Randomized Crossover Trial of Amoxapine Versus Vitamin B12 for Retrograde Ejaculation.

OBJECTIVE: To compare the efficacy and safety of amoxapine and vitamin B12 for treating retrograde ejaculation (RE). MATERIALS AND METHODS: Between May 2009 and November 2012, this open-label, randomized, crossover study enrolled 26 men suffering with RE at Department of Reproductive Medicine, Omori Hospital. Patients were randomly allocated into two groups (n=13 each). The amoxapine-B12 group received amoxapine (50 mg daily for 4 weeks, orally) followed (after a 1-week washout period) by vitamin B12 (500 µg three-times daily for 4 weeks). The B12-amoxapine group received the opposite regimen. All pa-tients masturbated to ejaculation at least twice during each treatment period. The primary outcome was antegrade ejaculation of semen, as reported by the patient, on more than one occasion during either treatment period (defined as treatment success). Any adverse events were noted. Success rates were compared between treatments using Fisher's exact test. RESULTS: One patient (B12-amoxapine group) withdrew for personal reasons (breakdown of marital relations); all other patients completed the study. Overall success rate was 88% (22/25). Success rate was higher for amoxapine than for vitamin B12 (80%, 20/25 vs 16%, 4/25; P<0.0001). 18 patients were responsive to amoxapine but not to vitamin B12, 2 patients were responsive to vitamin B12 but not amoxapine, 2 patients were responsive to both drugs, and 3 patients had no response to either drug. One patient (4%) reported sleepiness and 2 (8%) reported constipation while receiving amoxapine. No adverse events were reported during vitamin B12 treatment. CONCLUSIONS: Amoxapine may be an effective, safe and well-tolerated therapy for RE.

Effect of Antidepressants on Psychotic Symptoms in Parkinson Disease: A Review of Case Reports and Case Series.

OBJECTIVES: The treatment of Parkinson disease (PD) psychosis remains a challenge. Only a few treatments eliciting significant relief of psychotic symptoms have passed the test of randomized controlled trials. METHODS: Here, we conducted a review of the literature on the effect of antidepressants on PD psychosis. Because there is no randomized controlled trial that assessed the antipsychotic effects of antidepressants in PD, only case reports, case series, and open-label trials were available to review. Because of the scarce literature, statistical analysis could not be performed. RESULTS: The following antidepressants alleviated hallucinations in PD: amoxapine, citalopram, clomipramine, escitalopram, mianserin, mirtazapine, and venlafaxine. The antidepressants were generally well tolerated, with the exception of amoxapine, which exacerbated parkinsonism. CONCLUSIONS: Whereas the conclusions that can be drawn on the efficacy of antidepressants at reducing PD psychosis are limited because of the poor quality of the reported studies, it is encouraging to notice that there are positive anecdotal reports. Further studies are needed to confirm the potential of these drugs and also to determine if a subtype of patients or of psychotic features may be more likely to be improved by antidepressants.

New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection.

Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including C. difficile However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils.IMPORTANCEClostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal C. difficile infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to C. difficile Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.

Amoxapine as an atypical antipsychotic: a comparative study vs risperidone.

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.

Pharmacological and psychosomatic treatments for an elderly patient with severe nausea and vomiting in reaction to postoperative stress.

Here we present a case of successful treatment employing a mixed approach including pharmacological and psychosomatic treatments for a 72-year-old woman who experienced severe nausea and vomiting in reaction to postoperative stress from gastric cancer surgery. This case demonstrates that appropriate provision of psychosomatic treatments, including a psychotherapeutic session and autogenic training, enhances the efficacy of pharmacotherapy.

Is amoxapine an atypical antipsychotic? Positron-emission tomography investigation of its dopamine2 and serotonin2 occupancy.

BACKGROUND: All currently available atypical antipsychotics have, at clinically relevant doses: i) high serotonin (5-HT)2 occupancy; ii) greater 5-HT2 than dopamine (D)2 occupancy; and iii) a higher incidence of extrapyramidal side effects when their D2 occupancy exceeds 80%. A review of pharmacologic and behavioral data suggested that amoxapine should also conform to this profile; therefore, we undertook a positron-emission tomography (PET) study of its 5-HT2 and D2 occupancy. METHODS: Seven healthy volunteers received 50-250 mg/day of amoxapine for 5 days and then had [11C]-raclopride and [18F]-setoperone PET scans. RESULTS: 5-HT2 receptors showed near saturation at doses of 100 mg/day and above. The D2 receptor occupancies showed a dose-dependent increase, never exceeding 80%; at all doses 5-HT2 occupancy exceeded D2 occupancy. CONCLUSIONS: PET data show that amoxapine's profile is very similar to that of the established atypical antipsychotics. These data, together with amoxapine's in vitro pharmacologic profile, effectiveness in animal models, and efficacy in psychotic depression raise the possibility of amoxapine as an "atypical" antipsychotic agent in the treatment of schizophrenia.

Case report of withdrawal dyskinesia associated with amoxapine.

The antidepressant amoxapine is structurally related to the neuroleptic loxapine and can cause side effects related to hypothesized dopamine receptor blockade. This case of withdrawal dyskinesia after amoxapine discontinuation further demonstrates its potential for causing side effects associated with neuroleptics.

Amoxapine and imipramine in the treatment of depressed outpatients: a controlled study.

In a double-blind, controlled study 158 outpatients with unipolar depression were treated for six weeks with amoxapine, imipramine, or placebo to assess the antidepressant effects of the new dibenzooxazepine compound, amoxapine. Forty-five amoxapine, 43 imipramine, and 27 placebo patients completed at least four weeks of treatment. Active drugs produced significantly more improvement at treatment endpoint, according to several physician-rated measures, but patient-rated measures failed to differentiate among treatments. Both active drugs at daily doses up to 200 mg produced an equal amount of moderate and marked global improvement, and both produced significantly more side effects than did placebo.

Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression.

In a double-blind study lasting for 4 weeks, the authors compared the effectiveness of amoxapine, an antidepressant with potential antipsychotic properties, with a combination of amitriptyline plus perphenazine in the treatment of 38 patients who had the diagnosis of major depression with psychotic features (psychotic or delusional depression). Patients in each group showed similar improvement in depression and psychosis. There was a tendency for the patients treated with amitriptyline plus perphenazine to have higher global response rates. However, the patients given amoxapine had significantly fewer extrapyramidal side effects.

Efficacy of amoxapine in psychotic depression.

Psychotic depression is a distinct clinical entity in that its response to tricyclic antidepressants is poor but its response to tricyclic antidepressant-antipsychotics is better. The authors report the favorable outcome of four patients with psychotic depression treated with amoxapine, a derivative of the antipsychotic loxapine. The elevation of serum prolactin during treatment in three patients suggests that postsynaptic dopamine blockade occurs with amoxapine treatment. This might account for the efficacy of amoxapine in psychotic depression.

Amoxapine: a review of its pharmacology and efficacy in depressed states.

Amoxapine is an N-demethylated dibenzoxazepine closely related in the neuroleptic loxapine. Its tricyclic structure appears to give it antidepressant properties resembling imipramine and amitriptyline. In uncontrolled trials it was shown to have antidepressant activity in usual doses up to 200 to 400mg daily. In placebo and double-blind controlled studies comparing amoxapine with the standard tricyclic antidepressants imipramine and amitriptyline, it was shown to be comparable in efficacy with a possibly somewhat faster onset of improvement of selected symptoms of depression in some studies. Because of the small study groups and lack of placebo control, many reports do not show statistically significant differences of treatment over standard drugs. To date there have been no studies comparing amoxapine with electroconvulsive therapy. Side effects were qualitatively similar to standard drugs with a suggestion that in standard doses or overdose myocardial effects are mild. However, the final place of amoxapine in the therapy of depressed states is still to be decided.

Suppression of tardive dyskinesia with amoxapine: case report.

Evidence of the neuroleptic potency of amoxapine is rapidly accumulating. A case history is presented which complements the growing literature in this area. A depressed patient with persistent orofacial dyskinesia was placed on amoxapine and experienced a suppression of her involuntary movements. The therapeutic implications of this observation are discussed.

Amoxapine-induced cognitive impairment in two patients.

Two patients are described in whom subtle cognitive impairments are associated with therapeutic doses of amoxapine. The implications of this observation for the management of depression, particularly in patients with coexisting dementing illnesses, are discussed.

Amoxapine: once versus divided daily doses in neurotic and endogenous depression.

In a six-week, double-blind clinical study of 35 hospitalized patients with the diagnoses of endogenous depression (18 patients) and depressive neuroses (17 patients), two dosage schedules of amoxapine were compared. While no statistically significant difference in overall therapeutic and adverse effects between the groups treated with single daily doses and divided daily doses were found by the end of the six weeks investigational period, onset of therapeutic effect was faster in the group treated with single daily doses. There was a significantly greater improvement in Anxiety-Somatization and Sleep Disturbance (HAM-D factors) in the group with depressive neurosis than in the group with endogenous depression.

A critical appraisal of amoxapine.

The authors provide a literature review and assess amoxapine's clinical pharmacology, therapeutic efficacy and side effects. They conclude that Amoxapine is indicated for use in moderate to severe depressions, has a favorable side effect profile and probably has an earlier onset of action than other tricyclic antidepressants.

The efficacy of antidepressants in post-stroke depression.

The aim of the present study was to confirm the efficacy of antidepressants in post-stroke depression and to identify the factors related to outcome. Subjects consisted of 20 inpatients suffering from post-stroke in a rehabilitation hospital. The subjects were treated with various antidepressants, mainly imipramine, amitriptyline, and amoxapine. After 4 weeks of treatment, 13 showed some improvement; significant improvement in 5, moderate improvement in 5, mild improvement in 3 by a clinical global impression. Whereas all the patients aged less than 65 yr were responders, only 3 of the 10 patients over 65 yr were responders. All of the male patients, but only half of the female patients, were responders. With regards to the presence of a spouse, 13 of the 16 patients with a spouse, but none of 4 patients without, showed a response. No significant correlation was found between the occurrence of each depressive symptom and outcome. Thus, the responders were younger and had better social support in comparison with the non-responders. This result implies that antidepressants are effective for post-stroke depression.

Recent developments in the acute somatic treatment of major depression.

The subtypes of major depression are reviewed, and a decision tree for the acute somatic treatment of major depression, including delusional and nondelusional depression, is presented. Considerations in clinicians' decisions about initiation and selection of acute somatic treatment for patients with major depression are then discussed. Current somatic therapies for nondelusional depression are described, with emphasis on the mechanisms of action of the drugs employed, the relationship between mechanism of action and side effect profile, and the selection of a drug on the basis of its side effect profile. The three current strategies for the treatment of delusional depression--electroconvulsive therapy, the combination of an antidepressant and an antipsychotic agent, and amoxapine alone--are then reviewed.

Serum neuroleptic levels and extrapyramidal side effects in patients treated with amoxapine.

Serum neuroleptic levels were measured by radioreceptor assay in patients treated with the antidepressant amoxapine. When compared to standard neuroleptics, amoxapine produced relatively weak neuroleptic activity. Amoxapine dose correlated significantly with serum neuroleptic level. Three of eight patients developed significant extrapyramidal side effects. Neither dose of amoxapine nor neuroleptic level correlated with the presence or severity of EPS.

Amoxapine and amitriptyline: serum levels and clinical response in patients with primary unipolar depression.

Amoxapine, a new antidepressant of the dibenzoxazepine class, was compared with amitriptyline in 80 patients with primary unipolar depressive disorders. In a four-week double-blind trial, the two medications were equally effective and had similar onsets of therapeutic action. The range of side effects was similar, although there was a trend for fewer side effects in the amoxapine group. Serum levels were not related to therapeutic response for either medication.