), its underlying pathophysiology remains elusive. It is widely acknowledged that the disorder is strongly heritable, but the genetics are complex with less than full concordance in monozygotic twins and at least four susceptibility loci identified. We propose that bipolar disorder is the result of a genetic propensity for slow interhemispheric switching mechanisms that become ''stuck'' in one or the other state. Because slow switches are also ''sticky'' when compared with fast switches, the clinical manifestations of bipolar disorder may be explained by hemispheric activation being ''stuck'' on the left (mania) or on the right (depression). Support for this ''sticky'' interhemispheric switching hypothesis stems from our recent observation that the rate of perceptual alternation in binocular rivalry is slow in euthymic subjects with bipolar disorder (n = 18, median = 0.27 Hz) compared with normal controls (n = 49, median = 0.60 Hz, p < 0.0005). We have presented evidence elsewhere that binocular rivalry is itself an interhemispheric switching phenomenon. The rivalry alternation rate (putative interhemispheric switch rate) is robust in a given individual, with a test-retest correlation of more than 0.8, making it suitable for genetic studies. The interhemispheric switch rate may provide a trait-dependent biological marker for bipolar disorder.     

An underlying circannual rhythm in seasonal affective disorder?

A patient diagnosed with seasonal affective disorder (SAD) carried out prospective ratings of depression weekly for nearly a decade. A winter peak of depression and benzodiazepine intake was documented. However, over the years, the depressive episodes shifted toward spring in an apparent free-running circannual rhythm (periodogram peaks at 53 and 55 weeks). This patient may have an underlying seasonal propensity to depression no longer precisely entrained to environmental cues. (Chronobiology International, 18(2), 309-313, 2001)     

A review of evidence for GABergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: More support for a continuum hypothesis of “functional” psychosis

Virtually all antidepressant and antipsychotic drugs, including clozapine, rimcazole and lithium ion, are proconvulsants, and convulsive therapy, using metrazol, a known GABA-A antagonist, as well as electro-convulsive therapy, can be effective in treating both schizophrenia and affective psychoses. Many antidepressant and antipsychotic drugs, including clozapine, as well as some of their metabolites, reverse the inhibitory effect of GABA on³⁵S-TBPS binding, a reliable predictor of GABA-A receptor blockade. A review of relevant literature suggests that 1) functional psychoses constitute a continuum of disorders ranging from schizophrenia to affective psychoses with overlap of symptoms, heredity and treatments, 2) a weakening of GABergic inhibitory activity, or potentiation of counterbalancing glutamatergic neurotransmission, in the brain, may be involved in the therapeutic activities of both antidepressant and antipsychotic drugs, and 3) schizophrenia and the affective psychoses may be different expressions of the same underlying defect: GABergic preponderance/glutamatergic deficit. Schizophrenia and affective psychoses share the following: 1) several treatments are effective in both, 2) similar modes of inheritance, 3) congruent seasonal birth excesses, 4) enlarged cerebral ventricles and cerebellar vermian atrophy, 5) dexamethasone non-suppression. Both genetic and environmental factors are involved in both schizophrenia and affective psychoses, and several lines of evidence suggest that important environmental factors are neurotropic pathogens that selectively destroy glutamatergic neurons. One group of genes associated with psychoses may increase vulnerability to attack and destruction, by neurotropic pathogens, of excitatory glutamatergic neurons that counterbalance inhibitory GABergic neurons. A second group of genes may encode subunits of overactive GABA-A receptors, while a third group of genes may encode subunits of hypo-active glutamate receptors. Improved antipsychotic drugs may be found among selective blockers of GABA-A receptor subtypes and/or enhancers of glutamatergic neurotransmission. A mechanism similar to kindling, leading to long-lasting reduction of GABergic inhibition in the brain, may be involved in several treatments of psychoses.     

Functional genetic variation in the Rev-Erbα pathway and lithium response in the treatment of bipolar disorder

Bipolar disorder (BD) is characterized by disruptions in circadian rhythms such as sleep and daily activity that often normalize after lithium treatment in responsive patients. As lithium is known to interact with the circadian clock, we hypothesized that variation in circadian 'clock genes' would be associated with lithium response in BD. We determined genotype for 16 variants in seven circadian clock genes and conducted a candidate gene association study of these in 282 Caucasian patients with BD who were previously treated with lithium. We found that a variant in the promoter of NR1D1 encoding Rev-Erbα (rs2071427) and a second variant in CRY1 (rs8192440) were nominally associated with good treatment response. Previous studies have shown that lithium regulates Rev-Erbα protein stability by inhibiting glycogen synthase kinase 3β (GSK3β). We found that GSK3β genotype was also suggestive of a lithium response association, but not statistically significant. However, when GSK3β and NR1D1 genotypes were considered together, they predicted lithium response robustly and additively in proportion to the number of response-associated alleles. Using lymphoblastoid cell lines from patients with BD, we found that both the NR1D1 and GSK3β variants are associated with functional differences in gene expression. Our findings support a role for Rev-Erbα in the therapeutic mechanism of lithium and suggest that the interaction between Rev-Erbα and GSK3β may warrant further study.     

Therapeutic mechanism in seasonal affective disorder: do fluoxetine and light operate through advancing circadian phase?

In the context of Lewy's phase delay hypothesis, the present study tested whether effective treatment of winter Seasonal Affective Disorder (SAD) is mediated by advancing of circadian phase. Following a baseline week, 78 outpatients with SAD were randomized into 8 weeks of treatment with either fluoxetine and placebo light treatment or light treatment and placebo pill. Depression levels were measured on the Ham₁₇₊₇ and the BDI-II, and circadian phase was estimated on the basis of daily sleep logs and self-reported morningness-eveningness. Among the 61 outpatients with complete data, both treatments were associated with significant antidepressant effect and phase advance. However, pre- and post-treatment comparisons found that the degree of symptom change did not correlate with the degree of phase change associated with treatment. The study therefore provides no evidence that circadian phase advance mediates the therapeutic mechanism in patients with SAD. Findings are discussed in terms of the limitations of the circadian measures employed.     

De novo CNVs in bipolar disorder: recurrent themes or new directions?

In this issue of Neuron, Malhotra and colleagues report an enrichment of de novo copy number variants in bipolar disorder and schizophrenia when compared with those of controls. The study highlights the importance of a genetic model involving rare and disruptive variants to further our understanding of complex neuropsychiatric traits.     

Are short (blue) wavelengths necessary for light treatment of seasonal affective disorder?

Despite widely published speculation regarding a potential potency advantage of short-wavelength (blue-appearing) light for Seasonal Affective Disorder (SAD) treatment, there have been few systematic studies. Those comparing short-wavelength to broad-wavelength (white) light under actual clinical conditions suggest equivalent effectiveness. This multicenter, parallel-group design trial was undertaken to compare the effects of light therapy on SAD using blue (~465 nm) versus blue-free (595–612 nm) LED lights. Fifty-six medication-free subjects aged 21–64 years who met DSM-IV-TR criteria for recurrent major depression with winter-type seasonal pattern were enrolled in this blinded study at five participating centers between January and March 2012. Thirty-five subjects met the criteria for randomization to 30 min of either blue (~465 nm) or blue-free (595–612 nm) daily morning light therapy. Twenty-nine subjects completed the study; three subjects withdrew due to treatment-related adverse events, including migraines, and three withdrew for non-study-related reasons. The primary effectiveness variable was depression score (SIGH-ADS) after six weeks of daily light treatment. Secondary effectiveness variables included quality-of-life (QoL) and suicidality ratings. Using an intent-to-treat analysis, mean depression scores were different at baseline for the blue group (29 ± 5 versus 26 ± 5, p = 0.05 blue versus blue-free, respectively), and the initial score was used as a covariate. Baseline scores were not significantly different between treatment groups among those who completed the study, and no significant differences in depression scores were observed after 6 weeks (mean ± SD scores at 6 weeks: 5.6 ± 6.1 versus 4.5 ± 5.3, p = 0.74, blue versus blue-free, respectively). In addition, the proportion of subjects who met remission criteria, defined as a depression score ≤8, was not significantly different between the two groups (p = 0.41); among the 29 subjects who completed the study, 76% of subjects experienced remission by the end of the trial, which coincided with the beginning of spring. The QoL and suicidality ratings were also significantly improved from pre- to post-treatment, with no significant difference between treatments. No subject experienced worsening or non-improved symptoms over the 6-week trial. The main finding of this study is that subjects treated with blue light did not improve more than subjects treated with blue-free light; both showed substantial improvement on multiple measures. Failure to find differences may have resulted from methodological constraints, including a small sample size. Recruitment began mid-winter during an unusually mild season, and the trial was terminated earlier than planned by the study sponsor due to a failure to detect a difference. However, if confirmed in a larger randomized sample, these results suggest that blue wavelengths are not necessary for successful SAD treatment.     

Is aspirin useful in patients on lithium? A pharmacoepidemiological study related to bipolar disorder

ObjectivesAdministration to rats of mood stabilizers approved for bipolar disorder (BD) downregulates markers of the brain arachidonic acid (AA, 20:4n-6) metabolic cascade, including phospholipase A₂ (PLA₂) and cyclooxygenase (COX) expression. We hypothesized that other agents that target the brain AA cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, also would ameliorate BD symptoms.MethodsMedication histories on subjects who had been prescribed lithium were collected from the Netherlands PHARMO Record Linkage System. Data were stratified according to drug classes that inhibit PLA₂ and/or COX enzymes, and duration of use. Incidence density (ID) of medication events (dose increase or substance change) was used as a proxy for clinical worsening. ID ratios in patients with the inhibitors plus lithium were compared to ratios in patients using lithium alone.ResultsLow-dose acetylsalicylic acid (aspirin) significantly reduced the ID ratio of medication events, independent of use duration. The ID ratios of NSAIDs and glucocorticoids did not differ significantly from 1.0 if prescribed for ≥180 or ≥90 days, but exceeded 1.0 with shorter use. Selective COX-2 inhibitors had no significant effect and multiagent administration increased the ID ratio above 1.0.ConclusionsLow-dose aspirin produced a statistically significant duration-independent reduction in the relative risk of clinical deterioration in subjects on lithium, whereas other NSAIDs and glucocorticoids did not. These tentative findings could be tested on larger databases containing detailed information about diagnosis and disease course, as well as by controlled clinical trials.     

Bergmann and converse bergmann latitudinal clines in arthropods: two ends of a continuum?

Two seemingly opposite evolutionary patterns of clinal variationin body size and associated life history traits exist in nature.According to Bergmann's rule, body size increases with latitude,a temperature effect. According to the converse Bergmann rule,body size decreases with latitude, a season length effect. Athird pattern causally related to the latter is countergradientvariation, whereby populations of a given species compensateseasonal limitations at higher latitudes by evolving fastergrowth and larger body sizes compared to their low latitudeconspecifics. We discuss these patterns and argue that theyare not mutually exclusive because they are driven by differentenvironmental causes and proximate mechanisms; they thereforecan act in conjunction, resulting in any intermediate pattern.Alternatively, Bergmann and converse Bergmann clines can beinterpreted as over- and undercompensating countergradient variation,respectively. We illustrate this with data for the wide-spreadyellow dung fly, Scathophaga stercoraria (Diptera: Scathophagidae),which in Europe shows a Bergmann cline for size and a converseBergmann cline (i.e., countergradient variation) for developmenttime. A literature review of the available evidence on arthropodlatitudinal clines further shows a patterned continuum of responses.Converse Bergmann clines due to end-of-season time limitationsare more common in larger species with longer development times.Our study thus provides a synthesis to the controversy aboutthe importance of Bergmann's rule and the converse Bergmannrule in nature.     

Does childhood experience of attention-deficit hyperactivity disorder symptoms increase sleep/wake cycle disturbances as measured with actigraphy in adult patients with bipolar disorder?

ABSTRACT

Childhood attention-deficit hyperactivity disorder (ADHD) is a common precursor of adult bipolar disorders (BD). Furthermore, actigraphy studies demonstrate that each disorder may be associated with abnormalities in sleep and activity patterns. This study investigates whether the presence or absence of self-reported childhood experiences of ADHD symptoms is associated with different sleep and activity patterns in adults with BD. A sample of 115 euthymic adult patients with BD was assessed for childhood ADHD symptoms using the Wender Utah Rating Scale (WURS) and then completed 21 days of actigraphy monitoring. Actigraphic measures of sleep quantity and variability and daytime activity were compared between BD groups classified as ADHD+ (n = 24) or ADHD? (n = 91), defined according to established cutoff scores for the WURS; then we examined any associations between sleep–wake cycle parameters and ADHD dimensions (using the continuous score on the WURS). Neither approach revealed any statistically significant associations between actigraphy parameters and childhood ADHD categories or dimensions. We conclude that the sleep and activity patterns of adult patients with BD do not differ according to their self-reported history of ADHD symptoms. We discuss the implications of these findings and suggest how future studies might confirm or refute our findings.     

Neuronal cell adhesion genes: Key players in risk for schizophrenia,bipolar disorder and other neurodevelopmental brain disorders?

The major mental disorders, schizophrenia and bipolar disorder, are substantially heritable. Recent genomic studies have identified a small number of common and rare risk genes contributing to both disorders and support epidemiological evidence that genetic susceptibility overlaps between them. Prompted by the question of whether risk genes cluster in specific molecular pathways or implicate discrete mechanisms, we and others have developed hypothesis-free methods of investigating genome-wide association datasets at a pathway-level. The application of our method to the 212 experimentally-derived pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database identified significant association between the cell adhesion molecule (CAM) pathway and both schizophrenia and bipolar disorder susceptibility across three GWAS datasets. Interestingly, a similar approach applied to an autistic spectrum disorders (ASDs) sample identified a similar pathway and involved many of the same genes. Disruption of a number of these genes (including NRXN1, CNTNAP2 and CASK) are known to cause diverse neurodevelopmental brain disorder phenotypes including schizophenia, autism, learning disability and specific language disorder. Taken together these studies bring the CAM pathway sharply into focus for more comprehensive DNA sequencing to identify the critical genes, and investigate their relationships and interaction with environmental risk factors in the expression of many seemingly different neurodevelopmental disorders.Key words: schizophrenia, bipolar disorder, genome-wide association, molecular pathway analysis, cell adhesion molecules, neurexin-1Taken together the major mental disorders, schizophrenia and bipolar disorder, affect almost 2% of the adult population and are a major cause of global disability. In the absence of a clear understanding of the pathophysiological processes involved, diagnosis is based on a clinical assessment of symptoms (e.g., delusions, hallucinations, depression and mania) and course of illness. Modern treatments, which emerged in the mid-twentieth century, although efficacious for many, were discovered serendipitously and are far from perfect as both disorders are still associated with substantial morbidity and premature mortality. The statistics are sobering: people with severe mental illness die on average 25 years earlier than those in the general population. Intensive investigation of known mood stabilizers (e.g., lithium) and antipsychotic medications (e.g., haloperidol and clozapine) has yet to translate into better understanding of aetiology or a breakthrough in development of new therapies leading to improved outcome.What unites these disorders is that they are substantially heritable.¹ The emergence of molecular genetics offered the exciting possibility of identifying the causative genes as a key to understanding the biology involved. As has been the case with most complex genetic disorders, progress has been slow but has gathered pace as our ability to investigate the genome has improved and collaborative efforts have generated large sample sizes. Within five years we have advanced from looking through a narrow aperture at hundreds of polymorphic markers, in a selected region or widely scattered across the chromosomes in studies involving hundreds of individuals, to being able to examine most common genomic variation (>85%), captured by a million genetic markers in large-scale studies of thousands of patients. A number of common risk variants, albeit of small effect, have emerged from genome-wide association studies (GWAS) in schizophrenia and bipolar disorder, respectively.^2–6 Some genes (e.g., ZNF804A,² CACNA1C⁶) have been implicated in both disorders and there may be many more. Indeed, the genetic architecture of these disorders may include a substantial polygenic component involving thousands of common alleles of very small effect, many of which increase susceptibility to both schizophrenia and bipolar disorder.³ The bad news is that confirming such small effects may not be feasible even with very large sample sizes (n>100,000 patients). Having only a partial picture of the genes involved is likely to be a substantial barrier to translational research.What is more biologically informative than linking a gene or chromosomal region to a disorder is knowing if these small effects are concentrated in genes relating to a specific mechanism or implicating specific molecular pathways. Many groups have been developing pathway-based approaches to analyzing genome-wide association datasets and our SNP-ratio test (SRT) is just one such approach.^7–13 The SRT can be applied flexibly to different pathway resources as a hypothesis-free test, which simply identifies whether there are more nominally significant SNPs in genes mapping to that pathway in cases in a GWAS dataset than to genes mapping to all other indicated pathways.⁷ Applying this approach to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database of 212 experimentally-derived pathways we captured information on 4,760 genes.¹⁴ We performed a discovery analysis in the International Schizophrenia Consortium dataset, with nominally significant pathways being replicated in an independent, large schizophrenia GWAS dataset.^4,5 Pathways with confirmed association were then tested in a bipolar disorder GWAS dataset to investigate overlap between these conditions.¹⁵ The first step analysis identified 47 nominally significant pathways of which five were associated in the independent schizophrenia dataset. Of these five, only the cell adhesion molecule (CAM) pathway (hsa04514) (p = 0.001) exceeded a conservative testing for multiple testing. Of note, one of the other five identified pathways, the ‘Tight Junction’ pathway (hsa045130) overlaps with the CAM pathway at a molecular level and is involved in many of the same functions. In all, 28 CAM genes of 110 contributing to the analysis had significantly associated SNPs in both schizophrenia datasets and 14 SNPs across 6 CAM genes (NRXN1, CDH4, GLG1, HLA-DQA2, CNTN1 and PDCD1LG2) shared the same risk alleles (see Fig. 1). Association at a pathway-level was confirmed with bipolar disorder although only approximately half of the genes implicated in the discovery analysis showed evidence of association in the bipolar disorder dataset. Further work is required in additional samples to investigate whether this difference represents a lower total burden of contributory risk variants in bipolar disorder (a less severe phenotype) or whether different genes or mechanisms within the pathway may explain phenotypic differences between the disorders.Open in a separate windowFigure 1Genes involved in KEGG Cell Adhesion Molecules pathway (www.genome.jp/dbget-bin/www_bget?pathway+hsa04514) Color scheme: red, significant SNPs in gene in both ISC and GAIN datasets; red with emboldened border and gene name, replication of significant SNPs* in gene in ISC and GAIN datasets; orange, significant SNPs in gene in ISC dataset only; yellow, significant SNPs in gene in GAIN dataset only; grey, no significantly associated SNPs in gene for either dataset/No. SNPs in gene tested/Gene not included in SRT *Replication = same risk allele associated with SZ in the two datasets.That cell adhesion molecules (CAMs) would be implicated in the aetiology of schizophrenia and bipolar disorder is hardly surprising. There is strong evidence, particularly for schizophrenia, to support a neurodevelopmental contribution to aetiology and known (albeit weak) environmental risk factors include maternal starvation, infection and birth trauma (reviewed in ref. ¹⁶). There is growing support, including from neuropathological studies, to suggest that psychosis may be a disorder that involves aberrant brain wiring or dysconnectivity (reviewed in ref. ¹⁷). Cell adhesion molecules have an important role in brain development including in axonal/dendrite growth, synapse formation and plasticity. Neuronal CAMs are also known to have an important role in neurotransmission, including at glutamatergic and GABAergic synapses, which have been implicated in schizophrenia.¹⁸So what can we learn from the 28 CAM genes contributing to the pathway-level association in our analysis? The individual effect sizes at each gene involved are small. Taking stock of evidence from other common disorders (e.g., type 2 diabetes) these early findings are unlikely to be helpful for risk prediction or diagnosis.¹⁹ Their principle utility may be in understanding the aetiology of schizophrenia, bipolar disorder and possibly other neurodevelopmental brain disorders. So what do we know about these genes? Many of the genes involved in this pathway have been implicated in neuropsychiatric disorders or other brain phenotypes.²⁰ For example, this is the case for two of the five genes where SNPs directly replicate across GWAS samples. The sixth gene, HLA-DQA2 maps to the major histocompatibility complex (MHC) region on chromosome 6p, which has been implicated in neuronal plasticity, but presents challenges for genetic mapping.²¹ Disruption of the NRXN1 gene has been reported in both schizophrenia and autism cases or families (see below). Axonal neurexins form transmembrane complexes with neuroligins on dendrites and are required for the formation of synaptic contacts and for efficient neurotransmission-including maintaining postsynaptic NMDA receptor function. The gene is a direct interactor of the cytoskeleton membrane scaffolding protein gene CASK (OMIM:300171), which is associated in both schizophrenia samples in our study, but is assigned to the “Tight Junction” pathway in KEGG. CASK may have a role in synaptic plasticity by coupling synaptic vesicle exocytosis to neuronal cell adhesion.²² CDH4 is a classical cadherin thought to be involved in brain segmentation and neuronal outgrowth. This locus has not received particular support from prior linkage or association studies, but curiously association between a SNP at this gene and total cerebral brain volume was the only genome-wide significant finding to emerge from a GWAS study of brain aging using MRI and cognitive assessment of 705 healthy participants from the Framingham study.²³ Reduced brain volumes are a recognized feature of schizophrenia and this may point to a role in maintenance rather than formation of neuronal connections.Several other recent genomic studies have provided additional support for involvement of CAMs in both bipolar disorder and autistic spectrum disorders (ASDs). A recent GWAS study in bipolar disorder and subsequent replication efforts have provided some support for association with CDH7.²⁴ A GWAS study in ASDs identified association with the chromosome 5p14.1 region containing other members of the cadherin superfamily, CDH 9 and CDH 10.²⁵ Wang and colleagues went further and in a strategy not dissimilar to our approach applied two pathway-based association analyses to their genotype data. In the first they identified that a group of 25 cadherin genes showed more significant association with ASDs than all other genes (p = 0.02), a signal that was enriched by including eight neurexin family genes (p = 0.004). The result was confirmed using a second formal pathway-association method.²⁵ Although the methodologies differed, the genes NRXN1, CNTNAP2 and CDH4 were common to the risk pathways identified across the ASDs by Wang and colleagues in their study and in our investigation of schizophrenia and bipolar disorder.These findings add to growing molecular evidence for overlap between childhood-onset neurodevelopmental disorders (e.g., ASDs) and disorders of typical onset in adolescence or early adulthood like schizophrenia and bipolar disorder (reviewed in ref. ²⁶). The studies performed by our group and Wang and colleagues only investigated common SNP variation and there is increasing realization of the potential importance of rare, highly penetrant structural variation in the aetiology of neurodevelopmental brain disorders. A number of microdeletion/microduplication syndromes have been identified that are associated with ASDs, schizophrenia, intellectual disability, specific language delay and other neurodevelopmental phenotypes (reviewed in ref. ²⁷). Many of these disrupt genes involved in CAM pathways. For instance, disruption of NRXN1 has been reported in cases of both autism and schizophrenia; CASK deletions are reported in individuals with learning disability and brain malformation phenotypes; and disruption of CNTNAP2 has been reported in autism, language disorder and schizophrenia. Taking NRXN1 specifically, many of its post-synaptic binding partners (the neuroligins) and their postsynaptic density interactors (e.g., SHANK3) have been identified as rare causes of ASDs (reviewed in ref. ²⁸).Together these studies raise the possibility that susceptibility to ASDs and psychotic disorders may involve overlapping molecular aetiology where an accumulation of small effects from many common genetic risk variants or more highly penetrant mutations induce neuronal dysconnectivity by disrupting CAM function. This raises exciting new avenues for research into the mechanisms and processes involved. The next key step may be large-scale DNA sequencing of these genes and their interactors to identify whether smaller structural or point mutations, undetectable in the current studies, also contribute to risk. By neccessity these studies will require detailed phenotypic information and encompass different phenotypes to explore how genetic risk is expressed as seemingly different neurodevelopmental endophenotypes. This can inform functional studies and identification of potential therapeutic targets. Finally, although the common risk genes identified by our analysis are of limited clinical utility, more highly penetrant mutations although individually rare may be diagnostically significant across these neurodevelopmental disorders as is already being realised in ASDs.²⁹     

Red white and blue – bright light effects in a diurnal rodent model for seasonal affective disorder

Despite the common use of bright light exposure for treatment of seasonal affective disorder (SAD), the underlying biology of the therapeutic effect is not clear. Moreover, there is a debate regarding the most efficacious wavelength of light for treatment. Whereas according to the traditional approach full-spectrum light is used, recent studies suggest that the critical wavelengths are within the range of blue light (460 and 484 nm). Our previous work shows that when diurnal rodents are maintained under short photoperiod they develop depression- and anxiety-like behavioral phenotype that is ameliorated by treatment with wide-spectrum bright light exposure (2500 lux at the cage, 5000 K). Our current study compares the effect of bright wide-spectrum (3,000 lux, wavelength 420- 780 nm, 5487 K), blue (1,300 lux, wavelength 420-530 nm) and red light (1,300 lux, wavelength range 600-780 nm) exposure in the fat sand rat (Psammomys Obesus) model of SAD. We report results of experiments with six groups of sand rats that were kept under various photoperiods and light treatments, and subjected to behavioral tests related to emotions: forced swim test, elevated plus maze and social interactions. Exposure to either intense wide-spectrum white light or to blue light equally ameliorated depression-like behavior whereas red light had no effect. Bright wide-spectrum white light treatment had no effect on animals maintained under neutral photoperiod, meaning that light exposure was only effective in the pathological-like state. The resemblance between the effects of bright white light and blue light suggests that intrinsically photosensitive retinal ganglion cells (ipRGCs) are involved in the underlying biology of SAD and light therapy.     

Are atypical depression,borderline personality disorder and bipolar II disorder overlapping manifestations of a common cyclothymic diathesis?

The constructs of atypical depression, bipolar II disorder and borderline personality disorder (BPD) overlap. We explored the relationships between these constructs and their temperamental underpinnings. We examined 107 consecutive patients who met DSM-IV criteria for major depressive episode with atypical features. Those who also met the DSM-IV criteria for BPD (BPD+), compared with those who did not (BPD-), had a significantly higher lifetime comorbidity for body dysmorphic disorder, bulimia nervosa, narcissistic, dependent and avoidant personality disorders, and cyclothymia. BPD+ also scored higher on the Atypical Depression Diagnostic Scale items of mood reactivity, interpersonal sensitivity, functional impairment, avoidance of relationships, other rejection avoidance, and on the Hopkins Symptoms Check List obsessive-compulsive, interpersonal sensitivity, anxiety, anger-hostility, paranoid ideation and psychoticism factors. Logistic regression revealed that cyclothymic temperament accounted for much of the relationship between atypical depression and BPD, predicting 6 of 9 of the defining DSM-IV attributes of the latter. Trait mood lability (among BPD patients) and interpersonal sensitivity (among atypical depressive patients) appear to be related as part of an underlying cyclothymic temperamental matrix.     

Phosphoinositide-specific Phospholipase C β1 gene deletion in bipolar disorder affected patient

The involvement of phosphoinositides (PI) signal transduction pathway and related molecules, such as the Phosphoinositide-specific Phospholipase C (PI-PLC) enzymes, in the pathophysiology of mood disorders is corroborated by a number of recent evidences. Our previous works identified the deletion of PLCB1 gene, which codifies for the PI-PLC β1 enzyme, in 4 out 15 patients affected with schizophrenia, and no deletion both in major depression affected patients and in normal controls. By using interphase fluorescent in situ hybridization methodology, we analyzed PLCB1 in paraffin embedded samples of orbito-frontal cortex of 15 patients affected with bipolar disorder. Deletion of PLCB1 was identified in one female patient.     

Polyanion-mediated mineralization — a kinetic analysis of the calcium-carrier hypothesis in the phytoflagellatePleurochrysis carterae

Summary Polyanions are postulated intermediates in biomineralization because they sequester large numbers of calcium ions and occur in high concentrations at mineralizing foci in distantly related organisms. In this study mineral ion and polyanion metabolism was examined inPleurochrysis carterae to determine whether polyanions function as intermediate calcium-carriers during coccolith (mineralized scale) formation. In this organism mineralization occurs intracellularly in coccolith-forming saccules, and mature coccoliths are extruded through the plasma membrane into the coccosphere. The polyanions (acidic polysaccharides known as PS-1 and PS-2) are synthesized in medial Golgi cisternae and transported to the coccolith-forming saccule prior to the onset of mineral deposition; they also cover the mineral surface of mature coccoliths. Pulse-chase experiments with⁴⁵Ca²⁺ and¹⁴CO₃ ^– show the calcium uptake into the coccolith-forming saccule is much slower than carbonate uptake. The extended intracellular half-life of calcium ions destined for the coccosphere suggests that calcium is initially sequestered in more distal Golgi elements (perhaps in association with the polyanions) and enters the coccolith-forming saccule only after passage through the endomembrane system. This is consistent with previous cytochemical studies showing that the polyanions are complexed with calcium prior to mineral deposition. It has been suggested that polyanions may be degraded at the mineralization front in order to free calcium ions for precipitation with available carbonate or phosphate ions. However, this study demonstrates that the polyanions are not degraded; essentially all PS-1 and PS-2 are eventually secreted with the mineral phase into the coccosphere. The kinetics of mineral ion and polyanion secretion are consistent with a polyanion-mediated calcium transport; however, the manner in which calcium might be sequestered by and freed from the polyanions is still obscure.Abbreviations PS-1/2/3 polysaccharide 1/2/3 - EDTA ethylenediaminetetraacetic acid - TCA trichloroacetic acid     

What causes psychosis? An umbrella review of risk and protective factors

Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta‐analyses of observational studies which examined associations between socio‐demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non‐organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non‐significant according to a standardized classification based on: number of psychotic cases, random‐effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty‐five meta‐analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra‐high‐risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91‐17.72) and Black‐Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96‐6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North‐African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non‐right handedness). When only prospective studies were considered, the evidence was convincing for ultra‐high‐risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis.