Amoxapine (AMX) is an FDA-approved tricyclic antidepressant used to treat major depressive disorders by modulating monoaminergic neurotransmitters, including serotonin, dopamine, and noradrenaline. However, its clinical efficacy is limited due to poor aqueous solubility, rapid first-pass metabolism, and extensive biotransformation by cytochrome P450 enzymes, particularly CYP2D6, leading to reduced systemic and brain availability. Bergamottin (BER) and diosmetin (DIO), natural furanocoumarin and flavonoid compounds, respectively, are known inhibitors of CYP3A4 and CYP2D6 and may enhance AMX pharmacokinetics through drug-herb interactions. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of amoxapine during pharmacokinetic and neurotransmitter studies. In vitro and in vivo drug-herb interactions of AMX with bergamottin and diosmetin, as well as their impact on brain biodistribution and neurotransmitter levels in mice, were evaluated. In vitro CYP2D6 inhibition assays demonstrated that BER and DIO significantly suppressed CYP2D6-mediated dextromethorphan metabolism in a concentration-dependent manner, while rat liver microsome studies showed markedly improved metabolic stability of AMX, with reduced intrinsic clearance and extended half-life in the presence of BER and DIO compared with AMX alone. In vivo pharmacokinetic evaluation revealed a 1.26-fold and 2.13-fold increase in C max, along with enhanced bioavailability, when AMX was coadministered with bergamottin (BER) and diosmetin (DIO), respectively. Behavioral testing (forced swim test (FST), tail suspension test (TST) and open field test (OFT)) demonstrated significantly improved antidepressant-like responses with combination therapy versus AMX alone. Biodistribution studies confirmed increased AMX accumulation in the hippocampus and cortex, accompanied by elevated monoamine neurotransmitters, including serotonin, dopamine, norepinephrine, and epinephrine. These findings demonstrate that BER and DIO augment the pharmacokinetic and pharmacodynamic profiles of AMX through CYP2D6 inhibition and improved brain delivery, supporting their potential as natural bioenhancers to enhance antidepressant efficacy. This combination strategy represents a promising approach for developing superior AMX-based therapeutic regimens and warrants further clinical investigation.

There are no recommendations based on the efficacy of specific drugs for the treatment of psychotic depression. To address this evidence gap, we did a network meta-analysis to assess and compare the efficacy and safety of pharmacological treatments for psychotic depression.

Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such as antidepressants, hypnotics, and anxiolytics. If these drugs also inhibit acetylcholinesterase (AChE) activity, they may contribute to the suppression of AD progression by increasing brain acetylcholine concentrations. We tested the potential inhibitory effects of 31 antidepressants, 21 hypnotics, and 12 anxiolytics on recombinant human AChE (rhAChE) activity. At a concentration of 10[-4] M, 22 antidepressants, 19 hypnotics, and 11 anxiolytics inhibited rhAChE activity by <20%, whereas nine antidepressants (clomipramine, amoxapine, setiptiline, nefazodone, paroxetine, sertraline, citalopram, escitalopram, and mirtazapine), two hypnotics (triazolam and brotizolam), and one anxiolytic (buspirone) inhibited rhAChE activity by ≥20%. Brotizolam (≥10[-6] M) exhibited stronger inhibition of rhAChE activity than the other drugs, with its pIC50 value being 4.57 ± 0.02. The pIC50 values of the other drugs were <4, and they showed inhibitory activities toward rhAChE at the following concentrations: ≥3 × 10[-6] M (sertraline and buspirone), ≥10[-5] M (amoxapine, nefazodone, paroxetine, citalopram, escitalopram, mirtazapine, and triazolam), and ≥3 × 10[-5] M (clomipramine and setiptiline). Among these drugs, only nefazodone inhibited rhAChE activity within the blood concentration range achievable at clinical doses. Therefore, nefazodone may not only improve the depressive symptoms of BPSD through its antidepressant actions but also slow the progression of cognitive symptoms of AD through its AChE inhibitory actions.

Amoxapine is an FDA-approved drug belonging to the class of second-generation tricyclic dibenzoxazepine antidepressants. Generally, it is reserved for resistant or persistent depression. The goal of this activity is to familiarize practitioners with the proper usage of this drug and recognize the adverse effects of this medication. This activity also explores the roles of a cohesive interprofessional team in treating patients using amoxapine to treat their depression.

Amoxapine is a second-generation tricyclic antidepressant with a greater seizure risk than other antidepressants. If administered in large amounts, amoxapine can cause severe toxicity and death. Therefore, it is necessary to terminate seizures immediately if amoxapine toxicity occurs. However, intractable seizures often occur in these patients. We describe a case of intractable seizures caused by amoxapine poisoning, in which intravenous lipid emulsion (ILE) was used successfully.

Major depressive disorder is a common psychiatric disorder causing great burden on patients and societies. Tricyclic antidepressants are frequently used worldwide to treat patients with major depressive disorder. It has repeatedly been shown that tricyclic antidepressants reduce depressive symptoms with a statistically significant effect, but the effect is small and of questionable clinical importance. Moreover, the beneficial and harmful effects of all types of tricyclic antidepressants have not previously been systematically assessed. Therefore, we aim to investigate the beneficial and harmful effects of tricyclic antidepressants versus 'active placebo', placebo or no intervention for adults with major depressive disorder.

Antidepressants are well-known drugs to treat depression and major depressive disorder for humans. However, the misuse and abuse of antidepressants keep increasing with several side effects reported. The aim of this study was to assess the potential adverse effects of 18 antidepressants by monitoring zebrafish larval locomotor activity performance based on the total distance traveled, burst movement count, and total rotation count at four dark-light intercalated phases. In general, zebrafish larvae displayed sedative effects after antidepressant exposure by showing a significant reduction in all of the locomotor activity-related endpoints. However, three antidepressants i.e., amitriptyline, amoxapine, and sertraline were able to trigger a significantly high locomotor activity in zebrafish larvae during the light cycle. These differences might be due to the pharmacologic differences among the antidepressants. In addition, since each antidepressant possesses a different dosage range from the other, overdoses of these antidepressants might also be the causes of these differences. Furthermore, based on these results, a further study was conducted to observe the effect of these three antidepressants in lower concentrations. From the results, biphasic effects in terms of zebrafish larval locomotor activity were demonstrated by these drugs. Even though further studies are still required to validate the mechanism, these findings indicate that these antidepressants might share a common mechanism responsible for their effects on zebrafish larval locomotor activity although there were some differences in potency of these effects.

Introduction: Comorbidities of epilepsy may significantly interfere with its treatment as diseases in the general population are also encountered in epilepsy patients and some of them even more frequently (for instance, depression, anxiety, or heart disease). Obviously, some drugs approved for other than epilepsy indications can modify the anticonvulsant activity of antiepileptics. Areas covered: This review highlights the drug-drug interactions between antiepileptics and aminophylline, some antidepressant, antiarrhythmic (class I-IV), selected antihypertensive drugs and non-barbiturate injectable anesthetics (ketamine, propofol, etomidate, and alphaxalone). The data were reviewed mainly from experimental models of seizures. Whenever possible, clinical data were provided. PUBMED data base was the main search source.Expert opinion: Aminophylline generally reduced the protective activity of antiepileptics, which, to a certain degree, was consistent with scarce clinical data on methylxanthine derivatives and worse seizure control. The only antiarrhythmic with this profile of action was mexiletine when co-administered with VPA. Among antidepressants and non-barbiturate injectable anesthetics, trazodone, mianserin and etomidate or alphaxalone, respectively, negatively affected the anticonvulsant action of some antiepileptic drugs. Clinical data indicate that only amoxapine, bupropion, clomipramine and maprotiline should be used with caution. Possibly, drugs reducing the anticonvulsant potential of antiepileptics should be avoided in epilepsy patients.

People with epilepsy (PWE) frequently suffer from comorbid mood and anxiety disorders. Depression is one of the major psychiatric comorbidities having a negative impact on the quality of life in people with epilepsy. A review of the literature indicates that the majority of antidepressant-related seizures have been associated with either ultra-high doses or overdosing and, generally, the risk of antidepressant-associated seizures is low. Correspondingly, there is some evidence indicating that antidepressants of most widely used groups may additionally lower the risk of triggering seizures. Four antidepressants are not recommended for patients with epilepsy, i.e.: amoxapine, bupropion, clomipramine and maprotiline. Clinicians applying first line of depression treatment in patients with epilepsy should consider use of SSRIs or SNRIs, particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine. Implementation of anticonvulsive drugs in depressed patients should include valproate, carbamazepine, lamotrigine, gabapentin, pregabalin. The paper reviews the evidence for the clinical use of antidepressants in PWE.

The antidepressants are some of the most commonly prescribed medications in current use. They are also important causes of drug induced liver injury accounting for 2% to 5% of clinically apparent cases. The antidepressants can be grouped into four categories: monamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, and miscellaneous agents. The monamine oxidase inhibitors are a large group of hydrazide derivatives which were found to have antidepressant activity when first used in the therapy of tuberculosis in the 1950s. These agents inhibit the enzyme monamine oxidase that is responsible for inactivation of many amine neurotransmitters such as norepinephrine and serotonin, thus increasing their levels and activity in the brain. MAO inhibitors (with initial trade name and year of approval) currently in clinical use for depression include phenelzine (Nardil: 1961), tranylcypromine (Parnate: 1961), and isocarboxazid (Marplan: 1959). MAO inhibitors are currently not widely used, having been replaced by the tricyclic antidepressants and selective serotonin reuptake inhibitors which have greater potency and fewer adverse side effects. The MAO inhibitors can cause serum aminotransferase elevations and rarely lead to clinically apparent liver injury, generally with a hepatitis-like clinical presentation 1 to 3 months after starting therapy. The tricyclic antidepressants share a tricyclic chemical structure somewhat resembling the phenothiazines. The tricyclics are believed to act by inhibition of reuptake of serotonin and norephinephrine, thus increasing levels of these neurotransmitters. Tricyclic antidepressants in current use include amitriptyline (Elavil: 1961), clomipramine (Anafranil: 1989), desipramine (Norpramin: 1964), doxepin (Sinequan: 1969), imipramine (Tofranil: 1959), nortriptyline (Aventyl or Pamelor: 1964) and protriptyline (Vivactil: 1967). Two more recently approved agents are usually categorized as tricyclics, but have some unique characteristics: trimipramine (Surmontil: 1979) and amoxapine (Asendin: 1992). The various tricyclic antidepressants are capable of causing transient serum aminotransferase elevations to varying degrees and, in rare instances, clinically apparent acute liver injury. Various pattern of hepatic injury have been associated with different tricyclic antidepressants.

The rapid increase in bacterial resistance to antibiotics is a global healthcare crisis. Non-antibiotic pharmaceuticals that have attained approval by the United States Food and Drug Administration have the potential to be repurposed as bacterial resistance-modifying agents and therefore could become valuable resources in our battle against antibiotic-resistant microbes. Amoxapine is a tetracyclic antidepressant used in the treatment of major depressive disorder. Here we demonstrate the ability of amoxapine to resensitize methicillin-resistant Staphylococcus aureus strain ATCC 43300 to oxacillin in both agar diffusion and broth microdilution assays. Amoxapine also reduced the bacterial cleavage of nitrocefin in a dose-dependent manner, suggesting that it may exert its adjuvant effects through reduction of beta-lactamase activity.