Reporting trigger factors for (hypo)manic episodes in bipolar disorder: association with personality and prognosis.

OBJECTIVE: To investigate external factors that trigger manic and hypomanic relapses and how this is associated with personality and clinical outcome measured as number of affective episodes over a 7-year period. METHOD: This is a prospective cohort study of 204 meticulously characterized Swedish bipolar disorder patients. Personality was evaluated at baseline using the Swedish universities Scales of Personality in 170 patients, and 90 patients were followed up after approximately 7 years in order to evaluate clinical outcomes. RESULTS: We found that 44% of the patients reported trigger factors, including sleep disturbance, work- or family-related issues, medication, and illicit drug use. There were no significant differences in any of the personality traits when comparing the 74 patients that reported triggers with the 90 patients that did not. At 7-year follow-up, there was no difference between the groups in number of affective episodes (depressive, hypomanic, manic, or mixed), involuntary commitments, suicide attempts, or self-harm incidents since baseline. CONCLUSIONS: Around 40% of the patients reported external triggers for manic and hypomanic episodes. However, this was neither associated with personality traits nor number of affective episodes at 7-year follow-up.

Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis.

OBJECTIVE: Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein-1 (MCP-1) and chitinase-3-like protein 1 (YKL-40) were investigated in plasma and cerebrospinal fluid (CSF) in first-episode psychosis (FEP) patients. METHOD: CSF and blood were sampled from 42 first-episode psychosis (FEP) patients and 22 healthy controls. The levels of YKL-40 and MCP-1 were measured using electrochemiluminescence assay, and blood monocytes were counted using an XN-9000-hematology analyzer. RESULTS: We found higher plasma levels of MCP-1 and YKL-40 in FEP patients compared with healthy controls, a condition that was unrelated to antipsychotic and/or anxiolytic medication. This was combined with an increased number of blood monocytes and a borderline significant increase in YKL-40 levels in the CSF of tobacco-free FEP patients. Plasma or CSF chemokines or blood monocytes did not correlate with the severity of symptoms or the level of functioning. CONCLUSION: These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL-40 and MCP-1 in the initiation and progression of schizophrenia.

CSF GABA is reduced in first-episode psychosis and associates to symptom severity.

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.

Prevalence of current anxiety disorders in people with bipolar disorder during euthymia: a meta-analysis.

BACKGROUND: Anxiety disorders are highly prevalent in people with bipolar disorder, but it is not clear how many have anxiety disorders even at times when they are free of major mood episodes. We aimed to establish what proportion of euthymic individuals with bipolar disorder meet diagnostic criteria for anxiety disorders. METHOD: We performed a random-effects meta-analysis of prevalence rates of current DSM-III- and DSM-IV-defined anxiety disorders (panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder, specific phobia, obsessive-compulsive disorder, post-traumatic stress disorder, and anxiety disorder not otherwise specified) in euthymic adults with bipolar disorder in studies published by 31 December 2015. RESULTS: Across 10 samples with 2120 individuals with bipolar disorder, 34.7% met diagnostic criteria for one or more anxiety disorders during euthymia [95% confidence interval (CI) 23.9-45.5%]. Direct comparison of 189 euthymic individuals with bipolar disorder and 17 109 population controls across three studies showed a 4.6-fold increase (risk ratio 4.60, 95% CI 2.37-8.92, p < 0.001) in prevalence of anxiety disorders in those with bipolar disorder. CONCLUSIONS: These findings suggest that anxiety disorders are common in people with bipolar disorder even when their mood is adequately controlled. Euthymic people with bipolar disorder should be routinely assessed for anxiety disorders and anxiety-focused treatment should be initiated if indicated.

Patient-specific models of microglia-mediated engulfment of synapses and neural progenitors.

Engulfment of synapses and neural progenitor cells (NPCs) by microglia is critical for the development and maintenance of proper brain circuitry, and has been implicated in neurodevelopmental as well as neurodegenerative disease etiology. We have developed and validated models of these mechanisms by reprogramming microglia-like cells from peripheral blood mononuclear cells, and combining them with NPCs and neurons derived from induced pluripotent stem cells to create patient-specific cellular models of complement-dependent synaptic pruning and elimination of NPCs. The resulting microglia-like cells express appropriate markers and function as primary human microglia, while patient-matched macrophages differ markedly. As a demonstration of disease-relevant application, we studied the role of C4, recently implicated in schizophrenia, in engulfment of synaptic structures by human microglia. The ability to create complete patient-specific cellular models of critical microglial functions utilizing samples taken during a single clinical visit will extend the ability to model central nervous system disease while facilitating high-throughput screening.

An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation.

Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-ß-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.

A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder.

Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1ß and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.