Is the brain arachidonic acid cascade a common target of drugs used to manage bipolar disorder?

2009 ◽  
Vol 37 (5) ◽  
pp. 1104-1109 ◽  
Author(s):  
Richard P. Bazinet
Keyword(s):  
Bipolar Disorder ◽  
Valproic Acid ◽  
Arachidonic Acid ◽  
Rat Brain ◽  
Bipolar Depression ◽  
Chronic Administration ◽  
Mood Stabilizers ◽  
Arachidonic Acid Cascade ◽  
Brain Phospholipids ◽  
The Brain

Although lithium has been used therapeutically to treat patients with bipolar disorder for over 50 years, its mechanism of action, as well as that of other drugs used to treat bipolar disorder, is not agreed upon. In the present paper, I review studies in unanaesthetized rats using a neuropharmacological approach, combined with kinetic, biochemical and molecular biology techniques, demonstrating that chronic administration of three commonly used mood stabilizers (lithium, valproic acid and carbamazepine), at therapeutically relevant doses, selectively target the brain arachidonic acid cascade. Upon chronic administration, lithium and carbamazepine decrease the binding activity of activator protein-2 and, in turn, the transcription, translation and activity of its arachidonic acid-selective calcium-dependent phospholipase A2 gene product, whereas chronic valproic acid non-competitively inhibits long-chain acyl-CoA synthetase. The net overlapping effects of the three mood stabilizers are decreased turnover of arachidonic acid, but not of docosahexaenoic acid, in rat brain phospholipids, as well as decreased brain cyclo-oxygenase-2 and prostaglandin E2. As an extension of this theory, drugs that are thought to induce switching to mania, especially when administered during bipolar depression (fluoxetine and imipramine), up-regulate enzymes of the arachidonic acid cascade and turnover of arachidonic acid in rat brain phospholipids. Future basic and clinical studies on the arachidonic acid hypothesis of bipolar disorder are warranted.

Neural network dysfunction in bipolar depression: clues from the efficacy of lamotrigine

2009 ◽  
Vol 37 (5) ◽  
pp. 1080-1084 ◽  
Author(s):  
Charles H. Large ◽  
Elena Di Daniel ◽  
Xingbao Li ◽  
Mark S. George
Keyword(s):  
Bipolar Disorder ◽  
Valproic Acid ◽  
Protein Kinase ◽  
Glycogen Synthase ◽  
Bipolar Depression ◽  
Inhibitory Effect ◽  
Mood Stabilizers ◽  
Mitogen Activated Protein Kinase ◽  
Facilitatory Effect

One strategy to understand bipolar disorder is to study the mechanism of action of mood-stabilizing drugs, such as valproic acid and lithium. This approach has implicated a number of intracellular signalling elements, such as GSK3β (glycogen synthase kinase 3β), ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) or protein kinase C. However, lamotrigine does not seem to modulate any of these targets, which is intriguing given that its profile in the clinic differs from that of valproic acid or lithium, with greater efficacy to prevent episodes of depression than mania. The primary target of lamotrigine is the voltage-gated sodium channel, but it is unclear why inhibition of these channels might confer antidepressant efficacy. In healthy volunteers, we found that lamotrigine had a facilitatory effect on the BOLD (blood-oxygen-level-dependent) response to TMS (transcranial magnetic stimulation) of the prefrontal cortex. This effect was in contrast with an inhibitory effect of lamotrigine when TMS was applied over the motor cortex. In a follow-up study, a similar prefrontal specific facilitatory effect was observed in a larger cohort of healthy subjects, whereas valproic acid inhibited motor and prefrontal cortical TMS-induced BOLD response. In vitro, we found that lamotrigine (3–10 μM) enhanced the power of gamma frequency network oscillations induced by kainic acid in the rat hippocampus, an effect that was not observed with valproic acid (100 μM). These data suggest that lamotrigine has a positive effect on corticolimbic network function that may differentiate it from other mood stabilizers. The results are also consistent with the notion of corticolimbic network dysfunction in bipolar disorder.

Prescribing practices of Indian psychiatrists in the treatment of bipolar disorder

2019 ◽  
Vol 53 (5) ◽  
pp. 458-469 ◽  
Author(s):  
YC Janardhan Reddy ◽  
Venugopal Jhanwar ◽  
Rajesh Nagpal ◽  
MS Reddy ◽  
Nilesh Shah ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Maintenance Treatment ◽  
Bipolar Depression ◽  
Mood Stabilizer ◽  
Self Report ◽  
Mood Stabilizers ◽  
Prescribing Practices ◽  
Term Outcome ◽  
Cross Sectional ◽  
Long Term Outcome

Objective: The treatment of bipolar disorder is challenging because of its clinical complexity and availability of multiple treatment options, none of which are ideal mood stabilizers. This survey studies prescription practices of psychiatrists in India and their adherence to guidelines. Method: In total, 500 psychiatrists randomly selected from the Indian Psychiatric Society membership directory were administered a face-to-face 22-item questionnaire pertaining to the management of bipolar disorder. Results: For acute mania, most practitioners preferred a combination of a mood stabilizer and an atypical antipsychotic to monotherapy. For acute depression, there was a preference for a combination of an antidepressant and a mood stabilizer over other alternatives. Electroconvulsive therapy was preferred in the treatment of severe episodes and to hasten the process of recovery. Approximately, 50% of psychiatrists prescribe maintenance treatment after the first bipolar episode, but maintenance therapy was rarely offered lifelong. While the majority (85%) of psychiatrists acknowledged referring to various clinical guidelines, their ultimate choice of treatment was also significantly determined by personal experience and reference to textbooks. Limitations: The study did not study actual prescriptions. Hence, the responses to queries in the survey are indirect measures from which we have tried to understand the actual practices, and of course, these are susceptible to self-report and social-desirability biases. This was a cross-sectional study; therefore, temporal changes in responses could not be considered. Conclusion: Overall, Indian psychiatrists seemed to broadly adhere to recommendations of clinical practice guidelines, but with some notable exceptions. The preference for antidepressants in treating depression is contrary to general restraint recommended by most guidelines. Therefore, the efficacy of antidepressants in treating bipolar depression in the context of Indian psychiatrists’ practice needs to be studied systematically. Not initiating maintenance treatment early in the course of illness may have serious implications on the long-term outcome of bipolar disorder.

scholarly journals Decreased NOX2 expression in the brain of patients with bipolar disorder: association with valproic acid prescription and substance abuse

2017 ◽  
Vol 7 (8) ◽  
pp. e1206-e1206 ◽  
Author(s):  
T Seredenina ◽  
S Sorce ◽  
F R Herrmann ◽  
X-J Ma Mulone ◽  
O Plastre ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Substance Abuse ◽  
Valproic Acid ◽  
The Brain

scholarly journals General pharmacokinetic/pharmacodynamic concepts of mood stabilizers in the treatment of bipolar disorder

2016 ◽  
Vol 6 (1) ◽  
pp. 54-61 ◽  
Author(s):  
Kenric Ware ◽  
Erika Tillery ◽  
Lauren Linder
Keyword(s):  
Bipolar Disorder ◽  
Valproic Acid ◽  
Mood Stabilizer ◽  
Patient Characteristics ◽  
Well Being ◽  
Mood Stabilizers ◽  
Medline Search ◽  
Recommended Treatment ◽  
Clinical Databases ◽  
Mitigating Factors

Abstract Introduction Mood stabilizers are the recommended treatment for patients who receive a diagnosis of bipolar disorder. Because of the necessity of mood stabilizer treatment in patients with bipolar disorder and the extent of pharmacokinetic and pharmacodynamic principles involved, the purpose of this review is to summarize the pharmacokinetic principles of lithium in addition to the pharmacodynamics of lithium, carbamazepine, lamotrigine, and valproic acid/valproate. Methods Practice guidelines, review articles, and clinical trials were located using online databases PubMed, CINAHL, IDIS, and Medline. Search terms included at least one of the following: bipolar disorder, carbamazepine, lamotrigine, lithium, mood stabilizers, pharmacokinetics, pharmacodynamics, valproate, and valproic acid. Online clinical databases Dynamed® and Lexicomp® were also used in the study. Results Mood stabilizers collectively possess distinct qualities that are closely regarded before, during, and after therapeutic initiation. Individual patient characteristics, coupled with these observed traits, add to the complexity of selecting the most optimal neurologic agent. Each medication discussed uniquely contributes to both the maintenance and restoration of overall patient well-being. Discussion Introduction of mood stabilizers into drug regimens is often done in the presence of an array of mitigating factors. Safety and efficacy measures are commonly used to gauge desired results. Careful monitoring of patients' responses to selected therapies is paramount for arriving at appropriate clinical outcomes.

Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports

2021 ◽  
Author(s):  
Sandeep Nayak ◽  
Natalie Gukasyan ◽  
Frederick S. Barrett ◽  
Earth Erowid ◽  
Fire Erowid ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Bipolar Depression ◽  
Mood Stabilizer ◽  
Unipolar Depression ◽  
Mood Stabilizers ◽  
Medical Attention ◽  
Limited Information ◽  
Media Reports

Introduction: Psychedelics show promise in treating unipolar depression, though patients with bipolar disorder have been excluded from recent psychedelic trials. There is limited information on the use of classic psychedelics (e.g. LSD or psilocybin) in individuals using mood stabilizers to treat bipolar disorder. This is important to know as individuals with bipolar depression may attempt to treat themselves with psychedelics while on a mood stabilizer, particularly given enthusiastic media reports of the efficacy of psilocybin for depression.Methods: This study analyzed reports of classic psychedelics administered with mood stabilizers from three websites (Erowid.org, Shroomery.org, and Reddit.com).Results: Strikingly, 47% of 62 lithium plus psychedelic reports involved seizures and an additional 18% resulted in bad trips while none of 34 lamotrigine reports did. Further, 39% of lithium reports involved medical attention. Most of the lamotrigine reports (65%) but few (8%) of the lithium reports were judged to have no effect on the psychedelic experience.Discussion: Although further research is needed, we provisionally conclude that psychedelic use may pose a significant seizure risk for patients on lithium.

Molecular targets of lithium action

2003 ◽  
Vol 15 (6) ◽  
pp. 316-340 ◽  
Author(s):  
B Corbella ◽  
E Vieta
Keyword(s):  
Bipolar Disorder ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Mood Stabilizers ◽  
Lithium Cation ◽  
Therapeutic Effects ◽  
Term Outcome ◽  
Long Term Outcome ◽  
The Brain

Lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. However, the precise mechanism of lithium action is not yet well understood. Extensive research aiming to elucidate the molecular mechanisms underlying the therapeutic effects of lithium has revealed several possible targets. The behavioral and physiological manifestations of the illness are complex and are mediated by a network of interconnected neurotransmitter pathways. Thus, lithium's ability to modulate the release of serotonin at presynaptic sites and modulate receptor-mediated supersensitivity in the brain remains a relevant line of investigation. However, it is at the molecular level that some of the most exciting advances in the understanding of the long-term therapeutic action of lithium will continue in the coming years. The lithium cation possesses the selective ability, at clinically relevant concentrations, to alter the PI second-messenger system, potentially altering the activity and dynamic regulation of receptors that are coupled to this intracellular response. Subtypes of muscarinic receptors in the limbic system may represent particularly sensitive targets in this regard. Likewise, preclinical data have shown that lithium regulates arachidonic acid and the protein kinase C signaling cascades. It also indirectly regulates a number of factors involved in cell survival pathways, including cAMP response element binding protein, brain-derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases, and may thus bring about delayed long-term beneficial effects via under-appreciated neurotrophic effects. Identification of the molecular targets for lithium in the brain could lead to the elucidation of the pathophysiology of bipolar disorder and the discovery of a new generation of mood stabilizers, which in turn may lead to improvements in the long-term outcome of this devastating illness (1).

Sign in / Sign up

Export Citation Format

Share Document