Deprescribing of antidepressants: development of indicators of high-risk and overprescribing using the RAND/UCLA Appropriateness Method.

BACKGROUND: Antidepressants are first-line medications for many psychiatric disorders. However, their widespread long-term use in some indications (e.g., mild depression and insomnia) is concerning. Particularly in older adults with comorbidities and polypharmacy, who are more susceptible to adverse drug reactions, the risks and benefits of treatment should be regularly reviewed. The aim of this consensus process was to identify explicit criteria of potentially inappropriate antidepressant use (indicators) in order to support primary care clinicians in identifying situations, where deprescribing of antidepressants should be considered. METHODS: We used the RAND/UCLA Appropriateness Method to identify the indicators of high-risk and overprescribing of antidepressants. We combined a structured literature review with a 3-round expert panel, with results discussed in moderated meetings in between rounds. Each of the 282 candidate indicators was scored on a 9-point Likert scale representing the necessity of a critical review of antidepressant continuation (1-3 = not necessary; 4-6 = uncertain; 7-9 = clearly necessary). Experts rated the indicators for the necessity of review, since decisions to deprescribe require considerations of patient risk/benefit balance and preferences. Indicators with a median necessity rating of ≥ 7 without disagreement after 3 rating rounds were accepted. RESULTS: The expert panel comprised 2 general practitioners, 2 clinical pharmacologists, 1 gerontopsychiatrist, 2 psychiatrists, and 3 internists/geriatricians (total N = 10). After 3 assessment rounds, there was consensus for 37 indicators of high-risk and 25 indicators of overprescribing, where critical reviews were felt to be necessary. High-risk prescribing indicators included settings posing risks of drug-drug, drug-disease, and drug-age interactions or the occurrence of adverse drug reactions. Indicators with the highest ratings included those suggesting the possibility of cardiovascular risks (QTc prolongation), delirium, gastrointestinal bleeding, and liver injury in specific patient subgroups with additional risk factors. Overprescribing indicators target patients with long treatment durations for depression, anxiety, and insomnia as well as high doses for pain and insomnia. CONCLUSIONS: Explicit indicators of antidepressant high-risk and overprescribing may be used directly by patients and health care providers, and integrated within clinical decision support tools, in order to improve the overall risk/benefit balance of this commonly prescribed class of prescription drugs.

Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Importance: Insufficient treatment response and resulting chronicity constitute a major problem in depressive disorders. Remission rates range as low as 15% to 40% and treatment-resistant depression (TRD) is associated with low-grade inflammation, suggesting anti-inflammatory interventions as a rational treatment strategy. Minocycline, which inhibits microglial activation, represents a promising repurposing candidate in the treatment of TRD. Objective: To determine whether 6 weeks of minocycline as add-on to antidepressant treatment as usual can significantly reduce depressive symptoms in patients with TRD. Design, Setting, and Participants: The study was conducted in Germany and designed as a multicenter double-blind randomized clinical trial (RCT) of 200 mg/d minocycline treatment over a course of 6 weeks with a 6-month follow-up. Participants were recruited from January 2016 to August 2020 at 9 university hospitals that served as study sites. Key inclusion criteria were a diagnosis of major depressive disorder (according to Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] criteria), severity of depressive symptoms on the Hamilton Depression Rating Scale (HAMD-17) greater than or equal to 16 points, aged 18 to 75 years, body mass index 18 to 40, Clinical Global Impression Scale (CGI-S) greater than or equal to 4, failure to adequately respond to an initial antidepressant standard medication as per Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and stable medication for at least 2 weeks. A total of 258 patients were screened, of whom 173 were randomized and 168 were included into the intention-to-treat population. Statistical analysis was performed from April to November 2020. Interventions: Participants were randomized (1:1) to receive adjunct minocycline (200 mg/d) or placebo for 6 weeks. Main Outcomes and Measures: Primary outcome measure was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 6 analyzed by intention-to-treat mixed model repeated measures. Secondary outcome measures were response, remission, and various other clinical rating scales. Results: Of 173 eligible and randomized participants (84 randomized to minocycline and 89 randomized to placebo), 168 formed the intention-to-treat sample (79 [47.0%] were women, 89 [53.0%] were men, 159 [94.6%] were White, 9 [6.4%] were of other race and ethnicity, including Asian and unknown ethnicity), with 81 in the minocycline group and 87 in the placebo group. The mean (SD) age was 46.1 (13.1) years, and the mean (SD) MADRS score at baseline was 26.5 (5.0). There was no difference in rates of completion between the minocycline (83.3% [70 of 81]) and the placebo group (83.1% [74 of 87]). Minocycline treatment did not alter the course of depression severity compared with placebo as assessed by a decrease in MADRS scores over 6 weeks of treatment (1.46 [-1.04 to 3.96], P = .25). Minocycline treatment also exhibited no statistically significant effect on secondary outcomes. Conclusions and Relevance: In this large randomized clinical trial with minocycline at a dose of 200 mg/d added to antidepressant treatment as usual for 6 weeks, minocycline was well tolerated but not superior to placebo in reducing depressive symptoms in patients with TRD. The results of this RCT emphasize the unmet need for therapeutic approaches and predictive biomarkers in TRD. Trial Registration: EU Clinical Trials Register Number: EudraCT 2015-001456-29.

Biobanking in everyday clinical practice in psychiatry-The Munich Mental Health Biobank.

Translational research on complex, multifactorial mental health disorders, such as bipolar disorder, major depressive disorder, schizophrenia, and substance use disorders requires databases with large-scale, harmonized, and integrated real-world and research data. The Munich Mental Health Biobank (MMHB) is a mental health-specific biobank that was established in 2019 to collect, store, connect, and supply such high-quality phenotypic data and biosamples from patients and study participants, including healthy controls, recruited at the Department of Psychiatry and Psychotherapy (DPP) and the Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany. Participants are asked to complete a questionnaire that assesses sociodemographic and cross-diagnostic clinical information, provide blood samples, and grant access to their existing medical records. The generated data and biosamples are available to both academic and industry researchers. In this manuscript, we outline the workflow and infrastructure of the MMHB, describe the clinical characteristics and representativeness of the sample collected so far, and reveal future plans for expansion and application. As of 31 October 2021, the MMHB contains a continuously growing set of data from 578 patients and 104 healthy controls (46.37% women; median age, 38.31 years). The five most common mental health diagnoses in the MMHB are recurrent depressive disorder (38.78%; ICD-10: F33), alcohol-related disorders (19.88%; ICD-10: F10), schizophrenia (19.69%; ICD-10: F20), depressive episode (15.94%; ICD-10: F32), and personality disorders (13.78%; ICD-10: F60). Compared with the average patient treated at the recruiting hospitals, MMHB participants have significantly more mental health-related contacts, less severe symptoms, and a higher level of functioning. The distribution of diagnoses is also markedly different in MMHB participants compared with individuals who did not participate in the biobank. After establishing the necessary infrastructure and initiating recruitment, the major tasks for the next phase of the MMHB project are to improve the pace of participant enrollment, diversify the sociodemographic and diagnostic characteristics of the sample, and improve the utilization of real-world data generated in routine clinical practice.

Pharmacological treatment of major depressive disorder according to severity in psychiatric inpatients: results from the AMSP pharmacovigilance program from 2001-2017.

The International Classification of Diseases (10th Version) categorizes major depressive disorder (MDD) according to severity. Guidelines provide recommendations for the treatment of MDD according to severity. Aim of this study was to assess real-life utilization of psychotropic drugs based on severity of MDD in psychiatric inpatients. Drug utilization data from the program "Drug Safety in Psychiatry" (German: Arzneimittelsicherheit in der Psychiatrie, AMSP) were analyzed according to the severity of MDD. From 2001 to 2017, 43,868 psychiatric inpatients with MDD were treated in participating hospitals. Most patients were treated with ≥ 1 antidepressant drug (ADD; 85.8% of patients with moderate MDD, 89.8% of patients with severe MDD, and 87.9% of patients with psychotic MDD). More severely depressed patients were more often treated with selective serotonin-norepinephrine reuptake inhibitors and mirtazapine and less often with selective serotonin reuptake inhibitors (p < 0.001 each). Use of antipsychotic drugs (APDs), especially second-generation APDs, increased significantly with severity (37.0%, 47.9%, 84.1%; p < 0.001 each). APD + ADD was the most used combination (32.8%, 43.6%, 74.4%), followed by two ADDs (26.3%, 29.3%, 24.9%). Use of lithium was minimal (3.3%, 6.1% ,7.1%). The number of psychotropic drugs increased with severity of MDD-patients with psychotic MDD had the highest utilization of psychotropic drugs (93.4%, 96.5%, 98.7%; p < 0.001). ADD monotherapy was observed to a lesser extent, even in patients with non-severe MDD (23.2%, 17.1%, 4.4%). Findings reveal substantial discrepancies between guideline recommendations and real-life drug utilization, indicating that guidelines may insufficiently consider clinical needs within the psychiatric inpatient setting.

Effect of Concomitant Benzodiazepine Use on Efficacy and Safety of Esketamine Nasal Spray in Patients with Major Depressive Disorder and Acute Suicidal Ideation or Behavior: Pooled Randomized, Controlled Trials.

PURPOSE: The impact of benzodiazepines on the efficacy and safety of esketamine as a rapid-acting antidepressant remains unclear. MATERIALS AND METHODS: Data from two identically designed, randomized double-blind studies were pooled and analyzed on a post-hoc basis. In both studies, adults with major depressive disorder with acute suicidal ideation or behavior were randomized to placebo or esketamine 84 mg nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care (initial hospitalization and newly initiated or optimized oral antidepressant[s]). Efficacy and safety were analyzed in two groups based on whether patients used concomitant benzodiazepines, which were prohibited within 8 hours before and 4 hours after the first dose of esketamine and within 8 hours of the primary efficacy assessment at 24 hours. The primary efficacy endpoint - change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score - was analyzed using ANCOVA. RESULTS: Most patients (309/451, 68.5%) used concomitant benzodiazepines. Greater decrease in MADRS total score was observed with esketamine (mean [SD]: -16.1 [11.73]) versus placebo (-12.6 [10.56]) at 24 hours (least-squares mean difference: -3.7, 95% CI: -5.76, -1.59). The differences between the esketamine and placebo groups were clinically meaningful, irrespective of benzodiazepine use (benzodiazepine: -4.3 [-6.63, -1.89]; no benzodiazepine: -3.1 [-6.62, 0.45]). Among patients taking esketamine, change in MADRS total score was not significantly different between patients taking benzodiazepines (-15.8 [11.27]) versus those not taking benzodiazepines (-16.8 [12.82]) (least-squares mean difference: 1.1, [-2.24, 4.45]). Among esketamine-treated patients, the incidence of sedation was higher with benzodiazepine use, whereas dissociation was similar. CONCLUSION: Benzodiazepines do not meaningfully affect the rapid-acting antidepressant effect of esketamine at 24 hours post-first dose among patients with MDD and acute suicidal ideation or behavior.

Classical Risk Factors and Inflammatory Biomarkers: One of the Missing Biological Links between Cardiovascular Disease and Major Depressive Disorder.

BACKGROUND: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. METHODS: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. RESULTS: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1ß (IL-1ß) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. CONCLUSIONS: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention.

The sex-dependent role of the glucocorticoid receptor in depression: variations in the NR3C1 gene are associated with major depressive disorder in women but not in men.

Genetic variations in the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) have been associated with maladaptive stress responses and major depressive disorder (MDD). In a case-control study design, we examined whether single nucleotide polymorphisms (SNPs) and haploid genotype (haplotype) associations of MR gene NR3C2, GR gene NR3C1 and genes of GR chaperone molecules FK506 binding protein 5 (FKBP5) and corticotrophin-releasing hormone receptor 1 (CRHR1) differed between healthy subjects (n = 634) and inpatients with major depressive disorder (n = 412). All analyses were conducted for women and men separately. After conservative correction of Type-I-error to obtain reliable p values, one SNP in the NR3C1 gene, namely rs6195, showed a significant association with the presence of a major depression (p = 0.048) in females. In contrast, NR3C2, FKBP5 and CRHR1 polymorphisms were not significantly associated with MDD. No haplotype effects could be identified. Our results support the notion of an association between variants of GR-related genes in women and the pathophysiology of depression: females suffering from MDD showed a more than three times higher frequency of the T/C polymorphism compared to controls, which thus seems to increase the vulnerability to depression in females.

First results of a refeeding program in a psychiatric intensive care unit for patients with extreme anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is associated with a high mortality rate. This study describes a compulsory re-feeding program established in Munich for extremely underweight patients. METHODS: The contract between the patient and the therapeutic team included mandatory inpatient status, establishment of guardianship and compulsory re-feeding with a percutaneous gastric feeding tube, as indicated. The predefined target was a body mass index (BMI) of 17 kg/m(2). Data on the first 68 patients with AN are presented. RESULTS: 65 (95.6%) patients were female and mean age at admission was 26.5 ± 8.5 years. BMI increased from 12.3 ± 1.4 kg/m(2) at admission to 16.7 ± 1.7 kg/m(2) at discharge. Thirty-two (47.1%) patients had the restrictive subtype (ANR) and 36 (52.9%) had the binging and purging subtype (ANBP). Duration of illness before admission (p = .004), days of treatment until discharge (p = .001) and weight increase (p = .02) were significantly different between subgroups in favor of patients with ANR. Also, seasonal differences could be found. Comparison of feeding methods showed that percutaneous tube feeding was superior. Almost half of the patients were treated with psychotropic medication. To date, however, the number of patients included in this program is too small to assess rare complications of this acute treatment program and long term outcomes of AN. CONCLUSIONS: An intensive care program for severely ill AN patients has been successfully established. Besides averting physical harm in the short term, this program was designed to enable these patients to participate in more sophisticated psychotherapeutic programs afterwards. To our knowledge, this is the first such program that regularly uses percutaneous feeding tubes.

The influence of Hatha yoga as an add-on treatment in major depression on hypothalamic-pituitary-adrenal-axis activity: a randomized trial.

OBJECTIVES: The impact of Hatha yoga as add-on treatment to quetiapine fumarate extended release (QXR) or escitalopram (ESC) in depressed patients on hypothalamic-pituitary-adrenal (HPA) axis activity was assessed. METHODS: 60 inpatients suffering from major depressive disorder (MDD) according to DSM-IV were randomized for a 5 week treatment with Yoga or not (control group) and with either QXR (300 mg/day) or ESC (10 mg/day). Serial dexamethasone/corticotropin releasing hormone (DEX/CRH) tests were performed to assess HPA axis function. The Hamilton Depression Rating Scale (21-HAMD) was used weekly. RESULTS: A more pronounced down regulation of the HPA axis activity due to yoga could not be detected. The stepwise long term cortisol reduction was seen in both medication groups, irrespectively of yoga add-on treatment. In addition, cortisol improvers in week 1 of therapy (reduction in cortisol peak value within the DEX/CRH test) reached significant greater amelioration of depressive symptoms after 5 weeks. CONCLUSIONS: Our results suggest that antidepressant agents down regulate HPA axis function to a greater extent than additional Hatha yoga treatment. Moreover, an early reduction of HPA system hyperactivity after one week of pharmacological treatment seems to raise the possibility of a favorable treatment response.

Effects of escitalopram/quetiapine combination therapy versus escitalopram monotherapy on hypothalamic-pituitary-adrenal-axis activity in relation to antidepressant effectiveness.

The hypothalamic-pituitary-adrenocortical (HPA) system is believed to play an important role in the pathophysiology of major depressive disorder. In this context, the atypical antipsychotic quetiapine (QUE) has been shown to inhibit HPA system activity in healthy subjects. In this study we investigated whether the putative inhibitory effects of QUE on HPA system activity may contribute to its antidepressant efficacy. We analyzed the effects of QUE as an augmentation to the selective serotonin reuptake inhibitor (SSRI) escitalopram (ESC) on HPA system activity in comparison to a monotherapy with ESC in relation to the antidepressant effectiveness. HPA axis activity (cortisol and ACTH) was measured by means of the dexamethasone/corticotropin-releasing hormone (DEX/CRH) test which was performed before (week 0) and during (week 1, week 5) antidepressant psychopharmacotherapy. The combination therapy, but not the ESC monotherapy showed significantly inhibiting effects on HPA system activity leading to stepwise down-regulation. ACTH concentrations were reduced in the ESC/QUE group during five weeks of treatment. The inhibitory effect of QUE maybe involved in its antidepressant effects as an augmentation strategy.

Impact on cortisol and antidepressant efficacy of quetiapine and escitalopram in depression.

BACKGROUND: In this study, the impact of quetiapine fumarate extended release (QXR) and escitalopram (ESC) on HPA axis activity was investigated in depressed patients in relationship to antidepressant efficacy. METHODS: In a randomized, open-label 5-week trial 60 inpatients suffering from major depression (DSM-IV criteria) were treated for 5 weeks with either QXR (300 mg/day) or ESC (10mg/day). The dexamethasone/CRH (DEX/CRH) test was performed before treatment, after 1, and after 5 weeks of treatment. Cortisol (COR) AUC values were used to assess HPA axis function. The Hamilton Depression Rating Scale was used weekly to estimate antidepressant efficacy. RESULTS: QXR and ESC showed comparable antidepressant effects but strongly differed in their impact on HPA axis activity. In the QXR group, a marked inhibition of COR AUC levels was observed which was most pronounced after one week of treatment but showed a partial re-increase after 5 weeks of treatment. In contrast, ESC transiently stimulated COR AUC values (week 1) whereas COR AUC levels at week 0 and week 5 were comparable. COR improvement at week 1 (defined as COR peak value reduction between DEX/CRH test 1 and 2) was significantly associated with better clinical outcome. CONCLUSION: Apparently, different effects on HPA axis activity reflect distinct pharmacoendocrinological properties of psychotropic drugs.

The role of allopregnanolone in depression and anxiety.

Neuroactive steroids such as allopregnanolone do not only act as transcriptional factors in the regulation of gene expression after intracellular back-oxidation into the 5-α pregnane steroids but may also alter neuronal excitability through interactions with specific neurotransmitter receptors. In particular, certain 3α-reduced metabolites of progesterone such as 3α,5α-tetrahydroprogesterone (allopregnanolone) and 3α,5ß-tetrahydroprogesterone (pregnanolone) are potent positive allosteric modulators of the GABA(A) receptor complex. During the last years, the downregulation of neurosteroid biosynthesis has been intensively discussed to be a possible contributor to the development of anxiety and depressive disorder. Reduced levels of allopregnanolone in the peripheral blood or cerebrospinal fluid were found to be associated with major depression, anxiety disorders, premenstrual dysphoric disorder, negative symptoms in schizophrenia, or impulsive aggression. The importance of allopregnanolone for the regulation of emotion and its therapeutical use in depression and anxiety may not only involve GABAergic mechanisms, but probably also includes enhancement of neurogenesis, myelination, neuroprotection, and regulatory effects on HPA axis function. Certain pharmacokinetic obstacles limit the therapeutic use of natural neurosteroids (low bioavailability, oxidation to the ketone). Until now synthetic neuroactive steroids could not be established in the treatment of anxiety disorders or depression. However, the translocator protein (18 kDa) (TSPO) which is important for neurosteroidogenesis has been identified as a potential novel target. TSPO ligands such as XBD 173 increase neurosteroidogenesis and have anxiolytic effects with a favorable side effect profile.

Targeted high-throughput sequencing identifies a TARDBP mutation as a cause of early-onset FTD without motor neuron disease.

Targeted high-throughput sequencing of many amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) genes in parallel has the potential to reveal novel ALS- and/or FTD-phenotypes and to provide missing links on the ALS-FTD continuum. For example, although the 43-kDa transactive response DNA binding protein is the major pathologic hallmark linking ALS and FTD, mutations in the gene encoding 43-kDa transactive response DNA binding protein (TARDBP) have been appreciated only as a cause of ALS-phenotypes, but not yet of pure FTD. Thus, the genetic link is not yet well substantiated that TARDBP mutations can cause the full spectrum of the ALS-FTD continuum. High-throughput sequencing of 18 ALS and FTD genes in an index patient presenting with early-onset pure (behavioral) FTD and a positive family history for ALS revealed an established TARDBP mutation, A382T. This finding demonstrates that a TARDPB mutation can cause early-onset pure FTD without evidence for ALS even in advanced FTD disease stages. Moreover, it indicates that TARDPB screening might be considered even in young patients with "pure" neuropsychiatric disturbances and without evidence of neurodegenerative disease in the parental generation.

Tryptophan metabolism and immunogenetics in major depression: a role for interferon-γ gene.

The tryptophan metabolism and immune activation play a role in pathophysiology of major depressive disorders. The pro-inflammatory cytokine interferon-γ transcriptionally induces the indoleamine 2,3-dioxygenase enzyme that degrades the tryptophan and thus induces serotonin depletion. The polymorphism of certain cytokine genes was reported to be associated with major depression. We investigated the association between interferon-γ (IFNγ) gene CA repeat polymorphism, the profile of serotonin and tryptophan pathway metabolites and clinical parameters in 125 depressed patients and 93 healthy controls. Compared to controls, serum tryptophan and 5-hydroxyindoleacetic acid (5HIAA) concentrations in the patients were significantly lower and serum kynurenine concentrations were significantly higher at baseline (p<0.0001). The presence of IFNγ CA repeat allele 2 homozygous has significant association with higher kynurenine concentrations in controls (F=4.47, p=0.038) as well as in patients (F=3.79, p=0.045). The existence of interferon-γ CA repeat allele 2 (homo- or heterozygous) showed significant association with increase of tryptophan breakdown over time during the study period (F=6.0, p=0.019). The results indicated the association between IFNγ CA repeat allele 2, tryptophan metabolism and the effect of medication.

Translocator protein (18 kDa) (TSPO) as a therapeutic target for anxiety and neurologic disorders.

The translocator protein (18 kD) (TSPO) plays a crucial role for the synthesis of neurosteroids by promoting the transport of cholesterol to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Neurosteroids are allosteric modulators of GABA(A) receptor function, which plays an important role in the pathophysiology of anxiety disorders. The TSPO ligand XBD173 enhances GABAergic neurotransmission by promoting neurosteroidogenesis without direct effects at the GABA(A) receptor. In humans, XBD173 shows potent antipanic efficacy without sedation and withdrawal after 7 days of treatment. XBD173 therefore appears to be a promising compound for rapid anxiolytic efficacy with a favorable side-effect profile. Furthermore, TSPO ligands show neuroprotective and antiinflammatory effects in experimental models of peripheral neuropathies and traumatic brain injury. These compounds might therefore also be valuable for the treatment of neurologic diseases with inflammation-related pathophysiology.

DNA methylation analysis of the angiotensin converting enzyme (ACE) gene in major depression.

BACKGROUND: The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ~40%-50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood. MATERIALS AND METHODS: The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls. RESULTS: We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04). CONCLUSION: The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders.

Major depressive disorder is associated with cardiovascular risk factors and low Omega-3 Index.

OBJECTIVE: Cardiovascular disease (CVD) and major depressive disorder (MDD) are frequent worldwide and have a high comorbidity rate. Omega-3 fatty acids have been suggested as disease modulators for both CVD and MDD. Therefore, we studied whether polyunsaturated fatty acids and the Omega-3 Index may represent markers for assessment of the cardiovascular risk in somatically healthy patients suffering from MDD. METHOD: We conducted a case-control study from July 2004 to December 2007 in 166 adults (86 inpatients with MDD but without CVD from the Department of Psychiatry and Psychotherapy and 80 age- and sex-matched healthy controls from an outpatient clinic of the Division of Preventive Cardiology, Ludwig Maximilian University of Munich, Germany). Information gathered at baseline included MDD diagnosis according to DSM-IV criteria, depression ratings, conventional cardiovascular risk factors, and fatty acid and interleukin-6 determinations. Fatty acid composition was analyzed according to the HS-Omega-3 Index methodology. During the study, patients received no supplementation with omega-3 fatty acids. The main inclusion criteria were the diagnosis of MDD according to DSM-IV and a 17-item Hamilton Depression Rating Scale (HDRS-17) score of at least 17. Treatment response and remission were defined using the HDRS-17. RESULTS: Several conventional risk factors such as high triglyceride (mean, 152 mg/dL vs 100 mg/dL; P < .001) and fasting glucose (mean, 96 mg/dL vs 87 mg/dL; P = .005) values as well as greater waist circumference (mean, 97 cm vs 87 cm; P = .019) and higher body mass index (calculated as kg/m(2); mean, 26 vs 24; P = .011) were more prevalent in MDD patients in comparison with controls. The Omega-3 Index (mean, 3.9% vs 5.1%; P < .001) and individual omega-3 fatty acids were significantly lower in MDD patients. An Omega-3 Index < 4% was associated with high concentrations of the proinflammatory cytokine interleukin-6 (χ(2) = 7.8, P = .02). CONCLUSIONS: Conventional cardiovascular risk factors, the Omega-3 Index, and interleukin-6 levels indicated an elevated cardiovascular risk profile in MDD patients currently free of CVD. Our results support the employment of strategies to reduce the cardiovascular risk in still cardiovascularly healthy MDD patients by targeting conventional risk factors and the Omega-3 Index.