Depressive Phase of Bipolar Disorder
Dr. Ather Muneer in Mood Disorders, 2018
Eslicarbazepine (ESC), the active enantiomer of metabolized OXC, shares the dibenzazepine ring with its parent compound and CBZ. The drug was approved for epilepsy by the European Medicines Agency in 2009, and since then has been investigated in BD. Presently, it has no approved psychiatric indications, and in a recently published RCT in acute mania, the drug failed to differ from placebo. However, ESC showed valid efficacy on certain outcome measures, in particular the Clinical Global Impression Scale-Bipolar Version (CGI-BP) in the long term.15 While there are ongoing trials, the verdict is still out on the efficacy of this agent in BD.
Lysosomal Ion Channels and Human Diseases
Tian-Le Xu, Long-Jun Wu in Nonclassical Ion Channels in the Nervous System, 2021
To resolve the conflicting reports on the permeability and gating properties of TPCs, two groups recently suggest that the ion selectivity and gating properties of TPCs are likely determined by the activating ligands. By performing a Ca2+ imaging-based high-throughput screen, Gerndt et al. (2020) identified two lipophilic and structurally distinct TPC2 agonists TPC2-A1-N and TPC2-A1-P. TPC2-A1-N evokes robust Ca2+-signals and non-selective cation currents, whereas TPC2-A1-P induces Na+-selective currents with weaker Ca2+-signals. These properties are mirrored by the Ca2+-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Interestingly, TPC2-A1-N but not TPC2-A1-P also renders the channel H+-permeable. In the other study, Zhang et al. (2019) reported that five chemically closely related classes of dibenzazepine type tricyclic antidepressants (TCAs, i.e. clomipramine, desipramine, imipramine, amitriptyline, and nortriptyline that are named LyNa-VA1.1 to LyNa-VA1.5) and phenothiazine (i.e. chlorpromazine and triflupromazine that are named LyNa-VA2.1 and LyNa-VA2.2)-based antidepressants induce strong inwardly rectifying TPC currents. However, Riluzole (referred to as Lysosomal Na+ channel Agonist 1 [LyNA1]), an FDA-approved amyotrophic lateral sclerosis drug that is known to modulate voltage-gated Na+ channels, evokes TPC2 currents independent of voltage as in the case for PI(3,5)P2. In contrast to TPC2-A1-N and TPC2-A1-P that alter cation permeability in an agonist-dependent manner, LyNa-VA and LyNA do not change ion selectivity of the channel, that is, low Ca2+ but high Na+permeability. Furthermore, these compounds act on TPC1 and TPC2 differently. TPC2-A1-N and TPC2-A1-P only activate TPC2 but neither inhibits nor activates TPC1 (Gerndt et al., 2020); LyNa-VA1.1 and LyNa-VA1.2 activate both TPC2 and TPC1 in a voltage-dependent manner, while LyNa-VA2.1 and Riluzole inhibit TPC1 (Zhang et al., 2019). Overall, TPCs function as either NAADP-activated Ca2+ release channels (Brailoiu et al., 2010a; Grimm et al., 2014; Pitt et al., 2010; Ruas et al., 2015; Schieder et al., 2010b) or PI(3,5)P2-gated Na+ channels (Cang et al., 2013; Guo et al., 2017; Wang et al., 2012; Zhang et al., 2019). The dual activation mechanism allows TPCs to mediate diverse cellular functions in response to various environmental stimuli.
Utility of oxcarbazepine in the treatment of childhood and adolescent psychiatric symptoms
Published in Baylor University Medical Center Proceedings, 2021
Kyle Morrow, Keith A. Young, Shawn Spencer, Edgar Samuel Medina, Michaela A. Marziale, Alejandro Sanchez, James A. Bourgeois
Oxcarbazepine, a dibenzazepine carboxamide derivative of carbamazepine, is a voltage-gated sodium channel anticonvulsant.1 Common side effects of oxcarbazepine include dizziness, somnolence, syndrome of inappropriate antidiuretic hormone secretion, and nausea.2–4 Rare cutaneous reactions include maculopapular eruption, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which require discontinuation.5 Oxcarbazepine was cited as an effective treatment for treatment-resistant focal epilepsy in adults.6 Oxcarbazepine is also used off label as a psychotropic medication in adults7–13 and for treatment of epilepsy in children and adolescents.14–16 Unlike some other anticonvulsants, oxcarbazepine spares cognition and does not aggravate symptoms of co-occurring attention deficit hyperactivity disorder (ADHD) and epilepsy.17 Oxcarbazepine has been used to treat child and adolescent psychiatric disorders. While recent American Association of Child and Adolescent Psychiatry practice parameters do not include oxcarbazepine as a treatment option for autism spectrum disorder (ASD), oppositional defiant disorder, or depressive disorders, oxcarbazepine has been listed as a fifth-line option for treatment of child and adolescent bipolar disorder.18–21 Negative findings include a double-blind placebo-controlled trial to treat mania in children, which did not find efficacy for oxcarbazepine in this population.22 More recently, oxcarbazepine was found to be effective in reducing irritability and agitation in ASD.23,24 Oxcarbazepine was reported by clinicians to be perceived as one of the best-tolerated treatments for childhood behavioral problems associated with ASD and other conditions.25 To better document clinical impressions of oxcarbazepine in children and adolescents, we performed a retrospective chart review focusing on tolerability and treatment outcomes.
Eslicarbazepine in patients with brain tumor-related epilepsy: a single-center experience
Published in International Journal of Neuroscience, 2021
Marco Zoccarato, Anna Maria Basile, Marta Padovan, Mario Caccese, Vittorina Zagonel, Giuseppe Lombardi
ESL belongs to the dibenzazepine family and its main mechanism consists of the reduction in VGSC availability thorough enhancement of slow inactivation [20]. ESL is chemically related to carbamazepine (CBZ) and oxcarbazepine (OXC), which are widely used in focal epilepsy. Some structural differences result in different pharmacodynamic, pharmacokinetic and metabolic features, which can benefit its use in BTRE. First, the long half-life of ESL allows once-daily administration [21, 22]. It is well recognized that lower drug-dose frequency improves therapeutic adherence [23] and could reduce discomfort in patients with brain tumor, which, due to complex and chronic symptoms, can lead to prescription of a high number of medications [24]. Secondly, differently from CBZ, ESL has minimal or no effect on the activity of cytochrome P450 (CYP) isoforms and enzymes of the glucuronidation pathway. As a consequence, ESL should have fewer drug interactions [21, 25], which supports its use in BTRE, where AEDs with a better interaction profile are preferred since the efficacy of other chemotherapeutic drugs is not altered [26]. Side effects of AEDs in BTRE seem to be more frequent than in non-oncological patients [1]. In particular, dermatological complications and bone marrow suppression limit the use of CBZ in these patients, along with its unfavorable interaction profile. Like OXC, ESL is less associated with these side effects due to the lack of a toxic epoxide metabolite [27]. Hyponatremia is another common effect of the dibenzazepine family, especially OXC; but low sodium (defined as <125 μmol/L) has been reported in less than 0.5% of cases in trials with ESL as an add-on therapy [28] and in less than 3.5% in real-life studies [12, 13]. In our series, ESL was well tolerated. No dermatological or hematological events were recorded. Thirty-eight percent patients reported some mild adverse effects that never led to the discontinuation of the drug; only one patient developed mild hyponatremia (>125 μmol/L).
What place do carbamazepine-related antiepileptic drugs have in the modern day treatment of epilepsy?
Published in Expert Opinion on Pharmacotherapy, 2020
Simona Lattanzi, Vincenzo Belcastro
CBZ is featured by a dibenzazepine nucleus with a 5-carboxyamide substituent. OXC is a structurally related derivative with a ketone substitution at the 10-position and ESL is structurally different at the 10, 11-position on the dibenzazepine ring (Table 1) [2].
Related Knowledge Centers
- Benzazepine
- Benzene
- Carbamazepine
- Chemical Compound
- Functional Group
- Oxcarbazepine
- Depramine
- Dibenzothiepin
- Dibenzoxepin