Ma-Li Wong | Flinders University of South Australia (original) (raw)
Papers by Ma-Li Wong
Journal of Affective Disorders, 2021
Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability... more Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response. Method: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes. Results: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess. Limitations: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted. Conclusion: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response. Trial registration: ClinicalTrials.gov NCT00265291
Journal of Affective Disorders, 2021
Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability... more Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response. Method: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes. Results: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess. Limitations: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted. Conclusion: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response. Trial registration: ClinicalTrials.gov NCT00265291
Journal of Pediatric Endocrinology and Metabolism, 2009
Background: The few identified leptin-deficient children have immune deficiency. Aims: To evaluat... more Background: The few identified leptin-deficient children have immune deficiency. Aims: To evaluate whether a newly-identified leptin-deficient boy has immune defects; to assess the immune changes during leptin replacement. Methods: A 5 year-old boy with congenital leptin deficiency was evaluated before, 2 weeks and 6 weeks after the initiation of recombinant methionyl human leptin. Thymic volume was measured by computed tomography. Humoral immunity was assessed by measuring levels of several immunoglobulins. Cellular immunity was evaluated by the analysis of lymphocyte proliferation in response to mitogens. Lymphocyte subsets were quantified by flow cytometry. Results: At baseline, thymic volume was increased. The lymphocyte subsets count and humoral/cellular immunities were normal. After treatment, proliferative response to mitogens increased by 1.5-to 3-fold, and lymphocyte count decreased by 17%. Conclusions: Immune defects are not an obligatory feature of congenital leptin deficiency. Even in the absence of significant immune defects, leptin replacement therapy enhanced T-cell responsiveness.
International Journal of Molecular Sciences
Variations in anxiety-related behavior are associated with individual allostatic set-points in ch... more Variations in anxiety-related behavior are associated with individual allostatic set-points in chronically stressed rats. Actively offensive rats with the externalizing indicators of sniffling and climbing the stimulus and material tearing during 10 days of predator scent stress had reduced plasma corticosterone, increased striatal glutamate metabolites, and increased adrenal 11-dehydrocorticosterone content compared to passively defensive rats with the internalizing indicators of freezing and grooming, as well as to controls without any behavioral changes. These findings suggest that rats that display active offensive activity in response to stress develop anxiety associated with decreased allostatic set-points and increased resistance to stress.
European Neuropsychopharmacology
Frontiers in Behavioral Neuroscience
The concepts of allostatic load and overload, i. e., a dramatic increase in the allostatic load t... more The concepts of allostatic load and overload, i. e., a dramatic increase in the allostatic load that predisposes to disease, have been extensively described in the literature. Here, we show that rats engaging in active offensive response (AOR) behavioral strategies to chronic predator scent stress (PSS) display less anxiety behavior and lower plasma cortisol levels vs. rats engaging in passive defensive response (PDR) behavioral strategies to chronic PSS. In the same chronic PSS paradigm, AOR rats also have higher lactate and lower glutamate levels in amygdala but not in control-region hippocampus vs. PDR rats. The implications of these findings for regulation of allostatic and stress responses, and post-traumatic stress disorder (PTSD) are discussed.
Translational Psychiatry
Recent studies indicate that activation of hypothalamic Agouti-related protein (Agrp) neurons can... more Recent studies indicate that activation of hypothalamic Agouti-related protein (Agrp) neurons can increase foragerelated/repetitive behavior and decrease anxiety levels. However, the impact of physiological hunger states and food deprivation on anxiety-related behaviors have not been clarified. In the present study, we evaluated changes in anxiety levels induced by physiological hunger states and food deprivation, and identified the neuron population involved. Ad libitum fed and fasted mice were tested in the open field and elevated plus-maze behavioral tests. The DREADD approach was applied to selectively inhibit and stimulate neurons expressing Agrp in hypothalamic arcuate nucleus in Agrp-Cre transgenic mice. We found that anxiety levels were significantly reduced in the late light period when mice have increased need for food and increased Agrp neurons firing, in contrast to the levels in the early light period. Consistently, we also found that anxiety was potently reduced in 24-h fasted mice, relative to 12-h fasted mice or fed ad libitum. Mechanistically, we found that chemogenetic activation of Agrp neurons reduced anxiety in fed mice, and inactivation of Agrp neurons reduced fasting-induced anxiolytic effects. Our results suggest that anxiety levels may vary physiologically with the increasing need for food, and are influenced by acute fasting in a time-dependent manner. Agrp neurons contribute to fasting-induced anxiolytic effects, supporting the notion that Agrp neuron may serve as an entry point for the treatment of energy states-related anxiety disorders.
The Lancet Psychiatry
Psychological distress was measured by the Australian of Bureau of Statistics with the Kessler Ps... more Psychological distress was measured by the Australian of Bureau of Statistics with the Kessler Psychological Distress Scale (K10). Data was taken from Jorm 2018. 5 Prevalence of antidepressant use was measured by the Organisation for Economic Cooperation and Development. 6 Mental health treatment through Better Access was obtained from the AIHW mental health medicare dataset. 7 Table 2: Prevalence and treatment of common mental health disorders in Australia Correspondence e9 www.thelancet.com/psychiatry Vol 6 March 2019 short-term gains for major depression, with limited evidence for longterm benefits. 3 Similarly, CBT has small to modest short-term effects for anxiety and depression. 9 More effective treatments for depression and better public health approaches must be developed, with tangible and quantifiable evidence of their effect at the population level. We declare no competing interests.
Molecular Neurobiology
Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its inc... more Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its incidence is expected to increase. Despite tremendous efforts to understand its underlying biological mechanisms, MDD pathophysiology remains elusive and pharmacotherapy outcomes are still far from ideal. Low-grade chronic inflammation seems to play a key role in mediating the interface between psychological stress, depressive symptomatology, altered intestinal microbiology, and MDD onset. We review the available pre-clinical and clinical evidence of an involvement of pro-inflammatory pathways in the pathogenesis, treatment, and remission of MDD. We focus on caspase 1, inducible nitric oxide synthase, and interferon gamma, three inflammatory systems dysregulated in MDD. Treatment strategies aiming at targeting such pathways alone or in combination with classical therapies could prove valuable in MDD. Further studies are needed to assess the safety and efficacy of immune modulation in MDD and other psychiatric disorders with neuroinflammatory components.
Science Advances
Schizophrenia (SCZ) is a devastating mental disorder with poorly defined underlying molecular mec... more Schizophrenia (SCZ) is a devastating mental disorder with poorly defined underlying molecular mechanisms. The gut microbiome can modulate brain function and behaviors through the microbiota-gut-brain axis. Here, we found that unmedicated and medicated patients with SCZ had a decreased microbiome α-diversity index and marked disturbances of gut microbial composition versus healthy controls (HCs). Several unique bacterial taxa (e.g., Veillonellaceae and Lachnospiraceae) were associated with SCZ severity. A specific microbial panel (Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae) enabled discriminating patients with SCZ from HCs with 0.769 area under the curve. Compared to HCs, germ-free mice receiving SCZ microbiome fecal transplants had lower glutamate and higher glutamine and GABA in the hippocampus and displayed SCZ-relevant behaviors similar to other mouse models of SCZ involving glutamatergic hypofunction. Together, our findings suggest that t...
BioEssays
We propose the "microbiota-inflammasome" hypothesis of major depressive disorder (MDD, a mental i... more We propose the "microbiota-inflammasome" hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long-lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro-inflammatory pathways mediated by the Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut dysbiosis. In this review we describe MDD/chronic stress-induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive-like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co-morbid conditions. A number of testable predictions surface from this microbiota-gut-inflammasome-brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change. 2. The Microbiota-Gut-Inflammasome-Brain Axis The microbiome-gut-brain axis consists of a communication network that controls and integrates gut and brain function, and that seems to be a central modulator of health and disease. [6] More specifically, there seems to exist a bidirectional communication between the gut and the brain, which occurs through multiple intertwined pathways, mediated by the vagus nerve, [7] the immune system, [8,9] and the bacterial metabolome (the ensemble of bacterial metabolic by-products and end products). [10,11] Recently, the role of the gut microbiome in shaping behavior, its interconnectedness with brain processes, and its potential involvement in the pathophysiology of MDD have come to the
European Neuropsychopharmacology
European Neuropsychopharmacology
BMJ open, Jan 11, 2017
To examine the association between antidepressant use and weight gain, as well as the interaction... more To examine the association between antidepressant use and weight gain, as well as the interaction with lifestyle factors. Longitudinal study. We used data from 2334 adults from two stages (4.4 years apart) of the North West Adelaide Health Study, including validated diet and lifestyle questionnaires, measured body weight and linked pharmaceutical prescription data. Body weight change. 188 (8.1%) participants had a mean annual number of 1-2 antidepressant prescriptions, and 212 (9.1%) had over two prescriptions. The mean annual weight gain was 0.12, 0.18 and 0.28 kg in non-users, low (1-2 prescriptions/year) and high (>2 prescriptions/year) antidepressant users, respectively. In multivariable regression models, antidepressant use was positively associated with weight gain: high antidepressant users gained an extra 0.22 (95% CI 0.00 to 0.44) kg per year. This association was mainly due to selective serotonin reuptake inhibitor (SSRI) use. High SSRI users gained 0.48 (95% CI 0.20 to...
Current Trends and Developments, 2000
The pharmacogenomics journal, 2011
Earlier we had found that the CYP2C9*2 allelic frequency was lower in Mexican-Americans living in... more Earlier we had found that the CYP2C9*2 allelic frequency was lower in Mexican-Americans living in California than in Spaniards (SP). This was assumed to be related to the low CYP2C9*2 and *3 allele frequencies in Orientals. This study was therefore aimed at analyzing whether there were also differences in CYP2C9 allele frequencies between Mexican-Tepehuanos (MT) and Mexican-Mestizos (MM) living in northwestern Mexico and SP. The CYP2C9*2 frequency was expected to be lower in the indigenous MT than in the two other groups, and lower in MM than in SP as in our earlier study. CYP2C9 genotypes and allele frequencies of two populations of healthy volunteers, MT (n=99) and MM (n=102), were compared with a population of SP (n=327). The data were also compared with our previously published population of Mestizo-Mexican-Americans (MA). The CYP2C9 genotypes among the studied populations were in equilibrium. The frequencies of CYP2C9*2 were 0.01, 0.07, 0.08, and 0.16 for MT, MM, MA, and SP sub...
Progress in neuro-psychopharmacology & biological psychiatry, Jan 15, 2007
Modulations of serotonergic and noradrenergic systems are thought to be critical to the therapeut... more Modulations of serotonergic and noradrenergic systems are thought to be critical to the therapeutic effect of most antidepressants, and their efficacies have been shown to depend on a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR). Mirtazapine has a dual-action profile, combining the enhancement of the noradrenergic neurotransmitter system with specific actions on particular serotonergic receptor subtypes. The goal of this study was to elucidate whether the 5-HTTLPR polymorphism is associated with the mirtazapine antidepressant response in subjects with major depressive disorder (MDD). One hundred and one MDD patients were evaluated during 4 weeks of mirtazapine treatment. The severity of depression was assessed with the 21-item Hamilton Depression Rating scale, and the 5-HTTLPR genotypes in the patients were determined using the polymerase chain reaction. Our results showed that responses at the 2nd and 4th weeks were significantly b...
Drug Discovery Series, 2009
Biology of Depression, 2005
... le substrate fo r in d u cing d epression -like sympto ms in ro d en ts. Anhed o nia is the m... more ... le substrate fo r in d u cing d epression -like sympto ms in ro d en ts. Anhed o nia is the m arked ly d imin ished interest o r p leasu ... s re-sem b lin g th ose ob served in dep ression . Anhed onia-like behaviors are reversed by ch ron ic but n o t acu te antidepressant treatm ent. ...
Journal of Affective Disorders, 2021
Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability... more Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response. Method: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes. Results: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess. Limitations: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted. Conclusion: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response. Trial registration: ClinicalTrials.gov NCT00265291
Journal of Affective Disorders, 2021
Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability... more Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response. Method: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes. Results: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess. Limitations: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted. Conclusion: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response. Trial registration: ClinicalTrials.gov NCT00265291
Journal of Pediatric Endocrinology and Metabolism, 2009
Background: The few identified leptin-deficient children have immune deficiency. Aims: To evaluat... more Background: The few identified leptin-deficient children have immune deficiency. Aims: To evaluate whether a newly-identified leptin-deficient boy has immune defects; to assess the immune changes during leptin replacement. Methods: A 5 year-old boy with congenital leptin deficiency was evaluated before, 2 weeks and 6 weeks after the initiation of recombinant methionyl human leptin. Thymic volume was measured by computed tomography. Humoral immunity was assessed by measuring levels of several immunoglobulins. Cellular immunity was evaluated by the analysis of lymphocyte proliferation in response to mitogens. Lymphocyte subsets were quantified by flow cytometry. Results: At baseline, thymic volume was increased. The lymphocyte subsets count and humoral/cellular immunities were normal. After treatment, proliferative response to mitogens increased by 1.5-to 3-fold, and lymphocyte count decreased by 17%. Conclusions: Immune defects are not an obligatory feature of congenital leptin deficiency. Even in the absence of significant immune defects, leptin replacement therapy enhanced T-cell responsiveness.
International Journal of Molecular Sciences
Variations in anxiety-related behavior are associated with individual allostatic set-points in ch... more Variations in anxiety-related behavior are associated with individual allostatic set-points in chronically stressed rats. Actively offensive rats with the externalizing indicators of sniffling and climbing the stimulus and material tearing during 10 days of predator scent stress had reduced plasma corticosterone, increased striatal glutamate metabolites, and increased adrenal 11-dehydrocorticosterone content compared to passively defensive rats with the internalizing indicators of freezing and grooming, as well as to controls without any behavioral changes. These findings suggest that rats that display active offensive activity in response to stress develop anxiety associated with decreased allostatic set-points and increased resistance to stress.
European Neuropsychopharmacology
Frontiers in Behavioral Neuroscience
The concepts of allostatic load and overload, i. e., a dramatic increase in the allostatic load t... more The concepts of allostatic load and overload, i. e., a dramatic increase in the allostatic load that predisposes to disease, have been extensively described in the literature. Here, we show that rats engaging in active offensive response (AOR) behavioral strategies to chronic predator scent stress (PSS) display less anxiety behavior and lower plasma cortisol levels vs. rats engaging in passive defensive response (PDR) behavioral strategies to chronic PSS. In the same chronic PSS paradigm, AOR rats also have higher lactate and lower glutamate levels in amygdala but not in control-region hippocampus vs. PDR rats. The implications of these findings for regulation of allostatic and stress responses, and post-traumatic stress disorder (PTSD) are discussed.
Translational Psychiatry
Recent studies indicate that activation of hypothalamic Agouti-related protein (Agrp) neurons can... more Recent studies indicate that activation of hypothalamic Agouti-related protein (Agrp) neurons can increase foragerelated/repetitive behavior and decrease anxiety levels. However, the impact of physiological hunger states and food deprivation on anxiety-related behaviors have not been clarified. In the present study, we evaluated changes in anxiety levels induced by physiological hunger states and food deprivation, and identified the neuron population involved. Ad libitum fed and fasted mice were tested in the open field and elevated plus-maze behavioral tests. The DREADD approach was applied to selectively inhibit and stimulate neurons expressing Agrp in hypothalamic arcuate nucleus in Agrp-Cre transgenic mice. We found that anxiety levels were significantly reduced in the late light period when mice have increased need for food and increased Agrp neurons firing, in contrast to the levels in the early light period. Consistently, we also found that anxiety was potently reduced in 24-h fasted mice, relative to 12-h fasted mice or fed ad libitum. Mechanistically, we found that chemogenetic activation of Agrp neurons reduced anxiety in fed mice, and inactivation of Agrp neurons reduced fasting-induced anxiolytic effects. Our results suggest that anxiety levels may vary physiologically with the increasing need for food, and are influenced by acute fasting in a time-dependent manner. Agrp neurons contribute to fasting-induced anxiolytic effects, supporting the notion that Agrp neuron may serve as an entry point for the treatment of energy states-related anxiety disorders.
The Lancet Psychiatry
Psychological distress was measured by the Australian of Bureau of Statistics with the Kessler Ps... more Psychological distress was measured by the Australian of Bureau of Statistics with the Kessler Psychological Distress Scale (K10). Data was taken from Jorm 2018. 5 Prevalence of antidepressant use was measured by the Organisation for Economic Cooperation and Development. 6 Mental health treatment through Better Access was obtained from the AIHW mental health medicare dataset. 7 Table 2: Prevalence and treatment of common mental health disorders in Australia Correspondence e9 www.thelancet.com/psychiatry Vol 6 March 2019 short-term gains for major depression, with limited evidence for longterm benefits. 3 Similarly, CBT has small to modest short-term effects for anxiety and depression. 9 More effective treatments for depression and better public health approaches must be developed, with tangible and quantifiable evidence of their effect at the population level. We declare no competing interests.
Molecular Neurobiology
Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its inc... more Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its incidence is expected to increase. Despite tremendous efforts to understand its underlying biological mechanisms, MDD pathophysiology remains elusive and pharmacotherapy outcomes are still far from ideal. Low-grade chronic inflammation seems to play a key role in mediating the interface between psychological stress, depressive symptomatology, altered intestinal microbiology, and MDD onset. We review the available pre-clinical and clinical evidence of an involvement of pro-inflammatory pathways in the pathogenesis, treatment, and remission of MDD. We focus on caspase 1, inducible nitric oxide synthase, and interferon gamma, three inflammatory systems dysregulated in MDD. Treatment strategies aiming at targeting such pathways alone or in combination with classical therapies could prove valuable in MDD. Further studies are needed to assess the safety and efficacy of immune modulation in MDD and other psychiatric disorders with neuroinflammatory components.
Science Advances
Schizophrenia (SCZ) is a devastating mental disorder with poorly defined underlying molecular mec... more Schizophrenia (SCZ) is a devastating mental disorder with poorly defined underlying molecular mechanisms. The gut microbiome can modulate brain function and behaviors through the microbiota-gut-brain axis. Here, we found that unmedicated and medicated patients with SCZ had a decreased microbiome α-diversity index and marked disturbances of gut microbial composition versus healthy controls (HCs). Several unique bacterial taxa (e.g., Veillonellaceae and Lachnospiraceae) were associated with SCZ severity. A specific microbial panel (Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae) enabled discriminating patients with SCZ from HCs with 0.769 area under the curve. Compared to HCs, germ-free mice receiving SCZ microbiome fecal transplants had lower glutamate and higher glutamine and GABA in the hippocampus and displayed SCZ-relevant behaviors similar to other mouse models of SCZ involving glutamatergic hypofunction. Together, our findings suggest that t...
BioEssays
We propose the "microbiota-inflammasome" hypothesis of major depressive disorder (MDD, a mental i... more We propose the "microbiota-inflammasome" hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long-lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro-inflammatory pathways mediated by the Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut dysbiosis. In this review we describe MDD/chronic stress-induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive-like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co-morbid conditions. A number of testable predictions surface from this microbiota-gut-inflammasome-brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change. 2. The Microbiota-Gut-Inflammasome-Brain Axis The microbiome-gut-brain axis consists of a communication network that controls and integrates gut and brain function, and that seems to be a central modulator of health and disease. [6] More specifically, there seems to exist a bidirectional communication between the gut and the brain, which occurs through multiple intertwined pathways, mediated by the vagus nerve, [7] the immune system, [8,9] and the bacterial metabolome (the ensemble of bacterial metabolic by-products and end products). [10,11] Recently, the role of the gut microbiome in shaping behavior, its interconnectedness with brain processes, and its potential involvement in the pathophysiology of MDD have come to the
European Neuropsychopharmacology
European Neuropsychopharmacology
BMJ open, Jan 11, 2017
To examine the association between antidepressant use and weight gain, as well as the interaction... more To examine the association between antidepressant use and weight gain, as well as the interaction with lifestyle factors. Longitudinal study. We used data from 2334 adults from two stages (4.4 years apart) of the North West Adelaide Health Study, including validated diet and lifestyle questionnaires, measured body weight and linked pharmaceutical prescription data. Body weight change. 188 (8.1%) participants had a mean annual number of 1-2 antidepressant prescriptions, and 212 (9.1%) had over two prescriptions. The mean annual weight gain was 0.12, 0.18 and 0.28 kg in non-users, low (1-2 prescriptions/year) and high (>2 prescriptions/year) antidepressant users, respectively. In multivariable regression models, antidepressant use was positively associated with weight gain: high antidepressant users gained an extra 0.22 (95% CI 0.00 to 0.44) kg per year. This association was mainly due to selective serotonin reuptake inhibitor (SSRI) use. High SSRI users gained 0.48 (95% CI 0.20 to...
Current Trends and Developments, 2000
The pharmacogenomics journal, 2011
Earlier we had found that the CYP2C9*2 allelic frequency was lower in Mexican-Americans living in... more Earlier we had found that the CYP2C9*2 allelic frequency was lower in Mexican-Americans living in California than in Spaniards (SP). This was assumed to be related to the low CYP2C9*2 and *3 allele frequencies in Orientals. This study was therefore aimed at analyzing whether there were also differences in CYP2C9 allele frequencies between Mexican-Tepehuanos (MT) and Mexican-Mestizos (MM) living in northwestern Mexico and SP. The CYP2C9*2 frequency was expected to be lower in the indigenous MT than in the two other groups, and lower in MM than in SP as in our earlier study. CYP2C9 genotypes and allele frequencies of two populations of healthy volunteers, MT (n=99) and MM (n=102), were compared with a population of SP (n=327). The data were also compared with our previously published population of Mestizo-Mexican-Americans (MA). The CYP2C9 genotypes among the studied populations were in equilibrium. The frequencies of CYP2C9*2 were 0.01, 0.07, 0.08, and 0.16 for MT, MM, MA, and SP sub...
Progress in neuro-psychopharmacology & biological psychiatry, Jan 15, 2007
Modulations of serotonergic and noradrenergic systems are thought to be critical to the therapeut... more Modulations of serotonergic and noradrenergic systems are thought to be critical to the therapeutic effect of most antidepressants, and their efficacies have been shown to depend on a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR). Mirtazapine has a dual-action profile, combining the enhancement of the noradrenergic neurotransmitter system with specific actions on particular serotonergic receptor subtypes. The goal of this study was to elucidate whether the 5-HTTLPR polymorphism is associated with the mirtazapine antidepressant response in subjects with major depressive disorder (MDD). One hundred and one MDD patients were evaluated during 4 weeks of mirtazapine treatment. The severity of depression was assessed with the 21-item Hamilton Depression Rating scale, and the 5-HTTLPR genotypes in the patients were determined using the polymerase chain reaction. Our results showed that responses at the 2nd and 4th weeks were significantly b...
Drug Discovery Series, 2009
Biology of Depression, 2005
... le substrate fo r in d u cing d epression -like sympto ms in ro d en ts. Anhed o nia is the m... more ... le substrate fo r in d u cing d epression -like sympto ms in ro d en ts. Anhed o nia is the m arked ly d imin ished interest o r p leasu ... s re-sem b lin g th ose ob served in dep ression . Anhed onia-like behaviors are reversed by ch ron ic but n o t acu te antidepressant treatm ent. ...