The kynurenine pathway in bipolar disorder: a meta-analysis on the peripheral blood levels of tryptophan and related metabolites.

Growing evidence suggests that a dysregulation of the kynurenine pathway (KP) occurs in bipolar disorder (BD). This systematic review and meta-analysis aimed at assessing the possible differences in peripheral blood levels of KP metabolites between individuals with BD and healthy controls. We searched Medline, Embase, and PsycInfo electronic databases for articles indexed up to February 2020. We included any observational study comparing the peripheral blood levels of at least one KP metabolite between adults with BD and healthy controls. Random-effects meta-analyses were carried out generating pooled standardized mean differences (SMDs). Heterogeneity between studies was estimated using the I2 index. Meta-regression and sensitivity analyses were conducted. Sixteen studies met inclusion criteria and were included in our study. Meta-analyses showed that individuals with BD have lower peripheral blood levels of tryptophan (SMD = -0.29), kynurenine (SMD = -0.28), kynurenic acid (SMD = -0.30), and xanthurenic acid (SMD = -0.55), along with lower kynurenic acid to kynurenine (SMD = -0.60) and kynurenic acid to quinolinic acid (SMD = -0.37) ratios, than healthy controls. Individuals with a manic episode showed the greatest reductions in tryptophan levels (SMD = -0.51), whereas kynurenic acid levels were more reduced among subjects in a depressive phase (SMD = -0.70). Meta-regression and sensitivity analyses confirmed our results. The findings of the present meta-analysis support the hypothesis of an abnormality of the KP in BD. Considering the partial inconsistency of the findings and the small-to-medium magnitude of the estimated effect sizes, additional research assessing possible mediators or confounders is needed.

Elevated peripheral inflammation is associated with attenuated striatal reward anticipation in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is the leading cause of years lived with disability worldwide, and up to 40% of individuals with MDD do not respond to current treatments. Studies suggest that peripheral inflammation plays an important role in the striatal mesolimbic dopamine pathway and corticostriatal reward circuitry in MDD. Although MDD patients show blunted striatal responses to reward, the link between degree of inflammation and attenuation of reward processing is unclear. We investigated whether MDD patients with elevated peripheral inflammation exhibit attenuated reward responses to enhance our understanding of MDD pathophysiology and develop more effective treatments for current non-responders. METHODS: MDD subjects varying on serum C-reactive protein (CRP) concentrations (MDD-High CRP, >3 mg/L, n = 44; MDD-Low CRP, <3 mg/L, n = 44) and healthy comparisons (HC, n = 44) completed a monetary incentive delay (MID) task and provided blood samples to measure inflammation-related markers. MDD-High and MDD-Low were propensity score-matched on age, sex, body mass index (BMI), smoking status, exercise and MID task head motion. Percent change in blood oxygen level-dependent (BOLD) signal during anticipation of wins and losses was extracted from bilateral nucleus accumbens, dorsal caudate and dorsolateral putamen regions of interest (ROIs). A linear mixed-effects model was used to test group (MDD-High, MDD-Low and HC), condition (large-win, small-win and no win), and their interaction for these ROIs as well as whole-brain voxelwise data. Analyses also tested group differences in inflammatory mediators. Correlations were used to explore the relationship between inflammatory mediators and brain regions showing differences between MDD-High and MDD-Low. RESULTS: MDD-High exhibited: (a) lower BOLD signal change in dorsal caudate, thalamus, left insula and left precuneus during anticipation of small wins than MDD-Low; and (b) higher serum soluble intercellular adhesion molecule 1 (sICAM-1) and interleukin 6 (IL-6) concentrations than MDD-Low and HC. MDD as a whole, regardless of CRP-based inflammation, exhibited: (a) lower precuneus BOLD signal change to large wins than HC; and (b) higher Interleukin 1 receptor antagonist (IL-1ra), macrophage-derived chemokine (MDC) and macrophage inflammatory protein-1 alpha (MIP-1α) concentrations than HC. Higher serum sICAM-1 concentrations were associated with lower caudate BOLD signal change to small wins only within the MDD-High group. CONCLUSION: Within MDD patients, high inflammation (CRP, sICAM-1) was linked to reduced striatal activation recruited to discriminate intermediate reward magnitudes. These findings support an association between levels of peripheral inflammation and the degree of reward-related activation in individuals with MDD. REGISTRATION OF CLINICAL TRIALS: The ClinicalTrials.gov identifier for the clinical protocol associated with data published in this current paper is NCT02450240, "Latent Structure of Multi-level Assessments and Predictors of Outcomes in Psychiatric Disorders."

Neuroreceptor imaging in depression.

The in vivo study of receptor binding potential in the human brain is made possible by positron emission tomography (PET) imaging. Here we review PET studies of neuroreceptor function in mood disorders - specifically, major depressive disorder (MDD) and bipolar disorder (BD). We concentrate on the most widely studied receptors of the serotonergic and dopaminergic systems. Specifically, the serotonin 1A (5-HT(1A)), serotonin 2A (5-HT(2A)), serotonin 1B (5-HT(1B)), dopamine 1 (D1), and dopamine 2/3 (D2/3) receptors. We also review PET studies of the serotonin transporter (5-HTT), the dopamine transporter (DAT), monoamine oxidase A (MAO-A), and the muscarinic 2 receptor (M2). On the basis of the PET literature as well as supporting genetic studies, postmortem data, and preclinical models of depression, and several models of how monoaminergic function is altered in mood disorders are discussed with respect to inflammation, endocrine dysfunction, depression subtypes, and altered neurocircuitry.

Elevated serum leptin is associated with attenuated reward anticipation in major depressive disorder independent of peripheral C-reactive protein levels.

Major depressive disorder (MDD) is associated with immunologic and metabolic alterations linked to central processing dysfunctions, including attenuated reward processing. This study investigated the associations between inflammation, metabolic hormones (leptin, insulin, adiponectin), and reward-related brain processing in MDD patients with high (MDD-High) and low (MDD-Low) C-reactive protein (CRP) levels compared to healthy comparison subjects (HC). Participants completed a blood draw and a monetary incentive delay task during functional magnetic resonance imaging. Although groups did not differ in insulin or adiponectin concentrations, both MDD-High (Wilcoxon p = 0.004, d = 0.65) and MDD-Low (Wilcoxon p = 0.046, d = 0.53) showed higher leptin concentrations than HC but did not differ from each other. Across MDD participants, higher leptin levels were associated with lower brain activation during reward anticipation in the left insula (r = - 0.30, p = 0.004) and left dorsolateral putamen (r = -- 0.24, p = 0.025). In contrast, within HC, higher leptin concentrations were associated with higher activation during reward anticipation in the same regions (insula: r = 0.40, p = 0.007; putamen: r = 0.37, p = 0.014). Depression may be characterized by elevated pro-inflammatory signaling via leptin concentrations through alternate inflammatory pathways distinct to CRP.

The association of kynurenine pathway metabolites with symptom severity and clinical features of bipolar disorder: An overview.

BACKGROUND: The balance between neurotoxic and neuroprotective effects of kynurenine pathway (KP) components has been recently proposed as a key element in the pathophysiology of bipolar disorder (BD) and related mood episodes. This comprehensive overview explored the link of KP with symptom severity and other clinical features of BD. METHODS: We searched Medline, Embase, and PsycInfo electronic databases for studies assessing the association of peripheral and/or central concentrations of KP metabolites with putative clinical features, including symptom severity and other clinical domains in BD. RESULTS: We included the findings of 13 observational studies investigating the possible variations of KP metabolites according to symptom severity, psychotic features, suicidal behaviors, and sleep disturbances in BD. Studies testing the relationship between KP metabolites and depression severity generated mixed and inconsistent findings. No statistically significant correlations with manic symptoms were found. Moreover, heterogeneous variations of the KP across different clinical domains were shown. Few available studies found (a) higher levels of cerebrospinal fluid kynurenic acid and lower of plasma quinolinic acid in BD with psychotic features, (b) lower central and peripheral picolinic acid levels in BD with suicide attempts, and (c) no significant correlations between KP metabolites and BD-related sleep disturbances. CONCLUSIONS: An imbalance of KP metabolism toward the neurotoxic branches is likely to occur in people with BD, though evidence on variations according to specific clinical features of BD is less clear. Additional research is needed to clarify the role of KP in the etiopathogenesis of BD and related clinical features.

Neuronally-enriched exosomal microRNA-27b mediates acute effects of ibuprofen on reward-related brain activity in healthy adults: a randomized, placebo-controlled, double-blind trial.

This double-blind, randomized, within-subjects design evaluated whether acute administration of an anti-inflammatory drug modulates neuron-specific, inflammation-modulating microRNAs linked to macroscopic changes in reward processing. Twenty healthy subjects (10 females, 10 males) underwent a functional magnetic resonance imaging scan while performing a monetary incentive delay (MID) task and provided blood samples after administration of placebo, 200 mg, or 600 mg of ibuprofen. Neuronally-enriched exosomal microRNAs were extracted from serum and sequenced. Results showed that: (1) 600 mg of ibuprofen exhibited higher miR-27b-3p, miR-320b, miR-23b and miR-203a-3p expression than placebo; (2) higher mir-27b-3p was associated with lower insula activation during MID loss anticipation; and (3) there was an inverse relationship between miR-27b-3p and MID gain anticipation in bilateral putamen during placebo, a pattern attenuated by both 200 mg and 600 mg of ibuprofen. These findings are consistent with the hypothesis that miR-27b could be an important messaging molecule that is associated with regulating the processing of positive or negative valenced information.

Women with Major Depressive Disorder, Irrespective of Comorbid Anxiety Disorders, Show Blunted Bilateral Frontal Responses during Win and Loss Anticipation.

BACKGROUND: Electroencephalography (EEG) studies suggest that major depressive disorder (MDD) is associated with lower left than right frontal brain activity (asymmetry), a pattern appearing stronger in women than men, and when elicited during emotionally-relevant paradigms versus an uncontrolled resting state. However, it is unclear whether this asymmetry pattern generalizes to the common presentation of MDD with co-occurring anxiety. Moreover, asymmetry may differ for anxiety subtypes, wherein anxious apprehension (AnxApp: worry characteristic of generalized anxiety disorder) appears left-lateralized, but anxious arousal (AnxAro: panic characteristic of social anxiety, posttraumatic stress, and panic disorders) may be right-lateralized. METHODS: This analysis attempted to replicate frontal EEG asymmetry patterns using functional magnetic resonance imaging (fMRI). Participants completed clinical interviews and a monetary incentive delay (MID) task during fMRI recording. We compared five groups of right-handed women from the Tulsa 1000 study, MDD (n=40), MDD-AnxApp (n=26), MDD-AnxAro (n=34), MDD-Both (with AnxApp and AnxAro; n=26), and healthy controls (CTL; n=24), as a function of MID anticipation condition (no win/loss, win, loss) and hemisphere on frontal blood oxygen-level-dependent (BOLD) signal. RESULTS: CTL exhibited higher bilateral superior, middle, and inferior middle frontal gyrus BOLD signal than the four MDD groups for high arousal (win and loss) conditions. However, frontal attenuations were unrelated to current depression/anxiety symptoms, suggestive of a trait as opposed to a state marker. LIMITATIONS: This was a cross-sectional analysis restricted to women. CONCLUSIONS: Reduced prefrontal cortex recruitment during processing of both positively and negatively valenced stimuli is consistent with the emotion context insensitivity theory of MDD.

Neuropsychological task performance in bipolar spectrum illness: genetics, alcohol abuse, medication and childhood trauma.

INTRODUCTION: Impaired executive and memory function is a putative genetic trait marker of bipolar I disorder (BPD I). Although executive/memory function has been posited to be an endophenotype of BPD I, it is unclear whether this extends to bipolar spectrum illness. It is also unclear to what extent non-genetic factors such as childhood abuse, alcoholism and medication influence neurocognitive function. We assessed the neuropsychological performance of a large cohort of bipolar disorder probands and their affectively ill and healthy family members, while controlling for self-reported childhood sexual and emotional abuse, emotional neglect, alcohol abuse and medication. METHODS: A total of 230 largely euthymic participants from 47 families, comprising 49 subjects with BPD I, 19 with bipolar II disorder (BPD II), 44 with recurrent major depression (MDE-R), 33 with a single lifetime episode of depression (MDE-S), 20 with other DSM-IV diagnoses and 65 unaffected relatives, were assessed with a battery of neuropsychological tasks. RESULTS: Sexual abuse, emotional abuse and emotional neglect scores were associated with poorer cognitive performance. After controlling for childhood trauma, the BPD I group performed worse than unaffected relatives on tests of visual recall memory as well as verbal recall and recognition memory. In contrast, individuals with BPD II and bipolar spectrum illness did not differ significantly from unaffected relatives. Treatment with lithium and antipsychotic medication was associated with reduced executive and verbal recognition memory function. After controlling for medication and other covariates, only verbal recall memory was significantly impaired in the BPD I cohort. CONCLUSIONS: Verbal recall deficits may be one manifestation of a genetically driven dysfunction of frontal-striatal cortical networks in BPD I.

Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial.

Given evidence of chronic inflammation in bipolar disorder (BD), we tested the efficacy of aspirin and minocycline as augmentation therapy for bipolar depression. Ninety-nine depressed outpatients with BD were enrolled in a 6 week, double-blind, placebo-controlled trial, and randomized to one of four groups: active minocycline (100 mg b.i.d.) + active aspirin (81 mg b.i.d.) (M + A); active minocycline + placebo aspirin (M + P); placebo-minocycline + active aspirin (A + P); and placebo-minocycline + placebo aspirin (P + P). A blinded interim analysis mid-way through the study led to the dropping of the M + P and A + P arms from further enrollment giving numbers per group who were included in the final analysis of: 30 (M + A), 18 (M + P), 19 (A + P), and 28 (P + P). When the study started, there were three primary outcome measures. Based on the results of the interim analysis, the primary outcome variable, response to treatment as defined by >50% decrease in Montgomery-Äsberg Depression Rating Scale (MADRS) score was maintained. The other two (i.e., the change in mean MADRS score from baseline to end of study and the remission rate, with remission being defined as a score of <11 on the MADRS) were reduced to exploratory outcome measures because the interim analysis indicated that the study was adequately powered to test differences in response rate but not the mean change in MADRS scores or remission rates. CRP and IL-6 were assayed to measure inflammation. Urinary thromboxane B2 (11-D-TXB2) concentrations, which were significantly increased at baseline in the combined BD sample (n = 90) vs. a healthy control group (n = 27), served as an indirect marker of cyclooxygenase (COX) activity. In a two-group analysis, the M + A group showed a greater response rate than the P + P group (p(one-tailed) = 0.034, OR = 2.93, NNT = 4.7). When all four arms were included in the analysis, there was a main effect of aspirin on treatment response that was driven by both the M + A and the A + P groups (p(two-tailed) = 0.019, OR = 3.67, NNT = 4.0). Additionally, there was a significant 3-way interaction between aspirin, minocycline, and IL-6, indicating that response to minocycline was significantly greater in participants in the M + P group with higher IL-6 concentrations. Further, participants in the M + P group who responded to treatment had significantly greater decreases in IL-6 levels between baseline and visit 7 vs. non-responders. Regarding the exploratory outcomes, there was a main effect for aspirin on the remission rate (χ12 = 4.14, p(2t) = 0.04, OR = 2.52, NNT = 8.0). There was no significant main effect of aspirin or minocycline on the mean change in MADRS score across visits. Aspirin and minocycline may be efficacious adjunctive treatments for bipolar depression. Given their potential import, additional studies to confirm and extend these findings are warranted.

Co-altered functional networks and brain structure in unmedicated patients with bipolar and major depressive disorders.

Bipolar disorder (BD) and major depressive disorder (MDD) share similar clinical characteristics that often obscure the diagnostic distinctions between their depressive conditions. Both functional and structural brain abnormalities have been reported in these two disorders. However, the direct link between altered functioning and structure in these two diseases is unknown. To elucidate this relationship, we conducted a multimodal fusion analysis on the functional network connectivity (FNC) and gray matter density from MRI data from 13 BD, 40 MDD, and 33 matched healthy controls (HC). A data-driven fusion method called mCCA+jICA was used to identify the co-altered FNC and gray matter components. Comparing to HC, BD exhibited reduced gray matter density in the parietal and occipital cortices, which correlated with attenuated functional connectivity within sensory and motor networks, as well as hyper-connectivity in regions that are putatively engaged in cognitive control. In addition, lower gray matter density was found in MDD in the amygdala and cerebellum. High accuracy in discriminating across groups was also achieved by trained classification models, implying that features extracted from the fusion analysis hold the potential to ultimately serve as diagnostic biomarkers for mood disorders.

Resting-state functional network connectivity in prefrontal regions differs between unmedicated patients with bipolar and major depressive disorders.

BACKGROUND: Differentiating bipolar disorder (BD) from major depressive disorder (MDD) often poses a major clinical challenge, and optimal clinical care can be hindered by misdiagnoses. This study investigated the differences between BD and MDD in resting-state functional network connectivity (FNC) using a data-driven image analysis method. METHODS: In this study, fMRI data were collected from unmedicated subjects including 13 BD, 40 MDD and 33 healthy controls (HC). The FNC was calculated between functional brain networks derived from fMRI using group independent component analysis (ICA). Group comparisons were performed on connectivity strengths and other graph measures of FNC matrices. RESULTS: Statistical tests showed that, compared to MDD, the FNC in BD was characterized by more closely connected and more efficient topological structures as assessed by graph theory. The differences were found at both the whole-brain-level and the functional-network-level in prefrontal networks located in the dorsolateral/ventrolateral prefrontal cortex (DLPFC, VLPFC) and anterior cingulate cortex (ACC). Furthermore, interconnected structures in these networks in both patient groups were negatively associated with symptom severity on depression rating scales. LIMITATIONS: As patients were unmedicated, the sample sizes were relatively small, although they were comparable to those in previous fMRI studies comparing BD and MDD. CONCLUSIONS: Our results suggest that the differences in FNC of the PFC reflect distinct pathophysiological mechanisms in BD and MDD. Such findings ultimately may elucidate the neural pathways in which distinct functional changes can give rise to the clinical differences observed between these syndromes.

Neurocognitive function as an endophenotype for genetic studies of bipolar affective disorder.

The genetic basis of bipolar affective disorder remains opaque despite years of intensive investigation. One of the most serious difficulties for genetic research is the enormous phenotypic heterogeneity of psychiatric illnesses. As a response to this problem, geneticists have searched for alternative strategies to identify those individuals at genetic risk for developing the disorder. One approach is to use endophenotypes or intermediate traits. Gottesman and Gould (2003), in their discussion of endophenotypes, suggest five criteria that should be characteristic of a trait in order for it to qualify as an endophenotype. These five criteria are used in order to assess the viability of using measures of neuropsychological dysfunction as endophenotypes for genetic studies of bipolar disorder. A review of the literature suggests that executive dysfunction is characteristic of people with bipolar disorder in both the acute and chronic stages of the illness, that neurocognitive function is influenced by genetic factors and that neuropsychological deficits have been reported in the nonaffected relatives of bipolar probands. Nevertheless, it is unclear whether neuropsychological dysfunction co-segregates with affectively ill individuals. We conclude that the use of neurocognitive markers of bipolar illness suffers from a number of serious drawbacks but given the absence of more appropriate endophenotypes, the neuropsychological profiling of probands and their relatives may nevertheless prove to be a worthwhile exercise.

Neuropathological and neuromorphometric abnormalities in bipolar disorder: view from the medial prefrontal cortical network.

The question of whether BD is primarily a developmental disorder or a progressive, neurodegenerative disorder remains unresolved. Here, we review the morphometric postmortem and neuroimaging literature relevant to the neuropathology of bipolar disorder (BD). We focus on the medial prefrontal cortex (mPFC) network, a key system in the regulation of emotional, behavioral, endocrine, and innate immunological responses to stress. We draw four main conclusions: the mPFC is characterized by (1) a decrease in volume, (2) reductions in neuronal size, and/or changes in neuronal density, (3) reductions in glial cell density, and (4) changes in gene expression. These data suggest the presence of dendritic atrophy of neurons and the loss of oligodendroglial cells in BD, although some data additionally suggest a reduction in the cell counts of specific subpopulations of GABAergic interneurons. Based on the weight of the postmortem and neuroimaging literature discussed herein, we favor a complex hypothesis that BD primarily constitutes a developmental disorder, but that additional, progressive, histopathological processes also are associated with recurrent or chronic illness. Conceivably BD may be best conceptualized as a progressive neurodevelopmental disorder.

Habenula volume in post-traumatic stress disorder measured with high-resolution MRI.

BACKGROUND: The habenula plays an important role in regulating behavioral responses to stress and shows increased cerebral blood flow and decreased gray matter volume in patients with mood disorders. Here, we compare the volume of the habenula in unmedicated patients with post-traumatic stress disorder (PTSD) and healthy controls (HC) using MRI. FINDINGS: High-resolution images (resolution of approximately 0.4 mm3) were acquired using a 3T scanner and a pulse sequence optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. PTSD and HC participants did not differ significantly in absolute or normalized habenula volume. Post hoc analyses controlling for the effects of comorbid major depressive disorder (MDD) and type and age of trauma exposure were not significant. Further, there was no association between PTSD severity and habenula volume. CONCLUSIONS: Our data suggest that PTSD is not associated with robust structural changes in the habenula. The modest size of the PTSD sample may have reduced statistical power thereby accounting for the negative results obtained.

Habenula volume in bipolar disorder and major depressive disorder: a high-resolution magnetic resonance imaging study.

BACKGROUND: Increased activity of the habenula has been implicated in the etiology of major depressive disorder (MDD), in which reductions in habenula volume are present after death. We conducted the first magnetic resonance imaging analysis of habenula volume in MDD and bipolar disorder (BD). METHODS: High-resolution images (resolution approximately .4 mm(3)) were acquired with a 3T scanner, and a pulse sequence was optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. Seventy-four healthy control subjects (HC) were compared with both medicated (lithium/divalproex, n = 15) and unmedicated, depressed BD (n = 22) patients; unmedicated, depressed MDD patients (n = 28); and unmedicated MDD patients in remission (n = 32). RESULTS: The unmedicated BD patients displayed significantly smaller absolute (p < .01) and normalized (p < .05) habenula volumes than the HC subjects. In post hoc assessments analyzing men and women separately, the currently-depressed women with MDD had smaller absolute (p < .05) habenula volumes than the HC women. None of the other psychiatric groups differed significantly from the HC group. CONCLUSIONS: We provide further evidence for the involvement of the habenula in affective illness but suggest that a reduction in volume might be more pronounced in unmedicated, depressed BD subjects and female currently depressed MDD subjects. The habenula plays major roles in the long-term modification of monoamine transmission and behavioral responses to stress and in the suppression of dopamine cell activity after the absence of an expected reward. A reduction in habenula volume might thus have functional consequences that contribute to the risk for developing affective disease.

The relationship between childhood abuse and dissociation. Is it influenced by catechol-O-methyltransferase (COMT) activity?

Dissociation is a failure of perceptual, memorial and emotional integration that is associated with a variety of psychiatric disorders. Dissociative processes are usually attributed to the sequelae of childhood trauma although there are data to suggest that genetic influences are also important. Bipolar disorder (BD), a condition with a strong genetic basis, has also been associated with early psychological trauma. Since childhood trauma is a risk factor for both BD and dissociation, we tested for potential gene-childhood abuse interactions on dissociation in a pilot sample of BD probands and their affected and unaffected relatives (n=178). Dissociation was measured with the Dissociative Experiences Scale (DES II) and childhood maltreatment with the Childhood Trauma Questionnaire (CTQ). The BD and recurrent unipolar depression (MDE-R) groups showed higher levels of self-reported abuse and dissociation than their unaffected relatives. The low-activity Met allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene was associated with lower levels of self-reported dissociation. Further, the functional catechol-O-methyltransferase (COMT) Val158Met polymorphism interacted significantly with total CTQ abuse scores to impact perceived dissociation. The Val/Val genotype was associated with increasing levels of dissociation in participants exposed to higher levels of childhood trauma. The opposite was observed in people with Met/Met genotypes who displayed decreased dissociation with increasing self-reported childhood trauma. The current findings support the involvement of the COMT Val158Met polymorphism in mediating the relationship between trauma and psychopathology.

Personality: is it a viable endophenotype for genetic studies of bipolar affective disorder?

Progress in identifying the genetic basis of bipolar affective disorder has been disappointing, most probably because of the genetic and phenotypic heterogeneity of the condition. These setbacks have led to the adoption of alternative strategies such as the use of endophenotypes or intermediate traits to identify those individuals at genetic risk for developing the disorder. Gottesman and Gould [Am J Psychiatry (2003), 160:636], in a review of the endophenotypic concept, have suggested five criteria that should be characteristic of a trait in order for it to qualify as an endophenotype. These five criteria are used in order to assess the viability of using personality traits as endophenotypes for genetic analyses of bipolar disorder. A review of the literature suggests that certain personality traits or temperaments are associated with the illness in a state independent manner, that personality is at least partly heritable, and that various temperaments aggregate in the non-affected relatives of bipolar probands. Nevertheless, it is unclear whether specific personality traits co-segregate with affectively ill individuals. We conclude that personality profiling of probands and their relatives may facilitate molecular genetic work, but given the fact that personality is itself a complex trait, its use as an endophenotype has certain limitations.

Genetic variants implicated in personality: a review of the more promising candidates.

Alleles of the serotonin transporter gene (SERT) and the dopamine 4 receptor gene (DRD4) were first associated with anxiety-related and novelty-seeking personality traits, respectively, in 1996. These early successes precipitated a flood of research into the genetic basis of personality; a quest that has yet to yield decisive answers. Here, both the theoretical and the empirical evidence implicating specific loci-in particular SERT and DRD4-in the development of personality is evaluated. Despite a paucity of statistically significant results following post-hoc analysis, and an excess of positive results derived from studies with small sample sizes, the existence of a genuine effect is argued for: a gene-personality relationship rendered periodically latent through genetic epistasis, gene-environment interactions, variation in genetic background, and the presence of other confounding variables.