Mothering and mother-child interactions in the unaffected siblings of autistic children.

AIM: To investigate parenting and mother-child interactions in unaffected siblings of autistic children. METHOD: This cross-sectional study enrolled 274 probands with a DSM-5 diagnosis of autism spectrum disorder (ASD) (87.4% male; mean [SD] age = 11 years 4 months [3 years 2 months]), their unaffected siblings (n = 274, 46.72% male; mean [SD] age = 11 years 3 months [3 years 4 months]), and 296 age-balanced and sex-balanced typically developing children (82.77% male; mean [SD] age = 11 years 3 months [2 years 8 months]). Maternal parenting styles and mother-child interactions were assessed using maternal reporting. RESULTS: Regardless of the child's age, maternal educational level, or presence of attention-deficit/hyperactivity disorder, autistic children received more overprotective and controlling parental behaviour than unaffected children. Correlates for parenting, mother-child interactions, and behavioural problems in the home setting in children with ASD and typically developing children were autistic traits, maternal anxiety and depressive symptoms, and maternal autistic characteristics; those in unaffected siblings were age, autistic traits, maternal educational level, and maternal autistic characteristics. INTERPRETATION: The diagnosis of ASD in a child can significantly influence maternal parenting behaviours, mother-child interactions, and the child's behavioural problems in the home setting. Furthermore, maternal anxiety or depressive symptoms, along with autistic characteristics in both mother and child, might shape parenting practices and exacerbate behavioural difficulties in autistic children.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), somatic and fatigue symptoms in cardiovascular diseases comorbid major depressive disorder (MDD): A randomized controlled trial.

INTRODUCTION: Cardiovascular diseases (CVDs) and major depressive disorder (MDD) are the two most disabling diseases. Patients with CVDs comorbid depression had somatic and fatigue symptoms and were associated with chronic inflammation and omega-3 polyunsaturated fatty acid (n-3 PUFA) deficits. However, there have been limited studies on the effects of n-3 PUFAs on somatic and fatigue symptoms in patients with CVDs comorbid MDD. METHOD: Forty patients with CVDs comorbid MDD (58% males, mean age of 60 ± 9 years) were enrolled and randomised to receive either n-3 PUFAs (2 g of eicosapentaenoic acid [EPA] and 1 g of docosahexaenoic acid[DHA] per day) or placebo in a 12-week double-blind clinical trial. We assessed the somatic symptoms with Neurotoxicity Rating Scale (NRS) and fatigue symptoms with Fatigue Scale at baseline, weeks 1, 2, 4, 8 and 12, as well as blood levels of Brain-Derived Neurotrophic Factor (BDNF), inflammatory biomarkers and PUFAs, at the baseline and week 12. RESULTS: The n-3 PUFAs group had a greater reduction in Fatigue scores than the placebo group at Week 4 (p =.042), while there were no differences in the changes of NRS scores. N-3 PUFAs group also had a greater increase in EPA (p =.001) and a greater decrease in total n-6 PUFAs (p =.030). Moreover, in the subgroup analyses in the younger age group (age < 55), the n-3 PUFAs group had a greater reduction on NRS total scores at Week 12 (p =.012) and NRS Somatic scores at Week 2 (p =.010), Week 8 (p =.027), Week 12 (p =.012) than the placebo group. In addition, the pre- and post-treatment changes of EPA and total n-3 PUFAs levels were negatively associated with the changes of NRS scores at Weeks 2, 4, and 8 (all p <.05), and the changes of BDNF levels were negatively associated with NRS scores at Weeks 8 and 12 (both p <.05) in the younger age group. In the older age group (age ≥ 55), there were a lesser reduction on NRS scores at Weeks 1, 2 and 4 (all p <.05), but a greater reduction on Fatigue score at Week 4 (p =.026), compared to the placebo group. There was no significant correlation between the changes of blood BDNF, inflammation, PUFAs and NRS and Fatigue scores in general and in the older age group. CONCLUSION: Overall, n-3 PUFAs improved the fatigue symptoms in patients with CVDs comorbid MDD and the general somatic symptoms in specific subpopulation of younger age patients, and perhaps via the interplay between BDNF and EPA. Our findings provide promising rationales for future studies to investigate the treatment effects of omega-3 fatty acids on fatigue and somatic symptoms of chronic mental and medical diseases.

CASP3 gene expression and the role of caspase 3 in the pathogenesis of depressive disorders.

BACKGROUND: The aim of our study was to evaluate the expression of the CASP3 gene at both mRNA and protein levels in patients with depressive disorders and to determine the impact of caspase 3 in the pathogenesis of depression; METHODS: A total of 290 subjects, including 190 depressed patients and 100 healthy controls, participated in the study. Socio-demographic and clinical data were collected, and the severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Venous blood was collected and gene expression was evaluated using RT-PCR and ELISA at the mRNA and protein levels, respectively; RESULTS: The expression of the CASP3 gene was significantly lower in depressed patients compared to healthy controls at both the mRNA and protein levels. Additionally, a positive correlation was observed between CASP3 gene expression and disease duration as well as the number of depressive episodes; CONCLUSIONS: Further studies are needed to investigate the role of caspase 3 in depressive disorders.

The now and future of ChatGPT and GPT in psychiatry.

ChatGPT has sparked extensive discussions within the healthcare community since its November 2022 release. However, potential applications in the field of psychiatry have received limited attention. Deep learning has proven beneficial to psychiatry, and GPT is a powerful deep learning-based language model with immense potential for this field. Despite the convenience of ChatGPT, this advanced chatbot currently has limited practical applications in psychiatry. It may be used to support psychiatrists in routine tasks such as completing medical records, facilitating communications between clinicians and with patients, polishing academic writings and presentations, and programming and performing analyses for research. The current training and application of ChatGPT require using appropriate prompts to maximize appropriate outputs and minimize deleterious inaccuracies and phantom errors. Moreover, future GPT advances that incorporate empathy, emotion recognition, personality assessment, and detection of mental health warning signs are essential for its effective integration into psychiatric care. In the near future, developing a fully-automated psychotherapy system trained for expert communication (such as psychotherapy verbatim) is conceivable by building on foundational GPT technology. This dream system should integrate practical 'real world' inputs and friendly AI user and patient interfaces via clinically validated algorithms, voice comprehension/generation modules, and emotion discrimination algorithms based on facial expressions and physiological inputs from wearable devices. In addition to the technology challenges, we believe it is critical to establish generally accepted ethical standards for applying ChatGPT-related tools in all mental healthcare environments, including telemedicine and academic/training settings.

Kawasaki disease in childhood and psychiatric disorders: A population-based case-control prospective study in Taiwan.

BACKGROUND: Kawasaki disease (KD) is a common childhood acute inflammatory disease and potentially triggers a chronic inflammation. Although some researches have investigated neurodevelopmental consequences following KD, the findings have been inconsistent. This is the first population-based study targeted on KD and common psychiatric disorders. OBJECTIVES: We aimed to investigate the association between KD and psychiatric disorders and hypothesized that standard anti-inflammatory treatment by intravenous immunoglobulin (IVIG) may protect against development of psychiatric disorders. METHOD: We retrieved data from Taiwan's National Health Insurance Research database (NHIRD). Patients (n = 282,513) with psychiatric disorders (the case group) during 1997-2013 were included, and the control group was matched with age, sex, income and urbanization (1:1). We calculated the prevalence of KD in both groups and estimated odd ratios (ORs) and 95% confidence intervals (CIs) in the subgroup analyses for KD in conditions of age, severity, and common psychiatric comorbidity. RESULTS: Numbers of patients with KD were 460 in the cases and 380 in the controls (p = .006), and the crude OR of KD was 1.21 times greater (95% CI = 1.06-1.39, p = .006) in the case than the control groups. KD patients without IVIG treatment (n = 126) were higher in the cases than those in the controls (n = 54), with the OR of 2.33 (95% CI = 1.70-3.21, p < .0001). Subgroup analyses showed that KD survivors were at significant risk for autism spectrum disorders (ASD) (OR = 2.15, 95% CI = 1.27-3.65; p = .005) and attention deficit and hyperactivity disorders (ADHD) (OR = 1.19, 95% CI = 1.02-1.39; p = 0.03), and a trend of increased risk for anxiety disorders (OR = 1.36, 95%CI = 0.99-1.86; p = 0.05). CONCLUSIONS: Patients with KD were more likely to have comorbid psychiatric disorders, including ASD and ADHD. Moreover, anti-inflammatory treatment with IVIG may have potential prophylactic effects against the development of psychiatric disorders.

Genetic Variations of Ionotropic Glutamate Receptor Pathways on Interferon-α-induced Depression in Patients with Hepatitis C Viral Infection.

IMPORTANCE: The most supportive evidence of the inflammation theory of depression is that up to one-third of patients with Hepatitis C virus infection (HCV) develop clinical depressive episodes during interferon-α (IFN-α) therapy. As glutamate-mediated excitotoxicity has been found to be a consequence of excessive inflammation and a pathogenic mechanism of depression, it is plausible to investigate genes on ionotropic glutamate receptor pathways. OBJECTIVE: To identify the at-risk genetic variations on ionotropic glutamate receptor pathways for interferon-α-induced depression. METHOD: We assessed 291 patients with chronic HCV undergoing IFN-α therapy and analyzed the single nucleotide polymorphisms (SNPs) in genes related to ionotropic glutamate receptors in this prospective case-control study. Patients who developed IFN-α-induced depression anytime during the treatment were defined as the case group, while those who did not were defined as the control group. Genomic DNA was extracted from peripheral blood and analyzed by Affymetrix TWB array. Allelic and haplotype association tests were conducted using χ2 tests to assess the difference in allele and haplotype frequencies between cases and controls. Additionally, we performed 5000 permutations to control gene-wide family-wise error rates and create empirical p-values. Stratified analyses were then done to control for confounders and adjust odds ratios for our significant SNPs. We also did an additional stratified analysis to re-assess genes with near-significant SNPs (empirical p-value=0.05-0.10), employing Bonferroni correction with the effective number of independent tests to control gene-wide family-wise error rates. RESULTS: The minor and major allele frequencies of rs7542 (empirical p-value=0.0310) in MAPK3, rs3026685 (empirical p-value=0.0378) in PICK1, rs56005409 (empirical p-value=0.0332) in PRKCA, rs12914792 (empirical p-value=0.0096), rs17245773 (empirical p-value=0.0340) in RASGRF1, and rs78387863 (empirical p-value=0.0086), rs74365480 (empirical p-value=0.0200) in RASGRF2 were found significantly different between cases and controls. Haplotype association tests also revealed one significant haplotype in PRKCA (empirical p-value=0.0200) and one in RASGRF1 (empirical p-value=0.0048). Stratified analyses showed no signs of confounders for most of our significant SNPs, except for rs78387863 in RASGRF2. After a re-assessment of our near-significant genes by stratified analyses, two SNPs in GRIN2B turned significant. CONCLUSIONS: This study provided supportive evidence of the involvement of the RAS/RAF/mitogen-activated protein kinase (MAPK) signaling pathway and glutamate ionotropic receptor AMPA type subunit 2(GluR2) transportation in the pathogenesis of IFN-α-induced depression.

Nutrition and immunology in mental health: Precision medicine and integrative approaches to address unmet clinical needs in psychiatric treatments.

The 'monoamine hypothesis' is insufficient in approaching the aetiology of psychiatric disorders or in developing novel therapies. Accumulating evidence suggests that inflammatory regulation plays an important role in pathophysiology and therapeutic mechanism across the major psychiatric disorders. "Inflammation theory" might not be the full answer for the big picture of mental disorders, but it might explain high occurrence of somatic symptoms and comorbidity of physical illness in certain subtypes of the heterogeneous groups. Due to the complexity of clinical manifestations and bio-psycho-social etiology, each single treatment shows only small effectiveness with limited effect sizes when compared with placebo. Unfortunately, clinicians are still struggling with trial-and-error practice without any reliable clinical or biological markers to predict therapeutic responses. Therefore, it is important to open up our minds to integrative approaches such dietary modification and nutraceutical prescription. In this special issue, we included 15 papers discussing the role of nutrition (blueberries, omega-3 polyunsaturated fatty acids, melatonergic agonist, S-Adenosyl-L-Methionine, Cannabidiol and Kratom) in the context of immunoregulation across different psychiatric disorders from depression, bipolar disorders, and schizophrenia to alcohol-induced dementia and anorexia nervosa. Moreover, we also included research in perinatal depression that highlight the role of estradiol and the component of breast milk and the association with the neurodevelopment of the offspring. In addition, several articles focused on the role of microbiota in mental health and pain as recent research has pointed to the gut-brain axis as a main regulator of brain, behaviour and immunity. Lastly, inflammatory mechanisms underlying psychiatric disorders including alcohol induced dementia and anorexia nervosa are also highlighted in the special issue.

Melatonergic agonist regulates circadian clock genes and peripheral inflammatory and neuroplasticity markers in patients with depression and anxiety.

OBJECTIVE: Circadian dysfunction is a core manifestation and a risk factor for psychiatric disorders. Ramelteon (RMT), a melatonin receptor agonist, has been shown to induce sleep phase shifts and has been used to normalize sleep onset time. RMT has been used in sleep disorders, depression and anxiety. In this study, we aimed to investigate the effects of RMT in regulating gene expression profiles of the circadian clock and peripheral markers of inflammation and neuroplasticity. METHODS: Sixteen patients with a diagnosis of primary insomnia comorbid with depression and anxiety and ten healthy controls were recruited in an 8-week open-label trial. The patients with primary insomnia received RMT 8 mg/day. The morning expression profiles of 15 core clock genes from peripheral blood mononuclear cells (PBMCs), urine and plasma levels of melatonin and its metabolite levels, and plasma inflammatory markers and neurotrophin levels were evaluated at baseline, 4th and 8th week of RMT treatment. RESULTS: RMT treatment was associated with significant clinical improvement in depression scores at 8th week (Hamilton depression rating scale scores (Mean ±â€¯SEM) from 21.5 ±â€¯2.44 to 14.31 ±â€¯2.25, p ≤ 0.05). The overall poor sleep quality (Pittsburgh sleep quality index) of the patient group significantly improved (p ≤ 0.05) following RMT treatment. The mRNA level analysis showed a significant association between RMT treatment and alterations of the nine core circadian genes (CLOCK, PER1, PER2, CRY1, CRY2, NR1D1, NR1D2, DEC1 and TIMELESS) in the patient group when compared with the control group (p ≤ 0.05). Compared with the controls, the patient group had a decrease in neurotrophins (brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and beta-nerve growth factor; p ≤ 0.05) but an increase in pro-inflammatory cytokine levels (interleukin-6, interleukin-1b, tumour necrosis factor-alpha and interferon gamma; p ≤ 0.05); RMT treatment normalized the levels of neurotrophins and cytokine levels. CONCLUSION: RMT treatment is able to restore phase-shifted melatonin markers, normalized the altered expression of the circadian genes, the levels of inflammatory cytokines and neurotrophins in patients with insomnia comorbid anxiety and depression.

Cortisol, inflammatory biomarkers and neurotrophins in children and adolescents with attention deficit hyperactivity disorder (ADHD) in Taiwan.

BACKGROUND: Hypothalamus-Pituitary-Adrenal (HPA) axis dysregulation, inflammation and imbalance of neurotrophins have been suggested in attention deficit hyperactivity disorder (ADHD), but the results have not been conclusive. The aim of this study is to investigate the levels of salivary cortisol across 4-time points during the day, and of morning plasma inflammatory biomarkers and neurotrophins, in youth with ADHD and in typically developing youth (TD), with stratification by age, ADHD subtypes and oppositional defiant disorder (ODD) comorbidity in Taiwan. METHODS: We conducted a case-control study measuring saliva cortisol levels at 4 different time points during the day (at awakening, noon, 1800 h and bedtime) and morning plasma levels of inflammatory and neurotrophins biomarkers in youth with ADHD (n = 98, age 6-18 years old with mean age 9.32 ± 3.05 years) and TD (n = 21, age 6-18 years old with mean age 9.19 ± 2.96 years) in Taiwan. RESULTS: Our study showed that youth with ADHD had lower levels of bedtime salivary cortisol (effects size (ES) = -0.04, p = .023), with children with the combined form of the disorder (with inattention, hyperactivity and impulsivity all present) having the lowest awakening salivary cortisol levels. ADHD youth also had higher levels of plasma high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 (ES = 0.85-1.20, p < .0001), and lower plasma tumor necrosis factor-alpha (ES = -0.69, p = .009) and brain-derived neurotrophic factors (BDNF) (ES = -1.13, p < .0001). Both ADHD groups regardless of ODD comorbidity had higher levels of IL-6 (p < .0001) and lower levels BDNF (p < .0001). CONCLUSION: The lower bedtime salivary cortisol levels and higher levels of inflammatory biomarkers in youth with ADHD further support the role of abnormal HPA axis and inflammation in ADHD. Moreover, the lower levels of BDNF in ADHD also indicate that BDNF may be a potential biomarker in this disorder that is part of a broader biological dysfunction.

Depression-free after Interferon-α exposure indicates less incidence of depressive disorder: A longitudinal study in Taiwan.

BACKGROUND: IFN-α-induced depression in patients undergoing hepatitis C virus (HCV) treatment provides powerful support for the inflammation hypothesis of depression. Most studies have focused on the occurrence of depressive symptoms, but there has been no study yet in depression-free HCV patients receiving IFN-α. We hypothesized that HCV patients who did not develop depression after IFN-α exposure might have a lower incidence of depressive disorders after the IFN-α treatment. METHODS: We conducted a twelve-year population-based cohort study of chronic HCV patients who received IFN-α therapy. The data were obtained from the Taiwan National Health Insurance Research Database. The study cohort was patients without any depressive disorder nor antidepressant use before and during IFN-α therapy. They were matched randomly by age, sex income and urbanization at a ratio of 1:4 with the control cohort of HCV patients without IFN-α therapy. The follow-up started after the last administration of IFN-α, and the primary outcome was the incidence of depressive disorders after IFN-α therapy. RESULTS: A total of 20,468 depression-free subjects were identified from records of HCV patients receiving IFN-α therapy. Patients without IFN-α-induced depression were associated with a significantly lower incidence (per 10,000 person-years) of new-onset depressive disorders (126.8, 95% Confidential Interval [CI] of 118.5-135.6) as compared to the control cohort (145.2, 95% CI of 140.0-150.6) (p < 0.001). After adjusting for age, sex, income, urbanization and comorbid diseases, the crude hazard ratio for the incident depressive disorder was 0.87 (95% CI, 0.80-0.87) and the adjusted hazard ratios was 0.79 (95% CI, 0.72-0.87) for IFN-α-induced depression-free subjects as compared to the controls. DISCUSSION: Our study indicates that IFN-α treated depression-free patients have a lower risk for depressive disorders. This hypothesized mechanism might derive from an IFN-α-induced resilience factor as yet to be defined. CONCLUSIONS: Our study might suggest a new possibility for a new pharmacological strategy against depression.

Omega-3 polyunsaturated fatty acids in cardiovascular diseases comorbid major depressive disorder - Results from a randomized controlled trial.

INTRODUCTION: Cardiovascular diseases (CVDs) and major depressive disorder (MDD) will be the two most disabling diseases by 2030. Patients with CVDs comorbid depression had lower levels of total omega-3 polyunsaturated fatty acids (n-3 PUFAs), docosahexaenoic acid (DHA), and a higher omega-6 to omega-3 ratio. However, there have been limited studies on the effects n-3 PUFAs on MDD in patients with CVDs. METHOD: We have enrolled a total of 59 patients (64% males, mean age of 61.5 ±â€¯9.0 years and mean education of 10.2 ±â€¯4.2 years) with CVDs comorbid MDD. They were randomized into either receiving n-3 PUFAs (2 g per day of eicosapentaenoic acid (EPA) and 1 g of DHA) or placebo for 12 weeks. We assessed depression symptom severity with Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory (BDI), as well as blood fatty acid levels, electrocardiogram and blood biochemistry, at the baseline and at the endpoint. RESULTS: There were no differences between the n-3 PUFAs and placebo group in the changes of HAMD and BDI total scores, while PUFAs group had a greater reduction in HAMD Cognition subscale scores than the placebo group at week 8 (p < 0.05). Moreover, subgroup analyses found that the n-3 group had a greater reduction of HAMD Core subscale scores than the placebo group at the end of week 12 (p < 0.05) for the very severe DEP group (HAMD ≥ 23). CONCLUSION: Overall, n-3 PUFAs did not show a beneficial effect on depressive symptoms when compared with placebo. However, when stratified with depression severity, n-3 PUFAs supplementation improved core depression symptoms in the very severe MDD group. N-3 PUFAs supplementation may provide a treatment option for a subpopulation of patients with CVDs comorbid MDD.

Plasma estradiol levels and antidepressant effects of omega-3 fatty acids in pregnant women.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) reduce depressive symptoms through an anti-inflammatory effect, and injection of both omega-3 PUFAs and estradiol (E2) induces antidepressant-like effects in rats by regulating the expression of inflammatory cytokines. The aims of this study were to examine the association of increased E2 during pregnancy with depressive symptoms and with inflammatory cytokines in women who were and were not supplemented with omega-3 PUFAs. METHODS: Pregnant women with Edinburgh Postnatal Depression Scale scores ≥9 were recruited at 12-24 weeks of gestation. The participants were randomly assigned to receive 1800 mg omega-3 fatty acids (containing 1206 mg eicosapentaenoic acid [EPA]) or placebo for 12 weeks. E2, omega-3 PUFAs, high-sensitivity C-reactive protein, interleukin-6, and adiponectin were measured at baseline and at the 12-week follow-up. Multivariable regression analyses were conducted to examine the association of the changes of E2 and omega-3 PUFAs with the changes in depressive symptoms and with the changes of inflammatory cytokines at follow-up by intervention group. RESULTS: Of the 108 participants in the trial, 100 (92.6%) completed the follow-up assessment including blood sampling. Multivariable regression analyses revealed that the increase of EPA and E2 was significantly associated with a decrease in depressive symptoms among the participants assigned to the omega-3 group, but not among those assigned to the placebo group. Neither E2 nor any PUFAs were associated with a change in inflammatory cytokines. CONCLUSION: Supplementation with EPA and increased levels of E2 during pregnancy might function together to alleviate antenatal depression through a mechanism other than anti-inflammation.

Micromolar concentrations of citalopram or escitalopram inhibit glycoprotein VI-mediated and integrin αIIbß3-mediated signaling in human platelets.

Collagen and convulxin induce platelet aggregation through glycoprotein VI (GPVI)-FcRγ-Syk signaling pathway. In addition, fibrinogen induces platelet activation through integrin αIIbß3-FcγRIIa-Syk signaling pathway. We previously reported that high concentrations of selective serotonin reuptake inhibitors (SSRI) reduce platelet aggregation induced by collagen. We further investigated the effects of SSRI on GPVI- and αIIbß3-mediated signaling pathway. Citalopram and escitalopram, two relatively pure SSRI, were used in this study. Both citalopram and escitalopram concentration-dependently inhibited convulxin-induced platelet aggregation, serotonin (5-HT) release and the activation of αIIbß3. 5-HT concentration in washed platelets was unchanged after short-term treatment with citalopram. The additional 5-HT failed to fully rescue the inhibitory effect of citalopram on convulxin-induced aggregation. Convulxin-induced phosphorylation of Syk, LAT, and Akt was inhibited by citalopram and escitalopram. Citalopram inhibited the interaction between FcRγ and Syk, whereas the phosphorylation of FcRγ in response to convulxin remained unaltered. Further, citalopram inhibited the increase of the interaction between serotonin transporter and Syk induced by convulxin. In the presence of Mn2+, escitalopram inhibited the formation of lamellipodia on immobilized fibrinogen. Escitalopram did not influence the binding of fibrinogen to platelets. It inhibited the phosphorylation of Syk and PAK triggered by the adhesion on fibrinogen. Our data demonstrate that micromolar concentrations of citalopram and escitalopram inhibit GPVI- and αIIbß3-mediated platelet functions. The mechanism of the inhibitory effect of citalopram or escitalopram is not the influence on the activation of GPVI or the interaction between fibrinogen and αIIbß3, but the interaction between Syk and its upstream molecules.

Interferon-alpha-induced depression: Comparisons between early- and late-onset subgroups and with patients with major depressive disorder.

Interferon (IFN)-alpha, until recently the standard treatment of hepatitis C virus (HCV) infection, is associated with a significant risk of major depressive episode (MDE, or IFN-alpha-induced depression). However, it is little studied the comparisons of clinical manifestations between IFN-alpha-induced depression and major depressive disorder (MDD). In addition, IFN-alpha induces different neuroinflammation and neuroendocrine status throughput the HCV treatment course; however, the clinical presentations have never been compared between early-onset and later-onset IFN-alpha-induced depression. We assessed 200 HCV patients starting IFN-alpha therapy bi-weekly for 24 weeks, with the structured interview for confirmation of diagnosis of IFN-alpha-induced depression and with clinical rating scales for depressive symptoms and neuropsychiatric symptoms. Subjects developed IFN-alpha-induced depression (n = 59, 30%) during the first 6 weeks of IFN-alpha therapy were defined as the early-onset group (n = 32), while those developed depression after the 6th week were defined as the late-onset group (n = 27). A matched group of MDD patients (n = 60) was used to compare specific clusters of depressive symptoms with early- and late-onset IFN-alpha-induced depression. Compared to the matched group of MDD patients, IFN-alpha-induced depression was significantly associated with more somatic symptoms and fewer symptoms of mood, anxiety and negative cognition. More somatic symptoms were also found in those who became clinically depressed at early stage of IFN-alpha therapy. We suggest that the specific somatic features of interferon-alpha-induced depression, and especially of early-onset depression, characterise individuals who are more sensitive to cytokines-induced changes in mood.

Clinical Efficacy and Biological Regulations of ω-3 PUFA-Derived Endocannabinoids in Major Depressive Disorder.

BACKGROUND: Endocannabinoids (ECs) are one type of bioactive endogenous neuroinflammatory mediator derived from polyunsaturated fatty acids (PUFAs), which may regulate the emotional processes. Here, we assessed the effect of ω-3 PUFAs on EC levels, which may be the novel targets for the ω-3 PUFAs' antidepressive effects. METHODS: We conducted a 12-week double-blind, nonplacebo, randomized controlled trial. Eighty-eight major depressive disorder (MDD) participants were randomly assigned to receive eicosapentaenoic acid (EPA, 3.0 g/day), docosahexaenoic acid (DHA, 1.4 g/day), or a combination of EPA (1.5 g/d) and DHA (0.7 g/day). Eighty-five participants completed the trial, and their clinical remission and plasma PUFA-derived EC levels (pmol/mL) were measured. RESULTS: The cumulative rates of clinical remission were significantly higher in the EPA and EPA + DHA groups than the DHA group (51.85 and 53.84 vs. 34.37%; p =0.027 and p =0.024, respectively). EPA and EPA + DHA treatments increased the eicosapentaenoylethanolamide (EPEA) levels compared to DHA treatment (0.33 ± 0.18 and 0.35 ± 0.24 vs. 0.08 ± 0.12; p =0.002 and p =0.001, respectively), while EPA + DHA treatment increased the docosahexaenoylethanolamide levels more than EPA treatment (1.34 ± 2.09 vs. 0.01 ± 1.79; p =0.006). Plasma EPEA levels were positively correlated with rates of clinical remission (hazard ratio: 1.60, 95% confidence interval: 1.08-2.39). CONCLUSIONS: Treatments enriched with EPA increased plasma EPEA levels, which was positively associated with clinical remission. This finding may suggest that levels of plasma EPEA play a potential novel endogenous therapeutic target in MDD.

Differences between Japan and Taiwan in the treatment of pregnant women with depressive symptoms by omega-3 fatty acids: An open-label pilot study.

OBJECTIVES: Although safe approaches for improving depression in pregnancy are required and the efficacy of omega-3 polyunsaturated fatty acids (PUFAs) has been suggested, the amount of supplemental omega-3 PUFAs has varied among previous studies and adequate amount might be different among countries. The aim of this pilot study is to explore the feasibility of using 1800 mg of omega-3 PUFAs supplementation for our future double-blind, placebo-control trial, and to clarify the clinical difference and the similarity between two sites of Japan and Taiwan. METHODS: Pregnant women between 12 and 24 weeks' gestation with depressive symptoms were recruited. Participants were supplemented daily with omega-3 PUFAs capsules containing 1206 mg eicosapentaenoic acid and 609 mg docosahexaenoic acid for 12 weeks. The primary outcome was change in total score on the 17-item Hamilton Rating Scale for Depression (HAMD) at 12 weeks after supplementation. RESULTS: Eight pregnant women in Japan and five in Taiwan participated in the study. A substantial proportion of pregnant women reported high consumption of omega-3 supplements and dietary fish were excluded in Taiwan rather than in Japan sites. The decrease in HAMD score from baseline to 12 weeks after the start of the intervention was significantly larger in Japanese participants than in Taiwanese participants (Wilcoxon rank sum test; P = 0.045). DISCUSSION: The improvement of depressive symptoms was smaller at the Taiwan site than at the Japan site. Differences in psychopathology of recruited participants identified by self-rating scales might affect the degree of population heterogeneity and the treatment efficacy. A randomized-controlled trial is needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01948596.

Polyunsaturated fatty acids levels and initial presentation of somatic symptoms induced by interferon-alpha therapy in patients with chronic hepatitis C viral infection.

OBJECTIVES: Somatic symptoms are common in depressive disorder and are similar to sickness behaviors due to inflammatory activation after cytokine administration. Omega-3 polyunsaturated fatty acids (PUFAs) are natural anti-inflammatory agents and may reduce inflammation-induced behavioral changes. The aim of this study was to investigate the role of PUFAs on the development of somatic symptoms and depression in patients of hepatitis C virus infection (HCV) receiving interferon-alpha therapy (IFN-α) in a prospective manner. METHODS: In this 24-week, prospective cohort study, 43 patients with chronic HCV ongoing IFN-α therapy were assessed with the mini-international neuropsychiatric interview for major depressive episodes and neurotoxicity rating scale (NRS) for somatic symptoms. RESULTS: One-third later developed IFN-α-induced depression (depression (DEP) group). As compared to subjects without depression, DEP group had higher NRS scores (P < 0.001), lower eicosapentaenoic acid (EPA) levels (P = 0.038) at week 2. Somatic symptoms, regardless of painful/non-painful characteristics, had positive association with arachidonic acid (P < 0.05), and negative association with EPA (P < 0.05). CONCLUSION: This study implies that early intervention with omega-3 PUFAs might be a promising strategy to prevent depression and somatic symptoms in patients receiving cytokine therapy.

Polyunsaturated fatty acids (PUFAs) levels in patients with cardiovascular diseases (CVDs) with and without depression.

BACKGROUND: Cardiovascular diseases (CVDs) are commonly comorbid with depression and vice versa. Polyunsaturated fatty acids (PUFAs) have been suggested to mediate in CVDs and depression in cross-sectional and observational studies. With the patients of CVDs, we investigated the role of depression on the effect of PUFAs. METHODS: Forty-four patients with CVDs were recruited and assessed with Hamilton depression rating scale (HAMD). Patients' CVDs markers were measured by electrocardiogram and their red blood cell (RBC) samples were collected for PUFAs analyses. RESULTS: The data of 44 subjects were analyzed; where 10 participants (23%) with CVDs had moderate or severe depression, defined by a HAMD score more than 19 points. The moderate depression group had lower docosahexaenoic acid (DHA), omega-3 (N3) and omega-6(N6) to N3 (N6/N3) ratio than non-depression group (HAMD score less than 8), while no differences between the 2 groups in terms of corrected QT (QTc) intervals and high sensitivity C-reactive protein (hsCRP) levels. Furthermore, when we analyzed the data with an inclusion of a more heterogeneous depression group, where HAMD score is greater than or equal to 10 (mild depression group, N=24), the differences in PUFAs levels between the 2 groups disappear. Secondary analysis of the moderate depression group showed a positive correlation between DHA, N3 PUFAs, and N6/N3 ratio and total HAMD scores, a positive correlation between N3 PUFAs and QTc intervals in non-depression group. CONCLUSION: Moderate depression group of patients with CVDs had lower levels of DHA, N3, and N6/N3 ratio than non-depression group, while both groups had no differences in QTc and hsCRP. On the other hand, the differences in PUFAs levels disappear in the mild depression group after inclusion of patients with CVDs with greater heterogeneity of depression. Hence, the role of N3 PUFAs is implicated in depression of patients with CVDs if the depression status is more strictly defined.

Addressing methodological concerns in omega-3 trial for bipolar disorder relapse prevention.

Our response addresses concerns raised about our pilot trial on omega-3 for bipolar disorder. We clarify randomization procedures, highlight the benefits of eicosapentaenoic-predominant formulations for a specific bipolar patients subgroup, and justify the use of Kaplan-Meier analysis despite limitations. We acknowledge analytical challenges due to strict inclusion criteria and encourage future research on specific bipolar subtypes and larger-scale trials for robust validation.