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| 2. |
- Lavebratt, C., et al.
(författare)
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The KMO allele encoding Arg(452) is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression
- 2014
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 19:3, s. 334-341
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Tidskriftsartikel (refereegranskat)abstract
- The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P = 0.005, n = 19) or schizophrenia (P = 0.02, n = 36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P = 0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P = 0.03) and reduced lymphoblastoid and hippocampal KMO expression (P <= 0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.
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| 3. |
- Backlund, L., et al.
(författare)
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P2RX7: Expression Responds to Sleep Deprivation and Associates with Rapid Cycling in Bipolar Disorder Type 1
- 2012
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 27
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Tidskriftsartikel (refereegranskat)abstract
- Context: Rapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling. Objectives: To assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients. Design: Gene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients. Participants: Healthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044). Results: P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10(-9)). The P2RX7 rs2230912_A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45-0.49, p = 0.003-0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls. Conclusions: Sleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system.
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| 5. |
- Brundin, L., et al.
(författare)
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An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation
- 2016
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- 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-beta-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-Asberg 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.
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| 6. |
- Engström, Gunnar, et al.
(författare)
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Clinical characteristics and biological parameters in temperamental clusters of suicide attempters
- 1997
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Ingår i: Journal of Affective Disorders. - 1573-2517. ; 44:1, s. 45-55
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Tidskriftsartikel (refereegranskat)abstract
- A sample of 215 suicide attempters was categorized in a cluster analysis into four groups according to temperamental trails. Monoamine metabolites in the cerebrospinal fluid were analysed (n = 106). Dexamethasone suppression tests (DST) were performed (n = 154) and the activity of the enzyme monoamine oxidase in platelets (pl-MAO) was assessed (n = 103). Patients belonging to the two clusters with the most deviant temperament profiles (nos 2 and 3) were young and scored high on the Beck Hopelessness Scale and the Suicide Assessment Scale. "Cluster 3" ("neurotic, impulsive, aggressive") patients often had dysthymia and axis II, cluster B diagnoses (e.g. borderline or histrionic personality). "Cluster 2" ("neurotic and introverted") patients often had major depression. The "Cluster 1", with on the whole a normal temperament profile, had significantly higher levels of post-DST cortisol than the other clusters. The "Cluster 4" had a normal temperament profile. Adjustment disorders were most common in "Cluster 1" and "Cluster 4". The monoamine metabolite levels did not differ between the clusters, and the differences in pl-MAO activity disappeared after adjusting for age and gender. The results suggest that temperament profiles in suicide attempters are related to psychiatric diagnoses, suicidality, hopelessness, and post-DST cortisol, but are not predictive of completed suicide.
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| 7. |
- Fribergh, H, et al.
(författare)
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The Meta-Contrast Technique : a projective test predicting suicide
- 1992
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Ingår i: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 86:6, s. 7-473
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Tidskriftsartikel (refereegranskat)abstract
- Sixty-nine inpatients who had attempted suicide were studied by means of the Meta-Contrast Technique (MCT), a projective test measuring personality factors, especially defensive strategies. The patients were divided into 3 subgroups, one of which was defined as stereotypy only, which denotes stereotypy (perceptual retardation) without any other coded defenses. At follow-up 7 of 8 completed suicides belonged to this subgroup and they matched various main diagnoses according to DSM-III-R. When the MCT findings of all patients were compared with 99 depressed inpatients from a previous study, the latter group more often had mature defensive strategies. In both investigations most completed suicides were found in the stereotypy only group. Our findings indicate that, regardless of psychiatric diagnosis, stereotypy without other defenses in MCT predicts suicide.
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| 8. |
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| 9. |
- Johnson, Philip L., et al.
(författare)
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A key role for orexin in panic anxiety
- 2010
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 16:1, s. 111-149
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Tidskriftsartikel (refereegranskat)abstract
- Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate(1-3). In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses(4-9). The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin)(10), which have a crucial role in arousal(10,11), vigilance(10) and central autonomic mobilization(12), all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder. (C) 2010 Nature America, Inc. All rights reserved.
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| 10. |
- Johnsson Fridell, E., et al.
(författare)
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A 5-year follow-up study of suicide attempts
- 1996
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Ingår i: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 93:3, s. 151-157
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Tidskriftsartikel (refereegranskat)abstract
- Seventy-five patients were admitted to the ward of the Lund Suicide Research Center following a suicide attempt. After 5 years, the patients were followed up by a personal semistructured interview covering sociodemographic, psychosocial and psychiatric areas. Ten patients (13%) had committed suicide during the follow-up period, the majority within 2 years. They tended to be older at the index attempt admission, and most of them had a mood disorder in comparison with the others. Two patients had died from somatic diseases. Forty-two patients were interviewed, of whom 17 (40%) had reattempted during the follow-up period, most of them within 3 years. Predictors for reattempt were young age, personality disorder, parents having received treatment for psychiatric disorder, and a poor social network. At the index attempt, none of the reattempters had diagnoses of adjustment disorders or anxiety disorders. At follow-up, reattempters had more psychiatric symptoms (SCL-90), and their overall functioning (CAF) was poor compared to those who did not reattempt. All of the reattempters had had long-lasting treatment (> 3 years) as compared to 56% of the others. It is of great clinical importance to focus on treatment strategies for the vulnerable subgroup of self-destructive reattempters.
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| 11. |
- Lindqvist, D., et al.
(författare)
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Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters : associations with HPA-axis hyperactivity
- 2016
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Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre- and post-DST; all P-values < 2.98E - 12, Cohen's d ranging from 2.55 to 4.01). Pre-DST plasma levels of mtDNA were positively correlated with post-DST cortisol levels (rho = 0.49, P < 0.003). Suicide attempters may have elevated plasma levels of free-circulating mtDNA, which are related to impaired HPA-axis negative feedback. This peripheral index is consistent with an increased cellular or mitochondrial damage. The specific cells and tissues contributing to plasma levels of free-circulating mtDNA are not known, as is the specificity of this finding for suicide attempters. Future studies are needed in order to better understand the relevance of increased free-circulating mtDNA in relation to the pathophysiology underlying suicidal behavior and depression.
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