Distinguishing and treating demoralization syndrome in cancer: A review.

IMPORTANCE: Demoralization, characterized by a persistent inability to cope, as well as helplessness, hopelessness, and despair, is highly prevalent in oncology, with between 36% to 52% of patients exhibiting demoralization syndrome. Given established evidence linking demoralization in patients with cancer to physical symptom burden, quality of life, sleep disturbance, and suicidality, assessment and treatment of demoralization syndrome is critical for optimizing clinical and psychosocial outcomes. OBSERVATIONS: The term "demoralization" is highly relevant to the care of patients with cancer facing life-limiting illnesses. Indeed, demoralization can be conceptualized as a feeling state characterized by the perception of being unable to cope with some pressing problems and/or of lack of adequate support from others. Despite a considerable overlap in symptoms, demoralization and depression should be regarded as distinct and independent clinical syndromes. Patients who are demoralized but not clinically depressed often describe a sense of subjective incompetence and do not report anhedonia (i.e., loss of interest and inability to enjoy things). Although the definition of demoralization is now included as a distinct syndrome in the International Classification of Diseases (ICD)-11, it has been neglected by the current U.S. official nosology in psychiatry, such as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR). As such, demoralization syndrome may be under- or misdiagnosed and treated ineffectively in the oncology setting, potentially prolonging suffering and influencing cancer outcomes. CONCLUSIONS AND RELEVANCE: Optimization of methods to diagnose and assess demoralization syndrome is critical to underpin rigorous studies evaluating the efficacy of psychotherapeutic and pharmacological interventions for patients with cancer experiencing demoralization. Our review supports the use of specific diagnostic criteria for demoralization in cancer patients, introduces methodological considerations relevant to treatment studies, and presents a novel measurement approach to the assessment of demoralization severity with the Clinical Interview for Demoralization (CIDE).

Individuals with depression exhibiting a pro-inflammatory phenotype receiving omega-3 polyunsaturated fatty acids experience improved motivation-related cognitive function: Preliminary results from a randomized controlled trial.

Cognitive impairment related to major depressive disorder (MDD) is highly prevalent, debilitating and is lacking in effective treatments; dysregulated inflammatory physiology is a putative mechanism and may represent a therapeutic target. In depressed individuals exhibiting a pro-inflammatory phenotype who were enrolled in a 12-week randomized placebo-controlled trial of 3 doses of omega-3 polyunsaturated fatty acids (ω-3-FA), we examined: (i) the relationship between dysregulated inflammatory physiology and baseline cognitive impairment; (ii) improvement in cognitive impairment following treatment; and (iii) the association between baseline inflammatory biomarkers and change in cognitive impairment for those receiving treatment. We randomized 61 unmedicated adults aged 45.50 years (75% female) with DSM-5 MDD, body mass index >25 kg/m2, and C-reactive protein (CRP) ≥3.0 mg/L to three doses of ω-3-FA (1, 2, or 4 g daily) or matching placebo. Analyses focused on 45 study completers who had inflammatory biomarkers assessed [circulating CRP, interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) as well as lipopolysaccharide (LPS)-stimulated concentrations of IL-6 and TNFα in peripheral blood mononuclear cells (PBMC)] and on the highest dose ω-3-FA (4 g daily; n = 11) compared to placebo (n = 10). Impairment in motivational symptoms (e.g., alertness, energy, enthusiasm) and higher-order cognitive functions (e.g., word-finding, memory) were assessed by a validated self-report measure. Among all 45 participants at baseline, lower concentrations of IL-6 in LPS-stimulated PBMC were associated with greater impairment in higher-order cognitive functions (r = -0.35, p = .02). Based on hierarchical linear modeling, individuals receiving 4 g/day of ω-3-FA reported significant improvement in motivational symptoms compared to placebo (B = -0.07, p = .03); in the 4 g/day group, lower baseline concentrations of TNFα in LPS-stimulated PBMC were associated with significant improvement in motivational symptoms (Ρ = .71, p = .02) following treatment. In this exploratory clinical trial, daily supplementation with 4 g of ω-3-FA improves motivational symptoms in depressed individuals exhibiting an inflammatory phenotype.

Ages at menarche and menopause, hormone therapy, and the risk of depression.

OBJECTIVE: To examine the association between female reproductive factors and the risk of depression. METHOD: A retrospective cohort study was performed using a national database in South Korea. Among 945,729 eligible postmenopausal women, the associations between female reproductive factors including the age at menarche, age at menopause, parity, duration of oral contraceptive (OC) use, duration of breastfeeding, and use of menopausal hormone therapy (MHT), and the occurrence of depression were investigated. RESULTS: Compared to women with menarche at the age of ≤12 years, those with menarche at the age of ≥15 showed an increased risk of depression [adjusted hazard ratio (aHR) of 1.09 for 15-16 years and 1.18 for ≥17 years]. Compared to women with menopause at the age of 50-54, those with menopause at an earlier age showed an increased risk of depression (aHR of 1.20 for <40 years), and those with menopause at a later age showed a decreased risk of depression (aHR of 0.94 for ≥55 years). Use of MHT was associated with an increased risk of depression (aHR of 1.30 for ≥5 years). Duration of breastfeeding and duration of OC use had U-shaped but weak associations with depression. Whereas parity did not show a significant association with depression. CONCLUSION: Late menarche, early menopause, and the use of MHT were associated with an increased risk of depression in postmenopausal women.

High body weight variability is associated with increased risk of depression: a nationwide cohort study in South Korea.

BACKGROUND: Body weight variability (BWV) negatively affects the incidence and outcomes of various diseases, but the nature of the association between BWV and depression remains unclear. In this study, we aimed to test the hypothesis that BWV is associated with the risk of new-onset depression. METHODS: Data from a nationwide population-based cohort in the Korean National Health Insurance Service database were analyzed for 6 598 570 adults with no history of depression and reports of at least three health examinations. BWV was estimated using variability independent of the mean indices and divided into quartiles (Q1 lowest, Q4 highest BWV). Cox proportional hazard models were applied to assess the risk of depression according to the quartile of BWV. RESULTS: The incident rate for depression from Q1 to Q4 of BWV was 20.7, 20.3, 20.8, and 22.2 per 1000 person-years, respectively. BWV, especially high BWV, was associated with an increased risk of depression after adjusting for age, sex, smoking, alcohol consumption, physical activity, income, diabetes mellitus, hypertension, and dyslipidemia. The hazard ratio (HR) of new-onset depression was highest in Q4 relative to Q1 in the total population (HR 1.12, p < 0.0001) and was higher in women than in men (HR 1.72 v. 1.16, p < 0.0001). In stratified analyses, regardless of obesity or weight change status at baseline, the risk of depression was increased when bodyweight fluctuated highly during follow-up. CONCLUSIONS: High BWV was associated with an increased risk of depression. Further studies need to evaluate the role of high BWV with respect to the onset of depression.

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.Trial Registration: ClinicalTrials.gov identifier: NCT02553915.

Association between pre-pregnancy tobacco smoking and postpartum depression: A nationwide cohort study.

BACKGROUND: Prior literature examining the association between cigarette smoking and postpartum depression (PPD) has focused primarily on smoking behaviors during pregnancy or postpartum. However, there is a dearth of studies assessing pre-pregnancy smoking in relation to PPD. METHOD: A retrospective national cohort data from the National Health Insurance of South Korea were analyzed. A total of 392,394 women who gave birth between 2011 and 2015 and received health checkups within a year before pregnancy without a history of diagnosed depression were included. During the health checkup, participants self-reported their smoking status, amount, and duration in a health questionnaire. The diagnosis of PPD was defined by ICD-10 codes F32 and F33 during hospital visits within two years postpartum. RESULT: Overall, 24,441 (6.2 %) women were newly diagnosed with depression within two years postpartum. Those who reported that they had quit smoking or were currently smoking before pregnancy were more likely to be diagnosed with PPD compared to nonsmokers. A greater number of cigarettes smoked was associated with a higher risk of PPD for both current and former smokers. Results of cumulative lifetime smoking exposure demonstrated that even those with 2 pack-years of smoking had an increased risk of developing PPD within two years postpartum (HR: 1.44, 95 % CI: 1.29-1.60). Those who smoked >10 pack-years had the highest risk of developing PPD (HR: 1.86, 95 % CI: 1.14-3.04) compared to nonsmokers. CONCLUSION: Greater amount and duration of cigarette smoking in pre-pregnancy can increase the risk of PPD.

Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI).

Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral N-methyl-D-aspartate (NMDA) receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD).Methods: This double-blind, phase 3 trial, was conducted between June 2019 and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1-3, twice daily thereafter) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomatology-Self-Rated, Sheehan Disability Scale, and quality of life measures.Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P = .002). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all time points including week 1 (P = .007) and week 2 (P < .001). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; P < .001), and clinical response by 54.0% versus 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; P < .001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points (eg, CGI-S least-squares mean difference at week 6, -0.48; 95% CI, -0.48 to -0.79; P = .002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.Conclusions: In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated.Trial Registration: ClinicalTrials.gov Identifier: NCT04019704.

Exploration of baseline and early changes in neurocognitive characteristics as predictors of treatment response to bupropion, sertraline, and placebo in the EMBARC clinical trial.

BACKGROUND: Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner. METHODS: In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16. RESULTS: Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline. CONCLUSION: These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.

Patterns of Pretreatment Reward Task Brain Activation Predict Individual Antidepressant Response: Key Results From the EMBARC Randomized Clinical Trial.

BACKGROUND: The lack of biomarkers to inform antidepressant selection is a key challenge in personalized depression treatment. This work identifies candidate biomarkers by building deep learning predictors of individual treatment outcomes using reward processing measures from functional magnetic resonance imaging, clinical assessments, and demographics. METHODS: Participants in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study (n = 222) underwent reward processing task-based functional magnetic resonance imaging at baseline and were randomized to 8 weeks of sertraline (n = 106) or placebo (n = 116). Subsequently, sertraline nonresponders (n = 37) switched to 8 weeks of bupropion. The change in Hamilton Depression Rating Scale was measured after treatment. Reward processing, clinical measurements, and demographics were used to train treatment-specific deep learning models. RESULTS: The predictive model for sertraline achieved R2 of 48% (95% CI, 33%-61%; p < 10-3) in predicting the change in Hamilton Depression Rating Scale and number-needed-to-treat (NNT) of 4.86 participants in predicting response. The placebo model achieved R2 of 28% (95% CI, 15%-42%; p < 10-3) and NNT of 2.95 in predicting response. The bupropion model achieved R2 of 34% (95% CI, 10%-59%, p < 10-3) and NNT of 1.68 in predicting response. Brain regions where reward processing activity was predictive included the prefrontal cortex and cerebellar crus 1 for sertraline and the cingulate cortex, caudate, orbitofrontal cortex, and crus 1 for bupropion. CONCLUSIONS: These findings demonstrate the utility of reward processing measurements and deep learning to predict antidepressant outcomes and to form multimodal treatment biomarkers.

Increased metabolic variability is associated with newly diagnosed depression: A nationwide cohort study.

BACKGROUND: The effect of dynamic changes in metabolic parameters over time on the development of depression has yet to be examined. In this study, we aimed to determine the association between the variability of metabolic parameters and the development of depression using nationally representative data. METHODS: We used health examination data provided by the South Korean National Health Insurance System (NHIS) and included those who underwent the examination ≥ 3 times within five years of enrollment, without a previous history of depression (n = 9,058,424). The variability of each metabolic parameter including weight circumference, blood pressure, fasting blood glucose, high-density lipoprotein cholesterol, and triglyceride levels was estimated using variability independent of mean (VIM) indices. High variability was defined as the highest quartile (Q4) of variability. RESULTS: Each metabolic parameter with high variability was associated with a higher risk of newly diagnosed depression compared to those with low variability, after adjusting for age, sex, smoking, alcohol drinking, regular exercise, income status, baseline diabetes, hypertension, and dyslipidemia. As the number of highly variable metabolic parameters increased, the risk for newly diagnosed depression increased even after adjusting for the aforementioned covariates (hazard ratio (HR) = 1.4, 95% confidence interval (CI): 1.3 - 1.4 in those with five highly variable parameters compared to those with no highly variable parameter). LIMITATIONS: relatively short observation period; no systematic measure of depression severity. CONCLUSIONS: Our results suggest that the variability of metabolic parameters is an independent risk factor for depression.

Increased risk of depression before and after unilateral or bilateral oophorectomy: A self-controlled case series study using a nationwide cohort in South Korea.

BACKGROUND: There is insufficient evidence of the association between oophorectomy and depression. METHODS: A nationwide medical records database of South Korea was used to investigate incidence rate ratios (IRRs) of major depressive disorder before and after oophorectomy (n = 36,284) using a self-controlled case series design. Outcomes before and after hysterectomy (n = 25,415) were identified to compare with those around oophorectomy. RESULTS: In all oophorectomy and hysterectomy groups, the risk of depression was increased before and after surgery, peaking immediately before or after the operation, with no significant difference in the pattern of the results according to type of surgery. In the bilateral oophorectomy group, the IRR was increased between 2-3 months before the surgery, peaking immediately before surgery at 1.39 (95% CI: 1.30-1.49, p < .0001), and remained heightened for one-year postexposure. Subgroup analyses performed according to ovarian cancer, age group, and hormone replacement therapy produced results similar to those of the main outcome. LIMITATIONS: Because we used claims data, the detailed clinical information related to oophorectomy is lacking. There is possibility that time-varying confounder besides age and season might have affected the results CONCLUSIONS: The risk of depression increased before and after oophorectomy. The increase in risk of depression started before oophorectomy and peaked immediately before or after the operation, but no significant differences between unilateral and bilateral surgery and cancer and noncancer or among age groups were noted.

Predictive inflammatory biomarkers for change in suicidal ideation in major depressive disorder and panic disorder: A 12-week follow-up study.

Previous studies have investigated the role of inflammatory markers in suicidality of patients with major depressive disorder (MDD) or panic disorder (PD). However, few studies have investigated associations between serum inflammatory cytokine levels and suicidality. We hypothesized that MDD and PD status might be significantly associated with serum inflammatory cytokines and that we could predict levels of improvement in suicide ideation intensity using serum inflammatory biomarkers in patients with MDD and PD. For this study, 41 patients with MDD, 52 patients with PD, and 59 healthy control (HC) subjects were enrolled. Psychological measurements and serum inflammatory markers such as interleukin (IL) -6, -10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and C reactive protein (CRP) were examined. A total of five visits were completed during 12 weeks. After controlling for confounding factors, log-transformed IL-6 (ln_IL-6) at baseline (MDD: 0.297 ± 0.626; PD: 0.342 ± 0.723; HC: -0.121 ± 0.858; p = 0.007, >0.0017, 0.05/30) and mean ln_IL-6 (MDD: 0.395 ± 0.550, PD: 0.249 ± 0.544, HC: -0.139 ± 0.622, p = 0.002, >0.0017, 0.05/30) levels were trends towards significantly higher in patients with MDD and PD than in HC. In MDD patients, a higher level of basal ln_TNF-α was a significant predictor of ΔSSI (changes in SSI scores between baseline and week 12) even after controlling for changes of depression symptoms and baseline SSI scores (standardized ß = 0.541, p = 0.002 < 0.0028, 0.05/18). In conclusion, we could predict ΔSSI using baseline inflammatory biomarkers for patients with MDD.

Associations Between Smoking, Alcohol Consumption, Physical Activity and Depression in Middle-Aged Premenopausal and Postmenopausal Women.

Background: Changes in lifestyle factors are known to affect mood. However, there is insufficient evidence supporting the association between smoking, alcohol consumption, physical activity and depression in middle-aged women who are likely to experience rapid hormonal changes. Methods: We used a nationwide database of medical records in South Korea. 901,721 premenopausal and 943,710 postmenopausal women aged 40 years or older included in this study. Information on smoking, alcohol consumption, physical activity was identified from health examination data and followed up for the occurrence of depression using claims data. Results: Compared with never-smokers, ex-smokers and current smokers among premenopausal and postmenopausal women showed an increased risk of depression in a dose-dependent manner (aHR 1.13 for ex-smokers; aHR 1.23 for current smokers). Compared with non-drinkers, mild drinkers showed a decreased risk of depression (aHR 0.98 for premenopausal women; aHR 0.95 for postmenopausal women), and heavy drinkers showed an increased risk of depression both among premenopausal (aHR 1.20) and postmenopausal women (aHR 1.05). The risk of depression due to smoking and heavy alcohol consumption was higher in premenopausal women than in postmenopausal women. Compared with those who had not engaged in regular physical activity, those who had engaged showed a decreased risk of depression both among premenopausal (aHR 0.96) and postmenopausal women (aHR 0.95). Conclusions: Smoking and heavy alcohol consumption increased the risk of depression, and the increased risk was prominent in premenopausal than in postmenopausal women. Regular physical activity decreased the risk of depression both in premenopausal and postmenopausal women.

Pretreatment Reward Sensitivity and Frontostriatal Resting-State Functional Connectivity Are Associated With Response to Bupropion After Sertraline Nonresponse.

BACKGROUND: Standard guidelines recommend selective serotonin reuptake inhibitors as first-line antidepressants for adults with major depressive disorder, but success is limited and patients who fail to benefit are often switched to non-selective serotonin reuptake inhibitor agents. This study investigated whether brain- and behavior-based markers of reward processing might be associated with response to bupropion after sertraline nonresponse. METHODS: In a two-stage, double-blinded clinical trial, 296 participants were randomized to receive 8 weeks of sertraline or placebo in stage 1. Individuals who responded continued on another 8-week course of the same intervention in stage 2, while sertraline and placebo nonresponders crossed over to bupropion and sertraline, respectively. Data from 241 participants were analyzed. The stage 2 sample comprised 87 patients with major depressive disorder who switched medication and 38 healthy control subjects. A total of 116 participants with major depressive disorder treated with sertraline in stage 1 served as an independent replication sample. The probabilistic reward task and resting-state functional magnetic resonance imaging were administered at baseline. RESULTS: Greater pretreatment reward sensitivity and higher resting-state functional connectivity between bilateral nucleus accumbens and rostral anterior cingulate cortex were associated with positive response to bupropion but not sertraline. Null findings for sertraline were replicated in the stage 1 sample. CONCLUSIONS: Pretreatment reward sensitivity and frontostriatal connectivity may identify patients likely to benefit from bupropion following selective serotonin reuptake inhibitor failures. Results call for a prospective replication based on these biomarkers to advance clinical care.

Dose increase of S-Adenosyl-Methionine and escitalopram in a randomized clinical trial for major depressive disorder.

BACKGROUND: The optimal dose of S-adenosyl methionine (SAMe) for major depressive disorder (MDD) remains unclear. The objective of this analysis was to address whether a dose increase provided further improvement in cases of insufficient response using data from an existing randomized clinical trial. METHODS: Sixty-five patients with MDD who failed to respond to SAMe 1,600 mg/day, escitalopram 10 mg/day, or placebo for 6 weeks were treated with doubled doses of the allocated treatments for the following 6 weeks. Changes in 17-item Hamilton Depression Rating Scale, Inventory of Depressive Symptomatology-Self Rated, and Systematic Assessment for Treatment Emergent Events-Specific Inquiry were compared between the lower and higher dose treatments in each treatment group and among the higher dose treatments of SAMe, escitalopram, and placebo. RESULTS: Various depression severity scores decreased significantly for all three treatment arms during the higher dose treatment. No within-group and between-group differences were found in any of the efficacy measures when comparing the doses and treatments. There was a significant difference in reported abdominal discomfort among patients receiving the higher dose of SAMe (31.3%), compared to escitalopram (8.7%) and placebo (3.8%) (χ2=7.32, p = 0.026). LIMITATIONS: The sample size was relatively small. The study duration for dose increase was relatively short. CONCLUSIONS: Patients with MDD failing to respond to 1,600 mg/day of SAMe may improve after increasing the dose to 3,200 mg/day, but we cannot rule out the contribution of a placebo effect and time-related improvement. The risk of abdominal discomfort may be increased with higher doses of SAMe.

The allopregnanolone to progesterone ratio across the menstrual cycle and in menopause.

The neuroactive steroid 3α-5α-tetrahydroprogesterone (allopregnanolone), a metabolite of progesterone, is a positive allosteric modulator of GABAA receptors, and low levels have been implicated in the etiology of mood disorders. However, it is not known whether metabolism of progesterone to allopregnanolone varies across the menstrual cycle or is low after menopause. We hypothesized that the allopregnanolone/progesterone ratio would decrease from the follicular to luteal phase. We also hypothesized that postmenopausal women would have lower levels of progesterone and allopregnanolone but similar allopregnanolone/progesterone ratios as premenopausal women in the follicular phase. Serum fasting allopregnanolone and progesterone levels were measured by gas chromatography-mass spectrometry in ten premenopausal women at the follicular, mid-cycle, and luteal phases of the menstrual cycle and in twenty-four postmenopausal women. Although allopregnanolone and progesterone levels increased from the follicular to luteal phase, the allopregnanolone/progesterone ratio decreased 8-fold [0.33 ± 0.08 (follicular) vs 0.16 ± 0.09 (mid-cycle) vs 0.04 ± 0.007 (luteal), p = 0.0003]. Mean allopregnanolone and progesterone levels were lower in postmenopausal than premenopausal women at all menstrual cycle phases (p < 0.01). The mean allopregnanolone/progesterone ratio was similar in postmenopausal and premenopausal women in the follicular phase (0.39 ± 0.08 vs 0.33 ± 0.08, p = 0.94) but was significantly lower at mid-cycle and in the luteal phase than in postmenopausal women (p < 0.01). In conclusion, the serum allopregnanolone/progesterone ratio decreases 8-fold from the follicular to luteal phase and is lower at mid-cycle and the luteal phase than in postmenopausal women. Whether these data have implications for luteal phase and other mood disorders merits further study.

Pre-treatment peripheral biomarkers associated with treatment response in panic symptoms in patients with major depressive disorder and panic disorder: A 12-week follow-up study.

OBJECTIVE: Peripheral biomarkers have been studied to predict treatment response of panic symptoms. We hypothesized that depressive disorder (MDD) vs. panic disorder (PD) would exhibit different peripheral biomarkers, and their correlation with severity of panic attacks (PA) would also differ. METHODS: Forty-one MDD patients, 52 PD patients, and 59 healthy controls were followed for 12 weeks. We measured peripheral biomarkers along with the Panic Disorder Severity Scale (PDSS) at each visit-pre-treatment, 2, 4, 8, and 12 weeks on a regular schedule. Peripheral biomarkers including serum cytokines, plasma and serum brain-derived neurotrophic factor (BDNF), leptin, adiponectin, and C-reactive protein (CRP) were quantified using enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with MDD and PD demonstrated significantly higher levels of pre-treatment IL-6 compared to controls, but no differences were seen in plasma and serum BDNF, leptin, adiponectin, and CRP. Pre-treatment leptin showed a significant clinical correlation with reduction of panic symptoms in MDD patients at visit 5 (p=0.011), whereas pre-treatment IL-6 showed a negative correlation with panic symptom reduction in PD patients (p=0.022). An improvement in three panic-related items was observed to be positively correlated with pre-treatment leptin in MDD patients: distress during PA, anticipatory anxiety, and occupational interference. CONCLUSION: Higher pre-treatment leptin was associated with better response to treatment regarding panic symptoms in patients with MDD, while higher IL-6 was associated with worse response regarding panic symptoms in PD patients. Different predictive peripheral biomarkers observed in MDD and PD suggest the need for establishing individualized predictive biomarkers, even in cases of similar symptoms observed in different disorders.

Increased Morbidity of Major Depressive Disorder After Thyroidectomy: A Nationwide Population-Based Study in South Korea.

Background: The number of thyroidectomies in South Korea has been increasing rapidly due to extensive checkups for thyroid cancer. However, few studies have examined the association between thyroidectomy and major depressive disorder (MDD). We investigated the association between thyroidectomy and the risk of MDD. Methods: A population-based electronic medical records database from South Korea was used to identify 187,176 individuals who underwent partial or total thyroidectomy between 2009 and 2016. A self-controlled case series design and Cox regression analyses were used to identify risk factors for MDD. Results: Among the 187,176 individuals who underwent thyroidectomy, 16,744 (8.9%) were diagnosed with MDD during the observation period. Of those, 3837 (22.9%) underwent partial thyroidectomy and 12,907 (77.1%) underwent total thyroidectomy. An elevated MDD risk was found during the one-year period before thyroidectomy, with incidence rate ratios (IRRs) of 1.29 ([95% confidence interval [CI] 1.18-1.41], p < 0.0001) for subjects with partial thyroidectomy and 1.27 ([95% CI 1.21-1.33], p < 0.0001) for subjects with total thyroidectomy. After total thyroidectomy, the IRR increased for 31-60 days (IRR 1.81; [95% CI 1.59-2.06], p < 0.0001) and remained elevated for up to 540 days, whereas after partial thyroidectomy, the IRR increased for 31-60 days (IRR 1.68; [95% CI 1.32-2.13], p < 0.0001) but returned to baseline levels after 270 days. Total thyroidectomy was associated with a prolonged risk of MDD compared with partial thyroidectomy in patients with cancer, which was different from the results in patients without cancer. Conclusion: The incidence of MDD increased in the period immediately after thyroidectomy and remained high for one to two years. This study highlights the importance of relatively long-term regular psychiatric assessments in patients who undergo partial or total thyroidectomy.