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.

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.

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.

[Acne induced by amineptine]. / Acne induzida por amineptina.

We report one case of very severe acne-like lesions associated with amineptine (Survector). They were most prominent on the face and back, but were also observed on sites not affected by acne vulgaris, such as perineum, arms and legs. The lesions appeared after long-term self-medication of high doses. Keratoacanthoma-like lesions were also present, and the small ones were successfully treated with topical imiquimod. The case is significant since the disease is quite rare.

Acne induzida por amineptina / Acne induced by amineptine

Relata-se um caso grave de lesões acne-símile associada a amineptina (Survector®), proeminentes na face e dorso, acometendo outros sítios não afetados pela acne vulgar, como períneo, braços e pernas. As lesões apareceram após a auto-administração crônica de altas doses do medicamento. Lesões ceratoacantoma-símile também estavam presentes, tendo as lesões menores resposta satisfatória ao tratamento com imiquimod tópico. O relato é significativo pela raridade da doença.

We report one case of very severe acne-like lesions associated with amineptine (Survector®). They were most prominent on the face and back, but were also observed on sites not affected by acne vulgaris, such as perineum, arms and legs. The lesions appeared after long-term self-medication of high doses. Keratoacanthoma-like lesions were also present, and the small ones were successfully treated with topicalimiquimod. The case is significant since the disease is quite rare.

A phase I trial of continuous infusion of the multidrug resistance inhibitor zosuquidar with daunorubicin and cytarabine in acute myeloid leukemia.

Zosuquidar is a potent and specific inhibitor of P-glycoprotein (P-gp). In preliminary experiments, blockade of P-gp for at least 12 h was required to reverse daunorubicin resistance. Because of the short half-life of zosuquidar, we performed a phase I trial of this drug as a 72-h infusion (CIV) in 16 patients during leukemic induction with daunorubicin and cytarabine. Study goals were to establish safety and determine the dose required for P-gp inhibition in NK cells and AML blasts. > 90% P-gp inhibition was achieved within 2h at a plasma threshold of 132 ng/ml zosuquidar. The recommended phase II dose of zosuquidar is 700 mg/day.

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.

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.

Acneiform eruption caused by amineptine. A case report and review of the literature.

Acne caused by amineptine has always been described with typical characteristic clinical features, and the retentional and cutaneous lesions are dose related. We present a case of acne-like eruption due to amineptine in a woman under treatment for chronic depression.

WHO Expert Committee on Drug Dependence. Thirty-second report.

This report presents the recommendations of a WHO Expert Committee responsible for reviewing information on dependence-producing drugs to assess the need for their international control. The first part of the report contains a general discussion of the new guidelines for the review of dependence-producing psychoactive substances and their implications for the scheduling of ephedrine and of the guidelines that were drafted to clarify the scope of control of stereoisomers. A summary follows of the Committee's evaluations of six substances (4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-methylthioamphetamine (4-MTA), gamma-hydroxybutyric acid (GHB), N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MDBD), diazepam and zolpidem), four of which (2C-B, 4-MTA, GHB and zolpidem) were recommended for international control. The report also discusses the substances that were pre-reviewed by the Committee, five of which (amfepramone, amineptine, buprenorphine, dronabinol and tramadol) were recommended for critical review at a future meeting.

[Sexual dysfunction with antidepressive agents. Effect of the change to amineptine in patients with sexual dysfunction secondary to SSRI]. / Disfunción sexual con antidepresivos. Efecto del cambio a amineptino en pacientes con disfunción sexual secundaria a ISRS.

UNLABELLED: Sexual dysfunction secondary to the use of antidepressants, especially clomipramine or SSRI's is an adverse effect that is often underestimated and according to earlier studies, this can affect approximately 60% of the patients. This presents as a decrease in libido, alterations in the ability to reach orgasm/ejaculation, and an erectile dysfunction or a decreased vaginal lubrication. This dysfunction appears to be related with the resulting increase in serotonin and with the stimulation of serotonin 5HT2 receptors. OBJECTIVES: 1) Evaluate the effect of amineptine, a drug with an increased dopamine transmission and scant serotonin transmission, on the sexual function of depressed patients who begin treatment, and 2) evaluate whether the change to amineptine improves the sexual function in patients who presented sexual dysfunction after beginning treatment with a SSRI. MATERIAL AND METHODS: Prospective, observational, open and multicentric design. 111 patients with an average age of 41.3 years (36 men, 75 women) were distributed into three groups: Group 1 (n= 26): patients with depression (DSM IV) who begin de novo treatment with amineptine 200 mg/day. Group 2 (n= 47): depressed patients undergoing treatment with a SSRI who show a favorable response and who present sexual dysfunction secondary to a poorly tolerated treatment, so the treatment is changed to 200 mg/day of amineptine. Group 3 (n= 38): patients with the same characteristics as those of group 2, but whose treatment was changed to 20 mg/day of paroxetine. The <> (Montejo et al, 1996) was used together with the Hamilton Depression Scale, the IGC Scale, and an adverse events scale, over a 6 months follow up period during which visits took place at: baseline, month 1, month 2, month 3, and month 6. RESULTS: In group 1, treated with amineptine from the beginning, of the 5 patients who showed a decrease in the libido at the beginning of the treatment, only one still presented this in the 6th month. The Hamilton Scale decreased from 23.12 (baseline) to 5.25 after 6 months. After substituting amineptine for SSRI's in patients with sexual dysfunction, the incidence of any type of sexual dysfunction decreased significantly from 100% (baseline) to 55.3% after 6 months. (P< 0.001). The incidence of delayed orgasm dropped to 15.8%, anorgasmia to 17.4%, and impotence dropped to 15.8% in this group, with the antidepressant effect that had already been achieved with the SSRI being maintained. However, in group 3 there was barely any improvement on the sexual function after changing to paroxetine (20 mg/day), with the baseline incidence being 100% and the incidence after 6 months being 89.7%. In this last group the antidepressant effect present at the baseline level, was maintained. CONCLUSIONS: Amineptine was shown to be an effective antidepressant in the patients studied, and did not cause secondary sexual dysfunction, and even improved the dysfunction that was present in some patients. In those patients previously treated with SSRI's, amineptine is able to significantly improve the sexual dysfunction and yet maintain the efficacy of the antidepressive treatment used before these 6 months. On the other hand, Paroxetine did not improve the sexual dysfunction of the people in whom this drug substituted another SSRI, as this is an adverse effect common to the entire group of selective serotonin re-uptake inhibiting drugs. Amineptine showed a good safety and tolerance profile. Its most common side effect (anxiety/restlessness) disappeared 2 months after the beginning of the treatment.

Amisulpride versus amineptine and placebo for the treatment of dysthymia.

Amisulpride, a selective antagonist for D2 and D3 dopamine receptors, acts preferentially on presynaptic receptors increasing dopaminergic transmission at low doses. In a multicentre, 3-month, placebo-controlled study, amisulpride (50 mg/day) was compared to amineptine (200 mg/day) in the treatment of primary dysthymia. A total of 323 patients were enrolled. Amisulpride and amineptine were found to be statistically superior to placebo (p < 0.0001) on the Clinical Global Impression (item 2): 63, 64 and 33% responders, respectively; improvement of Montgomery-Asberg Depression Rating Scale and Scale for the Assessment of Negative Symptoms scores following amisulpride or amineptine treatment was twice as high as with placebo (p < 0.0001). The adverse event profile of amisulpride was similar to that of placebo except for endocrine symptoms in female patients; amineptine showed mainly events linked to psychic activation (insomnia, nervousness). Results show that amisulpride can improve symptoms of chronic depression in dysthymia.

[A case of Parkinson syndrome secondary to combined amineptine and bromazepam abuse]. / Un cas de syndrome parkinsonien secondaire à la surconsommation d'amineptine et de bromazépam.

A case report of parkinsonism secondary to chronic abuse of amineptine (3 gr/day) and bromazepam (35 mg/day) in a patient diagnosed of borderline personality disorder is presented. The patient did not take any other drugs and he was not recently on neuroleptic treatment; he recognized the abuse of amineptine, as a stimulant, and the bromazepam abuse, looking for a relief to the excessive anxiety secondary to amineptine. The parkinsonism improved after removing both drugs and taking biperiden and diazepam; lastly the patient was discharged without any medication. The patient did not suffer from other complications associated with amineptine or bromazepam abuse. There are some cases reported of parkinsonism secondary to benzodiazepines but there is none secondary to amineptine. We present a short review of the possible responsible mechanisms, thinking on a complex interaction of both drugs on dopamine and its modulatory systems.