| 1. |
- Andersson, Erik, et al.
(författare)
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d-Cycloserine vs Placebo as Adjunct to Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder and Interaction With Antidepressants A Randomized Clinical Trial
- 2015
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 72:7, s. 659-667
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE It is unclear whether D-cycloserine (DCS), a partial N-methyl-D-aspartate agonist that enhances fear extinction, can augment the effects of exposure-based cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD). OBJECTIVES To examine whether DCS augments the effects of CBT for OCD and to explore (post hoc) whether concomitant antidepressant medication moderates the effects of DCS. DESIGN, SETTING, AND PARTICIPANTS A 12-week, double-blind randomized clinical trial with 3-month follow-up conducted at an academic medical center between September 4, 2012, and September 26, 2013. Participants included 128 adult outpatients with a primary diagnosis of OCD and a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of 16 or higher. Concurrent antidepressant medication was permitted if the dose had been stable for at least 2 months prior to enrollment and remained unchanged during the trial. The main analysis was by intention-to-treat population. INTERVENTIONS All participants received a previously validated Internet-based CBT protocol over 12 weeks and were randomized to receive either 50 mg of DCS or placebo, administered 1 hour before each of 5 exposure and response prevention tasks. MAIN OUTCOMES AND MEASURES Clinician-administered Y-BOCS score at week 12 and at 3-month follow-up. Remission was defined as a score of 12 or lower on the Y-BOCS. RESULTS In the primary intention-to-treat analyses, DCS did not augment the effects of CBT compared with placebo (mean [SD] clinician-rated Y-BOCS score, DCS: 13.86 [6.50] at week 12 and 12.35 [7.75] at 3-month follow-up; placebo: 11.77 [5.95] at week 12 and 12.37 [6.68] at 3-month follow-up) but showed a significant interaction with antidepressants (clinician-rated Y-BOCS, B = -1.08; Z = -2.79; P = .005). Post hoc analyses revealed that antidepressants significantly impaired treatment response in the DCS group but not the placebo group, at both posttreatment and follow-up (clinician-rated Y-BOCS: t(62) = -3.00; P = .004; and t(61) = -3.49; P < .001, respectively). In the DCS group, a significantly greater proportion of antidepressant-free patients achieved remission status at follow-up (60% [95% CI, 45%-74%]) than antidepressant-medicated patients (24% [95% CI, 9%-48%]) (P = .008). Antidepressants had no effect in the placebo group (50% [95% CI, 36%-64%] remission rate in both groups). CONCLUSIONS AND RELEVANCE The findings suggest that antidepressants may interact with DCS to block its facilitating effect on fear extinction. Use of DCS may be a promising CBT augmentation strategy but only in antidepressant-free patients with OCD.
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| 2. |
- Isung, Josef, et al.
(författare)
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Association of chronic and acute inflammation of the mucosa-associated lymphoid tissue with psychiatric disorders and suicidal behavior
- 2019
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Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Immune dysregulation due to chronic inflammation is a hypothesized risk factor underlying psychiatric disorders and suicidal behavior. Whether tonsillectomy and acute appendicitis used, respectively, as proxies for chronic and acute inflammation within the mucosa-associated lymphoid tissue (MALT) are associated with psychiatric disorders and suicidal behavior is currently unknown. A birth cohort study was conducted including 3,052,875 individuals born in Sweden between 1973 and 2003. We identified 210,686 individuals ever exposed to tonsillectomy and 86,928 individuals ever exposed to acute appendicitis, as well as 317,214 clusters of siblings discordant for tonsillectomy, and 160,079 sibling clusters discordant for acute appendicitis. Outcomes were an aggregate risk of 'any psychiatric disorder', 'any suicidal behavior', 12 individual psychiatric disorders, suicide attempts and deaths by suicide. Tonsillectomy was associated with increased odds of 'any psychiatric disorder' (adjusted odds ratio [aOR] = 1.39; 95% confidence interval (CI) = 1.38-1.41) and 'any suicidal behavior' (aOR = 1.41; 95% CI = 1.37-1.44), and most individual disorders. Acute appendicitis also increased the odds of 'any psychiatric disorder' and 'any suicidal behavior' (aOR = 1.23; 95% CI = 1.20-1.25, and aOR = 1.32; 95% CI = 1.28-1.37, respectively). Exposure to both tonsillectomy and appendicitis was associated with the highest odds of 'any psychiatric disorder' (aOR = 1.70; 95% CI = 1.59-1.82) and 'any suicidal behavior' (aOR = 1.90; 95% CI = 1.70-2.12). In sibling comparisons, the associations were attenuated but remained significant. We conclude that inflammation within the MALT, particularly when chronic, is robustly associated with a broad range of psychiatric disorders and suicidal behavior.
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| 3. |
- Isung, Josef, et al.
(författare)
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Association of Primary Humoral Immunodeficiencies With Psychiatric Disorders and Suicidal Behavior and the Role of Autoimmune Diseases
- 2020
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Ingår i: JAMA psychiatry. - : American Medical Association. - 2168-6238 .- 2168-622X. ; 77:11, s. 1147-1154
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Tidskriftsartikel (refereegranskat)abstract
- Importance: The hypothesis that disrupted immune function is implicated in the pathophysiology of psychiatric disorders and suicide is gaining traction, but the underlying mechanisms are largely unknown. Primary humoral immunodeficiencies (PIDs) are rare deficiencies of the immune system-mainly dysfunction of antibody production-and are associated with adverse health problems, such as recurrent infections and autoimmune diseases.Objective: To establish whether PIDs that affect antibody function and level are associated with lifetime psychiatric disorders and suicidal behavior and whether this association is explained by the co-occurrence of autoimmune diseases.Design, Setting, and Participants: This population- and sibling-based cohort study included more than 14 million individuals living in Sweden from January 1, 1973, through December 31, 2013. Register-based data on exposure, outcomes, and covariates were collected through December 31, 2013. Individuals with a record of PID were linked to their full siblings, and a family identification number was created. Data were analyzed from May 17, 2019, to February 21, 2020.Exposures: Lifetime records of PID and autoimmune disease.Main Outcomes and Measures: Lifetime records of 12 major psychiatric disorders and suicidal behavior, including suicide attempts and death by suicide.Results: A lifetime diagnosis of PID affecting immunoglobulin levels was identified in 8378 patients (4947 women [59.0%]; median age at first diagnosis, 47.8 [interquartile range, 23.8-63.4] years). A total of 4776 clusters of full siblings discordant for PID was identified. After adjusting for comorbid autoimmune diseases, PIDs were associated with greater odds of any psychiatric disorder (adjusted odds ratio [AOR], 1.91; 95% CI, 1.81-2.01) and any suicidal behavior (AOR, 1.84; 95% CI, 1.66-2.04). The associations were also significant for all individual psychiatric disorders (range of AORs, 1.34 [95% CI, 1.17-1.54] for schizophrenia and other psychotic disorders to 2.99 [95% CI, 2.42-3.70] for autism spectrum disorders), death by suicide (AOR, 1.84; 95% CI, 1.25-2.71), and suicide attempts (AOR, 1.84; 95% CI, 1.66-2.04). In the sibling comparisons, the associations were attenuated but remained significant for aggregated outcomes (AOR for any psychiatric disorder, 1.64 [95% CI, 1.48-1.83]; AOR for any suicidal behavior, 1.37 [95% CI, 1.14-1.66]), most individual disorders (range of AORs, 1.46 [95% CI, 1.23-1.73] for substance use disorders to 2.29 [95% CI, 1.43-3.66] for autism spectrum disorders), and suicide attempts (AOR, 1.41; 95% CI, 1.17-1.71). Joint exposure for PID and autoimmune disease resulted in the highest odds for any psychiatric disorder (AOR, 2.77; 95% CI, 2.52-3.05) and any suicidal behavior (AOR, 2.75; 95% CI, 2.32-3.27). The associations with psychiatric outcomes (AORs, 2.42 [95% CI, 2.24-2.63] vs 1.65 [95% CI, 1.48-1.84]) and suicidal behavior (AORs, 2.43 [95% CI, 2.09-2.82] vs 1.40 [95% CI, 1.12-1.76]) were significantly stronger for women than for men with PID.Conclusions and Relevance: Primary humoral immunodeficiencies were robustly associated with psychopathology and suicidal behavior, particularly in women. The associations could not be fully explained by co-occurring autoimmune diseases, suggesting that antibody dysfunction may play a role, although other mechanisms are possible. Individuals with both PID and autoimmune disease had the highest risk of psychiatric disorders and suicide, suggesting an additive effect. Future studies should explore the underlying mechanisms of these associations.
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| 4. |
- Isung, Josef, et al.
(författare)
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Association of Tourette Syndrome and Chronic Tic Disorder With Cervical Spine Disorders and Related Neurological Complications
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 78:10, s. 1205-1211
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Severe forms of Tourette syndrome or chronic tic disorder (TS/CTD) may involve repeated head jerking. Isolated case reports have described a spectrum of severe neck disorders in individuals with TS/CTD. However, the nature and prevalence of cervical spine disorders in TS/CTD are unknown.Objective: To establish if TS/CTD are associated with an increased risk of cervical spine disorders and related neurological complications compared with individuals from the general population.Design, Setting, and Participants: All individuals born from 1973 to 2013 and living in Sweden between 1997 and 2013 were identified. Individuals with a record of TS/CTD diagnosed in specialist settings were matched on age, sex, and county of birth with 10 unexposed individuals randomly selected from the general population. Cox proportional hazards regression models were used to estimate the risk of vascular and nonvascular cervical spine disorders among exposed individuals, compared with unexposed individuals. Models were adjusted for other known causes of cervical spine injury. Data were analyzed from March 19 to May 16, 2021.Exposures: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of TS/CTD in the Swedish National Patient Register.Main Outcomes and Measures: Records of cervical vascular disorders (ie, aneurysm, cerebral infarction, transitory cerebral ischemia) and cervical nonvascular disorders (ie, spondylosis, cervical disc disorders, fractures of the cervical spine, cervicalgia) and cervical surgeries. Covariates included rheumatic disorders, traffic injuries, fall- or sport-related injuries, and attention-deficit/hyperactivity disorder comorbidity.Results: A total of 6791 individuals with TS/CTD were identified (5238 [77.1%] were male; median [interquartile] age at first diagnosis, 15.6 [11.4-23.7] years) and matched to 67 910 unexposed individuals. Exposed individuals had a 39% increased risk of any cervical spine disorder (adjusted hazard ratio, 1.39; 95% CI, 1.22-1.59). Adjusted hazard ratios for cervical vascular and nonvascular disorders were 1.57 (95% CI, 1.16-2.13) and 1.38 (95% CI, 1.19-1.60), respectively. Risks were similar among men and women.Conclusions and Relevance: Individuals with severe TS/CTD are at increased risk of cervical spine disorders. These outcomes are relatively rare but may lead to persistent disability in some individuals and thus require close monitoring to facilitate early interventions.
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| 5. |
- Isung, Josef, et al.
(författare)
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Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n=27, males=12, mean age 28.7, range 22-52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF.
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| 6. |
- Isung, Josef, et al.
(författare)
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Low plasma vascular endothelial growth factor (VEGF) associated with completed suicide
- 2012
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Ingår i: World Journal of Biological Psychiatry. - : Informa UK Limited. - 1562-2975 .- 1814-1412. ; 13:6, s. 468-73
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Immunological differences have previously been associated with depression and suicidal behaviour. Several cytokines have been identified as potentially important in understanding the pathophysiology of mood disorders and suicidality. Here we aimed to identify new inflammatory biomarkers for suicide prediction.METHODS: Plasma concentrations of interleukin (IL) 1-a , IL1-b, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (IFNG), tumor necrosis factor-a (TNF-a), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) were measured in 58 suicide attempters with a high throughput automated biochip immunoassay system. Patients were evaluated using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Suicide Intent Scale (SIS). All patients were followed up for cause of death.RESULTS: We found significantly lower levels of VEGF in the seven patients who upon a mean follow-up of 13 years were found to have completed suicide. VEGF also showed a trend for negative correlation with the planning subscale of SIS. A trend could be shown for lower IL-2 and for higher IFNG levels in suicide victims.CONCLUSIONS: Our study provides further support for a role of inflammation in the pathophysiology of suicidality. VEGF may be related with suicide risk.
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| 7. |
- Isung, Josef
(författare)
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Neuroinflammatory biomarkers in suicidal behavior
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Immune dysregulation is of importance in the pathophysiology underlying psychiatric disorders including major depression, bipolar disorder, and schizophrenia. Neurobiological alterations such as a dysregulated stress-hormonal axis and serotonergic alterations have been reported in suicide attempters at risk for subsequent suicide. Immune dysregulation in suicidal behavior is less well studied, but with some evidence for elevated proinflammatory cytokines and decreased levels of neurotrophins, such as brain-derived neurotrophic factor. The aim of this thesis was to study neuroinflammatory biomarkers with regard to suicidal behavior in patients with mood disorders. For the first part of this thesis (Studies I-III) we studied a high-risk cohort of patients with a recent suicide attempt. All were thoroughly assessed diagnostically and rated with regard to personality traits, severity of depression and suicidal intent. We did a follow-up on all patients regarding cause of death. 20 healthy controls were used for comparison. Patients were sampled for blood (n = 58) and cerebrospinal fluid (CSF) (n= 43). Samples were assayed using immune-based assay-systems for immune markers and growth factors. Seven patients who at follow-up, had completed suicide had lower plasma levels of vascular endothelial growth factor (VEGF). Furthermore, we found that the patients had lower CSF levels of both VEGF and interleukin- (IL-) 8 compared to the healthy comparison group. Lastly, we found that IL-6 levels in both plasma and CSF correlated with personality traits of impulsivity in suicide attempters. For the second part of this thesis (Study IV) we investigated the effects of physical activity on immune markers implied to be of importance in the pathophysiology of depression and suicidal behavior. The participants were completely healthy both somatically and psychiatrically. We studied the effects of an acute intensive exercise challenge during four days (n = 14), and a moderate exercise challenge during four weeks (n = 13). Paired sampling from blood and CSF before and after exercise intervention was compared. All rated mood before and after intervention. We found that CSF IL-8 was significantly elevated in both groups as a result of physical exercise. Serum IL-6 and IL-8 were significantly elevated in the total group, as well as IL-6 in the intensive group and IL-8 in the moderate group. We found no significant correlation between serum and CSF levels in the assayed analytes, suggesting that the effects of physical activity were segregated between the compartments. Furthermore, we found a negative correlation regarding mood ratings and CSF IL-8, suggesting relevance of CSF IL-8 as a state marker for mood. We propose that low VEGF may be a marker for treatment resistance and suicide risk, while high IL-6 seems to be related to impulsivity and violent methods of attempted suicide, both of which are important endophenotypes of suicidal behavior. Physical exercise is also an important confounder in immune biomarker studies.
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| 8. |
- Månsson, Kristoffer, et al.
(författare)
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Can Psychological Treatment Slow Down Cellular Aging in Social Anxiety Disorder? : An Intervention Study Evaluating Changes in Telomere Length and Telomerase Activity
- 2018
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 83:9, s. S351-S352
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Mental illness, including anxiety disorders, is linked to accelerated cell aging. This is evidenced by shorter leukocyte telomere length. Cells with critically short telomeres may undergo apoptosis. In dividing cells, telomere shortening is counteracted by the telomeraseenzyme. Telomerase is reportedly low following chronic psychological stress. We hypothesized that a psychological treatment may increase telomerase activity, less telomere attritionand greater symptom improvement.Methods: Forty-six patients (91% SSRI naïve) with social anxiety disorder(SAD; mean age 31, 63% females) underwent a 9-week waiting period, and 9 weeks of Internet-delivered cognitive behavior therapy(CBT). During treatment, symptoms were assessed weekly using the Liebowitz Social Anxiety Scale (LSAS-SR). Fasting blood samples were collected twice before treatment, and at post-treatment. Genomic DNA was extracted using DNeasy® Blood & Tissue Kit (Qiagene) to assess leukocyte telomere length. Telomerase activity was detected by real-time telomeric repeat amplification protocol (RT-TRAP).Results: Patients improved significantly on the LSAS-SR (p<.001; Cohen’s d=1.5). Pre-post changes in telomerase and telomere length correlated positively (Pearson’s r=.31, p=.05). Reduced telomerase activity (<33th percentile) was associated with less improvement and increased activity (>66th percentile) with more improvement on the LSAS-SR (Z=-2.4, p=.02).Conclusions: We demonstrate, to our knowledge for the first time, that altered telomerase activity is associated with clinical response to a psychological treatment in a psychiatric population. The observed CBT effect on telomerase in patients with SAD is consistent with results from animal trials and a small previous study of antidepressants in humans. Thus, telomerase activation may play an important role in clinical recovery.
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| 9. |
- Månsson, Kristoffer N. T., et al.
(författare)
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Improvement in indices of cellular protection after psychological treatment for social anxiety disorder
- 2019
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen’s d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.
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| 10. |
- Zhang, Tianyang, et al.
(författare)
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Prenatal and Early Childhood Infections and Subsequent Risk of Obsessive-Compulsive Disorder and Tic Disorders : A Nationwide, Sibling-Controlled Study
- 2023
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 93:11, s. 1023-1030
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Postinfectious autoimmune processes are hypothesized to be causally related to both obsessive-compulsive disorder (OCD) and tic disorders, but current evidence is conflicting. This study examined whether prenatal maternal (and paternal, as an internal control) infections and early childhood infections in the offspring (i.e., during the first 3 years of life) were associated with a subsequent risk of OCD and Tourette syndrome or chronic tic disorder (TS/CTD).METHODS: Individuals exposed to any prenatal maternal infection (n = 16,743) and early childhood infection (n = 264,346) were identified from a population-based birth cohort consisting of 2,949,080 singletons born in Sweden between 1973 and 2003 and were followed through 2013. Cox proportional hazard regression models were used to estimate hazard ratios (HRs). Sibling analyses were performed to control for familial confounding.RESULTS: At the population level, and after adjusting for parental psychiatric history and autoimmune diseases, a significantly increased risk of OCD and TS/CTD was found in individuals exposed to prenatal maternal (but not paternal) infections (OCD: HR, 1.33; 95% CI, 1.12-1.57; TS/CTD: HR, 1.60; 95% CI, 1.23-2.09) and early childhood infections (OCD: HR, 1.19; 95% CI, 1.14-1.25; TS/CTD: HR, 1.34; 95% CI, 1.24-1.44). However, these associations were no longer significant in the sibling analyses.CONCLUSIONS: The results do not support the hypothesis that prenatal maternal or early-life infections play a direct causal role in the etiology of either OCD or TS/CTD. Instead, familial factors (e.g., genetic pleiotropy) may explain both the propensity to infections and the liability to OCD and TS/CTD.
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