Comparison of the Metabolic Characteristics of Newer Second Generation Antipsychotics: Brexpiprazole, Lurasidone, Asenapine, Cariprazine, and Iloperidone With Olanzapine as a Comparator.

PURPOSE/BACKGROUND: Extensive research has been conducted comparing the metabolic characteristics of older second-generation antipsychotics (SGAs); minimal data exist comparing the long-term metabolic effects of SGAs approved in the last 10 years. METHODS/PROCEDURES: A retrospective chart review of patients treated with brexpiprazole, lurasidone, asenapine, cariprazine, and iloperidone (newer SGAs) for at least 6 weeks at an outpatient psychiatric practice was conducted. Patients treated with olanzapine, an older SGA, were included as a comparator. Metabolic characteristics were collected at baseline, approximately 6 weeks, 12 weeks, and for up to 12 months. FINDINGS/RESULTS: Of the newer SGAs, there were statistically significant increases in patients' average weight at 12 weeks and 1 year or less with brexpiprazole (2.48 lb, P = 0.02; 5.97 lb, P = 0.01) and iloperidone (4.54 lb, P < 0.01; 5.13 lb, P = 0.02). Brexpiprazole and iloperidone resulted in significant increases in body mass index, up to a 0.90-kg/m2 average increase in patients taking brexpiprazole at 1 year or less. Minimal weight gain was seen with cariprazine (4.25 lb, P = 0.42) and asenapine (1.80 lb, P = 0.62) at 1 year or less after treatment initiation. Although not statistically significant, lurasidone showed an average weight loss of up to 0.60 lb at 1 year or less (P = 0.56). IMPLICATIONS/CONCLUSIONS: Although some weight gain was seen with the newer SGAs, all demonstrated significantly favorable metabolic characteristics compared with olanzapine. Monitoring of weight and metabolic parameters remain important in patients treated with SGAs.

Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999.

Zosuquidar, which modulates P-glycoprotein (P-gp) with minimal delay of anthracycline clearance, may reverse P-gp-mediated resistance in acute myeloid leukemia without increased toxicity. A total of 449 adults older than 60 years with acute myeloid leukemia or high-risk myelodysplastic syndrome enrolled in a randomized placebo-controlled double-blind trial (Eastern Cooperative Oncology Group 3999). Overall survival was compared between patients receiving conventional-dose cytarabine and daunorubicin and either zosuquidar (550 mg; 212 patients) or placebo (221 patients). Median and 2-year overall survival values were 7.2 months and 20% on zosuquidar and 9.4 months and 23% on placebo, respectively (P = .281). Remission rate was 51.9% on zosuquidar and 48.9% on placebo. All cause mortality to day 42 was not different (zosuquidar 22.2% vs placebo 16.3%; P = .158). In vitro modulation of P-gp activity by zosuquidar and expression of P-gp, multidrug resistance-related protein 1, lung resistance protein, and breast cancer resistance protein, were comparable in the 2 arms. Poor-risk cytogenetics were more common in P-gp(+) patients. P-gp expression and cytogenetics were correlated, though independent prognostic factors. We conclude that zosuquidar did not improve outcome in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. This trial is registered at www.clinicaltrials.gov as #NCT00046930.

A Meta-Analysis of Antipsychotic-Induced Hypo- and Hyperprolactinemia in Children and Adolescents.

Objective: Antipsychotic-related prolactin changes may expose children and adolescents to severe adverse reactions (ARs) related to pubertal development and growth. We therefore aimed to assess the effects of antipsychotics on prolactin levels and associated somatic ARs in children and adolescents. Methods: We systematically searched PubMed and CENTRAL for placebo-controlled randomized trials of antipsychotics in children and adolescents aged ≤18 years, reporting prolactin levels and related ARs. We conducted a random-effect meta-analysis and assessed risk of bias version 2 (ROB2). Results: Thirty-two randomized controlled trials with an average trial duration of 6 weeks, covering 4643 participants with an average age of 13 years and a male majority of 65.3%. Risk of bias across domains was low or unclear. The following antipsychotic compounds: aripiprazole (n = 810), asenapine (n = 506), lurasidone (n = 314), olanzapine (n = 179), paliperidone (n = 149), quetiapine (n = 381), risperidone (n = 609), and ziprasidone (n = 16) were compared with placebo (n = 1658). Compared with placebo, statistically significant higher prolactin increase occurred with risperidone (mean difference [MD] = 28.24 ng/mL), paliperidone (20.98 ng/mL), and olanzapine (11.34 ng/mL). Aripiprazole significantly decreased prolactin (MD = -4.91 ng/mL), whereas quetiapine, lurasidone, and asenapine were not associated with significantly different prolactin levels than placebo. Our results on ziprasidone are based on a single study, making it insufficient to draw strong conclusions. On average, 20.8% of patients treated with antipsychotic developed levels of prolactin that were too high (hyperprolactinemia), whereas only 1.03% of patients reported prolactin-related ARs. Data were highly limited for long-term effects. Conclusions: In children and adolescents, risperidone, paliperidone, and olanzapine are associated with significant prolactin increase, whereas aripiprazole is associated with significant decrease. Despite the significant changes in prolactin level, few ARs were reported. Study protocol on PROSPERO: CRD42018116451.

Amineptine treatment of persistent catatonic symptoms in schizophrenia: a controlled study.

BACKGROUND: Data on the treatment response of enduring catatonic phenomena accompanying chronic schizophrenia are few and far between. The aim of this study was to explore the therapeutic effects of add-on amineptine, a dopamine agonist antidepressant in chronic catatonia occurring in schizophrenia. METHOD: Fifteen subjects with DSM-IV schizophrenia presenting with persistent catatonic features underwent a 15-week, double-blind, placebo-controlled cross-over trial; they were treated for 6 weeks each with amineptine and a placebo, with a 3-week wash-out period in between. The primary outcome measures were the sum scores of the Bush-Francis Catatonia Rating Scale and the Modified Rogers Scale. Changes in other aspects of psychopathology and extrapyramidal side effects (EPS) constituted the secondary outcome measures. RESULTS: Amineptine augmentation of antipsychotic treatment had no appreciable effect on either of the catatonia ratings. Apart from a statistically significant but clinically negligible improvement in the negative symptom scores, there were no changes in the psychopathology and EPS ratings. CONCLUSION: The lack of a therapeutic effect of the dopamine agonist amineptine on persistent catatonic signs and symptoms suggests that the dopamine system may not have a decisive role in the pathophysiology of chronic catatonic syndrome arising in the context of schizophrenia.

Phase I study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours.

BACKGROUND: Zosuquidar (LY335979) is an oral P-glycoprotein modulator. This phase I study was designed to determine the maximum tolerated dose (MTD) of zosuquidar in combination with vinorelbine. The effects of zosuquidar on vinorelbine pharmacokinetics were also examined. DESIGN: Patients with advanced solid tumours were treated with escalating doses of zosuquidar administered every 8-12 h on days 7-9 and 14-16 during cycle 1 then days 0-2, 7-9, and 14-16 from cycle 2 onwards, with vinorelbine 22.5-30 mg/m2 IV on days 1, 8 and 15 every 28 days. RESULTS: Of 21 patients registered, 19 were treated at four dose levels (zosuquidar 100-300 mg/m2). Two patients had prolonged and febrile neutropenia at the second dose level resulting in a reduction of the dose of vinorelbine in subsequent dose levels. There was another patient with dose-limiting febrile neutropenia at dose level four which resulted in the expansion of the dose level three. Eight patients had stable disease and no objective responses were seen. Vinorelbine pharmacokinetic studies showed reduced clearance when given with zosuquidar. CONCLUSIONS: The MTD was zosuquidar 300 mg/m2 orally every 12 h for 3 days weekly for 3 weeks with vinorelbine 22.5 mg/m2 IV weekly for 3 weeks every 28 days. Zosuquidar may inhibit vinorelbine clearance to a modest degree.

Electrophysiologic studies of perphenazine and protriptyline in a patient with psychotropic drug-induced ventricular fibrillation.

A 51 year old woman sustained ventricular fibrillation while receiving perphenazine and protriptyline. After successful resuscitation and clinical stabilization, cardiac electrophysiologic studies were performed before and after the administration of each of these medications. Perphenazine widened the ventricular echo zone and facilitated induction of short salvoes of ventricular tachycardia (repetitive ventricular response). Protriptyline also widened the ventricular echo zone and allowed easy induction of long runs of ventricular tachycardia. Both psychotropic agents increased the incidence of ventricular dysrhythmias in this patient. The electrophysiologic study is a useful technique in determining the interaction between psychotropic drugs and life-threatening arrhythmias; it may provide a means of identifying the patients with cardiac disease in whom administration of these agents may be fatal.

Plasma concentrations and cardiotoxic effects of desipramine and protriptyline in the rat.

1 Desipramine and protriptyline were administered to anaesthetized rats by two consecutive intravenous infusions in order to obtain a peak level (first infusion) followed by lower steady state concentrations (second infusion) (Wagner, 1974). Theoretical plasma level time courses were confirmed experimentally.2 Desipramine and protriptyline were measured in atria and ventricles. Increasing infusion rates led to proportional increases in plasma and atrial concentrations. The tissue/medium ratio ranged from 57 to 21 for desipramine and from 43 to 11 for protriptyline according to the time of determination during infusions.3 Heart rate changes, deviation of the electrical axis of the heart and prolongation of atrioventricular conduction were recorded at fixed times during infusion.4 Positive chronotropic effects were noted at plasma concentrations ranging from 0.035 to 0.1 mug/ml for desipramine and from 0.04 to 1.2 mug/ml for protriptyline. At higher plasma concentrations the positive chronotropic effect decreased and bradycardia developed. Both drugs induced right rotation of the electrical axis of the heart. Threshold plasma levels giving 40 degrees rotation were 1.35 mug/ml (desipramine) and 1.75 mug/ml (protriptyline). Atrioventricular conduction was prolonged at threshold plasma concentrations of 2.2 mug/ml for desipramine and 3.6 mug/ml for protriptyline.5 Desipramine is more cardiotoxic than protriptyline. This difference is discussed in relation to the plasma and heart concentration of the two drugs.

Clinical effects and P-glycoprotein inhibition in patients with acute myeloid leukemia treated with zosuquidar trihydrochloride, daunorubicin and cytarabine.

BACKGROUND AND OBJECTIVES: P-glycoprotein (P-gp) is a major cause of multidrug resistance (MDR) in acute myelogenous leukemia (AML) and is thought to contribute to the failure of chemotherapy. Zosuquidar trihydochloride (Z.3HCL) is a potent and selective inhibitor of P-gp which rapidly and effectively inhibits drug efflux. DESIGN AND METHODS: The aim of this study was to evaluate the clinical effects of Z.3HCL and determine its influence on P-gp activity. Sixteen AML patients were entered into a phase 1 dose ranging clinical trial of Z.3HCL, co-administered intravenously with daunorubicin and cytosine arabinoside (ARA-C). Clinical outcomes, toxicity abd adverse events were assessed. P-gp function was analyzed by flow cytometry. In vitro cytotoxicity was studied using the MTT assay. RESULTS: Eleven patients achieved a complete remission and one a partial remission with a median survival of 559 (range 38-906) days. Non-hematologic grade 3 and 4 toxicities were seen in 4 patients. Z.3HCL infusion was associated with rapid inhibition of Rh123 efflux in CD56+ cells in 16/16 patients and in CD33+ cells from 6/10 patients. The median inhibition was 95% for CD56+ cells and 85.25% for CD33+ cells was significantly elevated in 6/16 patients. The median IC50, using a MTT assay for daunorubicin, decreased significantly between Z.3HCL modulated and unmodulated cells (n=11,153 and 247 ng/mL respectively, p=0.01). INTERPRETATION AND CONCLUSIONS: The modulator Z.3HCL is a specific inhibitor of P-gp efflux and can be given safely to patients with AML in combination with induction doses of conventional cytotoxic drugs.

A double-blind comparison of moclobemide and amineptine in the treatment of depressed out-patients.

A randomized, double-blind, multicentre study was performed to compare the effects of moclobemide and amineptine in the treatment of endogenous depression in out-patients. Ninety patients received moclobemide, 450 mg/day and 94 received amineptine 200 mg/day in two parallel groups, over a trial period of 8 weeks. At the end of 4 weeks doses could be reduced to 300 mg/day, moclobemide and 100 mg/day, amineptine if required. All evaluated patients showed a significant clinical improvement during treatment, but no significant difference occurred between the groups. When patients were asked to assess the benefit of their treatment, 76% thought their condition had improved following moclobemide therapy, compared to 53% of those receiving amineptine. Both drugs were well tolerated, and over 60% of patients reported no side-effects. Moclobemide appeared to be as effective as amineptine in the treatment of these patients, and was significantly better tolerated.

Evaluation of butaclamol in chronic schizophrenic patients.

In a double-blind, placebo-controlled study, an attempt was made to evaluate butaclamol in chronic schizophrenic patients using chlorpromazine (CPZ) as the standard comparative drug. With doses up to 50 mg/day, butaclamol was shown to have significant antipsychotic activity comparable to CPZ but with a much higher incidence of extrapyramidal signs. A more reasonable maintenance dose may be in the range of 5 to 20 mg/day. Rebound insomnia was noted again with butaclamol, which warrants further study.

Dextromethorphan does not protect against quinolinic acid neurotoxicity in rat striatum.

Dextromethorphan (DM, 40 or 80 mg/kg, i.p.) and MK-801 (3 or 10 mg/kg, i.p.) were compared in their ability to prevent the depletion of choline acetyltransferase (ChAT) activity in the rat striatum following intrastriatal injection of quinolinic acid. DM did not reduce striatal ChAT depletion following injection of either 300 or 150 nmol of quinolinic acid. Following injection of 300 nmol of quinolinic acid, MK-801 significantly reduced striatal ChAT depletion at a dose of 3 mg/kg and completely prevented striatal ChAT depletion at a dose of 10 mg/kg. In contrast to the potent neuroprotective action of MK-801, DM does not protect striatal cholinergic neurons from an acute challenge by an NMDA receptor agonist.

Amineptine in the management of the depressive syndromes.

The antidepressant activity of amineptine was evaluated in 34 patients in a double-blind study vs clomipramine. Clinical results, assessed using the Hamilton rating scale for depression, failed to show any significant difference in the activity of the two drugs. Amineptine was however much better tolerated than clomipramine. The antidepressant activity of amineptine was further investigated in an open multicenter study carried out in 351 depressed patients. The significant reductions in the scores of the Hamilton rating scale for depression and the final clinical evaluations (87% favorable results, 69% of which excellent or good) confirmed the therapeutic efficacy of amineptine. Tolerance was excellent also in elderly, at risk patients.

Regional cerebral blood flow changes following chronic administration of antidepressant drugs.

1. Twenty-six patients with major unipolar depression were rated clinically and regional cerebral blood flow (rCBF) determined prior to and after six months of treatment with 75-100 mg/day amitriptyline (n. 16) or 200 mg/day amineptine (n. 10). 2. rCBF was measured in 16 regions over each hemisphere by the Xenon 133 inhalation method and was computed as the initial slope index (ISI). The severity of depression was quantified by the Hamilton rating scale for depression. 3. Baseline rCBF values of depressed patients tended to be lower than those of normal subjects. Significant reductions were observed for all probes exploring the frontal region of the left hemisphere and for some probes exploring the frontal region of the right hemisphere. Chronic treatment with amitriptyline induced a significant increase in rCBF in the left frontal region. Similar results were obtained after treatment with amineptine. 4. Besides confirming frontal lobe dysfunction in depressed patients which is reversed by treatment with classic tricyclic antidepressants, the present results show that this dysfunction may also be reversed by treatment with dopaminergic drugs.

A multi-centre general practitioner assessment of butriptyline hydrochloride ('Evadyne').

A multi-centre open study in general practice was carried out to assess the efficacy of and incidence of side-effects with the tricyclic antidepressant, butriptyline. Of a series of 153 patients with non-psychotic depression, with or without anxiety, 105 (69%) were judged as having a good or fair response to treatment with 75 mg to 150 mg butriptyline daily. Side-effects of an anticholinergic nature were seen in 13.7% of patients, but the incidence decreased to less than 4% in the 101 patients receiving treatment for over 7 weeks.

Double-blind trial of amineptine and clomipramine in the treatment of depression.

A double-blind trial was carried out in 62 depressed patients to compare the clinical efficacy and acceptability of amineptine and clomipramine. Patients were allocated at random to one or other of two treatment groups and received daily doses of amineptine ranging from 100 to 300 mg (mean 180 mg) or of clomipramine ranging from 50 to 150 mg (mean 84 mg) over a period of 6 weeks. Global assessment of response to treatment and Hamilton Rating Scale scores, assessed before and after 1,3 and 6 weeks of treatment, indicated that the two drugs appeared to be equally effective and no differences between them could be demonstrated in the analysis of the individual items or grouped items of the scale used. Measurements of ocular tone showed that there was significantly less risk of amineptine producing an increase in tone, and blood pressure and electrocardiographic investigations also underlined the greater cardiovascular tolerance of amineptine. Five (16%) of the 32 patients in the clomipramine group were withdrawn from the study because of adverse effects.

Depression in elderly people treated with amineptine (Survector 100): a synopsis.

Aging is one of the most important current problems. In fact, according to statistics, the elderly population of the world is continuously increasing, and depression represents the most frequent psychiatric problem in the aged. It is well known that the antidepressive treatment of the aged imposes particular problems because of the frequent presence of cardiovascular problems, ocular hypertension, and prostatic hypertrophia. Amineptine (Survector 100) is devoid of anticholinergic and cardiotoxic effects. For this reason we have studied it in the treatment of elderly depressed patients. This study comes from a multicenter clinical trial (32 hospital centers) in which 324 patients were recruited; it includes 63 depressed patients over the age of 60 years. The diagnosis of depression was stated according to DSM-III diagnostic criteria and INSERM classification, and assessed by Hamilton Depression Rating Scale (HDRS) (26 items). The patients were treated with amineptine (200 mg/day) for 39.3 days (mean). The overall clinical efficacy was positive in 68% of cases; the clinical judgment was confirmed by a decrease in the mean score of HDRS (after the 7th day). The good acceptability (clinical, cardiovascular) was also confirmed. The different biochemical parameters were generally not modified during the treatment. Amineptine appeared to be an antidepressant treatment that combines efficacy and a very good level of safety, essential qualities for the treatment of elderly depressed patients.

The efficacy of amineptine in the treatment of depressive patients with irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) often suffer from depression. In view of this, the effect of amineptine on the psychopathological condition of depressive patients with IBS was studied. Forty patients who satisfied the criteria for irritable bowel syndrome and had a Hamilton 24-item score above 15 were randomly assigned to receive either amineptine 200 mg/day or placebo in a double-blind clinical trial. Patients on amineptine were more improved at the end of the trial than patients on placebo (total Hamilton score). Amineptine was more effective on depressive mood, retardation, and cognitive dysfunction. Although these findings should be interpreted with caution because the baseline scores were higher in the amineptine than in the placebo group, they provide some evidence that amineptine may be a useful tool for the management of depressive patients with IBS.

The beneficial effects of amineptine (Survector 100) in the treatment of depression: preliminary results of an Indian multicenter trial.

A multicenter study of the efficacy and safety of amineptine in the treatment of depression has been performed in India. Patients fulfilling the DSM-III criteria for depression were included in this open clinical trial and treated with amineptine for 6 weeks. They received one 100-mg tablet or two (100 mg) tablets of amineptine per day. Efficacy of treatment was assessed using the Hamilton Depression Rating scale on D0, D7, D14, D21, D35, and D42. Liver function and cardiovascular function were examined on D0 and D42 to assess possible adverse effect of treatment. The preliminary results in 32 patients showed that amineptine was effective as soon as the 7th day of treatment and that this effect improved continuously throughout the study. Amineptine was found to be safe.

Fluoxetine versus amineptine in the treatment of outpatients with major depressive disorders.

Fluoxetine, a selective serotonin reuptake inhibitor, was compared to amineptine, a tricyclic antidepressant agent, in the treatment of 63 outpatients with major depressive disorders of mild or moderate severity. Patients were randomly assigned to 6 weeks of treatment with either fluoxetine or amineptine. Fluoxetine was found to have a more marked therapeutic effect than that of amineptine: better efficacy, fewer side-effects, and quicker and better improvement on the self evaluation scales.

The efficacy and acceptability of amineptine versus fluoxetine in major depression.

The temporal dimension, particularly anticipation, appears to be a very important component in the understanding of depressed patients. In a 90-day multicentre study, the efficacy and acceptability of amineptine and fluoxetine were compared in 169 patients with major depression. Comparison of the two antidepressants was based on double-blind methods, after random allocation of the treatments between two parallel groups. The two drugs did not differ over the whole course of the study, but the improvement in scores on day 4 was globally more marked in the amineptine than the fluoxetine group. Intragroup analysis showed that amineptine was significantly superior to fluoxetine on the retardation pole of the mood, anxiety, retardation, danger scale. The positive effect of amineptine on anticipation may enable the depressed patient to make plans for the future. Anticipation may be a key dimension to be more precisely explored in specific psychopharmacological protocols with antidepressants.