BackgroundTraumatic brain injury (TBI) is one of the leading causes of mortality and disability, with many patients developing long-term sequelae. Depression is among the most common psychiatric complications following TBI, yet its underlying mechanisms remain unclear. Transient receptor potential canonical 1 (TRPC1) has been implicated in neurological disorders, but its role in post-TBI depression is not well understood.MethodsA controlled cortical impact (CCI) model was used to induce moderate TBI in mice. At 4 weeks post-injury, depressive-like behaviors were assessed using the tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT). Subsequently, reactive astrocytes and microglia were quantified, along with the expression of inflammatory cytokines, in the ipsilateral hippocampus. Synaptic function was also evaluated.ResultsBehavioral tests revealed that TBI mice exhibited significant depressive- and anxiety-like behaviors at 4 weeks post-injury. Concurrently, TRPC1 expression was downregulated in the ipsilateral hippocampus, accompanied by reduced levels of synaptic-associated proteins, elevated pro-inflammatory cytokines, and increased reactive astrocytes and microglia. Further experiments demonstrated that TRPC1 overexpression attenuated neuroinflammation, restored synaptic function, and ameliorated depressive-like behaviors in TBI mice.ConclusionThis study suggests that TBI may trigger depression by downregulating TRPC1, thereby promoting neuroinflammation and synaptic dysfunction. Conversely, TRPC1 overexpression mitigates these effects, highlighting its potential as a therapeutic target for post-TBI depression.
Integrating evidence-based health approaches in U.S. healthcare settings: addressing the syndemics of poverty, health, and violence
Health disparities in the United States are not produced by single risk factors but by interacting social and biological conditions that cluster within structurally marginalized communities. Poverty, violence, and poor physical and mental health form a reinforcing system of disadvantage that traditional healthcare models—organized around isolated diseases—are poorly equipped to address. This perspective examines these dynamics through a syndemic framework, which conceptualizes co-occurring conditions as mutually interacting epidemics intensified by social inequality. Drawing on interdisciplinary evidence from public health, medicine, and social science, we describe how poverty-related stressors such as housing instability, food insecurity, and barriers to healthcare intersect with exposure to interpersonal and structural violence to amplify risks for depression, posttraumatic stress disorder, chronic disease, and premature mortality. These interactions produce compounded health burdens that are disproportionately experienced by marginalized populations. Despite increasing attention to social determinants of health, current healthcare responses remain fragmented. Health systems frequently identify risks through screening for social needs or trauma exposure but lack the institutional infrastructure, reimbursement mechanisms, and cross-sector partnerships required to address them effectively. We argue that advancing health equity requires moving beyond additive models of care coordination toward syndemic-informed healthcare systems that intervene simultaneously on clustered conditions and their shared upstream drivers. We outline key priorities for practice, policy, and research, including linking screening to actionable care pathways, strengthening partnerships between healthcare and social service systems, and expanding workforce training to include structural and syndemic competency.
Baseline Mismatch Negativity Amplitude Predicts Direction and Magnitude of Ketamine Effect in Healthy Volunteers — A “Disordinal” Effect
Mismatch negativity (MMN) is a component of the auditory event-related potential (ERP) that is elicited during a passive oddball paradigm where task-irrelevant infrequent deviants are presented in a stream of more frequent standard stimuli. MMN is believed to index a pre-attentive stage of auditory information processing closely linked to N-methyl-D-aspartate receptors (NMDAR) function. Ketamine is thought to act primarily as an NMDAR antagonist, has been used in clinical trials to model the symptoms of schizophrenia and is increasingly used in the clinic to treat depression.
[Comment] Magnetic seizure therapy: balancing efficacy and cognition
Few treatments in psychiatry match the antidepressant efficacy of convulsive therapy. Yet despite this therapeutic potency, persistent stigma and concerns about cognitive adverse effects—particularly autobiographical memory disturbance associated with electroconvulsive therapy, ECT—continue to limit its wider adoption.1 This tension is especially consequential in treatment-resistant depression (TRD), where convulsive therapies remain among the most effective treatments.2
Pregnancy Sickness Study Identifies New Genetic Links
The University of Southern California (USC) research team that identified the hormone-encoding gene GDF15 as a key driver of pregnancy sickness has identified nine additional genes linked to its most severe form, hyperemesis gravidarum (HG). Six of the identified genes had not been previously linked to the condition.
The Keck School of Medicine of USC team and international collaborators conducted a genome-wide association study (GWAS), scanning the entire genome for differences between women who developed HG during pregnancy and those who did not. They analyzed data from more than 10,000 women with the condition and more than 450,000 controls across European, Asian, African, and Latino ancestries. Their findings offer new clues about the condition and new hope for those affected.
Marlena Fejzo, PhD, a clinical assistant professor of population and public health sciences in the Center for Genetic Epidemiology at the Keck School of Medicine, led the present study and earlier research linking GDF15 to HG. Fejzo told GEN, “The study is much larger than previous studies and on a more diverse population allowing for identification of new genes associated with HG … The new genes give us new directions to explore for prediction, diagnosis, treatment, and response to therapies.”
Fejzo is first author of the team’s published report in Nature Genetics (“Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting”), in which the team stated, “Potential roles for candidate genes in appetite, insulin signaling, and brain plasticity provide pathways to explore etiological mechanisms and therapeutic avenues.”
HG, which affects about 2% of women, causes nausea and vomiting so severe that eating can become extremely difficult. “Most pregnancies are affected by nausea and vomiting (NVP), but in 0.3–10.8% of pregnancies the symptoms can be severe enough to cause maternal weight loss and adverse maternal and fetal outcomes,” the authors wrote. HG in its most severe form can even be life threatening.
HG was long misunderstood and often dismissed as psychological, growing evidence shows that it has a strong biological and genetic basis and can lead to severe malnourishment, putting both mother and baby at risk. Current treatments for HG are frequently ineffective in improving patient symptoms, the authors further pointed out, and so increase the risk of pregnancy termination, postpartum depression, and suicidal ideation, along with other maternal and offspring comorbidities. “Therefore, understanding of HG etiology is critical to begin to address the negative impact severe NVP has on maternal and child health.”
While historical hypotheses have previously centered around human chorionic gonadotropin (hCG), recent large-scale genetic studies have implicated the GDF15 gene encoding growth differentiation factor-15—a hormone associated with nausea and vomiting, the authors further pointed out. Earlier research by Fejzo and an international team had shown that the link between HG and GDF15 lies in women’s sensitivity to the hormone. They found that women exposed to lower levels of the hormone before pregnancy because of a mutation in the gene experience more severe symptoms, while women exposed to higher levels of the hormone before pregnancy have less severe nausea and vomiting symptoms.
“GDF15 was identified as the greatest genetic risk factor for HG in both a genome-wide and an exome-wide association study, and a rare mutation in GDF15 was associated with a greater than tenfold increased risk for HG,” the scientists noted in their newly reported study. Fejzo explained to GEN, “The mutation in GDF15 is rare. People who carry the mutation have abnormally low levels of GDF15 when they are not pregnant and that increases their risk of being hypersensitive to it during pregnancy when it is produced in massive amounts by the placenta.”
Commenting on their prior work implicating a role for GDF15 and HG, Fejzo further explained to GEN, “In our first GWAS study we found the association between the GDF15 gene and HG. Next, we published a whole-exome sequencing study that identified a mutation in GDF15 associated with HG. Then we published our study in Nature which provided strong evidence that hypersensitivity to the rise of GDF15 in pregnancy (due to low pre-pregnancy GDF15 in circulation) is the main driver of the condition.”
For their newly reported study the researchers carried out a multi-ancestry genome-wide association study of 10,974 HG/excessive vomiting in pregnancy cases and 461,461 controls across European, Asian, African, and Latino ancestries from nine contributing studies.
The results identified 10 genes that were linked to HG, including four that had previously been identified, and six new genes. “Because this is the largest study of HG ever conducted, we’ve been able to tease out important new details that were previously unknown,” said Fejzo. “The fact that we’ve studied women from multiple ancestry groups suggests that these results may be generalizable across a broad population.”
The four genes previously identified were growth differentiation factor 15 (GDF15), GFRAL, which produces the receptor for the GDF15 hormone of the same name, and IGFBP7 and PGR, both of which are involved in development of the placenta. The strongest link by far was to GDF15, which rises sharply during pregnancy. “We know that GDF15 and it’s receptor GFRAL are the main drivers and are in a signaling pathway that causes aversions, nausea, and vomiting,” Fejzo told GEN. “More work needs to be done to explore the other associations, but since studies suggest manipulating progesterone and/or IGFBP7 may not be safe in pregnancy, current studies are focusing on the GDF15 pathway.”
The six newly identified genes offer further clues that might help explain the basis of HG or point to new ways of treating it. They include FSHB, TCFL72 SLITRK1, SYN3, IGSF11, and CDH9. “Now that we’ve more than doubled the genes associated with HG, we can dig deeper into the biology behind this condition, as well as new possible pathways for treating it,” Fejzo said. Speaking to GEN, the researchers noted, “Because the new associations are novel, we need to understand the roles they may play in normal pregnancy and then compare that to pregnancies affected by HG.”
Of the newly identified genes, TCF7L2 stands out because it is one of the strongest genetic risk factors for type 2 diabetes and is also associated with gestational diabetes. “This is a brand-new target, and it’s not yet clear what it’s doing in pregnancy,” Fejzo said. In further commentary to GEN, Fejzo added, “The TCF7L2 gene is a type 2 diabetes-associated gene and a transcription factor that may control glucagon-like peptide-1 (GLP-1) expression and has been associated with liraglutide effects resulting in greater weight loss in obesity. So understanding its role in that rapidly evolving therapeutic arena has potential.”
Several of the other genes identified are involved in appetite and nausea, as well as brain plasticity, or how the brain learns and adapts to new information. Fejzo suggests the brain may learn to associate certain foods with feeling sick, leading to strong, lasting aversions during pregnancy. More research is needed to explore this possibility. “Other genes are associated with learning flexibility so we hypothesize that they may play a role in conditioned taste aversion and may provide new targets to alter or dampen learned aversions,” Fejzo told GEN. Historically, people believed the pregnancy hormone hCG was the cause, but we found no evidence to support that and instead, fascinatingly, we found a link to the follicle stimulating hormone receptor.”
Of the ten candidate genes six—GDF15, GFRAL, IGFBP7, PGR, TCF7L2 and SYN3—have been linked with cachexia—a wasting condition with similar symptoms to HG, including loss of appetite, weight loss and muscle wasting, the scientists noted. “Manipulation of GDF15, GFRAL, IGFBP7, PGR and TCF7L2 in animal models has shown effectiveness in reducing symptoms of cachexia. Thus, assuming analogous functions for these factors in HG, there is both genetic and biological support for causal and potentially reversible contributions for these genes in NVP.”
The researchers also found that some genes linked to HG were associated with other pregnancy outcomes. “This study also identified individual associations between risk genes and adverse outcomes including shorter pregnancy duration, pre-eclampsia, and birth weight,” they noted.
Several medications are available for treating HG, but even the most effective, Zofran, only partly relieves symptoms for about half of patients. The new findings reveal new potential treatment targets and could possibly also help match existing medications to patients based on their genetic profiles. “The ten genetic associations provide intriguing avenues to advance our understanding and pursue therapeutic pathways for a common pregnancy condition that in its most severe form is associated with substantial morbidity and even mortality for mothers and exposed offspring,” the scientists concluded.
Fejzo and her team just received approval to launch a clinical trial of metformin, a widely used diabetes medicine that increases GDF15 levels. The study will test whether taking metformin before pregnancy can desensitize women to the hormone, potentially reducing nausea and vomiting or preventing HG in women who have had it before. GEN was told, “We will be initiating a clinical trial to increase GDF15 prior to pregnancy in patients with a history of HG and planning to conceive to desensitize them to the hormone’s rapid rise in early pregnancy. We and others have shown preliminary evidence that this approach may work as in our retrospective study pre-pregnancy metformin use was associated with a significant reduction in HG risk.”
The post Pregnancy Sickness Study Identifies New Genetic Links appeared first on GEN – Genetic Engineering and Biotechnology News.
<![CDATA[Bupropion may cause dose-linked tinnitus; this case shows symptoms improve after dose reduction, helping manage depression without stopping treatment.]]>
<![CDATA[How clinicians choose TRD care: patient preferences, access barriers, and rapid glutamatergic options like esketamine for suicidal depression.]]>
Early tinnitus burden and subjective hearing are candidate markers of 2-year quality of life after cochlear implantation in single-sided deafness
BackgroundCochlear implantation is a common treatment for adults with single-sided deafness (SSD), but patient-reported benefits vary. The relationships among tinnitus burden, perceived hearing ability, psychological distress, disease-specific health-related quality of life, and whether early postoperative outcomes predict later results are not well understood.ObjectiveThis study explores how disease-specific quality of life relates to tinnitus burden, hearing, stress, depression, and anxiety after cochlear implantation in SSD. It also seeks early markers linked to 2-year outcomes.MethodsThis secondary complete-case analysis was based on a previously reported prospective longitudinal SSD cohort. Of 70 adults with postlingual SSD, 36 (51.4%) had complete Nijmegen Cochlear Implant Questionnaire (NCIQ) data at baseline and at 6 months, 1 year, and 2 years after unilateral cochlear implantation and were included. Additional measures included the Tinnitus Questionnaire (TQ), Oldenburg Inventory (OI), PerceivFed Stress Questionnaire (PSQ), General Depression Scale (ADS-L), Generalized Anxiety Disorder 7-item scale (GAD-7), and Freiburg Monosyllable Test (FMT) at 65 dB. Timepoint-specific correlations with the NCIQ were analyzed using Spearman’s rank correlations. Exploratory multivariable analyses employed linear regression on rank-transformed variables to assess whether baseline and 6-month patient-reported profiles were associated with 2-year NCIQ outcomes. Longitudinal within-patient comparisons were conducted as a secondary descriptive analysis.ResultsHigher NCIQ scores were linked to lower tinnitus burden and better hearing across all assessments. Associations with depression and anxiety persisted, while connections with perceived stress emerged after surgery. At baseline, higher tinnitus burden was associated with lower 2-year NCIQ scores. At 6 months, higher tinnitus is still associated with lower 2-year NCIQ scores, whereas better hearing is associated with higher 2-year NCIQ scores. Early postoperative improvement was followed by stabilization over 2 years.ConclusionImprovement in health-related quality of life after cochlear implantation in adults with SSD is complex and extends beyond hearing alone. Tinnitus was the most consistent negative factor, while improved subjective hearing at 6 months was associated with better outcomes at 2 years. These results support a structured, multidimensional approach to patient-reported follow-up after cochlear implantation in SSD and suggest that early postoperative patient-reported status may serve as an early candidate marker for later quality-of-life outcomes.
Direct and indirect associations of hypochondriasis with suicidality in psychiatric outpatients: mediating roles of anxiety and depression
IntroductionAlthough both hypochondriasis and suicidality are common in psychiatric patients and related to anxiety and depression, their association in psychiatric patients remains unclear. This study investigated the direct association of hypochondriasis with suicidality and the indirect associations via anxiety and depression in psychiatric patients.MethodsClinical records of 5484 psychiatric outpatients were reviewed. Hypochondriasis, Suicidality, Anxiety, and Depression were evaluated using the hypochondriasis item of the Hamilton Depression Rating Scale, the suicidality item of the 17-item Hamilton Depression Rating Scale (HAM-D17), the Hamilton Anxiety Rating Scale (HAM-A), and the 6-item subscale of the Hamilton Depression Rating Scale (HAM-D6), respectively. The associations among Hypochondriasis, Suicidality, Anxiety, and Depression were examined using a parallel mediation model. The model was estimated using the lavaan package in R with 10, 000 bootstrap resamples, adjusted for age and sex. Moderation by age and sex was also investigated.ResultsSignificant positive indirect associations via Anxiety (point estimate = 0.05, 95% CI [0.03, 0.06]) and Depression (point estimate = 0.17, 95% CI [0.15, 0.19]) were observed between Hypochondriasis and Suicidality. Conversely, the direct association between Hypochondriasis and Suicidality was also significant but in a negative direction (B = −0.16, p <.001). As the total indirect association was stronger than the direct association, the total association of Hypochondriasis with Suicidality was significantly positive (B = 0.05, p = 0.002). The negative direct association of Hypochondriasis with Suicidality was significantly stronger in younger patients (interaction term = 0.004, p <.001).ConclusionAnxiety and depression mediated the association between hypochondriasis and increased suicidality. In contrast, hypochondriasis was associated with decreased suicidality after accounting for the mediators. As the indirect association was stronger than the direct association, hypochondriasis was associated with increased suicidality overall. The direct association between hypochondriasis and decreased suicidality was stronger in younger patients.
Preoperative anxiety and depression symptoms are associated with poorer clinical outcomes following corrective surgery for adult equinocavovarus foot
PurposeThis study aimed to investigate the preoperative psychological status of adult patients with equinocavovarus foot deformity and to examine the association between preoperative anxiety/depressive symptoms and the clinical outcomes of corrective surgery in this population.MethodsA retrospective analysis was conducted on 103 adult patients who underwent corrective surgery for equinocavovarus foot at Xi’an Honghui Hospital between March 2014 and July 2023. Baseline data were collected. Patient psychological status, ankle-hindfoot function, pain, and quality of life were assessed preoperatively and at the final follow-up using the Hospital Anxiety and Depression Scale (HADS), the American Orthopedic Foot & Ankle Society (AOFAS) ankle-hindfoot score, the Visual Analog Scale (VAS), and the 36-Item Short Form Health Survey (SF-36). Based on preoperative HADS scores, patients were categorized into an anxiety/depression group (Group A) and a non-anxiety/depression group (Group B). The two groups were compared with respect to baseline characteristics (gender, age, disease duration, BMI, follow-up duration), clinical outcomes, and the degree of improvement in all assessment metrics.ResultsA total of 83 patients completed the follow-up, among whom 38 (45.78%) exhibited preoperative anxiety/depression symptoms. No significant differences were found in baseline characteristics between the two groups (all P > 0.05). At the final follow-up, both groups showed significant improvement in VAS, AOFAS, SF-36 (PCS/MCS), and HADS (A/D) scores compared to their preoperative baselines (all P < 0.001). Intergroup comparisons revealed that Group A had significantly lower AOFAS and SF-36 (PCS/MCS) scores, and significantly higher VAS and HADS (A/D) scores than Group B, both preoperatively and at the final follow-up (all P < 0.001). Regarding the degree of improvement, Group A demonstrated a smaller magnitude of improvement in VAS (P < 0.01), AOFAS (P < 0.01), and SF-36 PCS (P < 0.001) compared to Group B. Conversely, Group A showed a greater improvement in SF-36 MCS and HADS (A/D) scores (all P < 0.001).ConclusionsWhile surgery improved all outcomes, patients with preoperative anxiety/depression exhibited persistently worse clinical scores. Their improvement profile was distinct: smaller gains in pain and physical function but greater mental health improvement. Addressing preoperative psychological status may optimize comprehensive outcomes.