Sociodemographic Factors of Depression During the COVID-19 Pandemic in Malaysia: the COVID-19 Mental Health International Study.

OBJECTIVES: To determine the prevalence of depression and the sociodemographic factors associated with depression in Malaysia during the COVID-19 pandemic METHODS. This study is part of the COVID-19 Mental Health International Study to collect data on the impact of the pandemic on mental health through an online survey. People who were aged ≥18 years, able to read Malay or English, had access to the internet, and consented to participate were asked to complete a pro forma questionnaire to collect their sociodemographic data. The presence of distress and depression was assessed using the English or Malay version of the Center for Epidemiologic Studies Depression Scale. RESULTS: Of 963 participants, 451 (46.8%) had depression and 512 (53.2%) had no depression who were either normal (n = 169, 17.5%) or had distress (n = 343, 35.6%). Participants had higher odds of having depression when living with two people (adjusted odds ratio [AOR] = 3.896, p = 0.001), three people (AOR = 2.622, p < 0.001) or four people (AOR = 3.135, p < 0.001). Participants with three children had higher odds of having depression (AOR = 2.084, p = 0.008), whereas having only one child was a protective factor for depression (AOR = 0.481, p = 0.01). Participants had higher odds of having depression when self-employed (AOR = 3.825, p = 0.003), retired (AOR = 4.526, p = 0.001), being housekeeper (AOR = 7.478, p = 0.004), not working by choice (AOR = 5.511, p < 0.001), or unemployed (AOR = 3.883, p = 0.009). Participants had higher odds of depression when living in a small town (AOR = 3.193, p < 0.001) or rural area (AOR = 3.467, p < 0.001). Participants with no chronic medical illness had lower odds of having depression (AOR = 0.589, p = 0.008). CONCLUSION: In Malaysia during the COVID-19 pandemic, people who are living with two, three, or four people, having three children, living in a small town or rural areas, and having unstable income have higher odds of having depression. Urgent intervention for those at risk of depression is recommended.

Anxiety, Depression, and Trauma Among Immigrant Mexican Women up to Two-Years Post-partum.

Anxiety has significant consequences for maternal and infant health, and Mexican immigrant mothers are at significantly high-risk. This study examined whether maternal depressive symptoms and trauma are related to anxiety symptoms in perinatal Mexican immigrants. Data were collected from 103 Mexican women residing in the Midwestern United States who were pregnant or up to two years postpartum. Half were aged 30-34. The majority had two or more children and low socio-economic status. Linear regression analyses predicted current anxiety symptoms from current maternal depression symptoms, trauma history, and socio-demographics. Anxiety symptoms were significantly related to depressive symptoms (B = 0.87, 95% CI 0.73, 1.01) and trauma. Compared to women with no trauma history, women who experienced more than ten traumas had increased anxiety symptoms (B = 7.15, 95% CI 0.34, 13.96). Perinatal Mexican women with higher depression symptoms and trauma have increased anxiety symptoms, increasing the need for more comprehensive screening.

Intergenerational Trauma among Families in El Salvador: an Exploratory Study.

Adverse childhood events have been shown to impact individuals through adulthood, particularly the impact on relationships. This study aimed to examine intergenerational trauma exposure among a sample of parents living in a semi-urban Salvadoran community and the relationship between child trauma exposure with maternal perceived discrimination, internal strengths and external support. Survey data was collected from 49 mothers residing in El Salvador. Bivariate analyses and multivariate linear regression analyses were used to examine the relationship between children's exposure to adverse childhood events and parents' exposure to adverse childhood events, while controlling for discrimination. The results of the regression analysis indicate that the maternal number of adverse childhood events and experience of discrimination as an adult explained 52.9% of the variance (R 2 = 0.59, F(6, 43) = 10.18, p < .0001). The number of adverse childhood events was significantly predicted by maternal number of adverse events (B = 0.32, 95% CI = 0.17-0.48, p < .0001) and experience of discrimination as adults (B = 5.79, 95% CI = 3.51-8.07, p < .0001). Results suggest that parent exposure to adverse childhood events and parent experience with discrimination are related to the exposure to adverse childhood events of their children. Further research in this area is warranted to better understand the experiences of parents who have been exposed to childhood trauma and the day-to-day parenting challenges. Greater understanding of the impact of childhood trauma also encourages service providers to explore intergenerational interventions.

Childhood Trauma and Psychopathic Features Among Juvenile Offenders.

Despite growing interest in psychopathic personality features in juvenile offenders, few studies have examined the relationship between childhood trauma and psychopathy. The present study utilized two datasets: 253 adolescents in a residential facility for juvenile offenders in Pennsylvania and 723 institutionalized delinquents in Missouri. Zero-order correlations and linear regression techniques were employed for boys and girls to examine the relationships between trauma, assessed using the Massachusetts Youth Screening Instrument Version 2 (MAYSI-2) Traumatic Experiences Scale and the Childhood Trauma Questionnaire (CTQ), and psychopathy as measured by the Youth Psychopathic Traits Inventory (YPI) and the Psychopathic Personality Inventory-Short Form (PPI-SF). Results indicate that psychopathy is significantly correlated with childhood trauma. For the Missouri data, trauma significantly predicted psychopathy scores for both boys and girls. These results suggest that nuanced understanding of traumatic history of these adolescents may not only be a pathway to psychopathy but also a critical part of their overall assessment and treatment plan.

Characterization of 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a novel positive allosteric modulator of the {alpha}7 nicotinic acetylcholine receptor.

The α(7) nicotinic acetylcholine receptor (nAChR) is a potential therapeutic target for the treatment of cognitive deficits associated with schizophrenia, Alzheimer's disease, Parkinson's disease, and attention-deficit/hyperactivity disorder. Activation of α(7) nAChRs improved sensory gating and cognitive function in animal models and in early clinical trials. Here we describe the novel highly selective α(7) nAChR positive allosteric modulator, 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942). This compound enhances the choline-evoked rise in intracellular Ca(2+) levels in the GH4C1 cell line expressing the cloned human α(7) nAChR. JNJ-1930942 does not act on α4ß2, α3ß4 nAChRs or on the related 5-HT3A channel. Electrophysiological assessment in the GH4C1 cell line shows that JNJ-1930942 increases the peak and net charge response to choline, acetylcholine, and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide (PNU-282987). The potentiation is obtained mainly by affecting the receptor desensitization characteristics, leaving activation and deactivation kinetics as well as recovery from desensitization relatively unchanged. Choline efficacy is increased over its full concentration response range, and choline potency is increased more than 10-fold. The potentiating effect is α(7) channel-dependent, because it is blocked by the α(7) antagonist methyllycaconitine. Moreover, in hippocampal slices, JNJ-1930942 enhances neurotransmission at hippocampal dentate gyrus synapses and facilitates the induction of long-term potentiation of electrically evoked synaptic responses in the dentate gyrus. In vivo, JNJ-1930942 reverses a genetically based auditory gating deficit in DBA/2 mice. JNJ-1930942 will be a useful tool to study the therapeutic potential of α(7) nAChR potentiation in central nervous system disorders in which a deficit in α(7) nAChR neurotransmission is hypothesized to be involved.

Metabotropic glutamate receptor 1 blockade impairs acquisition and retention in a spatial Water maze task.

Metabotropic glutamate receptors, including the mGlu1 receptor, have received considerable attention as potential targets for anxiolytic, antidepressant, antipsychotic and antinociceptive drugs. mGlu1 receptors have also been suggested to play a role in the modulation of cognitive processes, but knowledge is still very limited. In the present study the effects of the selective mGlu1 receptor antagonist 3,4-dihydro-2H-pyrano[2,3]beta-quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone (JNJ16259685, 0.63-10 mg/kg s.c.) on more or less spatially demanding learning and spatial memory (retention and re-acquisition) were investigated in mice performing in a water maze. Selective mGlu1 receptor blockade with JNJ16259685 impaired spatial acquisition processes, irrespective of spatial load, as well as spatial re-acquisition, already at the lowest dose tested (0.63 mg/kg). In contrast, effects on spatial retention performance were relatively mild in mice that had learned to locate the position of the escape platform prior to treatment. Thigmotaxic behaviour and locomotor activity appeared to be unaffected by JNJ16259685. These data suggest that blockade of the mGlu1 receptor primarily affects learning of new information, but leaves retention of spatial information relatively unaffected. Blockade of the mGlu5 receptor with MPEP also impaired spatial learning, although only at the highest dose tested (10 mg/kg). An ex vivo receptor occupancy study in rats revealed that MPEP occupied central mGlu5 receptors with an ED(50) of 2.0 mg/kg one hour after subcutaneous administration. This is 50-150 times higher than the ED(50) reported for JNJ16259685 at central mGlu1 receptors and suggests that one reason why the two compounds cause cognitive effects at different doses might be due to differences in central mGlu receptor occupancy, rather than fundamentally different roles of mGlu1 and mGlu5 receptors in the modulation of cognitive function.

Effects of mGlu1 receptor blockade on anxiety-related behaviour in the rat lick suppression test.

RATIONALE: Group I metabotropic glutamate receptor antagonists, which block both the mGlu1 and mGlu5 receptors, have been shown to have anxiolytic effects in the lick suppression test in rats. OBJECTIVE: The anxiolytic potential of the selective mGlu1 antagonist 3,4-dihydro-2H-pyrano[2,3]beta-quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone (JNJ16259685) was investigated and compared with the mGlu5 antagonist MPEP. METHODS: Anxiety-related behaviour was assessed in lick suppression and in the elevated zero maze in rats. Non-specific effects on pain threshold, water intake and locomotor activity were also measured. RESULTS: Acute administration of JNJ16259685 or MPEP increased the number of licks (lowest active dose 2.5 mg/kg IP for each compound). JNJ16259685 did not increase water intake or reduce acute pain threshold, suggesting that the anxiolytic-like properties are specific. However, acute administration decreased locomotor activity. The effects of chronic administration of JNJ16259685 over 14 days (5 mg/kg bid) on lick suppression were comparable to those seen after acute administration, arguing against development of behavioural tolerance or sensitisation. Yet, there was a tendency for an increase in locomotor activity after cessation of chronic treatment. Acute co-administration of both JNJ16259685 and MPEP had additive effects on the number of licks. No anxiolytic-like properties of JNJ16259685 were observed in the elevated zero maze. CONCLUSION: Our data suggest that the anxiolytic-like effects induced by group I metabotropic glutamate receptor antagonists are mediated through both mGlu1 and mGlu5 receptors. Rather than producing a general anxiolytic-like effect, the effects seen following mGlu1 antagonism seem task-dependent, as prominent effects were seen in a conflict procedure, but not in a task based on spontaneous exploration.

Antagonist-induced supersensitivity of mGlu1 receptor signalling in cerebellar granule cells.

We investigated the effect of 24 h sustained treatment with the mGlu1 receptor antagonist CPCCOEt on mGlu1 receptor signalling in primary cultures of rat cerebellar granule cells. In the absence of ionotropic glutamate (iGlu) blockers, the maximal inositol phosphate (IP) response (E(max)) but not the potency of glutamate was significantly increased when cells were pre-exposed for 24 h with CPCCOEt. When the contribution of iGlu receptors to the glutamate-induced IP response was eliminated with the use of DNQX, the E(max) was again increased but also the concentration eliciting 50% of the maximal glutamate stimulus was significantly decreased. In the absence of iGlu receptor inhibitors, the E(max) of quisqualate, which likely mediates IP accumulation only via the mGlu1 receptor, was significantly increased in CPCCOEt-pretreated cells. Also, less quisqualate was needed to reach the same IP effect. The potency of R193845, a selective mGlu1 receptor antagonist, was significantly decreased in antagonist-pretreated cells. These findings demonstrate that 24 h sustained antagonist treatment can render mGlu1 receptors in neurons supersensitive to agonists, with a concomitant decrease in the effectiveness of antagonists.

Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists.

We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC(50) = 20 nM) in a cell-based signal transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mGlu1 receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlu1 receptor. We briefly present and discuss the in vitro metabolic stability of the compounds in human liver microsomes. We finally report the pharmacokinetic properties of our lead compound cis-64a.

JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist.

We examined the pharmacological profile of (3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl) (cis-4-methoxycyclohexyl) methanone (JNJ16259685). At recombinant rat and human metabotropic glutamate (mGlu) 1a receptors, JNJ16259685 non-competitively inhibited glutamate-induced Ca2+ mobilization with IC50 values of 3.24+/-1.00 and 1.21+/-0.53 nM, respectively, while showing a much lower potency at the rat and human mGlu5a receptor. JNJ16259685 inhibited [3H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone ([3H]R214127) binding to membranes prepared from cells expressing rat mGlu1a receptors with a Ki of 0.34+/-0.20 nM. JNJ16259685 showed no agonist, antagonist or positive allosteric activity toward rat mGlu2, -3, -4 or -6 receptors at concentrations up to 10 microM and did not bind to AMPA or NMDA receptors, or to a battery of other neurotransmitter receptors, ion channels and transporters. In primary cerebellar cultures, JNJ16259685 inhibited glutamate-mediated inositol phosphate production with an IC50 of 1.73+/-0.40 nM. Subcutaneously administered JNJ16259685 exhibited high potencies in occupying central mGlu1 receptors in the rat cerebellum and thalamus ( ED50=0.040 and 0.014 mg/kg, respectively). These data show that JNJ16259685 is a selective mGlu1 receptor antagonist with excellent potencies in inhibiting mGlu1 receptor function and binding and in occupying the mGlu1 receptor after systemic administration.

Metabotropic glutamate 1 receptor distribution and occupancy in the rat brain: a quantitative autoradiographic study using [3H]R214127.

We used the selective metabotropic glutamate (mGlu) 1 receptor antagonist [3H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone ([3H]R214127) to investigate the distribution of mGlu1 receptor binding sites in rat brain. We found high mGlu1 receptor binding in the cerebellum, thalamus, dentate gyrus and medial central gray, moderate binding within the CA3 of the hippocampus and hypothalamus, and low mGlu1 receptor binding in the basal ganglia and cortex. The mGlu1 receptor is also present in variable degree in the dorsal lateral septal nucleus, amygdala, interpeduncular nucleus and median raphe nucleus. Additionally, we employed [3H]R214127 autoradiography as a means of investigating the occupancy of central mGlu1 receptors following in vivo administration of mGlu1 receptor antagonists that prevent binding of this radioligand. We found that the mGlu1 receptor antagonist (3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), administered subcutaneously (s.c.) at 10 mg/kg, only occupied about 30% of cerebellar and thalamic mGlu1 receptors. The mGlu1/5 receptor antagonist 2-quinoxaline-carboxamide-N-adamantan-1-yl (NPS 2390) exhibited a relatively high potency in occupying mGlu1 receptors in rat cerebellum (ED50 = 0.75 mg/kg, s.c.) and thalamus (ED50 = 0.63 mg/kg, s.c). In the future, this method can be employed to gain more insight into the in vivo profile and central activity of potential therapeutic agents that act upon the mGlu1 receptor.

[3H]R214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists.

R214127 was shown to be a potent and noncompetitive metabotropic glutamate 1 (mGlu1) receptor-selective antagonist. The kinetics and pharmacology of [(3)H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone (R214127) binding to rat mGlu1a receptor Chinese hamster ovary (CHO)-dhfr(-) membranes was investigated, as well as the distribution of [(3)H]R214127 binding in rat brain tissue and sections. Specific binding to rat mGlu1a receptor CHO-dhfr(-) membranes was approximately 92% of total and was optimal at 4 degrees C. Full association was reached within 5 min, and [(3)H]R214127 bound to a single binding site with an apparent K(D) of 0.90 +/- 0.14 nM and a B(max) of 6512 +/- 1501 fmol/mg of protein. Inhibition experiments showed that [(3)H]R214127 binding was completely blocked by 2-quinoxaline-carboxamide-N-adamantan-1-yl (NPS 2390), (3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), and 7-(hydroxyimino)cyclo-propa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), but was not displaced by competitive mGlu1 receptor ligands such as glutamate and quisqualate, suggesting that R214127, NPS 2390, BAY 36-7620, and CPCCOEt bind to the same site or mutually exclusive sites. Experiments using rat cortex, striatum, hippocampus and cerebellum revealed that [(3)H]R214127 labeled a single high-affinity binding site (K(D) approximately 1 nM). B(max) values were highest in the cerebellum (4302 +/- 2042 fmol/mg of protein) and were 741 +/- 48, 688 +/- 125, and 471 +/- 68 fmol/mg of protein in the striatum, hippocampus, and cortex, respectively. The distribution of [(3)H]R214127 binding in rat brain was investigated in more detail by radioligand autoradiography. A high density of binding sites was detected in the molecular layer of the cerebellum. Moderate labeling was seen in the CA3 and dentate gyrus of the hippocampus, thalamus, olfactory tubercle, amygdala, and substantia nigra reticulata. The cerebral cortex, caudate putamen, ventral pallidum, and nucleus accumbens showed lower labeling. The high affinity and selectivity of [(3)H]R214127 for mGlu1 receptors renders this compound the ligand of choice to study the native mGlu1 receptor in brain.

Supersensitivity of human metabotropic glutamate 1a receptor signaling in L929sA cells.

The effect of antagonist pretreatment on the signaling properties of the human metabotropic glutamate 1a (hmGlu1a) receptor was examined in stably transfected L929sA cells. Pre-exposure of hmGlu1a receptor-expressing cells to the mGlu1 receptor antagonists (S)-4-carboxy-3-hydroxyphenylglycine and 7-(hydroxyimino)cyclo-propa[b]chromen-1a-carboxylate ethyl ester dramatically enhanced subsequent glutamate-induced phosphoinositide hydrolysis and intracellular [Ca(2+)] rise. We found clear indications that the antagonist-mediated enhancement of glutamate-evoked mGlu1a receptor signaling is caused by the development of mGlu1a receptor supersensitivity: the potency of glutamate was increased by 3-fold after 24 h antagonist pretreatment and the potency of the antagonists was significantly decreased in antagonist-pretreated cells. The kinetic profile of the antagonist-mediated enhancement showed that the maximal increase in intracellular [Ca(2+)] was already reached after 30-min pretreatment, suggesting that de novo receptor synthesis is not involved in the process of mGlu1a receptor supersensitization. Glutamate-mediated phosphoinositide hydrolysis increased up to 24 h after antagonist treatment. Although it seemed likely that the hmGlu1a receptor could desensitize after activation by endogenously present glutamate, removal of glutamate from the extracellular medium with GPT resulted in a much smaller enhancement of glutamate responsiveness. Moreover, the magnitude of antagonist-mediated receptor supersensitivity was much larger than the magnitude of agonist-induced receptor desensitization. These results suggest that antagonist-evoked mGlu1 receptor supersensitivity is not merely the result of a blockade of agonist-induced desensitization. Finally, we found that antagonist pretreatment doubled the amount of receptors at the cell surface. Our findings are the first lines of evidence that prolonged antagonist treatment can supersensitize the hmGlu1a receptor. In view of the potential therapeutic application of mGlu1 receptor antagonists, it will be important to know whether these phenomena occur in vivo.

Synthesis and biological activities of conformationally restricted cyclopentenyl-glutamate analogues.

An efficient method for preparing conformationally restricted cyclopentenyl-glutamate analogues in a regioselective and diastereoselective manner has been developed using a formal [3 + 2] cycloaddition reaction of dehydroamino acids. Methods for preparing optically active versions of these compounds have also been devised. Of these compounds, (S)-2 is an agonist at the mGlu5 (EC(50) 18 microM) and mGlu2 (EC(50) 45 microM) receptors.