Emergent treatments based on the pathophysiology of bipolar disorder: A selective review

Brady, Roscoe O.; Keshavan, Matcheri S.

doi:10.1016/j.ajp.2015.07.017

Cited by 10 publications

(4 citation statements)

References 58 publications

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“…These models are tested for their face (animals mimicking manic symptoms), construct (correlation of similar pathophysiological alteration at molecular level), and predictive (amelioration of symptoms by currently accepted treatments of mania) validity to enhance our understanding of BD [10]. Our advances in neuroimaging techniques, such as in vivo magnetic resonance imaging, and novel genetic approach, such as convergent functional genomics, are providing us endophenotypic characteristics of BD [11]. After 3 decades of intensive preclinical and translational research, protein kinase C (PKC) has come to be recognized to play a central role in the pathophysiology of BD [12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

et al. 2017

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Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD.

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Section: Introductionmentioning

confidence: 99%

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

et al. 2017

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“…While source localization was based on a mathematical model rather than direct physiological measures, our results provide direction for further studies using higher spatial resolution methods to investigate differences in neural activation patterns among BD patient subtypes and HCs during tasks that should evoke empathy. Furthermore, as previous treatment attempts have targeted specific neuroanatomic structures, such as transcranial magnetic stimulation4344, these findings may help define the most therapeutically effective targets for activity modulation.…”

Section: Discussionmentioning

confidence: 90%

Decreased empathy response to other people’s pain in bipolar disorder: evidence from an event-related potential study

Yang

et al. 2017

Sci Rep

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Bipolar disorder (BD) patients often demonstrate poor socialization that may stem from a lower capacity for empathy. We examined the associated neurophysiological abnormalities by comparing event-related potentials (ERP) between 30 BD patients in different states and 23 healthy controls (HCs, matched for age, sex, and education) during a pain empathy task. Subjects were presented pictures depicting pain or neutral images and asked to judge whether the person shown felt pain (pain task) and to identify the affected side (laterality task) during ERP recording. Amplitude of pain-empathy related P3 (450–550 ms) of patients versus HCs was reduced in painful but not neutral conditions in occipital areas [(mean (95% confidence interval), BD vs. HCs: 4.260 (2.927, 5.594) vs. 6.396 (4.868, 7.924)] only in pain task. Similarly, P3 (550–650 ms) was reduced in central areas [4.305 (3.029, 5.581) vs. 6.611 (5.149, 8.073)]. Current source density in anterior cingulate cortex differed between pain-depicting and neutral conditions in HCs but not patients. Manic severity was negatively correlated with P3 difference waves (pain – neutral) in frontal and central areas (Pearson r = −0.497, P = 0.005; r = −0.377, P = 0.040). Electrophysiological correlates of empathy processing are reduced in BD depending on manic symptom severity.

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“…Bipolar depression (BD) is a serious psychiatric condition with a high mortality rate due to suicide [ 2 ]. Between 25% and 60% of those with BD will attempt suicide at least once, and 10%-15% will die by suicide [ 3 - 5 ]. Several interventions, such as lithium, clozapine, electroconvulsive therapy, and cognitive behavioral therapy, have demonstrated antisuicidal properties [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Neural Correlates of the DEEPP (Anti-suicidal Response to Ketamine in Treatment-Resistant Bipolar Depression) Study: Protocol for a Pilot, Open-Label Clinical Trial

et al. 2023

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Background Suicide is among the top 10 leading causes of death worldwide. Of people who died by suicide, the majority are diagnosed with depression. It is estimated that 25%-60% of people with bipolar depression (BD) will attempt suicide at least once, and 10%-15% will die by suicide. Several treatments, such as lithium, clozapine, electroconvulsive therapy, and cognitive behavioral therapy, have been shown to be effective in treating suicidality. However, these treatments can be difficult to tolerate or may take months to take effect. Ketamine, a glutamate N-methyl-D-aspartate antagonist, has been shown to have rapid antisuicidal effect and antidepressant qualities, and is thus a promising intervention to target acute suicidality in patients with BD. However, the biological mechanism underlying its therapeutic action remains poorly understood. Enhancing our understanding of underlying mechanisms of action for ketamine’s effectiveness in reducing suicidality is critical to establishing biological markers of treatment response and developing tailored, personalized interventions for patients with BD. Objective This is an open-label clinical trial to test the safety and feasibility of repeated ketamine infusions to treat acute suicidality. The primary objective is to test the safety and feasibility of ketamine intervention. The secondary objective is to examine ketamine’s potential neurophysiological mechanisms of action by assessing cortical excitation and inhibition to determine potential biomarkers of clinical response. Other objectives are to evaluate the effect of ketamine on acute suicidality and other clinical outcomes, such as depressive symptoms and quality of life, to inform a future larger trial. Methods This open-label clinical trial aims to test the safety and feasibility of repeated ketamine infusions in patients with BD for suicidality and to assess ketamine’s neurophysiological effects. A sterile form of racemic ketamine hydrochloride will be administered over a 40-minute intravenous infusion 2 times per week on nonconsecutive days for 4 weeks (8 sessions). We will recruit 30 adults (24-65 year olds) over 2 years from an academic psychiatric hospital in Toronto, Canada. Results This study is currently ongoing and actively recruiting participants. So far, 5 participants have completed the trial, 1 is currently in active treatment, and 8 participants are on the waitlist to be screened. We anticipate initial results being available in the fall of 2023. This proposal was presented as a poster presentation at the Research to Reality Global Summit on Psychedelic-Assisted Therapies and Medicine, held in May 2022 in Toronto, Canada. Conclusions Developing effective interventions for acute suicidality in high-risk populations such as those with BD remains a major therapeutic challenge. Ketamine is a promising treatment due to its rapid antidepressant and antisuicidal effects, but its underlying neurophysiological mechanisms of action remain unknown. Trial Registration ClinicalTrials.gov NCT05177146; https://clinicaltrials.gov/ct2/show/NCT05177146 International Registered Report Identifier (IRRID) DERR1-10.2196/41013

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Emergent treatments based on the pathophysiology of bipolar disorder: A selective review

Cited by 10 publications

References 58 publications

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Decreased empathy response to other people’s pain in bipolar disorder: evidence from an event-related potential study

Neural Correlates of the DEEPP (Anti-suicidal Response to Ketamine in Treatment-Resistant Bipolar Depression) Study: Protocol for a Pilot, Open-Label Clinical Trial

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