Cognition, prior aggression, and psychopathic traits in relation to impaired multimodal emotion recognition in psychotic spectrum disorders.

Background: Psychopathic traits have been associated with impaired emotion recognition in criminal, clinical and community samples. A recent study however, suggested that cognitive impairment reduced the relationship between psychopathy and emotion recognition. We therefore investigated if reasoning ability and psychomotor speed were impacting emotion recognition in individuals with psychotic spectrum disorders (PSD) with and without a history of aggression, as well as in healthy individuals, more than self-rated psychopathy ratings on the Triarchic Psychopathy Measure (TriPM). Methods: Eighty individuals with PSD (schizophrenia, schizoaffective disorder, delusional disorder, other psychoses, psychotic bipolar disorder) and documented history of aggression (PSD+Agg) were compared with 54 individuals with PSD without prior aggression (PSD-Agg) and with 86 healthy individuals on the Emotion Recognition Assessment in Multiple Modalities (ERAM test). Individuals were psychiatrically stable and in remission from possible substance use disorders. Scaled scores on matrix reasoning, averages of dominant hand psychomotor speed and self-rated TriPM scores were obtained. Results: Associations existed between low reasoning ability, low psychomotor speed, patient status and prior aggression with total accuracy on the ERAM test. PSD groups performed worse than the healthy group. Whole group correlations between total and subscale scores of TriPM to ERAM were found, but no associations with TriPM scores within each group or in general linear models when accounting for reasoning ability, psychomotor speed, understanding of emotion words and prior aggression. Conclusion: Self-rated psychopathy was not independently linked to emotion recognition in PSD groups when considering prior aggression, patient status, reasoning ability, psychomotor speed and emotion word understanding.

A History of Psychosis in Bipolar Disorder is Associated With Gray Matter Volume Reduction.

Psychotic symptoms are prevalent in schizophrenia, bipolar disorder, and other psychiatric and neurological disorders, yet the neurobiological underpinnings of psychosis remain obscure. In the last decade, a large number of magnetic resonance imaging studies have shown differences in local gray matter volume between patients with different psychiatric syndromes and healthy controls. Few studies have focused on the symptoms, which these syndromes are constituted of. Here, we test the association between psychosis and gray matter volume by using a sample of 167 subjects with bipolar disorder, with and without a history of psychosis, and 102 healthy controls. Magnetic resonance images were analyzed on group level using a voxel-wise mass univariate analysis (Voxel-Based Morphometry). We found that patients with a history of psychosis had smaller gray matter volume in left fusiform gyrus, the right rostral dorsolateral prefrontal cortex, and the left inferior frontal gyrus compared with patients without psychosis and with healthy controls. There was no volume difference in these areas between the no-psychosis group and healthy controls. These areas have previously been structurally and functionally coupled to delusions and hallucinations. Our finding adds further evidence to the probability of these regions as key areas in the development of psychotic symptoms.

Significant grey matter changes in a region of the orbitofrontal cortex in healthy participants predicts emotional dysregulation.

The traditional concept of 'categorical' psychiatric disorders has been challenged as many of the symptoms display a continuous distribution in the general population. We suggest that this is the case for emotional dysregulation, a key component in several categorical psychiatric disorder constructs. We used voxel-based magnetic resonance imaging morphometry in healthy human subjects (n = 87) to study how self-reported subclinical symptoms associated with emotional dysregulation relate to brain regions assumed to be critical for emotion regulation. To measure a pure emotional dysregulation, we also corrected for subclinical symptoms of non-emotional attentional dysregulation. We show that such subclinical emotional symptoms correlate negatively with the grey matter volume of lateral orbitofrontal cortex bilaterally-a region assumed to be critical for emotion regulation and dysfunctional in psychiatric disorders involving emotional dysregulation. Importantly, this effect is mediated both by a decrease in volume associated with emotional dysregulation and an increase in volume due to non-emotional attentional dysregulation. Exploratory analysis suggests that other regions involved in emotional processing such as insula and ventral striatum also show a similar reduction in grey matter volume mirroring clinical disorders associated with emotional dysregulation. Our findings support the concept of continuous properties in psychiatric symptomatology.

Increased cerebrospinal fluid interleukin-8 in bipolar disorder patients associated with lithium and antipsychotic treatment.

Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL-8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication.

Elevated concentrations of neurofilament light chain in the cerebrospinal fluid of bipolar disorder patients.

Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.

Neurocognitive function in bipolar disorder: a comparison between bipolar I and II disorder and matched controls.

BACKGROUND: Cognitive deficits have been documented in patients with bipolar disorder. Further, it has been suggested that the degree and type of cognitive impairment differ between bipolar I and bipolar II disorder, but data is conflicting and remains inconclusive. This study aimed to clarify the suggested differences in cognitive impairment between patients with bipolar I and II disorder in a relatively large, clinically stable sample while controlling for potential confounders. METHODS: 67 patients with bipolar I disorder, 43 with bipolar II disorder, and 86 randomly selected population-based healthy controls were compared. A number of neuropsychological tests were administered, assessing verbal and visual memory and executive functions. Patients were in a stable phase during testing. RESULTS: Patients with bipolar type I and type II were cognitively impaired compared to healthy controls, but there were no statistically significant differences between the two subtypes. The strongest predictor of cognitive impairment within the patient group was current antipsychotic treatment. CONCLUSIONS: The present study suggests that the type and degree of cognitive dysfunction is similar in bipolar I and II patients. Notably, treatment with antipsychotics - but not a history of psychosis - was associated with more severe cognitive impairment. Given that patients with bipolar I disorder are more likely to be on antipsychotic drugs, this might explain why some previous studies have found that patients with type I bipolar disorder are more cognitively impaired than those with type II.

Decreased cerebrospinal fluid secretogranin II concentrations in severe forms of bipolar disorder.

BACKGROUND: Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of abnormally elevated mood and depression. Progressive structural brain changes in individuals with bipolar disorder have been suggested to be associated with defects in the secretion of neurotrophic factors. We sought to assess how the regulated secretory pathway in the brain is affected in patients with bipolar disorder by measuring chromogranin B and secretogranin II, which are 2 cerebrospinal fluid (CSF) biological markers for this process. METHODS: We measured the concentrations of chromogranin B (peptide 439-451) and secretogranin II (peptide 154-165) in the CSF of patients with well-defined bipolar disorder and healthy controls. The lifetime severity of bipolar disorder was rated using the Clinical Global Impression (CGI) scale. RESULTS: We included 126 patients with bipolar disorder and 71 healthy controls in our analysis. Concentrations of secretogranin II were significantly lower in patients with bipolar disorder type I than in healthy controls. The reduction was most pronounced in patients with high CGI scores (i.e., severe disease). LIMITATIONS: The cross-sectional design of the current study limits the ability to pinpoint the causalities behind the observed associations. CONCLUSION: This study shows that the CSF marker secretogranin II has the potential to act as a biological marker for severe forms of bipolar disorder. Our findings indicate that patients with bipolar disorder possess defects in the regulatory secretory pathway, which may be of relevance to the progressive structural brain changes seen in those with severe forms of the disease.

Altered concentrations of amyloid precursor protein metabolites in the cerebrospinal fluid of patients with bipolar disorder.

Bipolar disorder is a psychiatric disorder characterized by recurrent episodes of mania/hypomania and depression. Progressive cognitive dysfunction such as impairments in executive function and verbal memory is common in euthymic bipolar patients. The cerebrospinal fluid has previously been used to study neurodegenerative processes in Alzheimer's disease, from which changes in three core biomarkers have emerged as indicative of degeneration: amyloid ß, total tau, and hyperphosphorylated tau. Here, neurodegeneration in bipolar disorder was investigated by assessing the association between bipolar disorder and cerebrospinal fluid biomarkers for neurodegenerative processes. Cerebrospinal fluid was obtained from 139 bipolar disorder patients and 71 healthy controls. Concentrations of total and phosphorylated tau, amyloid ß1-42, amyloid ß38/ß40/ß42, and the soluble forms of amyloid precursor protein were measured in patients vs controls. The concentrations of the soluble forms of amyloid precursor protein were significantly lower in bipolar patients compared with controls. The amyloid ß42/amyloid ß38 and the amyloid ß42/amyloid ß40 ratios were higher in bipolar patients than controls. There were no discernible differences in the concentrations of total/phosphorylated tau, amyloid ß1-42, or amyloid ß38/ß40/ß42. The concentrations of the biomarkers within the bipolar patient group were further associated with different ongoing medical treatments and diagnostic subgroups. The findings suggest that the amyloid precursor protein metabolism is altered in bipolar disorder. The results may have implications for the understanding of the pathophysiology of bipolar disorder and for the development of treatment strategies. Importantly, there were no signs of an Alzheimer-like neurodegenerative process among bipolar patients.

Microscopic particles in two fractions of fresh cerebrospinal fluid in twins with schizophrenia or bipolar disorder and in healthy controls.

BACKGROUND: Using scanning electron microscopy, microscopic structures have been identified in fresh cerebrospinal fluid (CSF) in patients with schizophrenia and bipolar disorder, but only rarely in control subjects. However, it has not been determined whether these microscopic particles represent state or trait markers, i.e. if their presence is related to clinical manifestations of the disease or if they also can be found in as yet asymptomatic individuals with a genetic liability. This question can be addressed by studying twins discordant or concordant for schizophrenia or bipolar disorder. METHODOLOGY/PRINCIPAL FINDINGS: We investigated microscopic structures in CSF in 102 individuals: 21 monozygotic and 16 dizygotic twins affected or not affected with schizophrenia, schizoaffective disorder or bipolar disorder and in 65 healthy singleton controls. A first and a second fraction of CSF was freshly applied on filters and examined by scanning electron microscopy technique. Spherical particles with lipid appearance averaging between 0.1 to 8.0 µm in diameter were detected in the center of the filter as well as located in the margins of larger aggregates binding in a viscous state. Structures were found in 12 of 17 probands, 5 of 12 healthy co-twins and 3 of 73 healthy controls. Thus, a positive microscopic finding significantly increased the likelihood of belonging to the proband group (OR=48, 95% CL: 8.2-550, p<0.0001) and the co-twin-group (OR=16, 95% CL: 2.0-218, p=0.006). Age, sex, history of alcohol abuse or anxiety syndrome, somatic disorder and markers of acute inflammatory activity did not account for group differences; nor did exposure to psychotropic medication. CONCLUSION: Presence of microscopic particles in CSF may possibly reflect trait dependent genetic or environmental vulnerability in patients with schizophrenia, schizoaffective disorder or bipolar disorder.

Polymorphisms in AKR1C4 and HSD3B2 and differences in serum DHEAS and progesterone are associated with paranoid ideation during mania or hypomania in bipolar disorder.

Paranoia is commonly a mood-incongruent psychotic symptom of mania which may be related to dopamine dysregulation. Progesterone and its metabolite allopregnanolone (ALLO) have been found in animals to antagonize the effects of dopamine. We therefore examined serum progesterone, its endogenous antagonist DHEAS and polymorphisms of the genes coding for certain steroidogenetic enzymes (AKR1C4, HSD3B2, and SRD5A1) in 64 males and 96 females with bipolar 1 or 2 disorder with or without paranoid ideation during mood elevation. Euthymic morning serum progesterone, DHEAS and cortisol concentrations were measured in males and in premenopausal women who were in follicular phase and not taking oral contraceptives. In women only, SNPs in AKR1C4 reduced the likelihood of having exhibited paranoid ideation by circa 60%. The haplotype of all 4 SNPs in the AKR1C4 gene reduced the risk of exhibiting paranoia by 80% (OR 0.19, 95% CI 0.06-0.61, p=0.05). A history of paranoid ideation was not, however, related to progesterone or DHEAS concentration. Serum DHEAS and progesterone concentrations were lower in men who had shown paranoid ideation during mania/hypomania compared with those who had not (F=7.30, p=0.006) however this was not coupled to polymorphisms in the selected genes. The ancestral G in rs4659174 in HSD3B2 was in men associated with a lower risk of paranoid ideation (likelihood ratio χ(2) 3.97, p=0.046, OR 0.31 (95% CI 0.10-0.96)) but did not correlate with hormone concentrations. Hence, gene variants in the steroidogenetic pathway and steroids concentration differences may be involved in the susceptibility to paranoia during mood elevation.

AKR1C4 gene variant associated with low euthymic serum progesterone and a history of mood irritability in males with bipolar disorder.

BACKGROUND: Irritable mood during mood elevation is common in bipolar disorder. The progesterone metabolite allopregnanolone (ALLO) has been implicated in other disorders presenting with irritability. This study aimed to test whether a history of manic/hypomanic irritability is associated with low serum progesterone levels; and whether single nucleotide polymorphisms (SNPs) in gene coding for steroidogenetic enzymes (HSD3B2, SRD5A1 and AKR1C4 were coupled to previous manic irritability and/or with serum progesterone concentrations. METHODS: Morning serum progesterone concentrations during euthymic phase of bipolar illness types 1 and 2 were assessed in 71 males and 107 females. Previous manic/hypomanic irritability was assessed using the Affective Disorders Evaluation. Selected SNPs were analyzed: i) aldoketoreductase-type-4 (AKR1C4 - rs17306779, rs3829125, rs10904440, rs12762017, and rs11253048), ii) 3-ß-hydroxysteroid-dehydrogenase (HSD3B2 - rs4659174, rs2854964, and rs3765948), iii) steroid-5-α-reductase (SRD5A1 - rs8192139, rs181807, rs3822430, and rs3736316). RESULTS: In males, progesterone concentrations were lower in those who had shown manic/hypomanic irritability compared with nonirritable (F=7.05, p=0.0099). SNPs rs17306779, rs3829125, and rs10904440 were associated with manic/hypomanic irritability. A cystine to serine change at position 145 in AKR1C4 (rs3829125) was associated with lower serum progesterone (F=6.34, p=0.014). There were no associations in females. LIMITATIONS: Relatively small sample sizes. CONCLUSION: Low progesterone levels and a cystine to serine change at position 145 in AKR1C4 gene are associated with manic/hypomanic irritability in males. Given that the enzyme AKR1C4 has both dehydrogenating and reductive activities in the steroidogenetic pathway, a missense variation in the gene may predispose to manic/hypomanic irritability by altering the relationship between progesterone and ALLO concentrations in the brain.