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.

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.

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.

Defects in insulin signaling have been reported in schizophrenia and major depressive disorder, which also share certain negative symptoms such as avolition, anhedonia, and apathy. These symptoms reflect diminished motivational states, which have been modeled in rodents as increased immobility in the forced swimming test. We have discovered that loss-of-function mutations in the insulin receptor (daf-2) and syntaxin (unc-64) genes in Caenorhabditis elegans, brief food deprivation, and exposure to DMSO produce immobility and avolition in non-dauer adults. The animals remain responsive to external stimuli; however, they fail to forage and will remain in place for >12 days or until they die. Their immobility can be prevented with drugs used to treat depression and schizophrenia and that reduce immobility in the forced swimming test. This includes amitriptyline, amoxapine, clozapine, and olanzapine, but not benzodiazepines and haloperidol. Recovery experiments confirm that immobility is induced and maintained by excessive signaling via serotonergic and muscarinic cholinergic pathways. The immobility response described here represents a potential protophenotype for avolition/anhedonia in man. This work may provide clues about why there is a significant increase in depression in patients with diabetes and suggest new therapeutic pathways for disorders featuring diminished motivation as a prominent symptom.

Alzheimer's disease (AD) is a major and devastating neurodegenerative disease, and the amyloid-β (Aβ) hypothesis is still the central theory for AD pathogenesis. Meanwhile, another major mental illness, depression, is one of the risk factors for AD. From a high-throughput screening (HTS), amoxapine, a typical secondary amine tricyclic antidepressant (TCA), was identified to reduce Aβ production. A follow-up investigation on antidepressants showed that most of the TCAs harbour similar activity. Previous studies have indicated that TCAs improve cognitive function in AD mouse models as well as in preliminary clinical data; however, the underlying mechanism is controversial, and the effect on Aβ is elusive. Thus, we developed a secondary screening to determine the molecular target of amoxapine, and serotonin receptor 6 (HTR6) was identified. Knockdown of HTR6 reduced the amoxapine's effect, while the HTR6 antagonist SB258585 mimicked the activity of amoxapine. Further mechanistic study showed that amoxapine and SB258585 reduced Aβ generation through multiple HTR6-mediated targets, including β-arrestin2 and CDK5. Taken together, our study suggests that amoxapine, though no longer a first-line drug for the treatment of depression, may be beneficial for AD and further structural modification of TCAs may lead to desirable therapeutic agents to treat both AD and depression.

Amoxapine is a tetracyclic antidepressant used for relief of symptoms of depression caused by either reactive or psychotic depression. Amoxapine has been associated with a low rate of minor serum aminotransferase elevations during treatment and to very rare instances of clinically apparent acute liver injury.

Antidepressant drugs may have proconvulsant effects. Psychiatric comorbidity in epilepsy is common. Prescribers might be reluctant to initiate treatment with antidepressants in fear of seizure aggravation. The purpose of this review was to focus upon the current evidence for proconvulsant effects of antidepressants and possible clinical implications. Most antidepressants are regarded as safe and may be used in patients with epilepsy, such as the newer serotonin and/or noradrenaline reuptake inhibitors. Four older drugs should, however, be avoided or used with caution; amoxapine, bupropion, clomipramine and maprotiline. Proconvulsant effects are concentration-related. Optimization of drug treatment includes considerations of pharmacokinetic variability to avoid high serum concentrations of the most proconvulsant antidepressants. The risk of seizures is regarded as small and should, therefore, not hamper the pharmacological treatment of depression in people with epilepsy.

The current knowledge of the pharmacological actions of the tricyclic antidepressants (TCAs) has slowly evolved through their over 40-year history. Chronic pain represents one of the most important public health problems, and antidepressants are an essential part of the therapeutic strategy in addition to classical analgesics. This article reviews the available evidence on the efficacy and safety of antidepressants in chronic pain conditions; namely, headaches, low back pain, fibromyalgia, cancer pain and especially neuropathic pain. TCAs are traditionally the main type of depression medication used to treat chronic pain. Recently, new antidepressants were introduced into clinical use, with a significant reduction in side effects and equivalent efficacy on mood disorders. These new drugs that are effective for chronic pain belong to the tetracyclic antidepressants (TeCAs) group (amoxapine, maprotiline), the serotonin and noradrenaline reuptake inhibitors (SNRIs) group (duloxetine, venlafaxine, milnacipran) and the atypical antidepressants group (bupropion, trazodone, mirtazapine, nefazodone). In this review, we present the available publications on TCAs (amitriptyline, doxepin, imipramine, desipramine, nortriptyline), TeCAs (amoxapine, maprotiline), selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, paroxetine), SNRIs (duloxetine, venlafaxine, milnacipran) and atypical antidepressants (bupropion) for the treatment of neuropathic pain. We also review analgesics acting as both opioid receptor agonists and also acting as aminergic reuptake inhibitors. Existing data are insufficient to conclude which of these new classes of antidepressants has the best clinical profile and will be the most effective in the treatment of neuropathic pain; in addition, a lower incidence of side effects should be considered. Increased experimental and translational research is a key for further improvement of the treatment of chronic pain with antidepressants. However, evidence from basic science is needed to improve our understanding of the mechanisms of action and their possible pharmacodynamic interactions.

Various antidepressants are commonly used for the treatment of depression and several other neuropsychiatric disorders. In addition to their primary effects on serotonergic or noradrenergic neurotransmitter systems, antidepressants have been shown to interact with several receptors and ion channels. However, the molecular mechanisms that underlie the effects of antidepressants have not yet been sufficiently clarified. G protein-activated inwardly rectifying K(+) (GIRK, Kir3) channels play an important role in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to have therapeutic potential for several neuropsychiatric disorders and cardiac arrhythmias. In the present study, we investigated the effects of various classes of antidepressants on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2 or GIRK1/GIRK4 subunits, extracellular application of sertraline, duloxetine, and amoxapine effectively reduced GIRK currents, whereas nefazodone, venlafaxine, mianserin, and mirtazapine weakly inhibited GIRK currents even at toxic levels. The inhibitory effects were concentration-dependent, with various degrees of potency and effectiveness. Furthermore, the effects of sertraline were voltage-independent and time-independent during each voltage pulse, whereas the effects of duloxetine were voltage-dependent with weaker inhibition with negative membrane potentials and time-dependent with a gradual decrease in each voltage pulse. However, Kir2.1 channels were insensitive to all of the drugs. Moreover, the GIRK currents induced by ethanol were inhibited by sertraline but not by intracellularly applied sertraline. The present results suggest that GIRK channel inhibition may reveal a novel characteristic of the commonly used antidepressants, particularly sertraline, and contributes to some of the therapeutic effects and adverse effects.

It has been proposed that the lack of extrapyramidal side effects of atypical antipsychotic drugs is caused by their fast dissociation or low affinity for the D2 receptor or their concomitant high affinity for other receptors, for example, 5HT2 and D4. We noted that amoxapine, an established antidepressant, has affinity for 5HT2 and D2 receptors, and its effects in preclinical model are very similar to atypical antipsychotics. The objective of this study was to examine the antipsychotic effect and side effect profile of amoxapine versus haloperidol in a double-blind study for 6 weeks in patients with schizophrenia. A total of 54 patients with schizophrenia were titrated to the starting dose of 150 mg/d of amoxapine or 5 mg/d of haloperidol within 3 days. Clinical efficacy and side effects were monitored at baseline, and Weeks 2, 4, and 6.Forty-one patients completed 5 weeks, and 36 patients completed the 6 weeks of follow-up. Both treatment groups showed significant improvement in Positive and Negative Syndrome Scale positive (30%) and total scores (20%), without significant differences between the groups. In addition, in the amoxapine group, significant improvement was seen in the negative symptoms and the Clinical Global Impression. No significant changes were seen on Calgary Depression Scale for Schizophrenia, side effect checklists, and prolactin levels in both groups. The results suggest that amoxapine may be as effective an antipsychotic as haloperidol as predicted by its affinity for D2 and 5HT2 receptors, supporting earlier studies. However, it did not prove to have fewer extrapyramidal side effects than haloperidol, possibly because the baseline scores were very low.

A 43-year-old woman was found dead in a car in the supine position. She had been suffering from depression for 2 years and hesitation wounds on the left forearm and wrist were observed. On microscopic examination, pulmonary congestion and edema were observed with heart failure cells in many alveoli, thereby suggesting not only acute but also chronic heart failure. Drug screening in the blood by gas chromatography-mass spectrometry (GC-MS) revealed the presence of amoxapine and levomepromazine, and their concentrations in tissues were determined by GC-MS with three-step solvent extraction followed by acetylation. The concentration of amoxapine in the blood and liver was 0.86-1.77 and 18.76microg/ml, respectively; the levels were much higher than the therapeutic level but did not reach the lethal level. The concentrations of levomepromazine in tissues were within the therapeutic level. Based on the pathological and toxicological findings, the cause of death was determined to be amoxapine poisoning on the basis of chronic heart failure due to the chronic use of psychotropic drugs.

Irritable bowel syndrome (IBS) is a functional disease with good prognosis, which is diagnosed by exclusion of possible causative organic diseases. However, since the patients tend to have strong psychotic symptoms including anxiety, tension, depression, irritation and insomnia, this syndrome has to be elucidated as a psychosomatic disease. Although the symptoms are usually limited to gastrointestinal symptoms such as abdominal pain and abnormal bowel movements, many patients also manifest some kinds of psychiatric abnormalities such as hypochondria, depression, hysteria, panic disorder and posttraumatic stress disorder. Especially, the prevalence of depression is high. Therefore, use of psychotropic drugs is efficient in treating IBS. Antidepressant agents including tricyclic agents such as amitriptyline, trimipramine, imipramine, clomipramine, amoxapine and nortriptyline; tetracyclic antidepressant; antidepressants such as SSRI and SNRI; sulpiride; benzodiazepine class anxiolytic agents; tandospirone; and Chinese herbal medicine are being used. IBS is a stress-related disease. Therefore, in spite of the importance of pharmacotherapy, patients should also be instructed to avoid the stress that aggravates the symptoms in all aspects of daily life.

In the preset study, the authors investigated that effects of the antipsychotic drug risperidone on psychotic depression and examined the mechanism of risperidone to ameliorate psychotic depression. Fifteen patients met the DSM-IV criteria for major depressive disorder with psychotic features and the remaining five patients met those for bipolar I disorder (most recent episode depressed) with psychotic features (M/F: 8/12, age: 54+/-18). All patients were evaluated regarding their clinical improvement using the Hamilton Rating Scale for Depression (Ham-D), and Positive and Negative Syndrome Scale (PANSS). In addition, plasma concentrations of HVA and MHPG were analyzed by HPLC. Patients with a 50% or more improvement in Ham-D score were defined as responders. Three were prescribed risperidone alone, and the other 17 were administered risperidone as an addition to preexisting antidepressants or mood stabilizers. The preexisting antidepressants or mood stabilizers were as follows: paroxetine (6), lithium (3), valproic acid (3), clomipramine (2), fluvoxamine (1), amitriptyline (1), amoxapine (1). The average dose of risperidone was 1.8+/-0.5 mg/day. Eleven of twenty patients (55%) turned out to be responders 4 weeks after initiation of risperidone administration. No differences were observed between responders and nonresponders with respect to age, sex, Ham-D score before risperidone treatment, dose and plasma level of risperidone or its active metabolite, 9-hydroxyrisperidone. Plasma HVA levels before risperidone administration in responders were significantly higher than those in nonresponders. In addition, a significant correlation was observed between changes in plasma HVA level and the percentage improvement on Ham-D score. These results indicate that treatment with risperidone is effective to ameliorate psychotic depression, and the influence of risperidone on dopaminergic activity is associated with its efficacy.

Previously, with the administration of antidepressant drugs, it has been demonstrated that the rat model of clinical depression, known as the reduction of submissive behavior model (RSBM), has considerable validity. The present study is an attempt to extend the model to mice. Several antidepressant drugs as well as a number of non-antidepressant agents were administered to mice that had been identified as submissive in a behavioral testing situation. Imipramine, desipramine, amoxapine and fluoxetine, representing three different classes of antidepressant drugs, were each able to increase competitive behavior in submissive mice and to decrease the dominance level between dominant and submissive mice in the behavioral tests. The stimulant amphetamine also reduced submissive behavior while yohimbine (also a stimulant), and the antianxiety agent diazepam had no such effect. The neuroleptic drug thiothixen had antidepressant-like effect on submissive C57BL/6J mice behavior. We conclude that like the rat model of depression from which it was developed, the mouse model responds to various antidepressants as predicted and thus may serve as a potential model of clinical depression.

A 34-year-old man presented with severe refractory depression. He had failed to respond to various antidepressants, augmentation therapy with lithium carbonate, and modified electroconvulsive therapy. Switching from amoxapine 150 mg/day to selegiline 7.5 mg/day, a selective monoamine oxidase type-B inhibitor, produced a dramatic reduction in hypobulia and lassitude, leading to a complete remission of all depressive symptoms. The patient reverted to his former position at work after an interval of approximately 3 years. Although the biologic basis of the antidepressant effect of selegiline in this patient is unknown, it is suggested that the enhancement of dopaminergic neurotransmission or elevation of brain-derived neurotrophic factor levels in the brain by administration of selegiline is involved in the recovery of this patient from severe refractory depression. This report indicates the antidepressant effect of selegiline in a refractory depressed patient.

Amoxapine is marketed as an antidepressant. However, its in-vitro profile, receptor occupancy and preclinical effects are very similar to atypical antipsychotics. Amoxapine has also shown efficacy as an atypical antipsychotic in open trials. The objective of this study was to compare the antipsychotic and side effect profile of amoxapine and risperidone in a randomised assignment, standardized dosing, double-blind trial of acutely psychotic patients with schizophrenia. A total of 48 schizophrenic patients were enrolled and randomized in a double-blind 6-week trial to receive either risperidone (up to 5 mg/day) or amoxapine (up to 250 mg/day). Positive, negative, affective symptoms and motor side effects were measured using standardized weekly assessments. Prolactin levels were also determined at baseline and at the end of the study. A total of 39 patients (amoxapine, n=22; risperidone, n=21) completed the trial. Both pharmacological treatments, amoxapine 228.0 mg/day (SD=34.6) and risperidone 4.5 mg/day (SD=0.7), showed equivalent improvement in positive, negative, and depressive symptoms. Amoxapine was associated with less EPS and less prolactin elevation than risperidone. These data support previous reports about the efficacy of amoxapine as an atypical antipsychotic. Since amoxapine is off-patent, it may be a valuable low-cost alternative to new atypical antipsychotics, particularly in low-income countries where the majority of the patients are still treated with typical antipsychotics.