Search Results

Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders.

We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia.

Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50.

Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.

Although bipolar disorder (BD) is a fundamentally cyclical illness, a divided model of BD that emphasizes polarity over cyclicity has dominated modern psychiatric diagnostic systems since their advent in the 1980s. However, there has been a gradual return to conceptualizations of BD which focus on longitudinal course in the research community due to emerging supportive data. Advances in longitudinal statistical methods promise to further progress the field.

The current study employed hidden Markov modeling to uncover empirically derived manic and depressive states from longitudinal data [i.e. Young Mania Rating Scale and Montgomery–Asberg Depression Rating Scale responses across five occasions from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study], estimate participants’ probabilities of transitioning between these states over time (n = 3918), and evaluate whether clinical variables (e.g. rapid cycling and substance dependence) predict participants’ state transitions (n = 3229).

Analyses identified three empirically derived mood states (‘euthymic,’ ‘depressed,’ and ‘mixed’). Relative to the euthymic and depressed states, the mixed state was less commonly experienced, more temporally unstable, and uniquely associated with rapid cycling, substance use, and psychosis. Individuals assigned to the mixed state at baseline were relatively less likely to be diagnosed with BD-II (v. BD-I), more likely to present with a mixed or (hypo)manic episode, and reported experiencing irritable and elevated mood more frequently.

The results from the current study represent an important step in defining, and characterizing the longitudinal course of, empirically derived mood states that can be used to form the foundation of objective, empirical attempts to define meaningful subtypes of affective illness defined by clinical course.

A reliable biomarker signature for bipolar disorder sensitive to illness phase would be of considerable clinical benefit. Among circulating blood-derived markers there has been a significant amount of research into inflammatory markers, neurotrophins and oxidative stress markers.

To synthesise and interpret existing evidence of inflammatory markers, neurotrophins and oxidative stress markers in bipolar disorder focusing on the mood phase of illness.

Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a systematic review was conducted for studies investigating peripheral biomarkers in bipolar disorder compared with healthy controls. We searched Medline, Embase, PsycINFO, SciELO and Web of Science, and separated studies by bipolar mood phase (mania, depression and euthymia). Extracted data on each biomarker in separate mood phases were synthesised using random-effects model meta-analyses.

In total, 53 studies were included, comprising 2467 cases and 2360 controls. Fourteen biomarkers were identified from meta-analyses of three or more studies. No biomarker differentiated mood phase in bipolar disorder individually. Biomarker meta-analyses suggest a combination of high-sensitivity C-reactive protein/interleukin-6, brain derived neurotrophic factor/tumour necrosis factor (TNF)-α and soluble TNF-α receptor 1 can differentiate specific mood phase in bipolar disorder. Several other biomarkers of interest were identified.

Combining biomarker results could differentiate individuals with bipolar disorder from healthy controls and indicate a specific mood-phase signature. Future research should seek to test these combinations of biomarkers in longitudinal studies.

None.

There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.

To investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls.

Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls.

Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest.

Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.

R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

Lamotrigine is a commonly used drug in the treatment of bipolar disorder. Although there are reports of its effectiveness in the management of bipolar disorder and comorbid obsessive-compulsive disorder (OCD), lamotrigine has also been associated with obsessionality in patients with bipolar disorder.

Charts of 8 patients with bipolar disorder who had de novo onset of obsessions and compulsions after the use of lamotrigine were reviewed. The Naranjo scale was used to assess the likelihood of patients developing OCD due to lamotrigine use.

Two to 8 months after the initiation of lamotrigine, patients with no such prior history developed obsessions and compulsions meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for medication-induced OCD. In all except 1 patient, the symptoms resolved within a month of lamotrigine discontinuation.

Some patients with bipolar disorder may develop OCD after initiation of lamotrigine. Due to the inherent limitations of a case series, the findings should be interpreted with caution.

Cardiovascular diseases represent a major health issue in patients with schizophrenia (SCZ) and bipolar disorder (BD), but the exact nature of cardiometabolic (CM) abnormalities involved and the underlying mechanisms remain unclear. Psychiatric medications are known risk factors, but it is unclear whether there is a connection between the disorders (SCZ/BD) themselves and CM abnormalities.

Using polygenic risk scores and linkage disequilibrium score regression, we investigated the shared genetic bases of SCZ and BD with 28 CM traits. We performed Mendelian randomization (MR) to elucidate causal relationships between the two groups of disorders. The analysis was based on large-scale meta-analyses of genome-wide association studies. We also identified the potential shared genetic variants and inferred the pathways involved.

We found tentative polygenic associations of SCZ with glucose metabolism abnormalities, adverse adipokine profiles, increased waist-to-hip ratio and visceral adiposity (false discovery rate or FDR<0.05). However, there was an inverse association with body mass index. For BD, we observed several polygenic associations with favorable CM profiles at FDR<0.05. MR analysis showed that SCZ may be causally linked to raised triglyceride and that lower fasting glucose may be linked to BD. We also identified numerous single nucleotide polymorphisms and pathways shared between SCZ/BD with CM traits, some of which are related to inflammation or the immune system.

Our findings suggest that SCZ patients may be genetically predisposed to several CM abnormalities independent of medication side effects. On the other hand, CM abnormalities in BD may be more likely to be secondary. However, the findings require further validation.

The neurocognitive trajectory in bipolar disorder (BD) is variable, with controversial findings, and most evidence come from cross-sectional studies. We aimed to examine the course of neurocognitive functioning in a sample of euthymic BD patients in comparison with a control group during a 5-year follow-up.

Ninety-nine euthymic bipolar patients and 40 healthy controls were assessed using a comprehensive neurocognitive battery (six neurocognitive domains) at baseline (T1) and then at 5-year follow-up (T2) in a longitudinal study.

No evidence of a progression in neurocognitive dysfunction was found either in cognitive composite index or in any of the neurocognitive domains for the whole cohort. However, there was a negative correlation between number of manic episodes and hospitalisations due to manic episodes and change in neurocognitive composite index (NCI) during the follow-up. Moreover, patients with higher number of manic and hypomanic episodes have a greater decrease in NCI, working memory and visual memory. History of psychotic symptoms was not related to the trajectory of neurocognitive impairment.

Our results suggest that, although the progression of cognitive decline is not a general rule in BD, BD patients who have a greater number of manic or hypomanic episodes may constitute a subgroup characterised by the progression of neurocognitive impairment. Prevention of manic and hypomanic episodes could have a positive impact on the trajectory of cognitive function.

This study aimed to explore effects of adjunctive treatment with N-acetyl cysteine (NAC) on markers of inflammation and neurogenesis in bipolar depression.

This is a secondary analysis of a placebo-controlled randomised trial. Serum samples were collected at baseline, week 8, and week 32 of the open-label and maintenance phases of the clinical trial to determine changes in interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-α (TNF-α), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following adjunctive NAC treatment, and to explore mediation and moderator effects of the listed markers.

Levels of brain-derived neurotrophic factor (BDNF), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukins (IL) -6, 8, or 10 were not significantly changed during the course of the trial or specifically in the open-label and maintenance phases. There were no mediation or moderation effects of the biological factors on the clinical parameters.

The results suggest that these particular biological parameters may not be directly involved in the therapeutic mechanism of action of adjunctive NAC in bipolar depression.

The Treatment Algorithm Group (TAG) was supported logistically by Servier who provided financial assistance with travel and accommodation for those TAG members travelling interstate or overseas to attend the meeting in Sydney (held on 18 November 2017). None of the committee were paid to participate in this project and Servier have not had any input into the content, format or outputs from this project.

The long-term outcomes of bipolar disorder range from lasting remission to chronic course or frequent recurrences requiring admissions. The distinction between bipolar I and II disorders has limited utility in outcome prediction. It is unclear to what extent the clinical course of bipolar disorder predicts long-term outcomes.

A representative sample of 191 individuals diagnosed with bipolar I or II disorder was recruited and followed for up to 5 years using a life-chart method. We previously described the clinical course over the first 18 months with dimensional course characteristics and latent classes. Now we test if these course characteristics predict long-term outcomes, including time ill (time with any mood symptoms) and hospital admissions over a second non-overlapping follow-up period in 111 individuals with available data from both 18 months and 5 years follow-ups.

Dimensional course characteristics from the first 18 months prospectively predicted outcomes over the following 3.5 years. The proportion of time depressed, the severity of depressive symptoms and the proportion of time manic predicted more time ill. The proportion of time manic, the severity of manic symptoms and depression-to-mania switching predicted a greater likelihood of hospital admissions. All predictions remained significant after controlling for age, sex and bipolar I v. II disorder.

Differential associations with long-term outcomes suggest that course characteristics may facilitate care planning with greater predictive validity than established types of bipolar disorders. A clinical course dominated by depressive symptoms predicts a greater proportion of time ill. A clinical course characterized by manic episodes predicts hospital admissions.

Attention-deficit hyperactivity disorder (ADHD) and anxiety disorders have been proposed as precursors of bipolar disorder, but their joint and relative roles in the development of bipolar disorder are unknown.

To test the prospective relationship of ADHD and anxiety with onset of bipolar disorder.

We examined the relationship between ADHD, anxiety disorders and bipolar disorder in a birth cohort of 2 409 236 individuals born in Denmark between 1955 and 1991. Individuals were followed from their sixteenth birthday or from January 1995 to their first clinical contact for bipolar disorder or until December 2012. We calculated incidence rates per 10 000 person-years and tested the effects of prior diagnoses on the risk of bipolar disorder in survival models.

Over 37 394 865 person-years follow-up, 9250 onsets of bipolar disorder occurred. The incidence rate of bipolar disorder was 2.17 (95% CI 2.12–2.19) in individuals with no prior diagnosis of ADHD or anxiety, 23.86 (95% CI 19.98–27.75) in individuals with a prior diagnosis of ADHD only, 26.05 (95% CI 24.47–27.62) in individuals with a prior diagnosis of anxiety only and 66.16 (95% CI 44.83–87.47) in those with prior diagnoses of both ADHD and anxiety. The combination of ADHD and anxiety increased the risk of bipolar disorder 30-fold (95% CI 21.66–41.40) compared with those with no prior ADHD or anxiety.

Early manifestations of both internalising and externalising psychopathology indicate liability to bipolar disorder. The combination of ADHD and anxiety is associated with a very high risk of bipolar disorder.

None.

Fractional anisotropy in the uncinate fasciculus and the cingulum may be biomarkers for bipolar disorder and may even be distinctly affected in different subtypes of bipolar disorder, an area in need of further research.

This study aims to establish if fractional anisotropy in the uncinate fasciculus and cingulum shows differences between healthy controls, patients with bipolar disorder type I (BD-I) and type II (BD-II), and their unaffected siblings.

Fractional anisotropy measures from the uncinate fasciculus, cingulum body and parahippocampal cingulum were compared with tractography methods in 40 healthy controls, 32 patients with BD-I, 34 patients with BD-II, 17 siblings of patients with BD-I and 14 siblings of patients with BD-II.

The main effects were found in both the right and left uncinate fasciculus, with patients with BD-I showing significantly lower fractional anisotropy than both patients with BD-II and healthy controls. Participants with BD-II did not differ from healthy controls. Siblings showed similar effects in the left uncinate fasciculus. In a subsequent complementary analysis, we investigated the association between fractional anisotropy in the uncinate fasciculus and polygenic risk for bipolar disorder and psychosis in a large cohort (n = 570) of healthy participants. However, we found no significant association.

Fractional anisotropy in the uncinate fasciculus differs significantly between patients with BD-I and patients with BD-II and healthy controls. This supports the hypothesis of differences in the physiological sub-tract between bipolar disorder subtypes. Similar results were found in unaffected siblings, suggesting the potential for this biomarker to represent an endophenotype for BD-I. However, fractional anisotropy in the uncinate fasciculus seems unrelated to polygenic risk for bipolar disorder or psychosis.

None.

Lack of good animal models for affective disorders, including major depression and bipolar disorder, is noted as a major bottleneck in attempts to study these disorders and develop better treatments. We suggest that an important approach that can help in the development and use of better models is attention to variability between model animals.

Differences between mice strains were studied for some decades now, and sex differences get more attention than in the past. It is suggested that one factor that is mostly neglected, individual variability within groups, should get much more attention. The importance of individual differences in behavioral biology and ecology was repeatedly mentioned but its application to models of affective illness or to the study of drug response was not heavily studied. The standard approach is to overcome variability by standardization and by increasing the number of animals per group.

Possibly, the individuality of specific animals and their unique responses to a variety of stimuli and drugs, can be helpful in deciphering the underlying biology of affective behaviors as well as offer better prediction of drug responses in patients.

Magnesium (Mg2+) has received considerable attention with regards to its potential role in the pathophysiology of the mood disorders, but the available evidence seems inconclusive.

To review and quantitatively summarise the human literature on Mg2+ intake and Mg2+ blood levels in the mood disorders and the effects of Mg2+ supplements on mood.

Systematic review and meta-analyses.

Adherence to a Mg2+-rich diet was negatively associated with depression in cross-sectional (odds ratio = 0.66) but not in prospective studies. Mg2+ levels in bodily fluids were on average higher in patients with a mood disorder (Hedge's g = 0.19), but only in patients treated with antidepressants and/or mood stabilisers. There was no evident association between Mg2+ levels and symptom severity. Mg2+ supplementation was associated with a decline in depressive symptoms in uncontrolled (g = −1.60) but not in placebo-controlled trials (g = −0.21).

Our results provide little evidence for the involvement of Mg2+ in the mood disorders.

None.

Bipolar disorder (BD) has been associated with altered brain structural and functional connectivity. However, little is known regarding alterations of the structural brain connectome in BD. The present study aimed to use diffusion-tensor imaging (DTI) and graph theory approaches to investigate the rich club organization and white matter structural connectome in BD.

Forty-two patients with unmedicated BD depression and 59 age-, sex- and handedness-matched healthy control participants underwent DTI. The whole-brain structural connectome was constructed by a deterministic fiber tracking approach. Graph theory analysis was used to examine the group-specific global and nodal topological properties, and rich club organizations, and then nonparametric permutation tests were used for group comparisons of network parameters.

Compared with healthy control participants, the patients with BD showed abnormal global properties, including increased characteristic path length, and decreased global efficiency and local efficiency. Locally, the patients with BD showed abnormal nodal parameters (nodal strength, nodal efficiency, and nodal betweenness) predominantly in the parietal, orbitofrontal, occipital, and cerebellar regions. Moreover, the patients with BD showed decreased rich club and feeder connectivity density.

Our results may reflect the disrupted white matter topological organization in the whole-brain, and abnormal regional connectivity supporting cognitive and affective functioning in depressed BD, which, in part, be due to impaired rich club connectivity.

Cognitive deficits are a well-established feature of bipolar disorders (BD), even during periods of euthymia, but risk factors associated with cognitive deficits in euthymic BD are still poorly understood. We aimed to validate classification criteria for the identification of clinically significant cognitive impairment, based on psychometric properties, to estimate the prevalence of neuropsychological deficits in euthymic BD, and identify risk factors for cognitive deficits using a multivariate approach.

We investigated neuropsychological performance in 476 euthymic patients with BD recruited via the French network of BD expert centres. We used a battery of tests, assessing five domains of cognition. Five criteria for the identification of neuropsychological impairment were tested based on their convergent and concurrent validity. Uni- and multivariate logistic regressions between cognitive impairment and several clinical and demographic variables were performed to identify risk factors for neuropsychological impairment in BD.

One cut-off had satisfactory psychometric properties and yielded a prevalence of 12.4% for cognitive deficits in euthymic BD. Antipsychotics use were associated with the presence of a cognitive deficit.

This is the first study to validate a criterion for clinically significant cognitive impairment in BD. We report a lower prevalence of cognitive impairment than previous studies, which may have overestimated its prevalence. Patients with euthymic BD and cognitive impairment may benefit from cognitive remediation.

Prior studies have indicated that both high and low school grades are associated with development of bipolar disorder (BD), but these studies have not adjusted for parental history of mental disorder, which is a likely confounder. Furthermore, the association between school grades and bipolar I disorder (BD-I) has not been studied. Therefore, we aimed to study the association between school exam grades and subsequent development of BD and BD-I while adjusting for parental history of mental disorder.

We conducted a register-based nationwide cohort study following 505 688 individuals born in Denmark between 1987 and 1995. We investigated the association between school exam grades and development of BD or BD-I with a Cox model adjusting for family history of mental disorder and other potential confounders.

During follow-up, 900 individuals were diagnosed with BD and 277 of these with BD-I. The risk for BD and BD-I was significantly increased for individuals not having completed the exams at term [adjusted hazard ratio (aHR) for BD (aHR=1.71, 95% CI: 1.43–2.04) and for BD-I (aHR=1.57, 95% CI: 1.13–2.19)]. Also, having low exam grades in mathematics was associated with increased risk of both BD (aHR=2.41, 95% CI: 1.27–4.59) and BD-I (aHR=2.71, 95% CI: 1.41–5.21). Females with very high exam grades in Danish (percentile group>97.7) had a significantly increased risk of BD-I (aHR=2.49, 95% CI: 1.19–5.23).

The potential to develop BD seems to affect the school results of individuals negatively even before BD is diagnosed – with females having the potential to develop BD-I as a possible exception.