Psychosis in affective disorders — depression
Anne M. Hassett, David Ames, Edmond Chiu in Psychosis in the Elderly, 2005
Early depression treatment studies with tricyclic antidepressants revealed inferior outcomes for psychotic depressed patients, many of whom went on later to improve with ECT (Rothschild, 2003). The trials which established the selective serotonin reuptake inhibitors (SSRIs) as effective treatments for depression specifically excluded delusional subjects from treatment. A series of studies from Italy (Gatti et al, 1996; Zanardi et al, 1996, 2000) have reported good outcomes in psychotic depression patients treated with SSRI or selective serotonin and noradrenaline reuptake inhibitor (SNRI) monotherapy, but the studies lacked a placebo control arm, used a rating scale of questionable validity, and have not been replicated by other researchers (Rothschild and Phillips, 1999). Open-label studies of amoxapine in the treatment of psychotic depression also showed encouraging recovery rates of 60-80% (Anton and Sexauer, 1983).
Antidepressants: Predicting Response/Maximizing Efficacy
Mark S. Gold, R. Bruce Lydiard, John S. Carman in Advances in Psychopharmacology: Predicting and Improving Treatment Response, 2018
Amoxapine is a new antidepressant designated chemically as 2-chloro-11-(1-piperazinyl) dibenz (b, f)(1, 4) oxazepine. The antidepressant activity of amoxapine is related to the blockade of norepinephrine and serotonin uptake. There are two major metabolites, 7-OH-Amoxapine and 8-OH-Amoxapine, and it appears that these metabolites are responsible, more so than the parent compound, for pharmacological effects. 8-OH-Amoxapine is comparable to the parent compound’s norepinephrine reuptake blocking properties; however it is extremely potent on serotonin reuptake blockade. It has been demonstrated that 7-OH-Amoxapine has significant dopamine receptor blockade in laboratory animals and as such its dopamine (DA) blocking and neuroleptic activity in humans should be studied. We have recent data in amoxapine-treated humans which demonstrated potent DA blocking effects in some patients and negligible effects in others. Plasma samples were obtained on 30 patients maintained on amoxapine therapy for at least 3 weeks. Plasma was assayed for 8-OH-Amoxapine by gas liquid chromatography and for dopamine receptor-blocking activity by a Neuroleptic Radio Receptor Assay (NRRA). Significant dopamine blocking activity was noted by NRRA in samples independent of plasma 8-OH-Amoxapine level. 7-OH-Amoxapine concentrations correlate with dopamine blocking activity by NRRA. High concentrations of 7-OH-Amoxapine and NRRA activity may be correlated with akathisia, extrapyramidal symptoms (EPS), galactorrhea, antipsychotic efficacy. Occasional patients who are administered this compound on a chronic basis form high amounts of 7-OH-Amoxapine and may be at risk for tardive dyskinesia.
Psychotropic Use during Pregnancy
“Bert” Bertis Britt Little in Drugs and Pregnancy, 2022
A metabolite of loxapine, amoxapine is an antipsychotic and antidepressant. Data on its use in pregnancy are very limited. Among 19 infants, there were three (15.8 percent) with congenital anomalies (Rosa, unpublished), high compared to the expected rate of 5.3 percent but is based on a very small number of exposed infants. This is not a sufficiently large number of exposed infants on which to base any risk assessment.
Interactions of antiepileptic drugs with drugs approved for the treatment of indications other than epilepsy
Published in Expert Review of Clinical Pharmacology, 2020
Kinga K. Borowicz-Reutt, Stanisław J. Czuczwar, Marta Rusek
Data on the influence of antidepressant drugs on seizures in clinical conditions are relatively scarce. Certainly, their possible proconvulsant properties seem rather overestimated. In fact, FDA approval reports revealed lower standardized incidence rates of seizures related to the treatment with antidepressants vs. placebo. The only exceptions were two older drugs – clomipramine and bupropion [72]. The latter was even documented to induce seizures but after evident overdoses [72]. Some authors include amoxapine and maprotiline to this group as well [73]. There is one available study describing effects of reboxetine, citalopram and mirtazapine in 75 patients with major depression and temporal lobe epilepsy. Two years of observation confirmed antidepressant effectiveness of the two medications. However, no influence on frequency or severity of seizures was noticed [74].
The role of gut microbiota in the modulation of drug action: a focus on some clinically significant issues
Published in Expert Review of Clinical Pharmacology, 2018
β-Glucuronidase-producing intestinal bacteria have been involved in the pathophysiological mechanisms underlying the delayed diarrhea induced by irinotecan and the lower gastrointestinal toxicity caused by NSAIDs. These enzymes hydrolyze the ether or ester linkages between glucuronic acid and SN-38, the active metabolite of irinotecan, or some NSAIDs (including diclofenac, indomethacin, and ketoprofen), respectively, releasing the active molecules in the gut, which then trigger the pathogenic pathways leading to the toxic mucosal damage. So far, only experimental data obtained using mouse models of SN-38- and NSAID-induced toxicities have shown that bacterial β-glucuronidase inhibition significantly reduces the intestinal mucosa injury produced by irinotecan [38,39] and NSAIDs [48,49], and prevents the delayed diarrhea induced by irinotecan [38,39]. A molecule named Inhibitor-1 is the β-glucuronidase inhibitor most commonly used in these studies. It is highly selective for the bacterial enzyme and does not seem to induce any toxic effects on prokaryotic or eukaryotic cells. The pharmacokinetics of this compound have been investigated in mice and have been shown to be favorable (low bioavailability and short t1/2). Other bacterial β-glucuronidase inhibitors have been identified by high-throughput screening [39,40]. In addition, old drugs such as amoxapine, isocarboxazid, and nialamide have been shown to inhibit bacterial β-glucuronidases [41]. The therapeutic effects of some of these old and new drugs have been evaluated with success in the irinotecan-induced delayed diarrhea mouse model [39,42]. The big hope is now that these drugs will be shown to be effective in clinical trials also. Positive clinical results would significantly change the safety profiles of drugs such as NSAIDs, which are very frequently used and have important rates of serious complications.
Fifty years of experience with loxapine for the rapid non-coercive tranquilization of acute behavioral disturbances in schizophrenia patients, and beyond
Published in Expert Review of Neurotherapeutics, 2022
Philippe Nuss, Emmanuelle Corruble, Emmanuelle Baloche, Ricardo P. Garay, Pierre-Michel Llorca
Luo et al. [60] investigated the oxidative metabolism of loxapine by cytochrome P450 (CYP) enzymes in human liver microsomes (Figure 2). Loxapine was metabolized to (i) 8-hydroxyloxapine (by CYP1A2), (ii) 7-hydroxyloxapine (mainly by CYP2D6), (iii) amoxapine (N-desmethyloxapine; mainly by CYP3A4), and (iv) loxapine N-oxide (mainly by CYP3A4; loxapine N-oxide formation by flavin-containing monooxygenase [FMO] was also observed).
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