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Translational Psychiatry Jun 2023The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) is the... (Review)
Review
The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter in the brain, working primarily via GABA receptors, with an important role in virtually all physiologic functions in the brain. Some neuroactive steroids (NASs) are positive allosteric modulators (PAMs) of GABA receptors and potentiate phasic and tonic inhibitory responses via activation of synaptic and extrasynaptic GABA receptors, respectively. This review first discusses preclinical and clinical data that support the association of depression with diverse defects in the GABAergic system of neurotransmission. Decreased levels of GABA and NASs have been observed in adults with depression compared with healthy controls, while treatment with antidepressants normalized the altered levels of GABA and NASs. Second, as there has been intense interest in treatment approaches for depression that target dysregulated GABAergic neurotransmission, we discuss NASs approved or currently in clinical development for the treatment of depression. Brexanolone, an intravenous NAS and a GABA receptor PAM, is approved by the U.S. Food and Drug Administration for the treatment of postpartum depression (PPD) in patients 15 years and older. Other NASs include zuranolone, an investigational oral GABA receptor PAM, and PH10, which acts on nasal chemosensory receptors; clinical data to date have shown improvement in depressive symptoms with these investigational NASs in adults with MDD or PPD. Finally, the review discusses how NAS GABA receptor PAMs may potentially address the unmet need for novel and effective treatments with rapid and sustained antidepressant effects in patients with MDD.
Topics: Female; Adult; Humans; Depressive Disorder, Major; Neurosteroids; Receptors, GABA-A; gamma-Aminobutyric Acid; Antidepressive Agents
PubMed: 37365161
DOI: 10.1038/s41398-023-02514-2 -
JAMA Network Open Mar 2024Postpartum depression (PPD) is one of the most common mental health conditions during the perinatal and postpartum periods, which can have adverse effects on both mother... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Postpartum depression (PPD) is one of the most common mental health conditions during the perinatal and postpartum periods, which can have adverse effects on both mother and infant.
OBJECTIVE
To investigate the efficacy of perioperative adjunctive esketamine administration after cesarean deliveries in the prevention of PPD.
DESIGN, SETTING, AND PARTICIPANTS
A single-center, double-blind, placebo-controlled, randomized clinical trial was conducted from January 1, 2022, to January 1, 2023, at Fujian Provincial Hospital among 298 women aged 18 to 40 years, with an American Society of Anesthesiologists grade I to III classification and singleton full-term pregnancies who were scheduled for elective cesarean deliveries. Primary analyses were performed on a modified intention-to-treat basis.
INTERVENTIONS
Patients were randomly assigned to the esketamine (n = 148) and control (n = 150) groups. Those in the esketamine group received a single intravenous injection of 0.25 mg/kg of esketamine immediately after fetal delivery, followed by 50 mg of esketamine as an adjuvant in patient-controlled intravenous analgesia for 48 hours after surgery. Saline was given to the control group of patients.
MAIN OUTCOMES AND MEASURES
The primary outcome was assessments of PPD symptoms by using the Edinburgh Postnatal Depression Scale (EPDS) at postpartum day 7. Positive screening for PPD was defined as a score of 10 or more points on the EPDS. In addition, the EPDS was analyzed as a continuous variable to evaluate depressive symptoms. Secondary outcomes included the Numeric Rating Scale (NRS) of postoperative pain, along with safety evaluations including adverse events and clinical assessments at postpartum days 14, 28, and 42.
RESULTS
A total of 298 pregnant women were included, with 150 in the control group (median age, 31.0 years [IQR, 29.0-34.0 years]) and 148 in the esketamine group (median age, 31.0 years [IQR, 28.0-34.0 years]). The prevalence of depression symptoms was significantly lower among patients given esketamine compared with controls (23.0% [34 of 148] vs 35.3% [53 of 150]; odds ratio, 0.55; 95% CI, 0.33-0.91; P = .02) on postpartum day 7. In addition, the esketamine group also showed a significantly lower change in EPDS scores (difference of least-squares means [SE], -1.17 [0.44]; 95% CI, -2.04 to -0.31; effect size, 0.74; P = .008). However, there were no differences between the groups in the incidence of positive screening results for PPD or in changes from the baseline EPDS scores at postpartum days 14, 28, and 42. There were no differences in NRS scores at rest and on movement except on movement at 72 hours postoperatively, when scores were significantly lower in the esketamine group (median, 3.0 [IQR, 2.0-3.0] vs 3.0 [IQR, 3.0-3.5]; median difference, 0 [95% CI, 0-0]; P = .03).
CONCLUSIONS AND RELEVANCE
These results suggest that intravenous administration of esketamine during the perioperative period of elective cesarean delivery can improve depression symptoms during the early postpartum period. However, this antidepression effect may not be universally applicable to patients with low EPDS scores.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2100054199.
Topics: Adult; Female; Humans; Pregnancy; Adjuvants, Immunologic; Cesarean Section; Depression, Postpartum; Ketamine; Adolescent; Young Adult
PubMed: 38446480
DOI: 10.1001/jamanetworkopen.2024.0953 -
Social Psychiatry and Psychiatric... Nov 2023This systematic review of systematic reviews aims to provide the first global picture of the prevalence and correlates of perinatal depression, and to explore the... (Review)
Review
PURPOSE
This systematic review of systematic reviews aims to provide the first global picture of the prevalence and correlates of perinatal depression, and to explore the commonalities and discrepancies of the literature.
METHODS
Seven databases were searched from inception until April 2022. Full-text screening and data extraction were performed independently by two researchers and the AMSTAR tool was used to assess the methodological quality.
RESULTS
128 systematic reviews were included in the analysis. Mean overall prevalence of perinatal depression, antenatal depression and postnatal depression was 26.3%, 28.5% and 27.6%, respectively. Mean prevalence was significantly higher (27.4%; SD = 12.6) in studies using self-reported measures compared with structured interviews (17.0%, SD = 4.5; d = 1.0) and among potentially vulnerable populations (32.5%; SD = 16.7, e.g. HIV-infected African women) compared to the general population (24.5%; SD = 8.1; d = 0.6). Personal history of mental illness, experiencing stressful life events, lack of social support, lifetime history of abuse, marital conflicts, maternity blues, child care stress, chronic physical health conditions, preeclampsia, gestational diabetes mellitus, being exposed to second-hand smoke and sleep disturbance were among the major correlates of perinatal depression.
CONCLUSION
Although the included systematic reviews were all of medium-high quality, improvements in the quality of primary research in this area should be encouraged. The standardisation of perinatal depression assessment, diagnosis and measurement, the implementation of longitudinal designs in studies, inclusions of samples that better represent the population and better control of potentially confounding variables are encouraged.
Topics: Female; Humans; Pregnancy; Child; Depression; Prevalence; Systematic Reviews as Topic; Depression, Postpartum; Pregnancy Complications
PubMed: 36646936
DOI: 10.1007/s00127-022-02386-9 -
Nature Oct 2023Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including...
Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants. However, our understanding of GABAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAR assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1β2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABAR assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.
Topics: Animals; Mice; Binding Sites; Cryoelectron Microscopy; Depression, Postpartum; Flurazepam; gamma-Aminobutyric Acid; Hypnotics and Sedatives; Ion Channel Gating; Neurosteroids; Photobleaching; Pregnanolone; Protein Conformation; Protein Subunits; Receptors, GABA-A; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 37730991
DOI: 10.1038/s41586-023-06556-w -
Journal of Affective Disorders Oct 2023Postpartum depression (PPD) is a prevalent public health issue. Although ketamine has prophylactic effects on PPD in women undergoing cesarean section, the effects of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Postpartum depression (PPD) is a prevalent public health issue. Although ketamine has prophylactic effects on PPD in women undergoing cesarean section, the effects of esketamine on PPD remain unclear. This trial aimed to evaluate the efficacy of perioperative esketamine infusion on PPD risk by assessing Edinburgh Postnatal Depression Scale (EPDS) scores and blood biomarkers.
METHODS
A total of 150 participants undergoing elective cesarean section were randomly allocated to receive either esketamine or normal saline. Since 27 participants were excluded due to consent withdrawal or loss to follow-up, 123 patients were included. The primary outcome was the prevalence of PPD risk. Secondary outcomes included the prevalence of postpartum anxiety (PPA) risk, levels of biomarkers, postoperative pain intensity, and cumulative sufentanil consumption.
RESULTS
The prevalence of PPD and PPA risk at 3 days, 42 days, 3 months, and 6 months postpartum did not differ between the two groups. Furthermore, EPDS scores, pain intensity at rest, and during coughing on postoperative days (POD) 1 and 2 did not differ between the two groups. Sufentanil consumption during 0-12 h, 12-24 h, 0-24 h, and 0-48 h postoperatively were significantly lower in the esketamine group compared to the control group. Blood biomarkers did not differ between the two groups on POD 3.
LIMITATIONS
The sample size was small. PPD risk was simply screened, not diagnosed.
CONCLUSIONS
Perioperative administration of esketamine did not decrease the incidence of PPD risk in women after elective cesarean section. However, esketamine reduced opioid consumption.
Topics: Humans; Female; Pregnancy; Cesarean Section; Ketamine; Depression, Postpartum; Sufentanil; Biomarkers
PubMed: 37482224
DOI: 10.1016/j.jad.2023.07.103 -
Nursing Open Aug 2023Our aim is to clarify the concept of paternal perinatal depression including its definition, attributes, antecedents and consequences. (Review)
Review
AIM
Our aim is to clarify the concept of paternal perinatal depression including its definition, attributes, antecedents and consequences.
DESIGN
A concept analysis.
METHODS
To obtain relevant evidence, several databases were searched systematically including PubMed, EMBASE, Web of Science, CINAHL, PsycINFO and the Cochrane Library. Qualitative or quantitative articles published in English that focused on paternal perinatal depression were included. After the literature quality assessment, Walker and Avant's concept analysis strategy was used.
RESULTS
Five defining attributes (i.e. symptoms occur during the partner's pregnancy or 1-year postpartum and last at least 2 weeks, emotional symptoms, somatic symptoms, negative parenting behaviours and 'masked' symptoms), four antecedents (i.e. personal issues, pregnancy-related issues, infant-related issues, social issues) and three consequences (i.e. offspring outcomes, marital relationship, maternal negative emotions) were identified.
Topics: Female; Humans; Infant; Male; Pregnancy; Depression; Depressive Disorder; Fathers; Parenting; Postpartum Period
PubMed: 37147794
DOI: 10.1002/nop2.1797 -
Journal of Clinical Medicine Oct 2023Postpartum depression (PPD) is a disorder that impairs the formation of the relationship between mother and child, and reduces the quality of life for affected women to... (Review)
Review
Postpartum depression (PPD) is a disorder that impairs the formation of the relationship between mother and child, and reduces the quality of life for affected women to a functionally significant degree. Studying markers associated with PPD can help in early detection, prevention, or monitoring treatment. The purpose of this paper is to review biomarkers linked to PPD and to present selected theories on the pathogenesis of the disease based on data from biomarker studies. The complex etiology of the disorder reduces the specificity and sensitivity of markers, but they remain a valuable source of information to help clinicians. The biggest challenge of the future will be to translate high-tech methods for detecting markers associated with postpartum depression into more readily available and less costly ones. Population-based studies are needed to test the utility of potential PPD markers.
PubMed: 37892657
DOI: 10.3390/jcm12206519 -
EBioMedicine Dec 2023
Topics: Female; Humans; Depression; Depression, Postpartum; Postpartum Period
PubMed: 38099513
DOI: 10.1016/j.ebiom.2023.104925