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Antibiotic resistance poses a significant hurdle in combating global public health crises, prompting the development of novel therapeutics. Strategies to enhance the intracellular killing of mycobacteria by targeting host defense mechanisms offer numerous beneficial effects, which include reducing cytotoxicity caused by current lengthy anti-tubercular treatment regimens and slowing or circumventing the development of multidrug-resistant strains. The intracellular pathogen Mycobacterium tuberculosis infects macrophages and exploits host machinery to survive and multiply. Using a cell-based screen of FDA-approved drugs, we identified an antidepressant, Amoxapine, capable of inhibiting macrophage cytotoxicity during mycobacterial infection. Notably, this reduced cytotoxicity was related to the enhanced intracellular killing of Mycobacterium bovis BCG and M. tuberculosis within human and murine macrophages. Interestingly, we discovered that postinfection treatment with Amoxapine inhibited mTOR (mammalian target of rapamycin) activation, resulting in the induction of autophagy without affecting autophagic flux in macrophages. Also, inhibition of autophagy by chemical inhibitor 3-MA or knockdown of an essential component of the autophagic pathway, ATG16L1, significantly diminished Amoxapine's intracellular killing effects against mycobacteria in the host cells. Finally, we demonstrated that Amoxapine treatment enhanced host defense against M. tuberculosis in mice. In conclusion, our study identified Amoxapine as a novel host-directed drug that enhances the intracellular killing of mycobacteria by induction of autophagy, with concomitant protection of macrophages against death.

Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC.

The degradation behavior of eight tricyclic antidepressants (TCAs; amitriptyline, amoxapine (AMX), imipramine, clomipramine, desipramine, doxepin, dothiepin, and nortriptyline) in artificial gastric juice was investigated to estimate their pharmacokinetics in the stomach. As a result, among the eight TCAs, only AMX was degraded in artificial gastric juice. The degradation was a pseudo first-order reaction; activation energy (Ea) was 88.70 kJ/mol and activation entropy (ΔS) was -80.73 J/K·mol. On the other hand, the recovery experiment revealed that the degradation product did not revert to AMX and accordingly, this reaction was considered to be irreversible. In the AMX degradation experiment, peaks considered to be degradation products A (I) and B (II) were detected at retention times of around 3 min and 30 min in LC/UV measurements, respectively. Structural analysis revealed that compound (I) was [2-(2-aminophenoxy)-5-chlorophenyl]-piperazin-1-yl-methanone, a new compound, and compound (II) was 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one. As for the degradation behavior, it was estimated that AMX was degraded into (II) via (I), i.e., (II) was the final product. The results are expected to be useful in clinical chemistry and forensic science, including the estimation of drugs to be used at the time of judicial dissection and suspected drug addiction.

Seizures are life-threatening adverse drug reactions which are investigated late in drug development using rodent models. Consequently, if seizures are detected, a lot of time, money and animals have been used. Thus, there is a need for in vitro screening models using human cells to circumvent interspecies translation. We assessed the suitability of cocultures of human-induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes compared with rodent primary cortical cultures for in vitro seizure liability assessment using microelectrode arrays. hiPSC-derived and rodent primary cortical neuronal cocultures were exposed to 9 known (non)seizurogenic compounds (pentylenetetrazole, amoxapine, enoxacin, amoxicillin, linopirdine, pilocarpine, chlorpromazine, phenytoin, and acetaminophen) to assess effects on neuronal network activity using microelectrode array recordings. All compounds affect activity in hiPSC-derived cocultures. In rodent primary cultures all compounds, except amoxicillin changed activity. Changes in activity patterns for both cell models differ for different classes of compounds. Both models had a comparable sensitivity for exposure to amoxapine (lowest observed effect concentration [LOEC] 0.03 µM), linopirdine (LOEC 1 µM), and pilocarpine (LOEC 0.3 µM). However, hiPSC-derived cultures were about 3 times more sensitive for exposure to pentylenetetrazole (LOEC 30 µM) than rodent primary cortical cultures (LOEC 100 µM). Sensitivity of hiPSC-derived cultures for chlorpromazine, phenytoin, and enoxacin was 10-30 times higher (LOECs 0.1, 0.3, and 0.1 µM, respectively) than in rodent cultures (LOECs 10, 3, and 3 µM, respectively). Our data indicate that hiPSC-derived neuronal cocultures may outperform rodent primary cortical cultures with respect to detecting seizures, thereby paving the way towards animal-free seizure assessment.

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.

Loxapine is an antipsychotic medication used for the treatment of schizophrenia. In vivo, loxapine is metabolized to multiple metabolites. A high performance liquid chromatographic-tandem mass spectrometry (LC–MS/MS) method has been developed and validated for the determination of loxapine and 4 of its metabolites, loxapine N-oxide, amoxapine (N‐desmethyl loxapine), 8-hydroxyloxapine and 7-hydroxyloxapine, in human plasma to support regulated clinical development. During method development, several technical challenges such as poor chromatography, separation of structural isomers, and inadequate sensitivity were met and overcome. The final method utilized micro-elution solid phase extraction (SPE) to extract plasma samples (100 μL), and the resulting extracts were analyzed using reversed phase LC–MS/MS using a turbo-ionspray interface in positive ionization mode with selected reaction monitoring (SRM). The method was fully validated according to the current regulatory guidance for bioanalysis over the calibration curve range 0.0500–50.0 ng/mL for all analytes using 1/x2-weighted linear regression analysis. Based on three separate runs, the between-run precision and inter-day precision for all five analytes at all concentrations, including the LLOQ (lower limit of quantitation) quality control at 0.0500 ng/mL, varied from 0.0% to 13.8%, while the accuracy ranged from 86.4% to 109.3% of nominal. The extraction recoveries of loxapine and the four metabolites were above 80%. Various forms of short-term and long-term stability were established in both solutions and matrix, including the stability of loxapine and the four metabolites in human plasma for up to 260 days of storage at −20 °C. This method has been used to support a regulated clinical study, which included the successful execution of incurred sample reanalysis (ISR) testing. To the best of our knowledge, this is the first published methodology in which these five analytes were quantified with a single extraction and injection.

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.

GM3 synthase deficiency is due to biallelic pathogenic variants in ST3GAL5, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in ST3GAL5, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.

Amoxapine has been demonstrated to be a potent inhibitor of Escherichia coli β-glucuronidase. This study aims to explore the factors causing unsatisfactory efficacy of amoxapine in alleviating CPT-11-induced gastrointestinal toxicity in mice and to predict the outcomes in humans. Amoxapine (100 µM) exhibited poor and varied inhibition on β-glucuronidase activity in gut microbiota from 10 healthy individuals and their pool (pool, 11.9%; individuals, 3.6%-54.4%) with IC50 >100 µM and potent inhibition toward E. coli β-glucuronidase (IC50 = 0.34 µM). p-Nitrophenol formation from p-nitrophenyl-β-D-glucuronide by pooled and individual gut microbiota fitted classical Michaelis-Menten kinetics, showing similar affinity (Km = 113-189 µM) but varied catalytic capability (Vmax = 53-556 nmol/h/mg). Interestingly, amoxapine showed distinct inhibitory effects (8.7%-100%) toward β-glucuronidases of 13 bacterial isolates (including four Enterococcus, three Streptococcus, two Escherichia, and two Staphylococcus strains; gus genes belonging to OTU1, 2 or 21) regardless of their genetic similarity or bacterial origin. In addition, amoxapine inhibited the growth of pooled and individual gut microbiota at a high concentration (6.3%-30.8%, 200 µM). Taken together, these findings partly explain the unsatisfactory efficacy of amoxapine in alleviating CPT-11-induced toxicity and predict a poor outcome of β-glucuronidase inhibition in humans, highlighting the necessity of using a human gut microbiota community for drug screening.

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 patients 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

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.

We attempted the simultaneous determination of 5 drugs, mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem, detected in a gas chromatography–mass spectrometry screening test in an autopsy case. The solid-phase extraction of the analytes from biological samples was achieved using Oasis®HLB cartridges (Waters, Milford, MA, USA). Gas chromatography was performed on a HP-5MS fused silica capillary column (30 m × 0.25 mm i.d., 0.25 μm film thickness, Agilent Technologies). The mass spectrometer was operated with an electron energy of 70 eV in electron impact mode. The qualitative and quantitative analyses were performed in full-scan mode and the selected ion monitoring mode, respectively. The total ion chromatogram showed good separation of these drugs. Linear graphs were obtained with good correlation coefficients for these drugs from 0.001 to 2.0 μg/mL (r2 = 0.9909–0.9986) using imipramine-d6 as an internal standard. The recoveries of these drugs were found to be 62.8–88.0% in spiked whole blood. Mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem were found in post-mortem samples of the deceased at concentrations of 2.67, 0.07, 0.25, 0.32 and 0.68 μg/mL, respectively. The concentration of mirtazapine was within the lethal level and those of amoxapine and zolpidem were within the toxic level. We diagnosed that the cause of death was acute multiple drug poisoning. The simple and practical procedure used in this study is useful for the simultaneous determination of psychotropic drugs of various types in post-mortem biological samples.

Phase-solubility studies have been used to evaluate the solubilizing effects of cyclodextrins (CDs) on lipophilic, water-insoluble drugs. However, large amounts of CDs and drugs are required to measure solubility by phase-solubility studies. Thus, more efficient approaches to evaluate the interaction of CDs with drugs are needed. Herein we introduce a method that evaluates the interaction between immobilized β-cyclodextrin and psychotropic drugs by surface plasmon resonance assay with a Biacore(®) system. Association constants and stoichiometries observed were generally consistent with values calculated by traditional methods, such as phase-solubility and continuous variation methods. Results showed that the analytical method using Biacore(®) was suitable to evaluate CD-drug interactions.

The acute effects of single oral doses of antidepressants, maprotiline and amoxapine on serum levels of prolactin (PRL), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied in six normally cycling women. After oral administration of 25 mg maprotiline, no significant increase was observed in serum PRL levels, but PRL levels increased significantly (p

Tricyclic antidepressants (TCAs) have been reported to interact with the opioid system, but their pharmacological activity at opioid receptors has not yet been elucidated. In the present study, we investigated the actions of amoxapine, amitriptyline, nortriptyline, desipramine, and imipramine at distinct cloned and native opioid receptors. In Chinese hamster ovary (CHO) cells expressing delta-opioid receptors (CHO/DOR), TCAs displaced [3H]naltrindole binding and stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding at micromolar concentrations with amoxapine displaying the highest potency and efficacy. Amoxapine and amitriptyline inhibited cyclic AMP formation and induced the phosphorylation of signaling molecules along the extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase pathways. Amoxapine also activated delta-opioid receptors in rat dorsal striatum and nucleus accumbens and human frontal cortex. In CHO cells expressing kappa-opioid receptors (CHO/KOR), TCAs, but not amoxapine, exhibited higher receptor affinity and more potent stimulation of [(35)S]GTPgammaS binding than in CHO/DOR and effectively inhibited cyclic AMP accumulation. Amitriptyline regulated ERK1/2 phosphorylation and activity in CHO/KOR and C6 glioma cells endogenously expressing kappa-opioid receptors, and this effect was attenuated by the kappa-opioid antagonist nor-binaltorphimine. In rat nucleus accumbens, amitriptyline slightly inhibited adenylyl cyclase activity and counteracted the inhibitory effect of the full kappa agonist trans-(-)-3,4dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50,488). At the cloned mu-opioid receptor, TCAs showed low affinity and no significant agonist activity. These results show that TCAs differentially regulate opioid receptors with a preferential agonist activity on either delta or kappa subtypes and suggest that this property may contribute to their therapeutic and/or side effects.

A method for the simultaneous extraction of four tricyclic antidepressants from human plasma samples using pipette tip SPE with MonoTip C(18) tips is presented. Human plasma (0.1 mL) containing four tricyclic antidepressants (amitriptyline, amoxapine, imipramine, and trimipramine) and an internal standard (IS), protriptyline, was mixed with 0.4 mL of distilled water and 100 microL 1 M NaOH solution. After centrifugation of the mixture, the supernatant was extracted to the C(18) phase of the tip by 20 repeated aspirating/dispensing cycles using a manual micropipettor. The analytes retained in the tip were eluted with methanol by five repeated aspirating/dispensing cycles. Without evaporation and reconstitution, the eluate was directly injected into a gas chromatograph injector and detected by a mass spectrometer with SIM in the positive-ion electron impact mode. Recovery of the four antidepressants and IS spiked into human plasma was 80.2-92.1%. The regression equations for the four antidepressants showed excellent linearity in the range of 0.2-40 ng/0.1 mL. LODs and LOQs for the four drugs were 0.05-0.2 ng/0.1 mL and 0.2-0.5 ng/0.1 mL, respectively. Intra- and interday CVs for the four drugs in plasma were no greater than 9.5%.

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.

A simultaneous determination of 20 antidepressant drugs (imipramine, amitriptyline, desipramine, trimipramine, nortriptyline, clomipramine, amoxapine, lofepramine, dosulepin, maprotiline, mianserin, setiptiline, trazodone, fluvoxamine, paroxetine, milnacipran, sulpiride, tandspirone, methylphenidate and melitracen) in human plasma was developed using LC/MS with sonic spray ionization (SSI) method. These drugs showed good separation and sensitivity by LC–MS using an Inertsil C-8 column with methanol:10 mM ammonium acetate (pH 5.0):acetonitrile (70:20:10) as mobile phase at 0.10 mL/min at 35 °C. Solid-phase extraction of these drugs added to the human plasma was performed with an Oasis ® HLB cartridge column. Recovery and limit of detection of these drugs were between 69 and 102% and between 0.03 and 0.63 μg/mL, respectively. The present procedure offers an easier and more convenient screening method for antidepressants, and will be useful for forensic toxicology investigations.

Background Non-viral gene transfer efficiency is low as compared to viral vector systems. Here we describe the discovery of new drugs that are capable of enhancing non-viral gene transfer into mammalian cells using a novel two-stage screening procedure. Methods First, potential candidates are preselected from a molecular library at various concentrations by a semi-automated yeast transfection screen (YTS). The maximal transfection efficiency of every positive drug is subsequently determined in independent experiments at the optimal concentration and compared to the inhibitory effect of the drug on cell growth (IC50). In a subsequent mammalian cell transfection screen (MTS), the maximal transfection efficiency and the IC50 are determined for all preselected drugs using a human cell line and a luciferase reporter gene construct. Results Employing our novel system we have been able to identify a new class of transfection enhancers, the tricyclic antidepressants (i.e. doxepin, maprotiline, desipramine and amoxapine). All positive drugs enhanced gene transfer in both yeast and human cell lines, but lower concentrations were sufficient for mammalian cells. With a triple combination of doxepin, amoxapine and chloroquine we obtained a transfection efficiency that exceeded that of chloroquine, one of the best-known transfection enhancers of mammalian cells, by nearly one order of magnitude. Conclusions Non-viral gene transfer efficiency can be increased significantly using new transfection enhancers that are identified by a novel, semi-automated two-stage screening system employing yeast cells in the first and specific human target cells in the second round. Copyright © 2006 John Wiley & Sons, Ltd.

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.

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.

Objective: Amoxapine is marketed as an antidepressant. However, its receptor occupancy, in vitro and in vivo, and its effects in pre-clinical models are very similar to atypical antipsychotics. To examine if this leads to an atypical antipsychotic effect in the clinical context, the authors examined the antipsychotic and side-effect profile of amoxapine in acutely psychotic patients with schizophrenia. Methods: Seventeen patients were enrolled and 15 completed a prospective open-label 6-week study of amoxapine starting with a fixed-starting dose (150 mg/h) with standardized titration up to 250 mg/h, if required. Positive, negative, affective symptoms and side-effects were monitored using standardized weekly assessments. Results: Amoxapine (median final dose 210 mg/h) was well-tolerated and showed significant improvement in positive and negative symptoms (both p

A systematic search found 108 meta-analyses of the use of antidepressants in depressive disorders. Defining newer antidepressants as those introduced since the early 1980s, 18 meta-analyses were selected as being informative about their relative efficacy and tolerability in comparative randomised controlled studies (RCTs). Findings with higher confidence include: little difference in efficacy between most new and old antidepressants; superior efficacy of serotonin and noradrenaline re-uptake inhibitors (SNRIs) over selective serotonin re-uptake inhibitors (SSRIs); a slower onset of therapeutic action of fluoxetine over other SSRIs; a different side effect profile of SSRIs to TCAs with superior general tolerability of SSRIs over TCAs; poorer tolerability of fluvoxamine than other SSRIs in a within group comparison; no increased the risk of suicidal acts or ideation in fluoxetine compared with TCAs (or placebo) in low-risk patients. Findings with a lower level of confidence include: greater efficacy of TCAs than SSRIs in in-patients; greater efficacy of amitriptyline than SSRIs; better tolerability of moclobemide than TCAs; no demonstrable difference in tolerability between SSRIs and TCAs in the elderly; no better tolerability of fluvoxamine than TCAs; better tolerability of dothiepin (dosulepin) than SSRIs; better tolerability of sertraline and greater frequency of agitation on fluoxetine than other SSRIs in a within group comparison. In general, the meta-analyses were of uneven quality, as were the studies included, which limits the confidence in many of the results. Generalising from mostly short-term randomised controlled studies to clinical practice requires caution.

The diagnosis, classification, and course of psychotic major depression (PMD) is considered with regard to its status as a distinct syndrome. Several factors, especially biological markers, suggest, although as yet do not confirm, that PMD is distinct from nonpsychotic major depression (NPMD), particularly for the purposes of treatment. This article provides a critical review of somatic treatments for PMD, with attention to problems of inadequate treatment, as well as underused and more recently introduced treatments. The somatic treatment options reviewed include (1) combined antidepressant (AD) and antipsychotic (AP) therapy with tricyclic antidepressants (TCAs) and typical APs; (2) electroconvulsive therapy (ECT); (3) amoxapine; (4) selective serotonin reuptake inhibitors (SSRIs), alone and in combination; (5) several atypical APs, alone and in combination; (6) mood stabilizers and anticonvulsants; and (7) some experimental treatments and surgery. A comprehensive treatment algorithm (heuristic) is presented, which draws on some previous guidelines and the critical review. This heuristic is conservative in its aims, but forward-looking in its recommendations. The status of the TCA plus typical AP regime is challenged as the default first-line treatment, and preferable alternatives are discussed. ECT has been shown to be at least as effective in short-term treatment and should be considered more frequently, especially in severe presentations and as a maintenance treatment. Some single compounds should be considered as first-line monotherapies in less severe cases. For cases in which combined AD+AP regimes are instituted, SSRIs and atypical APs should be used before older classes of drugs are considered. These recommendations aim to minimize the number of treatments used and unwanted effects experienced.

The dibenzoxazepine neuroleptic loxapine, its N-demethylated metabolite amoxapine, and their 7- and 8-hydroxymetabolites were measured simultaneously in plasma by reversed-phase high-performance chromatographic method. An original liquid-liquid extraction procedure was performed, consisting in coextraction of the substances together with a water-miscible solvent (acetonitrile) by a non-water-miscible solvent (toluene). The substances were separated on a 5-microm CN 25-cm column, and eluted with a mobile phase consisting of acetonitrile-acetic acid 0.5 N (30:70) and hexylamine (0.05%). They were detected by ultraviolet spectrophotometry at 310 nm. Clozapine was used as internal standard. Linearity was demonstrated in the range of 10 to 250 microg/l, and detection limits were found to be 3.5 to 6.3 microg/l according to the substance. Within-day repeatability ranged from 2.7% to 6.5%, and between-day reproducibility ranged from 0.9% to 20.2%. The extraction procedure provided a mean absolute recovery of 51.1% (range, 40.7% to 58.6%) with a mean coefficient of variation of 4.2%. This technique was applied to the concurrent determination of plasma concentrations of the compounds in 10 patients administered loxapine 75 to 600 mg daily. Steady state plasma levels of loxapine were significantly correlated with oral doses (n = 10, r = 0.858, p < 0.002). In conclusion, the method proved to be a convenient and reproducible procedure allowing the simultaneous measurement of loxapine, amoxapine, and their metabolites in patients.

A selective and sensitive spectrofluorimetric method was developed and validated for the determination of amoxapine in human plasma and urine. The developed method is based on labeling with 5-dimethylaminonaphthalene-1-sulfonyl chloride (dansyl chloride) and monitoring at 397 nm (excitation)/514 nm (emission). The method was validated for linearity, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy, recovery and robustness. The calibration curves were linear over a concentration range of 250-2500 and 50-1250 ng/mL for plasma and urine, respectively. The LOD values were calculated to be 13.31 and 13.17 ng/mL for plasma and urine, respectively. The proposed method was applied to study of amoxapine in human plasma and urine.

Tonic-clonic seizure activity is a recognized complication of amoxapine overdose. Refractory drug-induced status epilepticus is associated with significant morbidity and mortality. Standard regimens for controlling status epilepticus may be ineffective for aborting drug-induced seizures. The authors report the case of a 30-year-old woman who presented with an amoxapine overdose that deteriorated into status epilepticus refractory to conventional therapy. Propofol given by intravenous bolus and maintenance infusion successfully halted the patient's seizure activity. This case suggests that propofol may be effective as an anticonvulsant in refractory drug-induced status epilepticus.

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.

A 39-year-old physician was diagnosed retrograde ejaculation due to diabetes and treated with amoxapine. This treatment was effective; he could ejaculate. He began receiving DPP-IV inhibitor (Sitagliptin 50 mg, daily), in lieu of insulin injection. Unusual effect on semen quality was occurred following the administration of the drug.

Patients with psychotic depression respond well when treated with a combination of an antidepressant and antipsychotic medication. We previously reported that they will respond in a similar fashion when treated with amoxapine monotherapy. There are few prospective studies on the pharmacologic treatment response of psychotic depression subtypes. We treated 37 inpatients, 21 with mood congruent (MC) psychotic depression and 16 with mood incongruent (MI) psychotic depression, in a randomized double-blind fashion with either the combination of amitriptyline and perphenazine or with amoxapine for 4 weeks. Depression and psychosis ratings improved in a similar manner in both the MC or MI patients irrespective of medication treatment group. Global response rates were similar in the MI patients and MC patients. The data suggest that classifying psychotic depression into MC versus MI subtypes may have limited acute prognostic value in pharmacotherapy response rates.

We have studied the effects of single oral doses of amoxapine (100 mg and 200 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced double-blind crossover design. Amitriptyline significantly reduced salivation and it significantly attenuated both miosis evoked by locally applied pilocarpine and sweat secretion evoked by locally applied carbachol. Amoxapine did not significantly alter any of these measures. Neither treatment significantly altered the pupillary light reflex (latency, amplitude, or 75% recovery time). Resting pupil diameter was significantly reduced by the higher dose of amoxapine but was not affected by the other treatments. The higher dose of amoxapine significantly increased supine systolic blood pressure, but did not affect heart rate or diastolic blood pressure; amitriptyline had no effect on any of these cardiovascular measures. These results confirm the antimuscarinic effects of amitriptyline in man, but provide no evidence for antimuscarinic effects of amoxapine.

Amoxapine, a dibenzoxazepine antidepressant, has been suggested to have atypical antipsychotic properties. We tested it to control psychosis in three patients with Parkinson's disease (PD). Two patients had significant improvement in hallucinations, whereas the third could not tolerate the drug for a sufficient period. All three patients experienced a decline in motor function; two also had concomitant reduction in dyskinesias. Therefore, although we found some support for amoxapine having antipsychotic properties, this drug seems to carry a risk of worsening motor function in patients with PD.

A new, selective and sensitive method has been developed for the determination of tricyclic antidepressant drugs, amoxapine and nortriptyline, in human blood plasma and serum, involving their reaction with allyl isothiocyanate and extraction of thiourea derivatives with water-miscible organic solvent acetonitrile. The phase separation was effected by addition of ammonium sulphate, a process called salt-assisted liquid-liquid microextraction. The extract was analyzed by HPLC with UV detection at 254 nm. The method has been optimized for derivatization reaction time and temperature, solvent for extraction, and salt for solvent phase separation. Under the optimal conditions, a linear calibration graph was obtained between the amount of drug and the peak area of thiourea derivatives in the range of 0.002-20 mg/L drugs. The correlation coefficient and limit of detection values for amoxapine and nortriptyline in serum/plasma samples were in the range of 0.9953-0.9999 and 0.46-0.58 μg/L, respectively. The recovery in spiking experiments ranged, respectively, 75-88% (RSD 3.4-7.2%) and 79-97% (RSD 3.7-7.9%) for the two drugs.

The antidepressant amoxapine has been linked to cases of QT prolongation, acute heart failure, and sudden death. Inhibition of cardiac hERG (Kv11.1) potassium channels causes prolonged repolarization and is implicated in apoptosis. Apoptosis in association with amoxapine has not yet been reported. This study was designed to investigate amoxapine effects on hERG currents, hERG protein trafficking, and hERG-associated apoptosis in order to elucidate molecular mechanisms underlying cardiac side effects of the drug. hERG channels were expressed in Xenopus laevis oocytes and HEK 293 cells, and potassium currents were recorded using patch clamp and two-electrode voltage clamp electrophysiology. Protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and cell viability was assessed in HEK cells by immunocytochemistry and colorimetric MTT assay. Amoxapine caused acute hERG blockade in oocytes (IC(50) = 21.6 microM) and in HEK 293 cells (IC(50) = 5.1 microM). Mutation of residues Y652 and F656 attenuated hERG blockade, suggesting drug binding to a receptor inside the channel pore. Channels were mainly blocked in open and inactivated states, and voltage dependence was observed with reduced inhibition at positive potentials. Amoxapine block was reverse frequency-dependent and caused accelerated and leftward-shifted inactivation. Furthermore, amoxapine application resulted in chronic reduction of hERG trafficking into the cell surface membrane (IC(50) = 15.3 microM). Finally, the antidepressant drug triggered apoptosis in cells expressing hERG channels. We provide evidence for triple mechanisms of hERG liability associated with amoxapine: (1) direct hERG current inhibition, (2) disruption of hERG protein trafficking, and (3) induction of apoptosis. Further experiments are required to validate a specific pro-apoptotic effect mediated through blockade of hERG channels.

A case of fatal poisoning involving ethanol with psychotropic drugs is presented. Quantitative toxicological analysis showed that the concentrations of ethanol, amoxapine and phenobarbital in the femoral blood were 2.86 mg/ml, 0.41 microg/ml and 6.80 microg/ml, respectively. We concluded that the cause of death was due to the combination use of ethanol, amoxapine and phenobarbital.

A 37-year-old woman was admitted to our hospital because of acute respiratory distress. Two weeks previously, amoxapine (75 mg/day) had been administered for the first time. Ten days later she developed a high fever, severe hypoxaemia and pulmonary infiltrates on chest CT, including patchy areas of ground-glass opacity, thickening of the interlobular septae and bronchial walls and pleural effusions. BAL showed a predominance of neutrophils, lymphocytes and erythrocytes but not eosinophils. Amoxapine was stopped, resulting in complete resolution of the pulmonary infiltrates. When the patient was re-exposed to amoxapine (52.5 mg total dose), high fever, reduced SaO(2) and pulmonary infiltrates reappeared. We concluded that acute respiratory distress may be associated with amoxapine treatment.

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.

A selective method for measuring tricyclic antidepressants in serum is reported. A single assay can be done within ca. 30 min and eight samples can be assayed in less than 150 min. A 1-ml serum sample was diluted and the drugs were extracted from it by passage through a graphitized carbon black (Carbopack B) cartridge. After one washing, this cartridge was connected on line to another one containing a silica-based strong acid exchanger. The tricyclics were removed from the Carbopack surface and selectively readsorbed onto the cation-exchange surface by passing 4 ml of methylene chloride-methanol (60:40, v/v) through the two cartridges. After another wash, the drugs were desorbed from the cation-exchange surface with 0.8 ml of acetonitrile-methanol-water (72:18:10, v/v) saturated with potassium chloride. An aliquot of this solution was chromatographed on a cyano column, and the absorbance of the effluent was measured at 215 nm. The mean analytical recoveries of tricyclic antidepressants added to serum within the range 10-200 micrograms/l exceeded 90%, except for 8-hydroxyamoxapine (mean recovery 85.3%) and amoxapine (mean recovery 83.8%) at the lowest serum concentration considered.

Objective:There is substantial evidence that tricyclic antidepressants are effective in the management of chronic pain, including cancer pain. In oncological settings, these agents are used as adjuvant analgesic drugs. However, cases of akathisia due to tricyclic antidepressants used as adjuvant analgesic therapy have not previously been reported.Case reports:Two cancer patients experiencing chronic pain who were refractory to nonsteroidal anti-inflammatory drugs and opioids were prescribed amoxapine as an adjuvant analgesic therapy for neuropathic pain. These patients developed inner restlessness and restless physical movements after amoxapine was prescribed. Although symptoms were atypical, akathisia was suspected and discontinuation of amoxapine resolved the symptoms.Results and significance of results:Akathisia should be considered in patients receiving adjuvant analgesic therapy with tricyclic antidepressants. Early detection and appropriate treatment will relieve this distressing symptom. Restless movements involving parts of the body other than the legs may be the clue to the diagnosis.

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.

Here we describe a liquid chromatography-tandem mass spectrometry method for the blood determination of tricyclic antidepressant drugs (amitriptyline, clomipramine, trimipramine, and imipramine, doxepin, mianserin, maprotyline, dosulepine, amoxapine), their active metabolites (desipramine, nortriptyline, demethylclomipramine, and nordoxepin), and monoamine oxidase inhibitors (toloxatone and moclobemide). A nontricyclic antidepressant (viloxazine) and two other anxiolytic drugs (buspirone and hydroxyzine) that could be encountered in toxicology have been included to this method. After a liquid-liquid extraction from blood, the compounds and their internal standard (methylrisperidone) were eluted on a XTerra RP18 column with a gradient of acetonitrile/ammonium formate buffer 4 mmol/L (pH 3.2). They were then detected by electrospray ionization mass spectrometry with multiple reaction monitoring mode. The calibration curves were linear over the range 5-100 ng/mL. The limit of quantification was 2 ng/mL for each compound. The bias were lower than 10%. Intraday and interday precisions, expressed as variation coefficient, were lower than 13%. The extraction recoveries were between 60 and 80% except for moclobemide, viloxazine, and toloxatone (10-60%). This specific and sensitive method allows management of intoxication and is suitable for the routine determination of antidepressants in forensic investigation.

The aim of this study was to determine remission rates during treatment with two different dosages of milnacipran, and the effect of milnacipran therapy for at least 1 year on the maintenance of remission and tolerability, in outpatients with major depression.The study included 41 outpatients with major depression who initially received milnacipran 50 mg/day for 1-2 weeks, followed by a dosage increase to 100 mg/day for 12 weeks. Patients who achieved remission (17-item Hamilton Depression Rating Scale [HDRS] scoresor=7) after 12 weeks of milnacipran 100 mg/day treatment continued at the same dosage and were followed for at least 1 year. For patients who had decreased HDRS scores, but failed to attain remission, the dosage of milnacipran was increased to 150 mg/day, and those who achieved remission were then followed for at least 1 year.Eight out of 41 patients were withdrawn from the study prematurely because of adverse events (eight events in six patients: nausea, thirst, urinary discomfort, rapid pulse, palpitations, staggering sensation or sweating) or as a result of the patient's decision (two patients). Thirteen (31.7%) of 41 patients achieved remission during treatment with milnacipran 100 mg/day. Of the remaining 20 patients, 17 underwent a dosage increase to 150 mg/day, and 13 achieved remission at a second assessment (cumulative remission rate: 63.4%). No adverse events or recurrence of symptoms were found in any of the patients who achieved remission during the subsequent follow-up period of a minimum of 1 year.The results of this study showed milnacipran 150 mg/day and 100 mg/day to be effective and well tolerated in the long-term treatment of outpatients with major depression, and indicated that a dosage of 150 mg/day is an effective therapeutic option for depression when a dosage of 100 mg/day does not provide a satisfactory response.

We investigated simultaneous determination of haloperidol (HAL), its three metabolites [reduced HAL (R-HAL), 3-(4-fluorobenzoyl)propionic acid (FBPA) and 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP)] and two related compounds [spiperone (SPI) and droperidol (DRO)] in phosphate-buffered saline using high-performance liquid chromatography (HPLC) coupled with dual ultraviolet detection (220 and 250 nm). Retention times of HAL, R-HAL, FBPA, CPHP, SPI and DRO were 16.8, 11.8, 10.2, 4.1, 12.6 and 8.3 min, respectively. Their lower limits of detection were 7.5, 14, 4.5, 12, 10 and 20 ng/mL in the same order. The coefficients of variation for their intra- and inter-day assays were less than 7.8 and 9.4%, respectively. Of the other centrally acting drugs, only amoxapine interfered with the peak of DRO. Using our procedure, the binding study of tested compounds to synthetic melanin, human serum albumin and alpha1-acid glycoprotein was performed by determining the unbound concentration to total concentration ratio. These results indicated that simultaneous assay of HAL, R-HAL, FBPA, CPHP, SPI and DRO in phosphate-buffered saline by HPLC equipped with dual ultraviolet detection is simple, sensitive and reproducible. Also, our assay system can be applied to the binding study of these compounds to synthetic melanin, human serum albumin and alpha1-acid glycoprotein.

We reported a case of drug eruption induced by combined treatment with three different kinds of drugs, amoxapine, mexiletine hydrochloride and cefaclor. A 63-year-old Japanese woman suffering from 11 years of standing reflex sympathetic dystrophy developed multiple erythematous papules on her trunk and extremities after taking 14 kinds of drugs. The provocation challenge produced positive reactions to amoxapine, mexiletine hydrochloride, and cefaclor, but was negative to the other drugs. We discussed the mechanism of simultaneous sensitization to three different kinds of drugs in our case.

We report a case of serotonin syndrome in a patient being treated with paroxetine for depression. Despite prompt discontinuation of medication, his serotonin syndrome continued for 10 days before full consciousness was restored. The patient was a 48-year-old male with chief complaints of hypobulia and suicidal thoughts. He consulted as a psychiatric outpatient, and oral paroxetine 20 mg/day, etizolam 1.0 mg/day, and brotizolam 0.25 mg/day were immediately started. Upsurge of feeling and disinhibition state were noted the following day, then on treatment day 6 his condition deteriorated to substupor state and he was admitted for further treatment. On admission, change of mental condition (consciousness disturbance), perspiration, hyperreflexia, myoclonus and tremor were seen, and serotonin syndrome caused by paroxetine was suspected. Paroxetine was thus discontinued, and under intravenous drip his condition gradually improved. However, it was not until the 10th hospital day that he became fully alert. In examinations, no infectious, metabolic or organic diseases were detected. The patient's condition often improves with in 24 hours of discontinuation of the causative medication in serotonin syndrome. Symptoms continued for 10 days in this patient, however, perhaps because paroxetine was administered for 6 days before discontinuation. In addition, interaction with other medications may have occurred. Therefore, when serotonin syndrome is suspected, prompt discontinuation of the suspected causative medication, followed by close monitoring of the pharmacokinetics is warranted.

Drug reactions are well-known complications of antidepressant therapy, often related to photosensitization. Herein is reported a singular case of antidepressant (amoxapine and citalopram) and anxiolytic related (perphenazine) photo-distributed neutrophilic dermatosis and adult respiratory distress syndrome (ARDS). The clinicopathologic findings displayed overlapping features with drug-induced Sweet's syndrome, acute generalized exanthematous pustulosis (AGEP), and so-called sterile neutrophilic folliculitis with perifollicular vasculopathy. Of the three medications, only amoxapine has been associated with AGEP. Treatment with high-dose systemic corticosteroids and cessation of drug therapy was followed by rapid resolution of the cutaneous eruption and respiratory distress. The possibility that neutrophil infiltration of the lung and/or accumulation of neutrophils in the skin and blood served as a source for reactive oxygen species, leading to lung injury and subsequent ARDS, is discussed.

A patient with a 7-year history of depression relapsed after self-discontinuation of antidepressant drugs. He was admitted to our hospital and re-administered amoxapine 150 mg. p.o. per day, and further given haloperidol 5 mg i.m. or p.o. per day because he was suicidal and excited. One month later, an area of alopecia was found on the back of his head. Immediately, he received dermatological treatment. The psychotropic drugs were continued, but the hair loss was unchanged after one month. So, haloperidol alone was discontinued. One week later, the hair loss had stopped and a month later alopecia had virtually disappeared. We suggest that alopecia areata is associated with haloperidol.

In this study, we investigated three female patients given a diagnosis of temporal lobe epilepsy preceded by depression. It is notable that all the patients complained of abnormal sensations, either in the throat or oral. The depression in the three patients showed no improvement with antidepressants, but carbamazepine was effective for both epileptic seizures and depression. EEG should be performed on patients who develop antidepressant treatment-refractory depression accompanied by hypochondriacal complaints.