In the realm of clinical psychopharmacology, we have had the privilege of collaborating with a team of esteemed experts to forge a consensus on the biological treatment of bipolar disorder, embarking on an investigative journey that spanned from intricate cellular landscapes to complex neural circuits, with a dedicated focus on deciphering the enigmatic mechanisms behind the therapeutic potency of mood stabilizers. Our exploration, enriched by insights from animal models, highlighted the pivotal role of neuroglial cells as integral targets of pharmacological interventions, alongside neurons, and at the molecular level, we unveiled mood stabilizers' pronounced acetylation effect on histone tails, marking them as formidable epigenetic regulators. Central to our discoveries was the identification of neuroglial cells as pivotal conduits for the mental disorder drug valproate, further characterizing valproate as an epigenetic maestro and amplifying our understanding of its therapeutic arsenal. These revelations align with the notion that mood disorders emerge from the intricate interplay between environmental stimuli and cerebral responses, underscoring the complex tapestry of mental afflictions and echoing the necessity for a holistic approach in both understanding and treating these conditions.
Cheng, C.M., et al., Taiwan consensus on biological treatment of bipolar disorder during the acute, maintenance, and mixed phases: The 2022 update. Asian J Psychiatr, 2023. 82: p. 103480.
Chang, C.C., et al., Mitochondrial DNA Copy Number Is Associated With Treatment Response and Cognitive Function in Euthymic Bipolar Patients Receiving Valproate. Int J Neuropsychopharmacol, 2022. 25(7): p. 525-533.
Hsueh, Y.S., et al., Changes in striatal dopamine transporters in bipolar disorder and valproate treatment. Eur Psychiatry, 2021. 64(1): p. e9.
Chen, P.S., et al., Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry, 2006. 11(12): p. 1116-25.
Peng, G.S., et al., Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Research (Molecular Brain Research) (Brain Res Mol Brain Res), 2005. 134(1): p. 162-9.
Wu, X., et al., Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol, 2008. 11(8): p. 1123-34.
Chen, P.S., et al., Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience, 2007. 149(1): p. 203-12.
Kim, H.J., et al., Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther, 2007. 321(3): p. 892-901.
Learning and memory shapes our behaviors and affects our future decision-making. Although memory could be exclusively reflecting self-experience and the interpretation is individually different, learning is a process that is not limited to self-educated, and sometimes group communication is more efficient. Depending on the way how animal acquires knowledge; there are two major learning strategies, self-learning, learning by self, and social learning, learning through communicating with others. We used Drosophila melanogaster as a model animal to study two different types of learning, self-learning and social learning.
Self-learning:
We employ classical olfactory aversive conditioning to study memory formation and loss. We focus on how different learning paradigm affects memory retention and cellular mechanisms involved in memory forgetting and retrieval. Our study showed that training schedule is important to determine memory formation and retention. Effective training schedules help to establish memory and prevent stored information from being lost.
Social learning:
Our recent work showed that social communication is able to transfer not only innate fear but also learned fear information. We found the experience of learned fear in the demonstrator flies could be detected by surrounding naïve flies and promoting avoidance behaviors. However, experience of isolation damages animals’ social learning, suggesting isolation-induced stress could disrupt animals’ communication. This behavior is similar to many psychological disorders.
Overall, we aim to reveal the detailed cellular regulation process in memory formation and further understand how memory is damaged in pathological conditions.
Wang CM, Wu CY, Lin CE, Hsu MC, Lin JC, Huang CC, Lien TY, Lin HK, Chang TW, Chiang HC* (2023) Forgotten memory storage and retrieval in Drosophila. Nature Communications7;14(1):7153
Wu MS, Liao TW, Wu CY, Hsieh TH, Kuo PC, Li YC, Cheng KC, Chiang HC* (2023) Aversiveconditioning information transmission in Drosophila. Cell Reports 42(10):113207
Hsieh TC, Chiang HC* (2023). IMD signaling in the gut and the brain modulates Amyloid-betainduced deficits in Drosophila. Life sciences, 332, 122118.
Hu YY, Hsu CW, Tseng YH, Lin CY, Chiang HC, Chiang AS, Chang ST, Chen SJ. (2023). Temporal focusing multiphoton microscopy with cross-modality multi-stage 3D U-Net for fast and clear bioimaging. Biomedical optics express, 14(6), 2478–2491.
Cheng KC, Huang CY, Hsieh TC, Chiang HC*. (2022) Disrupted cellular calcium homeostasis is responsible for Aβ-induced learning and memory damage and lifespan shortening in a model of Aβ transgenic fly. IUBMB Life. 74(8):754-762
Cheng KC, Huang YL, Chiang HC*. (2021) The double-edged sword effect of HDAC6 in Aβ toxicities. FASEB J. 36:e22072.
Cheng KC, Cheung CHA, Chiang HC*. (2021) Early Aβ42 exposure causes learning impairment in later life. Aging and Disease. doi: 10.14336/AD.2021.1015
Cheng KC, Chen YH, Wu CL, Lee WP, Cheung CHA, Chiang HC*. (2021) Rac1 and Akt Exhibit Distinct Roles in Mediating Aβ-Induced Memory Damage and Learning Impairment. Mol Neurobiol. doi: 10.1007/s12035-021-02471-1.
Shyu WH, Lee WP, Chiang MH, Chang CC, Fu TF, Chiang HC, Wu T, Wu CL. (2019) Electrical synapses between mushroom body neurons are critical for consolidated memory retrieval in Drosophila. PLoS Genet. 15(5):e1008153. doi:
Chen YR, Li YH, Hsieh TC, Wang CM, Cheng KC, Wang L, Lin TY, Cheung A CH, Wu CL, Chiang H* (2019) Aging-induced Akt activation involves in aging-related pathologies and Ab-induced toxicity. Aging Cell. 18(4):e12989.
Wu CL, Chang CC, Wu JK, Chiang MH, Yang CH, Chiang HC. (2018) Mushroom body
glycolysis is required for olfactory memory in Drosophila. Neurobiol Learn Mem. 150:13-19.
Cheng KC, Chiang HC*. (2018) XBP1 and PERK Have Distinct Roles in Aβ-Induced Pathology. Mol Neurobiol. 55(9):7523-7532
Ji XR, Cheng KC, Chen YR, Lin TY, Cheung CHA, Wu CL, Chiang HC*. (2018) Dysfunction of different cellular degradation pathways contributes to specific β- amyloid42-induced pathologies. FASEB J. 32(3):1375-1387.
The overlap of depression with metabolic disturbances creates a complex clinical scenario marked by treatment challenges, a poor prognosis, and an increased risk of cognitive decline. My research has highlighted a significant prevalence of metabolic issues in severe mood disorders, further complicated by the effects of mood disorder medications on metabolic balance. We've delved into the relationship between emotional regulation and metabolic stability, focusing on the mesolimbic reward system and the impact of dopamine and oxytocin receptor variations on metabolic control. Studies have shown that a high-fat diet can lead to metabolic and depressive disorders in mice, which can be alleviated by diabetes medication. Additionally, stress exacerbates insulin resistance in the amygdala, linking to cognitive issues in mood disorder patients. The use of antidepressants and mood stabilizers may also disrupt metabolic balance. The discovery of chronic low-grade inflammation in patients with both depression and metabolic disturbances underscores the need for a holistic treatment approach that addresses the intricate dance between emotional and metabolic health.
Chang, H.H., et al., High prevalence of metabolic disturbances in patients with bipolar disorder in Taiwan. J Affect Disord, 2009. 117(1-2): p. 124-9.
Chang, H.H., et al., The role of valproate in metabolic disturbances in bipolar disorder patients. J Affect Disord, 2010. 124(3): p. 319-23.
Lee, C.J., et al., Factors related to metabolic parameters in medicated patients with major depressive disorder--a naturalistic study. Psychiatry Res, 2018. 268: p. 28-33.
Lee, S.Y., et al., Inflammation's Association with Metabolic Profiles before and after a Twelve-Week Clinical Trial in Drug-Naive Patients with Bipolar II Disorder. PLoS One, 2013. 8(6): p. e66847.
Chang, H.H., et al., C825T polymorphism of the GNB3 gene on valproate-related metabolic abnormalities in bipolar disorder patients. J Clin Psychopharmacol, 2010. 30(5): p. 512-7.
Chang, T.T., et al., The DRD3 Ser9Gly Polymorphism Predicted Metabolic Change in Drug-Naive Patients With Bipolar II Disorder. Medicine (Baltimore), 2016. 95(24): p. e3488.
Chang, H.H., et al., The OXTR Polymorphism Stratified the Correlation of Oxytocin and Glucose Homeostasis in Non-Diabetic Subjects. Diabetes Metab Syndr Obes, 2019. 12: p. 2707-2713.
Tsai, S.F., et al., High-fat diet induces depression-like phenotype via astrocyte-mediated hyperactivation of ventral hippocampal glutamatergic afferents to the nucleus accumbens. Mol Psychiatry, 2022. 27(11): p. 4372-4384.
Kuo, Y.Y., et al., Glibenclamide promotes FGF21 secretion in interscapular BAT and attenuates depression-like behaviors in male mice with HFD-induced obesity. Life Sci, 2023. 328: p. 121900.
Tsai, S.F., et al., Stress Aggravates High-Fat-Diet-Induced Insulin Resistance via a Mechanism That Involves the Amygdala and Is Associated with Changes in Neuroplasticity. Neuroendocrinology, 2018. 107(2): p. 147-157.
Tsai, T.H., et al., The relationship between peripheral insulin resistance and social cognitive deficits among euthymic patients with bipolar disorder. J Affect Disord, 2023.
Chang, H.H., et al., Peripheral insulin sensitivity predicting cognitive function in euthymic bipolar disorder patients. CNS Spectr, 2022. 27(5): p. 598-603.
Chang, H.H., et al., The change of insulin levels after six weeks antidepressant use in drug-naive major depressive patients. J Affect Disord, 2013. 150(2): p. 295-9.
Chang, H.H., et al., FGF21 Is Associated with Metabolic Effects and Treatment Response in Depressed Bipolar II Disorder Patients Treated with Valproate. Int J Neuropsychopharmacol, 2018. 21(4): p. 319-324.
Chang, H.H. and P.S. Chen, Inflammatory Biomarkers for Mood Disorders - A Brief Narrative Review. Curr Pharm Des, 2020. 26(2): p. 236-243.
Chang, H.H., et al., C-reactive protein: A differential biomarker for major depressive disorder and bipolar II disorder. World J Biol Psychiatry, 2017. 18(1): p. 63-70.
Chen, P.S., L.Y. Tang, and H.H. Chang, Roles of C-reactive protein polymorphisms and life event changes on cognitive function in bipolar patients receiving valproate. Int J Immunopathol Pharmacol, 2022. 36: p. 3946320221084835.
Chang, H.H., et al., Treatment response and cognitive impairment in major depression: association with C-reactive protein. Brain Behav Immun, 2012. 26(1): p. 90-5.
Wei, S.Y., et al., Associations of leptin and corticostriatal connectivity in bipolar disorder. Sci Rep, 2022. 12(1): p. 21898.
Tseng, H.H., et al., Peripheral inflammation is associated with dysfunctional corticostriatal circuitry and executive dysfunction in bipolar disorder patients. Brain Behav Immun, 2021. 91: p. 695-702.
Chang, H.H., et al., Effect of memantine on C-reactive protein and lipid profiles in bipolar disorder. J Affect Disord, 2017. 221: p. 151-157.
Social cognition encompasses the mental operations that facilitate our comprehension, perception, and interpretation of social cues, including the emotions, intentions, and behaviors exhibited by others. This cognitive domain is instrumental in determining our emotional reactions and the quality of our social engagements. In animal experiments, we employed a model of autism to substantiate the connection between abnormal excitation in the amygdala, a central component of the emotional brain, and atypical social behaviors. Our previous clinical studies have also highlighted a noticeable impairment in social cognitive functions among individuals with emotional disorders. Moreover, traumatic social experiences and loneliness are pivotal in molding social cognition. Childhood trauma, in particular, stands out as a substantial element that profoundly impacts the onset and evolution of mood disorders. Thus, the enhancement of social cognitive abilities can be a significant stride towards bolstering emotional intelligence and fortifying social bonds. In collaborative laboratories, experiments are underway to explore various pharmacological treatments, aiming to mitigate the deficits in social cognition and, by extension, ameliorate the associated emotional and social challenges.
Lin, H.C., et al., The amygdala excitatory/inhibitory balance in a valproate-induced rat autism model. PLoS One, 2013. 8(1): p. e55248.
Tsai, Y.T., et al., Social cognitive deficit is associated with visuomotor coordination impairment and dopamine transporter availability in euthymic bipolar disorder. J Psychiatr Res, 2023. 165: p. 158-164.
Liu, Y.C., et al., The social cognitive ability in Han Chinese euthymic patients with bipolar I and bipolar II disorder. J Formos Med Assoc, 2020.
Lee, C.N., et al., Associations of emotion recognition, loneliness, and social functioning in euthymic patients with bipolar disorder. Kaohsiung J Med Sci, 2022. 38(7): p. 703-711.
Tsai, T.Y., et al., The Interaction of Oxytocin and Social Support, Loneliness, and Cortisol Level in Major Depression. Clin Psychopharmacol Neurosci, 2019. 17(4): p. 487-494.
Hsieh, Y.T., et al., Childhood neglect is associated with corticostriatal circuit dysfunction in bipolar disorder adults. Psychiatry Res, 2021. 295: p. 113550.
Wu, H.F., et al., Alleviation of N-Methyl-D-Aspartate Receptor-Dependent Long-Term Depression via Regulation of the Glycogen Synthase Kinase-3beta Pathway in the Amygdala of a Valproic Acid-Induced Animal Model of Autism. Mol Neurobiol, 2017. 54(7): p. 5264-5276.
Wang, C.C., et al., 5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model. Int J Neuropsychopharmacol, 2013. 16(9): p. 2027-39.
Digital medicine represents a cutting-edge approach that holds significant promise in the treatment of mood disorders. By leveraging technologies such as wearables, data analytics, teletherapy platforms, and more, it enables a more personalized and continuous care paradigm. Remote monitoring technologies allow for real-time tracking of mood indicators and vital signs, providing clinicians with timely insights for intervention. Over the past few years, I have been involved with a research team that utilized mobile devices to record digital behavioral markers of cases with bipolar disorder. We attempted to employ machine learning to track the trends in their emotional changes and identify behavioral markers associated with relapse. In addition to sending reminder messages to the patients, we also hoped to achieve early intervention by notifying family members and the medical team. Mental health apps and online platforms are on the rise, making evidence-based treatments easily accessible to patients, overcoming geographical and appointment barriers. Digital medicine, integrating data insights and improved traditional therapy, is transforming the treatment of mood disorders. This shift towards innovative healthcare promises personalized treatments tailored to each patient's unique needs.
Tseng, Y.C., et al., Associations among smartphone app-based measurements of mood, sleep and activity in bipolar disorder. Psychiatry Res, 2022. 310: p. 114425.
Hsu, J.H., et al., Digital Phenotyping-Based Bipolar Disorder Assessment Using Multiple Correlation Data Imputation and Lasso-MLP. IEEE Transactions on Affective Computing, 2023: p. 1-14.
NIBS refers to a set of techniques that modulate brain activity without the need for surgery or implantation of electrodes. These methods are employed for various purposes, including the treatment of neurological and psychiatric disorders, cognitive enhancement, and research into brain function. NIBS is a rapidly evolving field, offering promising avenues for understanding the brain, treating disorders, and enhancing cognitive functions. My previous and joint research and clinical trials had tried to uncover the full potential and limitations of brain stimulation technologies, ensuring their safe and effective application in various domains of psychiatric disorders. In the filed of mood disorders, we have showed high-frequency repetitive transcranial magnetic stimulation treatment over the left dorsolateral prefrontal cortex has been identified as an effective intervention for depression associated with bipolar disorder. This non-invasive brain stimulation technique can be integrated safely as an adjunct to pharmacotherapy, enhancing the overall treatment efficacy for individuals suffering from bipolar depression. Ongoing research into personalized treatment and optimization may further underscore its potential within mood disorders care.
Kuo, M.F., P.S. Chen, and M.A. Nitsche, The application of tDCS for the treatment of psychiatric diseases. Int Rev Psychiatry, 2017. 29(2): p. 146-167.
Wu, H.F., et al., Deep Brain Stimulation Modified Autism-Like Deficits via the Serotonin System in a Valproic Acid-Induced Rat Model. Int J Mol Sci, 2018. 19(9).
Lin, S.H., et al., Transcranial direct current stimulation (tDCS) may reduce the expired CO concentration among opioid users who smoke cigarettes: a randomized sham-controlled study. Psychiatry Res, 2021. 299: p. 113874.
Wu, C.L., et al., Comparative efficacy of rTMS add-on treatment for bipolar depression versus unipolar depression. Brain Stimul, 2023. 16(4): p. 1102-1104.