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Acta Psychiatrica Scandinavica Sep 2021Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We... (Review)
Review
OBJECTIVES
Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research.
METHOD
A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library.
RESULTS
Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone.
CONCLUSIONS
The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.
Topics: Antimanic Agents; Bipolar Disorder; Humans; Lithium Compounds; Polypharmacy; Valproic Acid
PubMed: 33960396
DOI: 10.1111/acps.13312 -
Current Neuropharmacology 2024Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with increased prevalence and incidence in recent decades. Its etiology remains largely unclear, but it... (Review)
Review
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with increased prevalence and incidence in recent decades. Its etiology remains largely unclear, but it seems to involve a strong genetic component and environmental factors that, in turn, induce epigenetic changes during embryonic and postnatal brain development. In recent decades, clinical studies have shown that inutero exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug, is an environmental factor associated with an increased risk of ASD. Subsequently, prenatal VPA exposure in rodents has been established as a reliable translational model to study the pathophysiology of ASD, which has helped demonstrate neurobiological changes in rodents, non-human primates, and brain organoids from human pluripotent stem cells. This evidence supports the notion that prenatal VPA exposure is a valid and current model to replicate an idiopathic ASD-like disorder in experimental animals. This review summarizes and describes the current features reported with this animal model of autism and the main neurobiological findings and correlates that help elucidate the pathophysiology of ASD. Finally, we discuss the general framework of the VPA model in comparison to other environmental and genetic ASD models.
Topics: Pregnancy; Animals; Female; Humans; Valproic Acid; Autism Spectrum Disorder; Disease Models, Animal; Prenatal Exposure Delayed Effects; Anticonvulsants; Rodentia
PubMed: 37873949
DOI: 10.2174/1570159X22666231003121513 -
Asian Journal of Psychiatry Jul 2023Mood stabilizers are psychotropic drugs mainly used to treat bipolar disorder in the acute phase or for maintenance therapy to prevent relapse. In clinical practice,...
OBJECTIVE
Mood stabilizers are psychotropic drugs mainly used to treat bipolar disorder in the acute phase or for maintenance therapy to prevent relapse. In clinical practice, mood stabilizers are commonly prescribed for conditions other than bipolar disorder. This study investigated the distribution of mood stabilizer prescriptions for different psychiatric diagnoses and studied differences in the drugs, dosage, and plasma concentration in 10 Asian countries including Taiwan, South Korea, Malaysia, China, Thailand, India, Pakistan, Singapore, Indonesia, and Myanmar.
METHODS
Patients prescribed mood stabilizers (lithium, carbamazepine, valproic acid, or lamotrigine) for a psychiatric condition other than bipolar disorder (codes F31.0-F31.9 in the International Classification of Diseases, 10th Edition, Clinical Modification) were recruited through convenience sampling. A website-based data entry system was used for data collection.
RESULTS
In total, 1557 psychiatric patients were enrolled. Schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders (F20-F29, 55.8 %) was the most common diagnosis, followed by non-bipolar mood disorders (F30, F31- F39, 25.3 %), organic mental disorder (F00-F09, 8.8 %), mental retardation (F70-F79, 5.8 %) and anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders (F40-F48, 4.4 %). The most frequently targeted symptoms (>20 %) were irritability (48 %), impulsivity (32.4 %), aggression (29.2 %), anger (20.8 %), and psychosis (24.1 %). Valproic acid was the most frequently used medication.
CONCLUSIONS
Clinicians typically prescribe mood stabilizers as empirically supported treatment to manage mood symptoms in patients with diagnoses other than bipolar disorders, though there is on official indication for these disorders. The costs and benefits of this add-on symptomatic treatment warrant further investigation.
Topics: Humans; Bipolar Disorder; Valproic Acid; Antimanic Agents; Antipsychotic Agents; Anticonvulsants; Pakistan
PubMed: 37163943
DOI: 10.1016/j.ajp.2023.103613 -
Biomedicine & Pharmacotherapy =... May 2021Autism spectrum disorder (ASD) is a sort of mental disorder marked by deficits in cognitive and communication abilities. To date no effective cure for this pernicious... (Review)
Review
Autism spectrum disorder (ASD) is a sort of mental disorder marked by deficits in cognitive and communication abilities. To date no effective cure for this pernicious disease has been available. Valproic acid (VPA) is a broad-spectrum, antiepileptic drug, and it is also a potent teratogen. Epidemiological studies have shown that children exposed to VPA are at higher risk for ASD during the first trimester of their gestational development. Several animal and human studies have demonstrated important behavioral impairments and morphological changes in the brain following VPA treatment. However, the mechanism of VPA exposure-induced ASD remains unclear. Several factors are involved in the pathological phase of ASD, including aberrant excitation/inhibition of synaptic transmission, neuroinflammation, diminished neurogenesis, oxidative stress, etc. In this review, we aim to outline the current knowledge of the critical pathophysiological mechanisms underlying VPA exposure-induced ASD. This review will give insight toward understanding the complex nature of VPA-induced neuronal toxicity and exploring a new path toward the development of novel pharmacological treatment against ASD.
Topics: Animals; Anticonvulsants; Autism Spectrum Disorder; Female; Humans; Neurotoxicity Syndromes; Pregnancy; Prenatal Exposure Delayed Effects; Valproic Acid
PubMed: 33761592
DOI: 10.1016/j.biopha.2021.111322 -
Cancer Letters Apr 2023Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic... (Review)
Review
Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic effects of valproate have been assessed in several in vitro and in vivo preclinical studies, suggesting that this agent significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. During the last years various clinical trials have tried to find out if valproate co-administration could enhance the antineoplastic activity of chemotherapy in glioblastoma patients and in patients suffering from brain metastases, demonstrating that the inclusion of valproate in the therapeutic schedule causes an improved median overall survival in some studies, but not in others. Thus, the effects of the use of concomitant valproate in brain cancer patients are still controversial. Similarly, lithium has been tested as an anticancer drug in several preclinical studies mainly using the unregistered formulation of lithium chloride salts. Although, there are no data showing that the anticancer effects of lithium chloride are superimposable to the registered lithium carbonate, this formulation has shown preclinical activity in glioblastoma and hepatocellular cancers. However, few but interesting clinical trials have been performed with lithium carbonate on a very small number of cancer patients. Based on published data, valproate could represent a potential complementary therapeutic approach to enhance the anticancer activity of brain cancer standard chemotherapy. Same advantageous characteristics are less convincing for lithium carbonate. Therefore, the planning of specific phase III studies is necessary to validate the repositioning of these drugs in present and future oncological research.
Topics: Humans; Valproic Acid; Lithium Carbonate; Lithium; Bipolar Disorder; Pharmaceutical Preparations; Lithium Chloride; Glioblastoma; Antimanic Agents; Brain Neoplasms
PubMed: 36914086
DOI: 10.1016/j.canlet.2023.216125 -
Medical Science Monitor : International... Feb 2020BACKGROUND Multiple myeloma is featured by the proliferation of malignant plasma cell in bone marrow. We aimed to demonstrate the effects of valproic acid combined with...
BACKGROUND Multiple myeloma is featured by the proliferation of malignant plasma cell in bone marrow. We aimed to demonstrate the effects of valproic acid combined with GANT61 on multiple myeloma cell proliferation and clarify its mechanism. MATERIAL AND METHODS Multiple myeloma cells were exposed to valproic acid, GANT61, or the combination of valproic acid and GANT61, respectively. MTT assay was performed to detect the cell viability. Quantitative reverse transcriptase polymerase chain reaction and western blotting were used to detect mRNA and expression levels of proteins in Hedgehog signaling pathway. The Q-value of the combination regime was calculated to evaluate the drug combination effect. RESULTS Both valproic acid and GANT61 alone inhibited multiple myeloma cell proliferation in a dose-dependent manner compared to the control. In the presence of GANT61 or not, valproic acid inhibited multiple myeloma cell proliferation in a time-dependent manner. These 2 drugs had a synergistic effect at valproic acid concentration of ≥4 mM. Expression analysis showed that valproic acid significantly inhibited the expression levels of PTCH1, GLI1, and HES-1. GANT61 enhanced the inhibition of Hedgehog signaling pathway mediated by valproic acid. CONCLUSIONS GANT61 and valproic acid inhibited multiple myeloma cell proliferation synergistically by inhibiting the Hedgehog signaling pathway. The present study may provide a combination regime for the therapy of multiple myeloma.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Drug Synergism; Hedgehog Proteins; Humans; Multiple Myeloma; Pyridines; Pyrimidines; Signal Transduction; Valproic Acid
PubMed: 32054823
DOI: 10.12659/MSM.920541 -
Scientific Reports Jan 2021Valproic acid (VPA) is widely prescribed to treat epilepsy. Maternal VPA use is, however, clinically restricted because of the severe risk that VPA may cause...
Valproic acid (VPA) is widely prescribed to treat epilepsy. Maternal VPA use is, however, clinically restricted because of the severe risk that VPA may cause neurodevelopmental disorders in offspring, such as autism spectrum disorder. Understanding the negative action of VPA may help to prevent VPA-induced neurodevelopmental disorders. Astrocytes play a vital role in neurodevelopment and synapse function; however, the impact of VPA on astrocyte involvement in neurodevelopment and synapse function has not been examined. In this study, we examined whether exposure of cultured astrocytes to VPA alters neuronal morphology and synapse function of co-cultured neurons. We show that synaptic transmission by inhibitory neurons was small because VPA-exposed astrocytes reduced the number of inhibitory synapses. However, synaptic transmission by excitatory neurons and the number of excitatory synapses were normal with VPA-exposed astrocytes. VPA-exposed astrocytes did not affect the morphology of inhibitory neurons. These data indicate that VPA-exposed astrocytes impair synaptogenesis specifically of inhibitory neurons. Our results indicate that maternal use of VPA would affect not only neurons but also astrocytes and would result in perturbed astrocyte-mediated neurodevelopment.
Topics: Animals; Anticonvulsants; Astrocytes; Cells, Cultured; Coculture Techniques; Female; GABAergic Neurons; Maternal-Fetal Exchange; Mice; Mice, Inbred ICR; Neurons; Pregnancy; RNA, Messenger; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Synapses; Synaptic Transmission; Valproic Acid
PubMed: 33420078
DOI: 10.1038/s41598-020-79520-7 -
The Journal of International Medical... Jun 2023To investigate the effects of valproic acid (VPA) on skin wound healing in mice.
OBJECTIVE
To investigate the effects of valproic acid (VPA) on skin wound healing in mice.
METHODS
Full-thickness wounds were created in mice, and then VPA was applied. The wound areas were quantified daily. In the wounds, granulation tissue growth, epithelialization, collagen deposition, and the mRNA levels of inflammatory cytokines were measured; furthermore, apoptotic cells were labeled. , VPA was added to RAW 264.7 cells (macrophages) stimulated with lipopolysaccharide, and apoptotic Jurkat cells were cocultured with the VPA-pretreated macrophages. Then, phagocytosis was analyzed, and the mRNA levels of phagocytosis-associated molecules and inflammatory cytokines were measured in the macrophages.
RESULTS
VPA application significantly accelerated wound closure, granulation tissue growth, collagen deposition, and epithelialization. In wounds, the levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β were decreased by VPA, whereas those of IL-10 and transforming growth factor-β1 were increased. Additionally, VPA reduced the number of apoptotic cells. , VPA inhibited the inflammatory activation of macrophages and promoted the phagocytosis of apoptotic cells by macrophages.
CONCLUSION
VPA accelerated skin wound healing, which could be partly attributable to its anti-inflammatory and apoptotic cell clearance-promoting effects, indicating that VPA could be a promising candidate for enhancing skin wound healing.
Topics: Animals; Mice; Valproic Acid; Phagocytosis; Anti-Inflammatory Agents; Cytokines; Interleukin-6; RNA, Messenger; Apoptosis; Wound Healing
PubMed: 37389885
DOI: 10.1177/03000605231184038 -
Seizure Jul 2019We systematically reviewed studies to provide current evidence about the incidence and risk of alopecia in patients undergoing valproic acid (VPA) therapy. (Meta-Analysis)
Meta-Analysis
PURPOSE
We systematically reviewed studies to provide current evidence about the incidence and risk of alopecia in patients undergoing valproic acid (VPA) therapy.
METHODS
We retrieved relevant publications and gathered data on alopecia in patients taking VPA and other drugs from prospective studies.
RESULTS
Twenty-five articles met the inclusion criteria, and the overall incidence of alopecia in patients receiving VPA therapy was 11% (95% confidence interval (CI): 0.08-0.13). The pooled risk of alopecia showed a significant difference between patients treated with VPA and all other drugs (odds ratio (OR) 5.02, 95% CI: 3.58-7.03), other epileptic drugs (AEDs) (OR 4.82, 95% CI: 3.32-7.00) and other non-AEDs (OR 5.84, 95% CI: 2.67-12.81). Compared to other drugs, VPA increased the risk of alopecia both in patients with migraine headaches (OR 6.05, 95% CI: 2.89-12.63) and patients with epilepsy (OR 5.29, 95% CI: 3.53-7.92), and the increase risk was reported more frequently in patients with migraine. Both lower doses (OR 4.38, 95% CI: 2.32-8.25) and shorter treatments (OR 4.98, 95% CI: 2.41-10.25) with VPA posed a high risk of alopecia compared to other drugs, as did higher doses and longer treatment times.
CONCLUSIONS
Based on our findings, VPA was significantly associated with a risk of alopecia compared to other drugs, and the risk did not depend on the dose and treatment time.
Topics: Alopecia; Anticonvulsants; Epilepsy; Humans; Incidence; Prospective Studies; Valproic Acid
PubMed: 30981051
DOI: 10.1016/j.seizure.2019.04.003 -
Journal of Biomedical Science Jan 2022Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no successful therapeutics are available. Valproic acid (VPA), a monocarboxylate...
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no successful therapeutics are available. Valproic acid (VPA), a monocarboxylate derivative, is a known antiepileptic drug and a histone deacetylase inhibitor.
METHODS
To investigate whether monocarboxylate transporter 1 (MCT1) and sodium-coupled MCT1 (SMCT1) are altered in ALS cell and mouse models, a cellular uptake study, quantitative real time polymerase chain reaction and western blot parameters were used. Similarly, whether VPA provides a neuroprotective effect in the wild-type (WT; hSOD1WT) and ALS mutant-type (MT; hSOD1G93A) NSC-34 motor neuron-like cell lines was determined through the cell viability assay.
RESULTS
[H]VPA uptake was dependent on time, pH, sodium and concentration, and the uptake rate was significantly lower in the MT cell line than the WT cell line. Interestingly, two VPA transport systems were expressed, and the VPA uptake was modulated by SMCT substrates/inhibitors in both cell lines. Furthermore, MCT1 and SMCT1 expression was significantly lower in motor neurons of ALS (G93A) model mice than in those of WT mice. Notably, VPA ameliorated glutamate- and hydrogen peroxide-induced neurotoxicity in both the WT and MT ALS cell lines.
CONCLUSIONS
Together, the current findings demonstrate that VPA exhibits a neuroprotective effect regardless of the dysfunction of an MCT in ALS, which could help develop useful therapeutic strategies for ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Mice; Mice, Transgenic; Monocarboxylic Acid Transporters; Motor Neurons; Neuroprotective Agents; Superoxide Dismutase; Symporters; Valproic Acid
PubMed: 35012534
DOI: 10.1186/s12929-022-00785-3