Identification of the exosomal PD-L1 inhibitor to promote the PD-1 targeting therapy of gastric cancer.

Programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) targeting therapy is widely applied in clinics for gastric cancer treatment. Nevertheless, the clinical response is not well acceptable due to the exosomal PD-L1. Hence, abrogation of the exosomal PD-L1 may be a strategy to sensitize the gastric cancer cell to PD-1 targeting therapy. With the aid of CD63 targeting antibody and PD-L1 targeting aptamer, HTRF based assay was established to quantify the exosomal PD-L1, and applied to our in-house compound library, resulting in the identification of moclobemide. Further optimization of moclobemide lead to EP16, which can inhibit the generation of exosomal PD-L1 with IC50 = 0.108 µM. By applying EP16 to gastric cancer cell line coupled with T-cell activity related experiment, it was validated to activate T-cell and can promote the response of PD-1 targeting therapy for gastric cancer treatment in vitro and in vivo. Collectively, our findings give a promising tool to promote the sensitivity of anti-PD-1 for gastric cancer treatment, and EP16 can serve as a leading compound for exosomal PD-L1 abrogation.

Effect of antidepressants for cessation therapy in betel-quid use disorder: a randomised, double-blind, placebo-controlled trial.

AIMS: More than one-half of betel-quid (BQ) chewers have betel-quid use disorder (BUD). However, no medication has been approved. We performed a randomised clinical trial to test the efficacy of taking escitalopram and moclobemide antidepressants on betel-quid chewing cessation (BQ-CC) treatment. METHODS: We enrolled 111 eligible male BUD patients. They were double-blinded, placebo-controlled and randomised into three treatment groups: escitalopram 10 mg/tab daily, moclobemide 150 mg/tab daily and placebo. Patients were followed-up every 2 weeks and the length of the trial was 8 weeks. The primary outcome was BQ-CC, defined as BUD patients who continuously stopped BQ use for ⩾6 weeks. The secondary outcomes were the frequency and amount of BQ intake, and two psychological rating scales. Several clinical adverse effects were measured during the 8-week treatment. RESULTS: Intention-to-treat analysis shows that after 8 weeks, two (5.4%), 13 (34.2%) and 12 (33.3%) of BUD patients continuously quit BQ chewing for ⩾6 weeks among placebo, escitalopram, moclobemide groups, respectively. The adjusted proportion ratio of BQ-CC was 6.3 (95% CI 1.5-26.1) and 6.8 (95% CI 1.6-28.0) for BUD patients who used escitalopram and moclobemide, respectively, as compared with those who used placebo. BUD patients with escitalopram and moclobemide treatments both exhibited a significantly lower frequency and amount of BQ intake at the 8th week than those with placebo. CONCLUSIONS: Prescribing a fixed dose of moclobemide and escitalopram to BUD patients over 8 weeks demonstrated treatment benefits to BQ-CC. Given a relatively small sample, this study provides preliminary evidence and requires replication in larger trials.

Administration of moclobemide facilitates fear extinction and attenuates anxiety-like behaviors by regulating synaptic-associated proteins in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a long-lasting mental disorder and accompanied by worse fear extinction. Enhanced fear memory or poor fear extinction are typical features of PTSD. Dysfunction of the serotonergic neurotransmitter system is involved in numerous mental and behavioral disorders. Monoamine oxidase A (MAOA) is important in the metabolism of serotonin and play an important role in behavious. The aim of this study was to explore the change of MAOA and effect of MAOA on fear memory in PTSD. We used single prolonged stress (SPS) to create animal model of PTSD. A startle/fear box and elevated plus maze were used to observe fear memory and anxiety level, respectively. We examined the expression of MAOA and synaptic marker protein, as well as the immunological activity of MAOA in the infralimbic cortex (IL) area, which is a critical brain region involved in emotions, especially fear regulation. We found increased anxiety-like behavior, dysfunction in fear extinction, and increased MAOA in SPS rats. After treatment with moclobemide (a selective inhibitor of MAOA), SPS rats showed significantly improved fear memory and decreased anxiety-like behavior, which indicated that moclobemide could reverse fear extinction deficit and attenuate abnormally increased levels of anxiety caused by SPS in short term. On the contrary, decreased PSD-95 and SYN1 expression in the IL region were also reversed by moclobemide. These results suggest that increased MAOA play a negative role in fear extinction and levels of anxiety in PTSD, which may be involved in change in PSD-95 and SYN1.

Monoamine oxidase A inhibition protects the myocardium after experimental acute volume overload.

OBJECTIVE: The molecular pathway leading to myocardial cellular destruction after acute volume overload (AVO) may include monoamine oxidases. The aim of the present study was to investigate whether moclobemide (Mo), a monoamine oxidase inhibitor, protects the myocardium after AVO. METHODS: Sixty syngeneic Fischer rats underwent surgical abdominal aortocaval fistula to induce AVO. Eighteen rats were treated with Mo 10 mg/kg/day and were compared with 42 untreated rats with AVO without treatment. Myocardial recovery was analyzed using quantitative reverse transcription polymerase chain reaction for hypoxia-inducible factor 1-alpha, inducible nitric oxide synthase, interleukin 6, E-selectin, atrial natriuretic peptide (ANP), brain natriuretic peptide, vascular endothelial growth factor-alpha, matrix metalloproteinase 9, chitinase 3-like protein (YKL-40), and transforming growth factor-beta. RESULTS: After 3 days, the relative number of ischemic intramyocardial arteries in the left ventricle was lower in AVO treated with Mo than in without [0.04 (0.02-0.07) vs. 0.09 (0.07-0.14), point score unit]. After 1 day, ANP was lower in AVO treated with Mo than in without [0.95 (0.37-1.84) vs. 2.40 (1.33-3.09), fold changes from the baseline (FC), p=0.044], whereas after 1 and 3 days, YKL-40 was higher in AVO treated with Mo than in without [22.66 (14.05-28.83) vs. 10.06 (6.23-15.02), FC, p=0.006 and 6.03 (4.72-7.18) vs. 3.70 (2.62-5.35), FC, p=0.025]. CONCLUSION: Mo decreases intramyocardial arterial ischemia of the left ventricle after AVO while increases YKL-40, reflecting cellular protection during early cardiac remodeling. In the future, adding Mo may be a simple means for myocardial protection after AVO.

Resting functional connectivity in social anxiety disorder and the effect of pharmacotherapy.

Neuroimaging research has reported differences in resting-state functional connectivity (RFC) between social anxiety disorder (SAD) patients and healthy controls (HCs). Limited research has examined the effect of treatment on RFC in SAD. We performed a study to identify differences in RFC between SAD and HC groups, and to investigate the effect of pharmacotherapy on RFC in SAD. Seed-based RFC analysis was performed on technetium-99m hexamethylpropylene amine oxime (Tc-99m HMPAO) SPECT scans using a cross-subject approach in SPM-12. Seeds were chosen to represent regions in a recently published network model of SAD. A second-level regression analysis was performed to further characterize the underlying relationships identified in the group contrasts. Twenty-three SAD participants were included, of which 18 underwent follow-up measures after an 8-week course of citalopram or moclobemide. Fifteen healthy control (HC) scans were included. SAD participants at baseline demonstrated several significant connectivity disturbances consistent with the existing network model as well as one previously unreported finding (increased connectivity between cerebellum and posterior cingulate cortex). After therapy, the SAD group demonstrated significant increases in connectivity with dorsal anterior cingulate cortex which may explain therapy-induced modifications in how SAD sufferers interpret emotions in others and improvements in self-related and emotional processing.

Dose equivalents of antidepressants: Evidence-based recommendations from randomized controlled trials.

BACKGROUND: Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method. METHODS: We used data from all randomized, double-blind, flexible-dose trials comparing fluoxetine or paroxetine as standard drugs with any other active antidepressants as monotherapy in the acute phase treatment of unipolar depression. We calculated the ratio of the mean doses for each study and weighted it by the total sample size to find the weighted mean ratio for each drug, which was then used to define the drug׳s dosage equivalent to fluoxetine 40mg/d. RESULTS: We included 83 studies (14 131 participants). In the primary analysis, fluoxetine 40mg/day was equivalent to paroxetine dosage of 34.0mg/day, agomelatine 53.2mg/day, amitriptyline, 122.3mg/day, bupropion 348.5mg/day, clomipramine 116.1mg/day, desipramine 196.3mg/day, dothiepin 154.8mg/day, doxepin 140.1mg/day, escitalopram 18.0mg/day, fluvoxamine 143.3mg/day, imipramine 137.2mg/day, lofepramine 250.2mg/day, maprotiline 118.0mg/day, mianserin, 101.1mg/day, mirtazapine 50.9mg/day, moclobemide 575.2mg/day, nefazodone 535.2mg/day, nortriptyline 100.9mg/day, reboxetine 11.5mg/day, sertraline 98.5mg/day, trazodone 401.4mg/day, and venlafaxine 149.4mg/day. Sensitivity analyses corroborated the results except for doxepin. LIMITATIONS: The number of studies for some drugs was small. The current method assumes dose response relationship of antidepressants. CONCLUSIONS: Our findings can be useful for clinicians when they switch antidepressants and for researchers when they compare various antidepressants in their research.

Antidepressant-like effects of ferulic acid: involvement of serotonergic and norepinergic systems.

Ferulic acid is a polyphenol that has antioxidant, anti-inflammatory and anticancer properties. The present study analyzed the antidepressant-like potential of ferulic acid using two well-validated mouse models of despair test, tail suspension and forced swim tests. The results suggested that ferulic acid treatment at doses of 10, 20, 40 and 80 mg/kg (p.o.) significantly reduced the immobility time in both of these two tests. These doses that affected the depressive-like behaviors did now show any effect on locomotion counts. The further neurochemical assays suggested that ferulic acid increased monoamine neurotransmitter levels in the brain regions that are relative to mood disorders: the hippocampus and frontal cortex. The increased tend to serotonin and norepinephrine was also found in the hypothalamus after higher dose of ferulic acid treatment. The subsequent study suggested that monoamine oxidase A (MAO-A) activity was inhibited in the frontal cortex and hippocampus when treatment with 40 and 80 mg/kg ferulic acid; while MAO-B activity did not change significantly. The current study provides the first lines of evidence that serotonin and norepinephrine, but not dopamine levels were elevated in mouse hippocampus and frontal cortex after ferulic acid treatment. These changes may be attributable to the inhibition of MAO-A activities in the same brain regions.

Lack of efficacy of moclobemide or imipramine in the treatment of recurrent brief depression: results from an exploratory randomized, double-blind, placebo-controlled treatment study.

'Recurrent brief depression' (RBD) is a common, distressing and impairing depressive disorder for which there is no current proven pharmacological or psychological treatment. This multicentre, randomized, fixed-dose, parallel-group, placebo-controlled study of the reversible inhibitor of monoamine oxidase moclobemide (450 mg/day) and the tricyclic antidepressant imipramine (150 mg/day) evaluated the potential efficacy of active medication, when compared with placebo, in patients with recurrent brief depression, recruited in the mid-1990s. After a 2-4-week single-blind placebo run-in period, a total of 35 patients were randomized to receive double-blind medication for 4 months, but only 16 completed the active treatment period. An intention-to-treat analysis of the 34 evaluable patients found no evidence for the efficacy of moclobemide or imipramine, when compared with placebo, in significantly reducing the severity, duration or frequency of depressive episodes. A total of 28 patients experienced at least one adverse event, and four patients engaged in nonfatal self-harm. Limitations of the study include the small sample size and the high rate of participant withdrawal. The lack of efficacy of these antidepressant drugs and the previous finding of the lack of efficacy of the selective serotonin reuptake inhibitor fluoxetine together indicate that medications other than antidepressant drugs should be investigated as potential treatments for what remains a common, distressing and potentially hazardous condition.

The antinociceptive effect of reversible monoamine oxidase-A inhibitors in a mouse neuropathic pain model.

Neuropathic pain is a debilitating condition that is often resistant to common analgesics, such as opioids, but is sensitive to some antidepressants, an effect that seems to be mediated by spinal cord 5-HT3 receptors. Because the analgesic potential of monoamine oxidase-A (MAO-A) inhibitors is understudied, we evaluated the potential antinociceptive effect of the reversible MAO-A inhibitors moclobemide and 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in a mouse neuropathic pain model induced by chronic constriction injury (CCI) of the sciatic nerve. Neuropathic mice showed a decreased mechanical paw withdrawal threshold (PWT) 7 days after lesion compared with the baseline PWT, characterizing the development of hyperalgesia. Moclobemide (100-300 µmol/kg, s.c.) and 2-DMPI (30-300 µmol/kg, s.c.) treatments were able to reverse the CCI-induced hyperalgesia, with 50% inhibitory dose (ID50) values of 39 (18-84) and 11 (4-33) µmol/kg, and maximum inhibition (Imax) values of 88±14 and 98±15%, respectively, at the 300 µmol/kg dose. In addition, we observed a significant increase in the MAO-A activity in the lumbar spinal cord of CCI-submitted mice compared with sham-operated animals. Furthermore, the antihyperalgesic effects of both 2-DMPI and moclobemide were largely reversed by intrathecal injection of the 5-HT3 receptor antagonist ondansetron (10 µg/site). These results suggest a possible involvement of MAO-A in the mechanisms of neuropathic pain and a potential utility of the reversible inhibitors of MAO-A in the development of new therapeutic approaches to treat it.

Antidepressive treatment with monoamine oxidase inhibitors and the occurrence of intraoperative hemodynamic events: a retrospective observational cohort study.

OBJECTIVE: To investigate the occurrence of intraoperative hemodynamic events when antidepressive treatment with monoamine oxidase inhibitors (MAOIs) was continued during anesthesia. METHOD: A retrospective observational cohort study was conducted among patients who were admitted for elective surgery requiring anesthesia in 8 Dutch hospitals (2004-2010). The index group included current users of irreversible (tranylcypromine) and reversible (moclobemide) MAOIs. The reference group included a sample of nonusers matched to the index group on hospital, type and period of surgery, and type of anesthesia (ratio 1:3). The outcome of interest was the occurrence of the following intraoperative hemodynamic events: hypotension or hypertension and tachycardia or bradycardia. RESULTS: Approximately 280,000 surgical procedures were performed in the participating hospitals in the total observational period of 33 years. The index group included 26 and 25 users of tranylcypromine and moclobemide, respectively. The reference groups included 149 nonusers. Intraoperative hypotension occurred less frequently in users of tranylcypromine (46%) than in nonusers (73%) (P = .01). The occurrence of hypertension, bradycardia, and tachycardia during anesthesia was not different between users of tranylcypromine (27%, 50%, and 12%, respectively) and those in the reference group (35%, 61%, and 26%, respectively). The occurrence of hypotension, hypertension, bradycardia, and tachycardia was not different between users of moclobemide and the reference group. CONCLUSIONS: Severe adverse hemodynamic events, such as hypertension and tachycardia, did not occur more frequently in users of both the irreversible MAOI tranylcypromine and the reversible MAO-A inhibitor moclobemide compared to nonusers. These findings suggest that there is no longer much justification to discontinue these MAOIs before surgery, with the considerable risk of compromising patients' psychiatric status.

Monoamine oxidase inhibitors (MAOIs) for fibromyalgia syndrome.

BACKGROUND: Fibromyalgia (FM) syndrome is a chronic condition of unknown aetiology characterised by musculoskeletal pain that often co-exists with sleep disturbance, cognitive dysfunction and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of FM, drug therapy focuses on pain reduction and improvement of other bothersome symptoms. OBJECTIVES: The objective of this review was to assess the effectiveness and safety of monoamine oxidase inhibitors (MAOIs) in the treatment of FM syndrome. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE (1966 to November 2010), EMBASE (1980 to November 2010) and the reference lists of reviewed articles. SELECTION CRITERIA: We selected all randomised, double-blind trials of MAOIs used for the treatment of FM pain in adult participants. DATA COLLECTION AND ANALYSIS: Two authors assessed risk of bias and extracted data independently onto a specially designed pro forma and a third review author cross-checked them. MAIN RESULTS: We included two studies of inconsistent risk of bias with a total of 230 patients diagnosed with FM. We evaluated two MAOIs: pirlindole and moclobemide. Pirlindole showed statistically significant results compared with placebo for several outcomes (pain, tender points and overall assessment by the patient and the physician), whereas moclobemide did not show statistically significant differences between groups. Pooled results of the two studies displayed a modest effect size in pain (mean difference (MD) -1.45 (121 patients; 95% confidence interval (CI) -2.71 to -0.20; number needed to treat (NNT) 2 (95% CI 1 to 12); I(2) = 59%)), implying a minimal clinically important difference (MCID) and a small effect on tender points (standardised mean difference (SMD) -0.36 (121 patients; 95% CI -0.72 to -0.00; I(2) = 31%)). No effect was seen on global assessment by patient. Physical function and sleep disturbance were not measured. The most frequent adverse events were nausea and vomiting, with statistically significant differences between groups (risk ratio (RR) 7.82 (89 patients; 95% CI 1.02 to 59.97; NNT 7 (95% CI 4 to 33)). AUTHORS' CONCLUSIONS: Data suggest that the effectiveness of MAOIs for the treatment of FM symptoms is limited. Although we observed a moderate effect size on pain and a small one on tender points, these results should be taken with caution as they are only based on two studies with a small number of patients and inconsistent risk of bias among them.

The predictive validity of atypical neurovegetative depressive symptoms identified by the first principal component in the DUAG trial of moclobemide versus clomipramine.

OBJECTIVE: To investigate to what extent the primary depression subtype atypical depression can predict differential outcome of the mono-amino-oxidase inhibitor (MAO-I) moclobemide and the tricyclic antidepressant clomipramine in the Danish University Antidepressant Group Study (DUAG). METHODS: In a randomised, double blind trial, a total of 117 patients with major depression were treated over 6 weeks with either 400 mg moclobemide or 150 mg clomipramine. A baseline principal component analysis (PCA) was performed to identify atypical symptoms on the combined depression scales (Hamilton Depression Scale (HAM-D(17)) and the Quantitative Scale for Atypical Depression (QSAD)). The primary outcome scale was the subscale HAM-D(6) which contains the pure items of depression. RESULTS: PCA identified two items with loadings opposite to the other depression items within HAM-D(17) and QSAD, namely increased duration of sleep and increased appetite (atypical neurovegetative symptoms). Patients with a positive score at baseline on these items were classified as having atypical depression. In total 13 patients were classified as having atypical depression. Within this group of patients 8 received clomipramine and 5 patients received moclobemide. At endpoint the moclobemide treated patients had a significantly better response than the clomipramine treated (P=0.036), effect size 1.42, when using HAM-D(6) as outcome. However, in the 104 patients classified as having typical depression clomipramine was superior to moclobemide (P=0.034), effect size 0.47. LIMITATIONS: The number of patients with atypical neurovegetative symptoms was very small and no placebo arm was included. CONCLUSIONS: It is very important to screen for atypical depression (increased duration of sleep/increased appetite) in the acute therapy of patients with major depression. Our results add to the body of evidence that monoamine oxidase inhibitors are superior to tricyclic antidepressants in this sub-group of patients.

[Obstructive sleep apnoea syndrome as the cause of atypical depression]. / Obstruktives Schlaf-Apnoe-Syndrom als Ursache einer atypischen Depression.

Sleep apnoea is a common disorder presenting with somatic comorbidities and psychiatric symptoms. This case report describes a 43-year-old man with an organic depressive disorder due to obstructive sleep apnoea. Initially, an atypical depressive episode or schizophrenic residual syndrome had been considered likely diagnoses; subsequent polysomnography results, however, suggested obstructive sleep apnoea instead. Upon nasal continuous positive airway pressure (nCPAP), the respiratory distress symptoms improved. The case report highlights the association between sleep disturbances and depressive symptoms. In patients presenting with symptoms of atypical depression and excess body weight sleep apnoea should be considered.

Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John's wort: an [11C]-harmine PET study.

BACKGROUND: Monoamine oxidase A (MAO-A) inhibitor antidepressants raise levels of multiple monoamines, whereas the selective serotonin reuptake inhibitors (SSRIs) only raise extracellular serotonin. Despite this advantage of MAO-A inhibitors, there is much less frequent development of MAO inhibitors compared with SSRIs. We sought to measure brain MAO-A occupancy after 6 weeks of treatment in depressed patients with a clinically effective dose of a selective MAO-A inhibitor and measure MAO-A occupancy after repeated administration of St. John's wort, an herb purported to have MAO-A inhibitor properties. METHODS: Participants underwent 2 [(11)C]-harmine positron emission tomography scans. Healthy controls completed a test-retest condition, and depressed patients were scanned before and after repeated administration of moclobemide or St. John's wort for 6 weeks at the assigned dose. We measured MAO-A VT, an index of MAO-A density, in the prefrontal, anterior cingulate and anterior temporal cortices, putamen, thalamus, midbrain and hippocampus. RESULTS: We included 23 participants (10 controls and 13 patients with major depressive disorder [MDD]) in our study. Monoamine oxidase A VT decreased significantly throughout all regions after moclobemide treatment in patients with MDD compared with controls (repeated-measures analysis of variance, F1,15 = 71.08-130.06, p < 0.001 for all regions, mean occupancy 74% [standard deviation 6%]). Treatment with St. John's wort did not significantly alter MAO-A VT. LIMITATIONS: The occupancy estimates are limited by the sample size of each treatment group; hence, our estimate for the overall moclobemide occupancy of 74% has a 95% confidence interval of 70%-78%, and we can estimate with 95% certainty that the occupancy of St. John's wort is less than 5%. CONCLUSION: For new MAO-A inhibitors, about 74% occupancy at steady-state dosing is desirable. Consistent with this, St. John's wort should not be classified as an MAO-A inhibitor. The magnitude of MAO-A blockade during moclobemide treatment exceeds the elevation of MAO-A binding during illness by at least 30%, suggesting that the treatment effect should exceed the disease effect when designing selective antidepressants for this target.

Amisulpride versus moclobemide in treatment of clozapine-induced hypersalivation.

OBJECTIVES: Previous publications demonstrated substitute benzamides as effective agents in treatment of clozapine-induced sialorrhea (CIS). The aim of this study was to compare efficacy of amisulpride and moclobemide (both from the substitute benzamide group) in controlling, or at least minimizing, CIS. METHODS: The study was designed as a 6-week, two-center, fixed-dose, comparison study of 400 mg/day of amisulpride versus 300 mg/day of moclobemide as an adjunctive treatment in 53 schizophrenia and schizoaffective disorder patients (diagnosed according to DSM-IV) suffering from CIS. The patients were treated with each medication during 2 weeks, followed by a washout period of 2 weeks. Primary outcome measures included the reduction in the five-point Nocturnal Hypersalivation Rating Scale (NHRS). Secondary outcomes included the Positive and Negative Syndrome Scale (PANSS), Manic State Assessment Scale, and Extrapyramidal Symptom Rating Scale (ESRS). RESULTS: Both amisulpride and moclobemide were very effective in reducing CIS. Almost 74% of patients treated with amisulpride and 83% of patients treated with moclobemide showed some level of improvement on NHRS. Only in one patient treated with amisulpride, CIS worsened. CONCLUSIONS: Both medications were safe and effective as treatment of CIS. Although moclobemide exceeded amisulpride in antisalivation activity, treatment of CIS with amisulpride leads to improvement in psychotic symptoms.

Improved statistical analysis of moclobemide dose effects on panic disorder treatment.

Clinical trials with several measurement occasions are frequently analyzed using only the last available observation as the dependent variable [last observation carried forward (LOCF)]. This ignores intermediate observations. We reanalyze, with complete data methods, a clinical trial previously reported using LOCF, comparing placebo and five dosage levels of moclobemide in the treatment of outpatients with panic disorder to illustrate the superiority of methods using repeated observations. We initially analyzed unprovoked and situational, major and minor attacks as the four dependent variables, by repeated measures maximum likelihood methods. The model included parameters for linear and curvilinear time trends and regression of measures during treatment on baseline measures. Significance tests using this method take into account the structure of the error covariance matrix. This makes the sphericity assumption irrelevant. Missingness is assumed to be unrelated to eventual outcome and the residuals are assumed to have a multivariate normal distribution. No differential treatment effects for limited attacks were found. Since similar results were obtained for both types of major attack, data for the two types of major attack were combined. Overall downward linear and negatively accelerated downward curvilinear time trends were found. There were highly significant treatment differences in the regression slopes of scores during treatment on baseline observations. For major attacks, all treatment groups improved over time. The flatter regression slopes, obtained with higher doses, indicated that higher doses result in uniformly lower attack rates regardless of initial severity. Lower doses do not lower the attack rate of severely ill patients to those achieved in the less severely ill. The clinical implication is that more severe patients require higher doses to attain best benefit. Further, the significance levels obtained by LOCF analyses were only in the 0.05-0.01 range, while significance levels of <0.00001 were obtained by these repeated measures analyses indicating increased power. The greater sensitivity to treatment effect of this complete data method is illustrated. To increase power, it is often recommended to increase sample size. However, this is often impractical since a major proportion of the cost per subject is due to the initial evaluation. Increasing the number of repeated observations increases power economically and also allows detailed longitudinal trajectory analyses.

Moclobemide treatment of clozapine-induced hypersalivation: pilot open study.

OBJECTIVES: Clozapine-induced hypersalivation (CIHS) affects a mean of approximately 30% patients and is a troublesome adverse effect that leads to massive compliance problems in patients with schizophrenia. For the management of this distressing adverse effect, different pharmacological agents have been recommended, yet none of them have been proven to be effective. The aim of our study was to investigate moclobemide, a reversible monoamine oxidase inhibitor-A, as an additional possibility for controlling or at least minimizing CIHS. METHODS: We enrolled 14 patients with schizophrenia who experienced CIHS. Moclobemide (150-300 mg/d) was added to their conventional regular treatment during 14 days. Hypersalivation was assessed at the start of the treatment and at its end point by the 5-point Nocturnal Hypersalivation Rating Scale. RESULTS: Two thirds of the subjects who experienced CIHS have demonstrated a beneficial effect after the addition of moclobemide, whereas one third of them have been nonresponders. None of the patients had any adverse effects. CONCLUSIONS: We assume that moclobemide can be another additional and safe medication for the treatment of CIHS; however, more data, based on controlled studies, are needed.

[Seronin syndrome and cardiac arrest caused by high-dose moclobemide (case report)].

Serotonin syndrome is the syndrome resulting from brain tissue serotonin accumulation and accompanying by central nervous system dysfunction and circulatory collapse, which leads to a serious mortal danger to life. A female patient aged 31 years, diagnosed as having chronic psychosis in the history, was admitted to an intensive care unit in a critical state for having taking an increased moclobemide dose. The patient developed cardiac arrest and cardiopulmonary resuscitation (CPR) was initiated. A 15-minute CPR recovered sinus rhythm and pulse on the peripheral arteries of the limbs. When consciousness and respiration improved, the patient was weaned from resuscitation and extubated on the second day. On day 4, the patient was transferred from the intensive care unit to the department of psychiatry. The authors consider that patients with overdosage of antipsychotic agents at a risk for such serious complications, such as cardiac arrest, should be necessarily monitored in the intensive care unit.

Uncovering the potential risk of serotonin toxicity in Australian veterans using pharmaceutical claims data.

AIMS: We examined potential risk of serotonin toxicity in Australian veterans by quantifying the concomitant use of serotonergic medicine combinations from claims data collected by the Department of Veterans' Affairs (DVA). METHODS: This was a retrospective cohort study of 273 228 Australian veterans, war widows, widowers and dependents aged >or=55 years and holding full treatment entitlement for the period July 2000 to June 2004 or until death. The main outcome measure was potential concomitant use, estimated as the number of cohort members with an overlap in days of supply for serotonergic medicine combinations over the 4 year period for all medicine combinations and potentially life threatening combinations. RESULTS: From July 2000 to June 2004, 115 969 (42%) cohort members were dispensed at least one serotonergic medicine. 20 658 (8%) had at least one episode of potential concomitant use. We identified 1811 (0.7%) cohort members with at least one overlapping period of potentially life-threatening serotonergic medicine combinations, 937 of whom had the combinations dispensed within the recommended washout period. Three hundred and seventeen of these individuals were dispensed potentially life-threatening medicine combinations on the same day. The most common combinations were moclobemide with a selective serotonin reuptake inhibitor or tramadol. CONCLUSIONS: The individuals potentially at risk of mild to moderate serotonin toxicity were considerable and potentially life threatening combinations were not infrequent. While we were unable to determine how many individuals experienced serotonin toxicity this study indicates, for the first time, the potential size of the problem in a subgroup of elderly Australians. Clinicians and patients need to be vigilant regarding inadvertent concomitant use, especially that of moclobemide with a selective serotonin reuptake inhibitor or tramadol.

Efficacy of moclobemide in burning mouth syndrome: a nonrandomized, open-label study.

AIMS: To compare burning mouth syndrome (BMS) patients with age- and gender-matched controls for psychologic conditions, to analyze the effect of menstrual state on the intensity of burning, and to assess the efficacy of an antidepressant medication on the burning pain and psychologic status. METHODS: Ninety-four patients with BMS and 94 matched control subjects participated in the study. Anxiety and depression were analyzed by means of the Spielberger State-Trait Anxiety Inventory and Zung Self-Rating Depression Scale, and the severity of the burning sensation was measured by means of a visual analog scale (VAS). In female BMS patients and controls, the menstrual state was noted (menstruating, menopausal, or postmenopausal). BMS patients were treated with the antidepressant moclobemide (150 mg 2 times daily) for 3 months. Thereafter, anxiety, depression, and burning pain intensity were reassessed. Patient-perceived satisfactory improvement for burning sensation was assessed using a 5-point categorical rating of change scale. RESULTS: BMS patients had significantly higher anxiety and depression scores than controls (P < .05). After treatment, anxiety and depression scores as well as the VAS values for burning pain decreased significantly (P < .001). Thirty-seven patients reported good to very good improvement, and 44 reported satisfactory improvement. No adverse reactions were reported. CONCLUSIONS: The study confirmed earlier reports that BMS patients have higher anxiety and depression levels than controls. An antidepressant medication may be effective in alleviating the burning pain, at least in the short-term.