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Objective To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC). Methods In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9 to 11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point. Results SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. PBMC mtDNA-cn did not significantly correlate with plasma ccf-mtDNA in patients. Conclusion This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.

Objective To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC). Methods In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9 to 11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point. Results SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. PBMC mtDNA-cn did not significantly correlate with plasma ccf-mtDNA in patients. Conclusion This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.

Objective To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC). Methods In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9 to 11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point. Results SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. PBMC mtDNA-cn did not significantly correlate with plasma ccf-mtDNA in patients. Conclusion This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.

Objective To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC). Methods In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9 to 11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point. Results SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. PBMC mtDNA-cn did not significantly correlate with plasma ccf-mtDNA in patients. Conclusion This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.

Objective To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC). Methods In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9 to 11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point. Results SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. PBMC mtDNA-cn did not significantly correlate with plasma ccf-mtDNA in patients. Conclusion This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.

OBJECTIVE: To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC). METHODS: In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9-11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point. RESULTS: SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. Plasma ccf-mtDNA did not significantly correlate with PBMC mtDNA-cn in patients. CONCLUSION: This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.

OBJECTIVE: To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC). METHODS: In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9-11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point. RESULTS: SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. Plasma ccf-mtDNA did not significantly correlate with PBMC mtDNA-cn in patients. CONCLUSION: This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.

Mitochondrial dysfunction has been implicated in major depressive disorder (MDD). A measure of mitochondrial respiratory chain (RC) enzymatic activity-the Mitochondrial Health Index (MHI)-has previously been found to correlate with stress and emotional states in caregivers. We here report mitochondrial RC activities, mitochondrial DNA copy number (mtDNAcn), and the composite MHI in unmedicated and somatically healthy subjects with MDD (n = 47) and healthy controls (HC) (n = 11). We also explore, in a subset of the MDD sample (n = 33), whether these markers are associated with response to 8 weeks of SSRI treatment. Mitochondrial RC complexes I, II, IV, citrate synthase (CS), mtDNAcn, and the MHI were assayed in peripheral blood mononuclear cells. Treatment response was defined as >50% decrease on the 25-item Hamilton Depression Rating Scale (HRDS-25). There were no significant differences in MHI or any of the mitochondrial markers between MDD subjects and HCs. Compared to SSRI nonresponders, SSRI responders had significantly higher baseline mitochondrial content markers CS (p = 0.02) and mtDNAcn (p = 0.02), and higher complex I activity (p = 0.01). Complex II activity increased significantly over treatment, irrespective of clinical response (p = 0.03). Complex I activity decreased in responders (n = 9), but increased in nonresponders (n = 18) (group x time interaction, p = 0.02). Absolute treatment-associated change in HDRS-25 scores correlated significantly with change in complex I activity between baseline and week 8 (r = 0.47, p = 0.01). Although mitochondrial markers did not distinguish MDD from controls, they did distinguish SSRI responders from nonresponders. If larger studies validate these mitochondrial differences, they may become useful biomarkers and identify new drug targets.

Background: Depressed suicide attempters are, according to some earlier studies, treated more often with antipsychotics than depressive non-suicide attempters. Cluster B personality disorders, especially borderline personality disorder, are associated with a high suicide risk, and antipsychotics are commonly used for the reduction of symptoms. However, no previous study has taken comorbid personality disorders into account when assessing the use of antipsychotics in patients with unipolar depression. Therefore, the aim of this study was to investigate the clinical selection of pharmacotherapy in unipolar depression with and without a previous suicide attempt, taking into account potential confounders such as cluster B personality disorders. Methods: The study sample consisted of 247 patients with unipolar depression. The study was approved by the Regional Ethical Review Board in Lund, Sweden. Study participants were recruited from 4 different secondary psychiatric care clinics in Sweden and were diagnosed according to the DSM-IV-TR with the MINI and SCID II. Previous and ongoing psychiatric treatments were investigated in detail and medical records were assessed. Results: Thirty percent of the patients had made previous suicide attempts. Depressed suicide attempters underwent both lifetime treatment with antipsychotics and an ongoing antipsychotic treatment significantly more often than non-attempters. Significances remained after a regression analysis, adjusting for cluster B personality disorders, symptom severity, age at the onset of depression, and lifetime psychotic symptoms. Conclusions: This is the first study to consider the effect of comorbidity with cluster B personality disorders when comparing treatment of depressive suicide and non-suicide attempters. Our findings suggest that suicide attempters are more frequently treated with antipsychotics compared to non-suicide attempters, regardless of cluster B personality disorder comorbidity. These findings are, Funding Agencies|province of Skane, Sweden; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-01428]; Southern Health Care Region, Sweden

BACKGROUND: Plasma circulating cell-free mitochondrial DNA (ccf-mtDNA) is an immunogenic molecule and a novel biomarker of psychiatric disorders. Some previous studies reported increased levels of ccf-mtDNA in unmedicated depression and recent suicide attempters, while other studies found unchanged or decreased ccf-mtDNA levels in depression. Inconsistent findings across studies may be explained by small sample sizes and between-study variations in somatic and psychiatric co-morbidity or medication status. METHODS: We measured plasma ccf-mtDNA in a cohort of 281 patients with depressive disorders and 49 healthy controls. Ninety-three percent of all patients were treated with one or several psychotropic medications. Thirty-six percent had a personality disorder, 13% bipolar disorder. All analyses involving ccf-mtDNA were a priori adjusted for age and sex. RESULTS: Mean levels in ccf-mtDNA were significantly different between patients with a current depressive episode (n = 236), remitted depressive episode (n = 45) and healthy controls (n = 49) (f = 8.3, p<0.001). Post-hoc tests revealed that both patients with current (p<0.001) and remitted (p = 0.002) depression had lower ccf-mtDNA compared to controls. Within the depressed group there was a positive correlation between ccf-mtDNA and "inflammatory depression symptoms" (r = 0.15, p = 0.02). We also found that treatment with mood stabilizers lamotrigine, valproic acid or lithium was associated with lower ccf-mtDNA (f = 8.1, p = 0.005). DISCUSSION: Decreased plasma ccf-mtDNA in difficult-to-treat depression may be partly explained by concurrent psychotropic medications and co-morbidity. Our findings suggest that ccf-mtDNA may be differentially regulated in different subtypes of depression, and this hypothesis should be pursued in future studies.

BACKGROUND: Plasma circulating cell-free mitochondrial DNA (ccf-mtDNA) is an immunogenic molecule and a novel biomarker of psychiatric disorders. Some previous studies reported increased levels of ccf-mtDNA in unmedicated depression and recent suicide attempters, while other studies found unchanged or decreased ccf-mtDNA levels in depression. Inconsistent findings across studies may be explained by small sample sizes and between-study variations in somatic and psychiatric co-morbidity or medication status. METHODS: We measured plasma ccf-mtDNA in a cohort of 281 patients with depressive disorders and 49 healthy controls. Ninety-three percent of all patients were treated with one or several psychotropic medications. Thirty-six percent had a personality disorder, 13% bipolar disorder. All analyses involving ccf-mtDNA were a priori adjusted for age and sex. RESULTS: Mean levels in ccf-mtDNA were significantly different between patients with a current depressive episode (n = 236), remitted depressive episode (n = 45) and healthy controls (n = 49) (f = 8.3, p<0.001). Post-hoc tests revealed that both patients with current (p<0.001) and remitted (p = 0.002) depression had lower ccf-mtDNA compared to controls. Within the depressed group there was a positive correlation between ccf-mtDNA and "inflammatory depression symptoms" (r = 0.15, p = 0.02). We also found that treatment with mood stabilizers lamotrigine, valproic acid or lithium was associated with lower ccf-mtDNA (f = 8.1, p = 0.005). DISCUSSION: Decreased plasma ccf-mtDNA in difficult-to-treat depression may be partly explained by concurrent psychotropic medications and co-morbidity. Our findings suggest that ccf-mtDNA may be differentially regulated in different subtypes of depression, and this hypothesis should be pursued in future studies.

Mitochondrial dysfunction has been implicated in major depressive disorder (MDD). A measure of mitochondrial respiratory chain (RC) enzymatic activity-the Mitochondrial Health Index (MHI)-has previously been found to correlate with stress and emotional states in caregivers. We here report mitochondrial RC activities, mitochondrial DNA copy number (mtDNAcn), and the composite MHI in unmedicated and somatically healthy subjects with MDD (n = 47) and healthy controls (HC) (n = 11). We also explore, in a subset of the MDD sample (n = 33), whether these markers are associated with response to 8 weeks of SSRI treatment. Mitochondrial RC complexes I, II, IV, citrate synthase (CS), mtDNAcn, and the MHI were assayed in peripheral blood mononuclear cells. Treatment response was defined as >50% decrease on the 25-item Hamilton Depression Rating Scale (HRDS-25). There were no significant differences in MHI or any of the mitochondrial markers between MDD subjects and HCs. Compared to SSRI nonresponders, SSRI responders had significantly higher baseline mitochondrial content markers CS (p = 0.02) and mtDNAcn (p = 0.02), and higher complex I activity (p = 0.01). Complex II activity increased significantly over treatment, irrespective of clinical response (p = 0.03). Complex I activity decreased in responders (n = 9), but increased in nonresponders (n = 18) (group x time interaction, p = 0.02). Absolute treatment-associated change in HDRS-25 scores correlated significantly with change in complex I activity between baseline and week 8 (r = 0.47, p = 0.01). Although mitochondrial markers did not distinguish MDD from controls, they did distinguish SSRI responders from nonresponders. If larger studies validate these mitochondrial differences, they may become useful biomarkers and identify new drug targets.

Background: Depressed suicide attempters are, according to some earlier studies, treated more often with antipsychotics than depressive non-suicide attempters. Cluster B personality disorders, especially borderline personality disorder, are associated with a high suicide risk, and antipsychotics are commonly used for the reduction of symptoms. However, no previous study has taken comorbid personality disorders into account when assessing the use of antipsychotics in patients with unipolar depression. Therefore, the aim of this study was to investigate the clinical selection of pharmacotherapy in unipolar depression with and without a previous suicide attempt, taking into account potential confounders such as cluster B personality disorders. Methods: The study sample consisted of 247 patients with unipolar depression. The study was approved by the Regional Ethical Review Board in Lund, Sweden. Study participants were recruited from 4 different secondary psychiatric care clinics in Sweden and were diagnosed according to the DSM-IV-TR with the MINI and SCID II. Previous and ongoing psychiatric treatments were investigated in detail and medical records were assessed. Results: Thirty percent of the patients had made previous suicide attempts. Depressed suicide attempters underwent both lifetime treatment with antipsychotics and an ongoing antipsychotic treatment significantly more often than non-attempters. Significances remained after a regression analysis, adjusting for cluster B personality disorders, symptom severity, age at the onset of depression, and lifetime psychotic symptoms. Conclusions: This is the first study to consider the effect of comorbidity with cluster B personality disorders when comparing treatment of depressive suicide and non-suicide attempters. Our findings suggest that suicide attempters are more frequently treated with antipsychotics compared to non-suicide attempters, regardless of cluster B personality disorder comorbidity. These findings are, Funding Agencies|province of Skane, Sweden; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-01428]; Southern Health Care Region, Sweden

Background: Depressed suicide attempters are, according to some earlier studies, treated more often with antipsychotics than depressive non-suicide attempters. Cluster B personality disorders, especially borderline personality disorder, are associated with a high suicide risk, and antipsychotics are commonly used for the reduction of symptoms. However, no previous study has taken comorbid personality disorders into account when assessing the use of antipsychotics in patients with unipolar depression. Therefore, the aim of this study was to investigate the clinical selection of pharmacotherapy in unipolar depression with and without a previous suicide attempt, taking into account potential confounders such as cluster B personality disorders. Methods: The study sample consisted of 247 patients with unipolar depression. The study was approved by the Regional Ethical Review Board in Lund, Sweden. Study participants were recruited from 4 different secondary psychiatric care clinics in Sweden and were diagnosed according to the DSM-IV-TR with the MINI and SCID II. Previous and ongoing psychiatric treatments were investigated in detail and medical records were assessed. Results: Thirty percent of the patients had made previous suicide attempts. Depressed suicide attempters underwent both lifetime treatment with antipsychotics and an ongoing antipsychotic treatment significantly more often than non-attempters. Significances remained after a regression analysis, adjusting for cluster B personality disorders, symptom severity, age at the onset of depression, and lifetime psychotic symptoms. Conclusions: This is the first study to consider the effect of comorbidity with cluster B personality disorders when comparing treatment of depressive suicide and non-suicide attempters. Our findings suggest that suicide attempters are more frequently treated with antipsychotics compared to non-suicide attempters, regardless of cluster B personality disorder comorbidity. These findings are, Funding Agencies|province of Skane, Sweden; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-01428]; Southern Health Care Region, Sweden

Background: Depressed suicide attempters are, according to some earlier studies, treated more often with antipsychotics than depressive non-suicide attempters. Cluster B personality disorders, especially borderline personality disorder, are associated with a high suicide risk, and antipsychotics are commonly used for the reduction of symptoms. However, no previous study has taken comorbid personality disorders into account when assessing the use of antipsychotics in patients with unipolar depression. Therefore, the aim of this study was to investigate the clinical selection of pharmacotherapy in unipolar depression with and without a previous suicide attempt, taking into account potential confounders such as cluster B personality disorders. Methods: The study sample consisted of 247 patients with unipolar depression. The study was approved by the Regional Ethical Review Board in Lund, Sweden. Study participants were recruited from 4 different secondary psychiatric care clinics in Sweden and were diagnosed according to the DSM-IV-TR with the MINI and SCID II. Previous and ongoing psychiatric treatments were investigated in detail and medical records were assessed. Results: Thirty percent of the patients had made previous suicide attempts. Depressed suicide attempters underwent both lifetime treatment with antipsychotics and an ongoing antipsychotic treatment significantly more often than non-attempters. Significances remained after a regression analysis, adjusting for cluster B personality disorders, symptom severity, age at the onset of depression, and lifetime psychotic symptoms. Conclusions: This is the first study to consider the effect of comorbidity with cluster B personality disorders when comparing treatment of depressive suicide and non-suicide attempters. Our findings suggest that suicide attempters are more frequently treated with antipsychotics compared to non-suicide attempters, regardless of cluster B personality disorder comorbidity. These findings are, Funding Agencies|province of Skane, Sweden; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-01428]; Southern Health Care Region, Sweden

Background: Depressed suicide attempters are, according to some earlier studies, treated more often with antipsychotics than depressive non-suicide attempters. Cluster B personality disorders, especially borderline personality disorder, are associated with a high suicide risk, and antipsychotics are commonly used for the reduction of symptoms. However, no previous study has taken comorbid personality disorders into account when assessing the use of antipsychotics in patients with unipolar depression. Therefore, the aim of this study was to investigate the clinical selection of pharmacotherapy in unipolar depression with and without a previous suicide attempt, taking into account potential confounders such as cluster B personality disorders. Methods: The study sample consisted of 247 patients with unipolar depression. The study was approved by the Regional Ethical Review Board in Lund, Sweden. Study participants were recruited from 4 different secondary psychiatric care clinics in Sweden and were diagnosed according to the DSM-IV-TR with the MINI and SCID II. Previous and ongoing psychiatric treatments were investigated in detail and medical records were assessed. Results: Thirty percent of the patients had made previous suicide attempts. Depressed suicide attempters underwent both lifetime treatment with antipsychotics and an ongoing antipsychotic treatment significantly more often than non-attempters. Significances remained after a regression analysis, adjusting for cluster B personality disorders, symptom severity, age at the onset of depression, and lifetime psychotic symptoms. Conclusions: This is the first study to consider the effect of comorbidity with cluster B personality disorders when comparing treatment of depressive suicide and non-suicide attempters. Our findings suggest that suicide attempters are more frequently treated with antipsychotics compared to non-suicide attempters, regardless of cluster B personality disorder comorbidity. These findings are, Funding Agencies|province of Skane, Sweden; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-01428]; Southern Health Care Region, Sweden

Background: Depressed suicide attempters are, according to some earlier studies, treated more often with antipsychotics than depressive non-suicide attempters. Cluster B personality disorders, especially borderline personality disorder, are associated with a high suicide risk, and antipsychotics are commonly used for the reduction of symptoms. However, no previous study has taken comorbid personality disorders into account when assessing the use of antipsychotics in patients with unipolar depression. Therefore, the aim of this study was to investigate the clinical selection of pharmacotherapy in unipolar depression with and without a previous suicide attempt, taking into account potential confounders such as cluster B personality disorders. Methods: The study sample consisted of 247 patients with unipolar depression. The study was approved by the Regional Ethical Review Board in Lund, Sweden. Study participants were recruited from 4 different secondary psychiatric care clinics in Sweden and were diagnosed according to the DSM-IV-TR with the MINI and SCID II. Previous and ongoing psychiatric treatments were investigated in detail and medical records were assessed. Results: Thirty percent of the patients had made previous suicide attempts. Depressed suicide attempters underwent both lifetime treatment with antipsychotics and an ongoing antipsychotic treatment significantly more often than non-attempters. Significances remained after a regression analysis, adjusting for cluster B personality disorders, symptom severity, age at the onset of depression, and lifetime psychotic symptoms. Conclusions: This is the first study to consider the effect of comorbidity with cluster B personality disorders when comparing treatment of depressive suicide and non-suicide attempters. Our findings suggest that suicide attempters are more frequently treated with antipsychotics compared to non-suicide attempters, regardless of cluster B personality disorder comorbidity. These findings are, Funding Agencies|province of Skane, Sweden; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-01428]; Southern Health Care Region, Sweden

Major depressive disorder (MDD) has been linked to mitochondrial defects, which could manifest in mitochondrial DNA (mtDNA) polymorphisms or mutations. Additionally, copy number of mtDNA (mtDNA-cn) can be quantified in peripheral blood mononuclear cells (PBMC)s, indirectly reflecting cellular energetics, or in the circulating cell-free mtDNA (ccf-mtDNA) levels, which may reflect a fraction of the mitochondrial genome released during cellular stress. Few studies have examined ccf-mtDNA in MDD, and no studies have tested its relationship with intracellular mtDNA-cn or with antidepressant treatment response. Here, mtDNA levels were quantified in parallel from: (i) PBMCs and (ii) cell-free plasma of 50 unmedicated MDD subjects and 55 controls, in parallel with PBMC telomere length (TL) and antioxidant enzyme glutathione peroxidase (GpX) activity. MtDNA measures were repeated in 19 MDD subjects after 8 weeks of open-label SSRI treatment. In analyses adjusted for age, sex, BMI, and smoking, MDD subjects had significantly elevated levels of ccf-mtDNA (F = 20.6, p = 0.00002). PBMC mtDNA-cn did not differ between groups (p > 0.4). In preliminary analyses, we found that changes in ccf-mtDNA with SSRI treatment differed between SSRI responders and non-responders (F = 6.47, p = 0.02), with the non-responders showing an increase in ccf-mtDNA and responders not changing. Baseline ccf-mtDNA was positively correlated with GpX (r = 0.32, p = 0.001), and PBMC mtDNA correlated positively with PBMC TL (r = 0.38, p = 0.0001). These data suggest that plasma ccf-mtDNA and PBMC mtDNA-cn reflect different cellular processes and that the former may be more reflective of certain aspects of MDD pathophysiology and of the response to SSRI antidepressants.

Major depressive disorder (MDD) has been linked to mitochondrial defects, which could manifest in mitochondrial DNA (mtDNA) polymorphisms or mutations. Additionally, copy number of mtDNA (mtDNA-cn) can be quantified in peripheral blood mononuclear cells (PBMC)s, indirectly reflecting cellular energetics, or in the circulating cell-free mtDNA (ccf-mtDNA) levels, which may reflect a fraction of the mitochondrial genome released during cellular stress. Few studies have examined ccf-mtDNA in MDD, and no studies have tested its relationship with intracellular mtDNA-cn or with antidepressant treatment response. Here, mtDNA levels were quantified in parallel from: (i) PBMCs and (ii) cell-free plasma of 50 unmedicated MDD subjects and 55 controls, in parallel with PBMC telomere length (TL) and antioxidant enzyme glutathione peroxidase (GpX) activity. MtDNA measures were repeated in 19 MDD subjects after 8 weeks of open-label SSRI treatment. In analyses adjusted for age, sex, BMI, and smoking, MDD subjects had significantly elevated levels of ccf-mtDNA (F = 20.6, p = 0.00002). PBMC mtDNA-cn did not differ between groups (p > 0.4). In preliminary analyses, we found that changes in ccf-mtDNA with SSRI treatment differed between SSRI responders and non-responders (F = 6.47, p = 0.02), with the non-responders showing an increase in ccf-mtDNA and responders not changing. Baseline ccf-mtDNA was positively correlated with GpX (r = 0.32, p = 0.001), and PBMC mtDNA correlated positively with PBMC TL (r = 0.38, p = 0.0001). These data suggest that plasma ccf-mtDNA and PBMC mtDNA-cn reflect different cellular processes and that the former may be more reflective of certain aspects of MDD pathophysiology and of the response to SSRI antidepressants.

Objectives Depression is a common illness with substantial economic consequences for society and a great burden for affected individuals. About 30% of patients with depression do not respond to repeated treatments. Psychiatric comorbidity is known to affect duration, recurrence and treatment outcome of depression. However, there is a lack of knowledge on the extent to which psychiatric comorbidity is identified in the clinical setting for depressed patients in secondary psychiatric care. Therefore, the aim of this study was to compare the agreement between traditional diagnostic assessment (TDA) and a structured and comprehensive diagnostic procedure (SCDP) for identification of personality and anxiety disorder comorbidity in depressed patients in secondary psychiatric care. Methods 274 patients aged 18-77 were referred from four secondary psychiatric care clinics in Sweden during 2012-2017. ICD-10 diagnoses according to TDA (mostly unstructured by psychiatric specialist and residents in psychiatry), were retrieved from medical records and compared to diagnoses resulting from the SCDP in the study. This included the Mini International Neuropsychiatric Interview, the Structured Interview for DSM Axis II Personality Disorders and semi-structured questions on psychosocial circumstances, life-events, psychiatric symptoms, psychiatric treatments, substance use, and suicidal and self-harm behaviour. The assessment was carried out by psychiatric specialists or by residents in psychiatry with at least three years of psychiatric training. Results SCDP identified personality disorder comorbidity in 43% of the patients compared to 11% in TDA (p<0,0001). Anxiety disorder comorbidity was identified in 58% with SCDP compared to 12% with TDA (p<0,0001). Conclusions Important psychiatric comorbidity seems to be unrecognized in depressive patients when using TDA, which is routine in secondary psychiatric care. Comorbidities are better identified using the proposed mode, Funding Agencies|Southern Health Care Region, Sweden; OM Persson Foundation; province of Skane (Sweden) state grants, ALF

Objectives Depression is a common illness with substantial economic consequences for society and a great burden for affected individuals. About 30% of patients with depression do not respond to repeated treatments. Psychiatric comorbidity is known to affect duration, recurrence and treatment outcome of depression. However, there is a lack of knowledge on the extent to which psychiatric comorbidity is identified in the clinical setting for depressed patients in secondary psychiatric care. Therefore, the aim of this study was to compare the agreement between traditional diagnostic assessment (TDA) and a structured and comprehensive diagnostic procedure (SCDP) for identification of personality and anxiety disorder comorbidity in depressed patients in secondary psychiatric care. Methods 274 patients aged 18-77 were referred from four secondary psychiatric care clinics in Sweden during 2012-2017. ICD-10 diagnoses according to TDA (mostly unstructured by psychiatric specialist and residents in psychiatry), were retrieved from medical records and compared to diagnoses resulting from the SCDP in the study. This included the Mini International Neuropsychiatric Interview, the Structured Interview for DSM Axis II Personality Disorders and semi-structured questions on psychosocial circumstances, life-events, psychiatric symptoms, psychiatric treatments, substance use, and suicidal and self-harm behaviour. The assessment was carried out by psychiatric specialists or by residents in psychiatry with at least three years of psychiatric training. Results SCDP identified personality disorder comorbidity in 43% of the patients compared to 11% in TDA (p<0,0001). Anxiety disorder comorbidity was identified in 58% with SCDP compared to 12% with TDA (p<0,0001). Conclusions Important psychiatric comorbidity seems to be unrecognized in depressive patients when using TDA, which is routine in secondary psychiatric care. Comorbidities are better identified using the proposed mode, Funding Agencies|Southern Health Care Region, Sweden; OM Persson Foundation; province of Skane (Sweden) state grants, ALF

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

A modern ghter aircraft has an advanced ight control system which highly augmentsthe control inputs from the pilot. To verify a new iteration of the control system is a timeconsuming and expensive task. It is desired to nd qualities that is not satisfactory to thepilot as early as possible in the verication process to reduce the cost for design changes.The primary objective of this thesis is to develop methods that can be used for automaticalevaluation of aircraft ying qualities from the data provided by a desktop simulator. A desktopsimulator is cheap to use compared to ight tests and tests with a pilot in a simulator.Only ghter aircraft in the precision ight phase are studied however the methods developedcould easily be extended to include other types of aircraft and other phases of ight.To evaluate the ying qualities two sets of criteria are used the MIL-F-8785C standardand the Gibson criteria. The MIL-F-8785C standard uses a second order linear system toevaluate the aircraft's ying qualities. The linear system is estimated from the nonlineardata and evaluated against the MIL-F-8785C standard. The Gibson criteria studies the timeand frequency domain directly and are designed to work with highly augmented aircraft.The set of Gibson criteria used in this thesis primary evaluates data from the time domainhowever one criterion from the frequency domain is studied.The methods developed to evaluate the ying qualities from the MIL-F-8785C standardonly works for a small part of the ight envelope furthermore they show a large dierencefor what is considered acceptable ying qualities. Because of this the methods developed forthe MIL-F-8785C standard are considered not to be suited for evaluating ying qualities forhighly augmented aircraft. The methods developed to evaluate the ying qualities againstthe Gibson criteria works for a large part of the ight and also show a high accuracy. Thismakes the methods suited for evaluation of the ying qualities.

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

IntroductionCurrent pharmacological treatments of post-traumatic stress disorder (PTSD) have limited efficacy. Although the diagnosis is based on psychopathological criteria, it is frequently accompanied by somatic comorbidities and perhaps "accelerated biological aging," suggesting widespread physical concomitants. Such physiological comorbidities may affect core PTSD symptoms but are rarely the focus of therapeutic trials.MethodsTo elucidate the potential involvement of metabolism, inflammation, and mitochondrial function in PTSD, we integrate findings and mechanistic models from the DOD-sponsored "Systems Biology of PTSD Study" with previous data on these topics.ResultsData implicate inter-linked dysregulations in metabolism, inflammation, mitochondrial function, and perhaps the gut microbiome in PTSD. Several inadequately tested targets of pharmacological intervention are proposed, including insulin sensitizers, lipid regulators, anti-inflammatories, and mitochondrial biogenesis modulators.ConclusionsSystemic pathologies that are intricately involved in brain functioning and behavior may not only contribute to somatic comorbidities in PTSD, but may represent novel targets for treating core psychiatric symptoms.

A modern ghter aircraft has an advanced ight control system which highly augmentsthe control inputs from the pilot. To verify a new iteration of the control system is a timeconsuming and expensive task. It is desired to nd qualities that is not satisfactory to thepilot as early as possible in the verication process to reduce the cost for design changes.The primary objective of this thesis is to develop methods that can be used for automaticalevaluation of aircraft ying qualities from the data provided by a desktop simulator. A desktopsimulator is cheap to use compared to ight tests and tests with a pilot in a simulator.Only ghter aircraft in the precision ight phase are studied however the methods developedcould easily be extended to include other types of aircraft and other phases of ight.To evaluate the ying qualities two sets of criteria are used the MIL-F-8785C standardand the Gibson criteria. The MIL-F-8785C standard uses a second order linear system toevaluate the aircraft's ying qualities. The linear system is estimated from the nonlineardata and evaluated against the MIL-F-8785C standard. The Gibson criteria studies the timeand frequency domain directly and are designed to work with highly augmented aircraft.The set of Gibson criteria used in this thesis primary evaluates data from the time domainhowever one criterion from the frequency domain is studied.The methods developed to evaluate the ying qualities from the MIL-F-8785C standardonly works for a small part of the ight envelope furthermore they show a large dierencefor what is considered acceptable ying qualities. Because of this the methods developed forthe MIL-F-8785C standard are considered not to be suited for evaluating ying qualities forhighly augmented aircraft. The methods developed to evaluate the ying qualities againstthe Gibson criteria works for a large part of the ight and also show a high accuracy. Thismakes the methods suited for evaluation of the ying qualities.

Objectives Depression is a common illness with substantial economic consequences for society and a great burden for affected individuals. About 30% of patients with depression do not respond to repeated treatments. Psychiatric comorbidity is known to affect duration, recurrence and treatment outcome of depression. However, there is a lack of knowledge on the extent to which psychiatric comorbidity is identified in the clinical setting for depressed patients in secondary psychiatric care. Therefore, the aim of this study was to compare the agreement between traditional diagnostic assessment (TDA) and a structured and comprehensive diagnostic procedure (SCDP) for identification of personality and anxiety disorder comorbidity in depressed patients in secondary psychiatric care. Methods 274 patients aged 18-77 were referred from four secondary psychiatric care clinics in Sweden during 2012-2017. ICD-10 diagnoses according to TDA (mostly unstructured by psychiatric specialist and residents in psychiatry), were retrieved from medical records and compared to diagnoses resulting from the SCDP in the study. This included the Mini International Neuropsychiatric Interview, the Structured Interview for DSM Axis II Personality Disorders and semi-structured questions on psychosocial circumstances, life-events, psychiatric symptoms, psychiatric treatments, substance use, and suicidal and self-harm behaviour. The assessment was carried out by psychiatric specialists or by residents in psychiatry with at least three years of psychiatric training. Results SCDP identified personality disorder comorbidity in 43% of the patients compared to 11% in TDA (p<0,0001). Anxiety disorder comorbidity was identified in 58% with SCDP compared to 12% with TDA (p<0,0001). Conclusions Important psychiatric comorbidity seems to be unrecognized in depressive patients when using TDA, which is routine in secondary psychiatric care. Comorbidities are better identified using the proposed mode, Funding Agencies|Southern Health Care Region, Sweden; OM Persson Foundation; province of Skane (Sweden) state grants, ALF

Objectives Depression is a common illness with substantial economic consequences for society and a great burden for affected individuals. About 30% of patients with depression do not respond to repeated treatments. Psychiatric comorbidity is known to affect duration, recurrence and treatment outcome of depression. However, there is a lack of knowledge on the extent to which psychiatric comorbidity is identified in the clinical setting for depressed patients in secondary psychiatric care. Therefore, the aim of this study was to compare the agreement between traditional diagnostic assessment (TDA) and a structured and comprehensive diagnostic procedure (SCDP) for identification of personality and anxiety disorder comorbidity in depressed patients in secondary psychiatric care. Methods 274 patients aged 18-77 were referred from four secondary psychiatric care clinics in Sweden during 2012-2017. ICD-10 diagnoses according to TDA (mostly unstructured by psychiatric specialist and residents in psychiatry), were retrieved from medical records and compared to diagnoses resulting from the SCDP in the study. This included the Mini International Neuropsychiatric Interview, the Structured Interview for DSM Axis II Personality Disorders and semi-structured questions on psychosocial circumstances, life-events, psychiatric symptoms, psychiatric treatments, substance use, and suicidal and self-harm behaviour. The assessment was carried out by psychiatric specialists or by residents in psychiatry with at least three years of psychiatric training. Results SCDP identified personality disorder comorbidity in 43% of the patients compared to 11% in TDA (p<0,0001). Anxiety disorder comorbidity was identified in 58% with SCDP compared to 12% with TDA (p<0,0001). Conclusions Important psychiatric comorbidity seems to be unrecognized in depressive patients when using TDA, which is routine in secondary psychiatric care. Comorbidities are better identified using the proposed mode, Funding Agencies|Southern Health Care Region, Sweden; OM Persson Foundation; province of Skane (Sweden) state grants, ALF

Objectives Depression is a common illness with substantial economic consequences for society and a great burden for affected individuals. About 30% of patients with depression do not respond to repeated treatments. Psychiatric comorbidity is known to affect duration, recurrence and treatment outcome of depression. However, there is a lack of knowledge on the extent to which psychiatric comorbidity is identified in the clinical setting for depressed patients in secondary psychiatric care. Therefore, the aim of this study was to compare the agreement between traditional diagnostic assessment (TDA) and a structured and comprehensive diagnostic procedure (SCDP) for identification of personality and anxiety disorder comorbidity in depressed patients in secondary psychiatric care. Methods 274 patients aged 18-77 were referred from four secondary psychiatric care clinics in Sweden during 2012-2017. ICD-10 diagnoses according to TDA (mostly unstructured by psychiatric specialist and residents in psychiatry), were retrieved from medical records and compared to diagnoses resulting from the SCDP in the study. This included the Mini International Neuropsychiatric Interview, the Structured Interview for DSM Axis II Personality Disorders and semi-structured questions on psychosocial circumstances, life-events, psychiatric symptoms, psychiatric treatments, substance use, and suicidal and self-harm behaviour. The assessment was carried out by psychiatric specialists or by residents in psychiatry with at least three years of psychiatric training. Results SCDP identified personality disorder comorbidity in 43% of the patients compared to 11% in TDA (p<0,0001). Anxiety disorder comorbidity was identified in 58% with SCDP compared to 12% with TDA (p<0,0001). Conclusions Important psychiatric comorbidity seems to be unrecognized in depressive patients when using TDA, which is routine in secondary psychiatric care. Comorbidities are better identified using the proposed mode, Funding Agencies|Southern Health Care Region, Sweden; OM Persson Foundation; province of Skane (Sweden) state grants, ALF

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.

Aging is associated with complex biological changes that can be accelerated, slowed, or even temporarily reversed by biological and non-biological factors. This article focuses on the link between biological aging, psychological stressors, and mental illness. Rather than comprehensively reviewing this rapidly expanding field, we highlight challenges in this area of research and propose potential strategies to accelerate progress in this field. This effort requires the interaction of scientists across disciplines - including biology, psychiatry, psychology, and epidemiology; and across levels of analysis that emphasize different outcome measures - functional capacity, physiological, cellular, and molecular. Dialogues across disciplines and levels of analysis naturally lead to new opportunities for discovery but also to stimulating challenges. Some important challenges consist of 1) establishing the best objective and predictive biological age indicators or combinations of indicators, 2) identifying the basis for inter-individual differences in the rate of biological aging, and 3) examining to what extent interventions can delay, halt or temporarily reverse aging trajectories. Discovering how psychological states influence biological aging, and vice versa, has the potential to create novel and exciting opportunities for healthcare and possibly yield insights into the fundamental mechanisms that drive human aging.

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.

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 (Cohens 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., Funding Agencies|Swedish Brain Foundation [FO2016-0106, FO2018-0255]; Swedish Research CouncilSwedish Research Council [2016-0228, 201500387, 2014-10171]; Riksbankens Jubileumsfond-the Swedish Foundation for Humanities and Social Sciences [2017-0639:1]; Marie Sklodowska Curie Actions [INCA 600398]; Swedish Society of Medicine; Soderstrom-Konigska Foundation; Sjobring Foundation; OM Persson Foundation; province of Scania (Sweden); Swedish Brain Foundation; Stockholm County CouncilStockholm County Council; Karolinska InstitutetKarolinska Institutet; Ekhaga Foundation

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.

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.

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 (Cohens 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., Funding Agencies|Swedish Brain Foundation [FO2016-0106, FO2018-0255]; Swedish Research CouncilSwedish Research Council [2016-0228, 201500387, 2014-10171]; Riksbankens Jubileumsfond-the Swedish Foundation for Humanities and Social Sciences [2017-0639:1]; Marie Sklodowska Curie Actions [INCA 600398]; Swedish Society of Medicine; Soderstrom-Konigska Foundation; Sjobring Foundation; OM Persson Foundation; province of Scania (Sweden); Swedish Brain Foundation; Stockholm County CouncilStockholm County Council; Karolinska InstitutetKarolinska Institutet; Ekhaga Foundation

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.

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.

BACKGROUND:Less than half of patients with major depressive disorder (MDD) respond to their first antidepressant trial. Our understanding of the underlying mechanisms of selective serotonin reuptake inhibitors (SSRIs) remains poor, and there is no reliable method of predicting treatment response. METHODS:Thirty-seven MDD subjects and 41 healthy controls, somatically healthy and medication-free for at least six weeks, were recruited, and plasma serotonin (5-HT) levels were assessed at baseline. Twenty-six of the MDD subjects were then treated in an open-label manner with clinically appropriate doses of sertraline for 8 weeks, after which plasma 5-HT levels were again assessed. Response to treatment was defined as an improvement of 50% or more on the Hamilton Depression Rating Scale. RESULTS:Non-responders to sertraline treatment had significantly lower pre-treatment 5-HT levels compared to both healthy controls and responders (F = 4.4, p = 0.004 and p = 0.036, respectively). There was a significant decrease in 5-HT levels over treatment in all MDD subjects (t = 6.2, p = 0.000003). The decrease was significantly more prominent in responders compared to non-responders (t = 2.1, p = 0.047). There was no significant difference in post-treatment 5-HT levels between responders and non-responders. LIMITATIONS:The study had a modest sample size. 5-HT levels in plasma may not reflect 5-HT levels in the brain. CONCLUSIONS:The results indicate that SSRI response may be facilitated by adequate baseline plasma 5-HT content and that successful SSRI treatment is associated with greater decreases in circulating 5-HT. Plasma 5-HT content may be a predictor of SSRI treatment outcome. Potential underlying mechanisms are discussed.

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.

Posttraumatic stress disorder (PTSD) is associated with impaired major domains of psychology and behavior. Individuals with PTSD also have increased co-morbidity with several serious medical conditions, including autoimmune diseases, cardiovascular disease, and diabetes, raising the possibility that systemic pathology associated with PTSD might be identified by metabolomic analysis of blood. We sought to identify metabolites that are altered in male combat veterans with PTSD. In this case-control study, we compared metabolomic profiles from age-matched male combat trauma-exposed veterans from the Iraq and Afghanistan conflicts with PTSD (n = 52) and without PTSD (n = 51) ('Discovery group'). An additional group of 31 PTSD-positive and 31 PTSD-negative male combat-exposed veterans was used for validation of these findings ('Test group'). Plasma metabolite profiles were measured in all subjects using ultrahigh performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. We identified key differences between PTSD subjects and controls in pathways related to glycolysis and fatty acid uptake and metabolism in the initial 'Discovery group', consistent with mitochondrial alterations or dysfunction, which were also confirmed in the 'Test group'. Other pathways related to urea cycle and amino acid metabolism were different between PTSD subjects and controls in the 'Discovery' but not in the smaller 'Test' group. These metabolic differences were not explained by comorbid major depression, body mass index, blood glucose, hemoglobin A1c, smoking, or use of analgesics, antidepressants, statins, or anti-inflammatories. These data show replicable, wide-ranging changes in the metabolic profile of combat-exposed males with PTSD, with a suggestion of mitochondrial alterations or dysfunction, that may contribute to the behavioral and somatic phenotypes associated with this disease.

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.

We are currently lacking clinically useful predictors of treatment response in common psychiatric disorders. Non-invasive and increasingly accessible neuroimaging techniques like functional magnetic resonance imaging (fMRI) could be a useful tool. In contrast to the conventional approach investigating the brain’s average responses, the brain’s signal variability could be a better estimate of the brain’s dynamic operations (Garrett et al., 2010, 2015). In addition, 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, we investigate if baseline BOLD-fMRI signal variability, and indices of cellular protection, predicts social anxiety disorder patient’s response to internet-delivered cognitive behavior therapy. Forty-six patients with social anxiety disorder (SAD) were scanned twice with a 3 Tesla fMRI before initiating CBT. Treatment outcome was assessed the Liebowitz Social Anxiety Scale (self-report). 1) BOLD-fMRI acquisition was performed while passively viewing emotional faces flashing on the screen for 80 seconds. Raw BOLD-fMRI data was implemented in an Independent Component Analysis in order to manually denoise images by carefully remove noise from neural signal. Across time, each voxel’s standard deviation was calculated and used as an index of variability. Multivariate partial least squares regression models were used for second level analysis. 2) Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. Significant latent level brain scores, and baseline analytes were implemented in linear regressions with LSAS-SR change score as the outcome. Results will be presented and discussed., Unknown total number of authors. All are not listed in the abstract book.

Aging is associated with complex biological changes that can be accelerated, slowed, or even temporarily reversed by biological and non-biological factors. This article focuses on the link between biological aging, psychological stressors, and mental illness. Rather than comprehensively reviewing this rapidly expanding field, we highlight challenges in this area of research and propose potential strategies to accelerate progress in this field. This effort requires the interaction of scientists across disciplines - including biology, psychiatry, psychology, and epidemiology; and across levels of analysis that emphasize different outcome measures - functional capacity, physiological, cellular, and molecular. Dialogues across disciplines and levels of analysis naturally lead to new opportunities for discovery but also to stimulating challenges. Some important challenges consist of 1) establishing the best objective and predictive biological age indicators or combinations of indicators, 2) identifying the basis for inter-individual differences in the rate of biological aging, and 3) examining to what extent interventions can delay, halt or temporarily reverse aging trajectories. Discovering how psychological states influence biological aging, and vice versa, has the potential to create novel and exciting opportunities for healthcare and possibly yield insights into the fundamental mechanisms that drive human aging.

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.

Posttraumatic stress disorder (PTSD) is associated with impaired major domains of psychology and behavior. Individuals with PTSD also have increased co-morbidity with several serious medical conditions, including autoimmune diseases, cardiovascular disease, and diabetes, raising the possibility that systemic pathology associated with PTSD might be identified by metabolomic analysis of blood. We sought to identify metabolites that are altered in male combat veterans with PTSD. In this case-control study, we compared metabolomic profiles from age-matched male combat trauma-exposed veterans from the Iraq and Afghanistan conflicts with PTSD (n = 52) and without PTSD (n = 51) ('Discovery group'). An additional group of 31 PTSD-positive and 31 PTSD-negative male combat-exposed veterans was used for validation of these findings ('Test group'). Plasma metabolite profiles were measured in all subjects using ultrahigh performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. We identified key differences between PTSD subjects and controls in pathways related to glycolysis and fatty acid uptake and metabolism in the initial 'Discovery group', consistent with mitochondrial alterations or dysfunction, which were also confirmed in the 'Test group'. Other pathways related to urea cycle and amino acid metabolism were different between PTSD subjects and controls in the 'Discovery' but not in the smaller 'Test' group. These metabolic differences were not explained by comorbid major depression, body mass index, blood glucose, hemoglobin A1c, smoking, or use of analgesics, antidepressants, statins, or anti-inflammatories. These data show replicable, wide-ranging changes in the metabolic profile of combat-exposed males with PTSD, with a suggestion of mitochondrial alterations or dysfunction, that may contribute to the behavioral and somatic phenotypes associated with this disease.

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.