Brain antioxidant effect of mirtazapine and reversal of sedation by its combination with alpha-lipoic acid in a model of depression induced by corticosterone.

BACKGROUND: Depression is accompanied by activated neuro-oxidative and neuro-nitrosative pathways, while targeting these pathways has clinical efficacy in depression. This study aimed to investigate the effects of mirtazapine (MIRT) alone and combined with alpha-lipoic acid (ALA) against corticosterone (CORT) induced behavioral and oxidative alterations. METHODS: Male mice received vehicle or CORT 20mg/kg during 14 days. From the 15th to 21st days they were divided in groups administered: vehicle, MIRT 3mg/kg or the combinations MIRT+ALA100 or MIRT+ALA200. On the 21st day of treatment, the animals were subjected to behavioral tests. Twenty-four hours after the last drug administration hippocampus (HC) and striatum (ST) were dissected for the determination reduced glutathione (GSH), lipid peroxidation (LP) and nitrite levels. RESULTS: CORT induced anxiety- and depressive-like behaviors as observed by increased immobility time in the tail suspension test and decreased sucrose consumption. MIRT or MIRT+ALA are effective in reversing anxiety- and depressive-like behaviors induced by CORT. CORT and MIRT alone prolonged sleeping time and this effect was reversed by MIRT+ALA. CORT significantly increased LP, which was reversed by MIRT or MIRT+ALA. Nitrite levels were increased in CORT-treated animals and reversed by MIRT+ALA200 (HC), MIRT or MIRT+ALA (ST). LIMITATION: A relative small sample size and lack of a washout period between drug administration and behavioral testing. CONCLUSIONS: MIRT or MIRT+ALA reverse CORT-induced anxiety- and depressive-like behaviors probably via their central antioxidant effects. Augmentation of MIRT with ALA may reverse sedation, an important side effect of MIRT. Randomized controlled studies are needed to examine the clinical efficacy of this combination in human depression.

Mirtazapine does not improve sleep disorders in Alzheimer's disease: results from a double-blind, placebo-controlled pilot study.

AIM: The aim of this study was to test the efficacy and safety of mirtazapine in the treatment of sleep disorders in patients with Alzheimer's disease by means of a randomized, double-blind, placebo-controlled trial. Measurements were obtained for 7 days before intervention (baseline) and for 2 weeks after the onset of treatment. METHODS: Alzheimer's disease patients with sleep disorders (n = 24) received 15-mg mirtazapine (n = 8) or placebo (n = 16) once daily at 2100 hours for 2 weeks. Patients were evaluated with actigraphy and structured scales before and after intervention. Historical control was employed. RESULTS: Treatment with mirtazapine or placebo had no effect on cognitive and functional status as assessed by the Mini-Mental State Examination and the Katz scale, respectively. There were no differences between groups in the frequency or severity of the adverse events reported. Compared with the placebo group, mirtazapine users showed increased daytime sleepiness but no improvement in the duration or efficiency of nocturnal sleep after treatment. CONCLUSIONS: This study showed no significant therapeutic effects of 15-mg mirtazapine in community-dwelling Alzheimer's disease patients with sleep disorders. Instead, this study found evidence of worsening of daytime sleep patterns.

Antidepressant combination for major depression in incomplete responders--a systematic review.

BACKGROUND: Antidepressant combination has been suggested as a strategy to increase treatment efficacy. The objective of this study was to perform a systematic review and meta-analysis of studies that assessed the effect of antidepressant combination for major depression in patients with incomplete response to an initial antidepressant. METHODS: Studies were retrieved from PubMed (1966-February, 2012), Cochrane Library (-February, 2012), Embase (1980-February, 2012), PsycINFO (1980-February, 2012), Lilacs (1982-February, 2012), clinical trials registry, thesis database (www.capes.gov.br), and secondary references. Included studies had an open label phase in which an initial antidepressant was used for the treatment of major depression and a double blind phase for the incomplete responders that compared monotherapy with the first antidepressant versus the association of a second antidepressant to the first one. RESULTS: Out of the 4,884 studies retrieved, only five satisfied the inclusion criteria. The total number of patients included was 483. Only two small trials reported benefits of adding a second antidepressant to the initial antidepressant. Dropouts due to side effects were not reported in three studies. Meta-analysis was not performed due to the small number of studies, the inconsistency in the direction of effect and the possible instability of effect size. Only limited kinds of combination, involving mianserin, mirtazapine and desipramine were studied. Some properties of the first two drugs such as the anxiolytic, sedative, and orexigenic effects, can mimic depression improvement. LIMITATIONS: Publication bias cannot be ruled out. Only one study included a monotherapy arm with the antidepressant used for augmentation of the first antidepressant. CONCLUSIONS: The practice of using a combination of antidepressants for major depression in incomplete responders is not warranted by the literature.

[Mirtazapine and antiretroviral therapy in the treatment of progressive multifocal leukoencephalopathy associated with HIV-1 infection: report of a case and review of literature]. / Tratamiento conjunto con mirtazapina y terapia antiretroviral para la leucoencefalopatía multifocal progresiva asociada a infección por VIH-1: presentación de un caso clínico y revisión de la literatura.

We report a 43 years old HIV-1 infected male who developed a severe subacute neurological damage because of a progressive multifocal leukoencephalopathy confirmed by PCR for JC virus. The patient was treated with antiretroviral therapy in adequate doses for CNS penetration and mirtazapine, an antidepressant inhibitor of serotonin receptors. His evolution during one year follow up has been favorable in both, clinically and images.

Tratamiento conjunto con mirtazapina y terapia antiretroviral para la leucoencefalopatía multifocal progresiva asociada a infección por VIH-1: presentación de un caso clínico y revisión de la literatura / Mirtazapine and antiretroviral therapy in the treatment of progressive multifocal leukoencephalopathy associated with HIV-1 infection: report of a case and review of literature

We report a 43 years old HIV-1 infected male who developed a severe subacute neurological damage because of a progressive multifocal leukoencephalopathy confirmed by PCR for JC virus. The patient was treated with antiretroviral therapy in adequate doses for CNS penetration and mirtazapine, an antidepressant inhibitor of serotonin receptors. His evolution during one year follow up has been favorable in both, clinically and images.

Se presenta el caso clínico de un paciente de sexo masculino, de 43 años portador de VIH que desarrolló un grave daño neurológico subagudo debido a una leucoencefalopatía multifocal progresiva diagnosticada mediante reacción de polimerasa en cadena de virus JC. El paciente fue tratado con terapia anti-retroviral de penetración eficiente al SNC y con mirtazapina, un antidepresivo inhibidor de los receptores de serotonina. Su evolución durante un año de seguimiento ha sido favorable tanto del punto de vista clínico como de imágenes.

Antidepressants differentially modify the extinction of an aversive memory task in female rats.

Treatment of major depression, posttraumatic stress disorder and other psychopathologies with antidepressants can be associated with improvement of the cognitive deficits related to these disorders. Although the mechanisms of these effects are not completely elucidated, alterations in the extinction of aversive memories are believed to play a role in these psychopathologies. We have recently verified that female rats present low levels of extinction when submitted to the plus-maze discriminative avoidance task. In the present study, female rats were treated long term with clinically used antidepressants (fluoxetine, nortriptyline or mirtazapine) and subjected to the plus-maze discriminative avoidance task to evaluate learning, memory, extinction and anxiety-related behaviors as well as behavioral despair in the forced swimming test. All groups learned the task and exhibited retrieval. Chronic treatment with fluoxetine (but not with the other antidepressants tested) increased extinction of the discriminative task. In the forced swimming test, the animals treated with fluoxetine and mirtazapine showed decreased immobility duration. In conclusion, fluoxetine potentiated extinction, while both fluoxetine and mirtazapine were effective in ameliorating depressive-like behavior in the forced swimming test, suggesting a possible dissociation between the effects on mood and the extinction of aversive memories in female rats.

Mirtazapine (Remeron) as treatment for non-mechanical vomiting after gastric bypass.

Two morbidly obese patients are reported who underwent gastric bypass and suffered nausea and vomiting 1 month after the operation. Endoscopy and upper GI series showed no evidence of stomal stenosis or other mechanical cause for a GI obstruction. Control of vomiting by current antiemetic drugs such as bromopride and ondansetrone was unsuccessful. The patients were then given Remeron Soltab (mirtazapine, Organon, Brazil) 30 mg once per day orally for 2 to 8 months. Nausea and vomiting disappeared within days after beginning the medication. Stomal stenosis is the main cause of vomiting after gastric bypass. After ruling out mechanical causes, other reasons for postoperative vomiting must be considered. Mirtazapine is a noradrenergic and specific serotonergic antidepressant, which blocks the 5HT3 receptor, leading to an antiemetic effect. It has successfully been used as an antiemetic drug in patients undergoing chemotherapy. We concluded that mirtazapine may be a successful option to treat non-mechanical postoperative vomiting in morbidly obese patients after gastric bypass.

Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients.

INTRODUCTION: Depression is a major global problem associated with large medical, sociological and economic burdens. Mirtazapine (Remeron, Organon NV, The Netherlands) is an antidepressant with a unique mechanism of action that has similar or superior efficacy to TCAs and SSRIs in moderate-to-severe depression. However, this agent has not yet been tested in patients with severe depression alone. OBJECTIVE: To compare the antidepressant efficacy and tolerability of mirtazapine and fluoxetine and their effects on anxiety and quality of life in patients with severe depression (> or = 25 points on the first 17 items of the Hamilton Depression Rating Scale [HDRS-17]). METHODS: In this double-blind study, 297 severely depressed patients were randomised to receive mirtazapine 15-60 mg/day (n = 147) or fluoxetine 20-40 mg/day (n = 152) for 8 weeks. 294 subjects were actually treated and 292 included in the intent-to-treat population. Symptom severity was measured by the HDRS-17, Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) rating scale. Quality of life was self-assessed by patients using the Leeds Sleep Evaluation Questionnaire and the Quality of Life, Enjoyment and Satisfaction Questionnaire. Adverse events were recorded throughout the study. RESULTS: No statistically significant differences were noted between the two groups in change from baseline HDRS-17 score at any time point; both treatments were associated with large (approximately 15 points) decreases by study end. However, more mirtazapine-treated patients tended to exhibit a > or = 50% decrease in HDRS score (significant at day 7; 9.0% vs 0.7%, p = 0.002). Significant differences in favour of mirtazapine were also observed at day 14 for changes in MADRS scores (-10.9 vs -8.5, p = 0.006) and the proportion of patients with > or = 50% decrease in MADRS score (21.4% vs 10.9%, p = 0.031). On the CGI, the proportion of 'much/very much improved' patients tended to be greater with mirtazapine (significant at day 7; 9.7% vs 3.4%, p = 0.032). No significant between-group differences were observed for the majority of quality-of-life measures. However, mirtazapine produced significantly better improvements on 'sleeping assessment 1' (14.9 +/- 5.2 vs 13.7 +/- 5.4, p = 0.028) and 'sleeping assessment 2' (p = 0.013) than fluoxetine. Both agents were generally well tolerated but mirtazapine-treated patients experienced a mean weight gain of 0.8 +/- 2.7 kg compared with a mean decrease in weight of 0.4 +/- 2.1 kg for fluoxetine-treated patients (p < 0.001). CONCLUSIONS: Mirtazapine is as effective and well tolerated as fluoxetine in the treatment of patients with severe depression.

[Clinical management of patients with depression and cardiac disease]. / Abordaje terapético de la depresión en pacientes con enfermedad cardíaca.

Depression occurs in 15 % to 20 % of patients with acute coronary syndromes and it is also and independent risk factor for morbidity and mortality. Treatment with selective serotonin reuptake inhibitors is effective, safe and may improve survival after myocardial infarction in patients with depression.

Effectiveness of mirtazapine in the treatment of sleep apnea/hypopnea syndrome (SAHS).

Several drugs have been described as possible treatments for Sleep Apnea/Hypopnea Syndrome (SAHS) but the data available does not support their use. In an animal model of central apnea the use of mirtazapine produced a significant reduction of apneas. We present a male patient, 82 years old, with excessive daytime sleepiness and loud snoring during at least 10 years. An overnight polysomnography (PSG) revealed an apnea/hypopnea index of 54.9 events per hour of sleep with a minimum pulse oximetric saturation (SaO(2)) of 78% and an arousal index of 40.4 per hour. A nasal CPAP titration in the second half of the night showed suppression of apneas with a CPAP level of 8 cmH(2)O. The patient refused to use the CPAP device and began with 15 mg of mirtazapine at bedtime. A second PSG performed after 3 months of mirtazapine showed a significant reduction in the apnea/hypopnea index (9.3 events per hour of sleep; 81% minimal oxygen saturation (SaO(2))). Clinically, the patient and his wife reported a clear reduction of excessive daytime sleepiness and an improvement in self-reported functioning and well-being without any important side effects. This successful case appears to be the first report with mirtazapine in human SAHS and supports the need for an appropriate clinical trial with this drug.

Taurine concentration in human blood peripheral lymphocytes: major depression and treatment with the antidepressant mirtazapine.

Major depression is a serious disease with various systemic effects, including dysfunction of the immune response. Taurine has been known to be related to certain modifications of the immune system. The aim of this study was to determine the taurine concentration in lymphocytes of patients with major depression and to evaluate the influence of the antidepressant treatment with mirtazapine for six weeks on the levels of taurine. Gamma-aminobutyric acid, aspartate, glutamate and glutamine were also determined. Taurine, aspartate and glutamine levels were increased in the lymphocytes of depressed patients before mirtazapine treatment compared to the control group, and were normalized after treatment. Gamma-aminobutyric acid and glutamate did not differ between patients and controls. There was a significant and positive correlation between the severity of the disorder, measured by the Hamilton Rating Scale, and the concentration of taurine in the lymphocytes of depressed patients before treatment. This correlation was not observed after treatment and neither was there a correlation observed for the other amino acids. The present observations could be an indication of the relevance of taurine as a protective agent in the lymphocytes of patients with severe depression, and could be the result of modifications of taurine transport or efflux processes.

Serotonin transporter modulation in blood lymphocytes from patients with major depression.

1. Serotonin is a neurotransmitter in the central nervous system which has been implicated in the aetiology and pathogenesis of affective disorders. The serononergic system also plays several roles in the immune system through the expression of a number of its receptor subtypes in the immune cells. 2. Following release serotonin is inactivated by reuptake into neurons and other cells by a specific serotonin sodium and chloride-dependent transporter molecule, whose structure has been elucidated. 3. Measurement [3H]paroxetine binding showed that human lymphocytes contain a high-affinity serotonin transporter. 4. To assess the serotonin function in major depression, we investigated serotonin transporter density in blood lymphocytes from patients with this disorder and selected according to the interview of the American Psychiatric Association. 5. Patients were divided into two groups and treated with two different antidepressant drugs, one group receiving fluoxetine, a selective serotonin reuptake inhibitor, and another mirtazapine, an antagonist of alpha2-adrenergic auto and heteroreceptors, for a period of 6 weeks. 6. Blood samples were obtained before and after the treatment, lymphocytes were isolated by Ficoll/Hypaque gradient, subjected to differential adhesion to plastic, and cell membranes were prepared for binding assay of [3H]paroxetine. 7. Lymphocytes serotonin transporter number was significantly reduced, while the affinity was unchanged, in patients with major depression disorder as compare to controls. 8. In addition, there was a partial recovery in lymphocytes serotonin (5HT) transporter number in the period posterior to the antidepressants administration, accompanied with clinical and depression rating scales improvement. Serotonin was determined in platelet-poor plasma and in lymphocytes before and after drugs administration, showing a significant decrease in the patients treated compared to untreated and controls. 9. These results are evidence of the potential interaction between the nervous and immune systems. The mechanisms underlying this interaction are under study, and might be related to modifications in the expression or function of the serotonin transporters in lymphocytes of depressed patients.

Mirtazapine versus fluoxetine in the treatment of panic disorder.

Mirtazapine is an antidepressant whose side effect profile differs from that of first-line agents (selective serotonin reuptake inhibitors) used in the treatment of panic disorder. The present study compared the effect of mirtazapine and fluoxetine in the treatment of panic disorder in a double-blind, randomized, flexible-dose trial conducted with outpatients. After a 1-week single-blind placebo run-in, 27 patients entered an 8-week double-blind phase in which they were randomly assigned to treatment with either mirtazapine or fluoxetine. Both groups improved significantly in all but one efficacy measure (P < or = 0.01). ANOVA showed no significant differences between the two treatment groups in number of panic attacks, Hamilton Anxiety Scale or Sheehan Phobic Scale, whereas measures of patient global evaluation of phobic anxiety were significantly different between groups (F1,20 = 6.91, P = 0.016) favoring mirtazapine. For the 22 patients who completed the study, the mean daily dose of mirtazapine was 18.3 +/- 1.3 vs 14.0 +/- 1.0 mg for fluoxetine at the endpoint. Weight gain occurred more frequently in the mirtazapine group (50 vs 7.7%, P = 0.04) and nausea and paresthesia occurred more often in the fluoxetine group (P = 0.01). Results suggest that mirtazapine has properties that make it attractive for the treatment of panic disorder.

O perfil clìnico da mianserina / The clinical profile of mianserin

As autoridades responsaveis pelo licenciamento de drogas em todo mundo compartilham a mesma opiniäo em assegurar que as drogas aprovadas sejam efetivas e ao mesmo tempo seguras. Entretanto, um número relativamente baixo de pacientes expostos à droga em ensaios clìnicos faz com que seja extremamente improvável que reaçöes adversas sérias, mas raras, sejam detectadas precocemente num programa de teste clìnico. Estimativas de incidência de ocorrência de reaçöes adversas raras podem ser realizadas apenas durante a vigilância pós-comercializaçäo do produto. Mortes devido a reaçöes adversas sérias säo menos comuns do que mortes por toxicidade devido a dose excessiva (overdose) com antidepressivos tricìclicos antigos. Nomifensina, por exemplo, foi retirada do mercado depois que ficou demonstrado que ela estava relacionada a sete mortes por milhäo de prescriçöes nenhuma morte por superdosagem, ao passo que a amitriptilina continua a ser usada a despeito de ter sido demonstrada sua associaçäo com 48 mortes por superdosagem por milhäo de prescriçöes. No cálculo do risco/benefìcio, a vantagem da mianserina em termos de segurança aumentada em superdosagem necessita ser avaliada em relaçäo ao risco de discrasia. Os antidepressivos mais novos parecem ser mais seguros do que os antidepressivos tricìclicos antigos. O relatório de Coroner na Inglaterra e Paìs de Gales fornece uma base para os cálculos de toxicidade relativa de diferentes antidepressivos associados com morte por superdosagem e pode ser usado como uma forma independente de vigilância após comecializaçäo. Os antidepressivos tricìclicos antigos com uma média de 30 mortes por milhäo de prescriçöes parecem ser muito mais perigosos em superdosagem que os antidepressivos mais novos. Amitriptilina e dotiepina parecem ser, de longe, os mais perigosos com 46-48 mortes por milhäo de prescriçöes. A relativa segurança em superdosagem com os mais novos antidepressivos como mianserina (seis por milhäo), lofepramina (0) e trazodone (11 por milhäo) säo suportados por estes cálculos. Mianserina tem mostrado reduzir seletivamente os pensamentos suicidas, comparado a maprotilina. Esta caracterìstica foi originalmente atribuìda ao efeito serotoninérgico da mianserina, mediado, talvez, com seu antagonismo receptor 5-HT, 5HT ou 5HT. Dados recentes sugerem, entretanto, que a maprotilina está associada a um aumento de tentativas de suicìdio, comparado ao placebo em tratamento prolongado, o que realça a questäo que outros antidepressivos podem induzir tentativas suicìdas

Tratamento da depressäo no idoso com antidepressivos tricíclicos e de segunda geraçäo / Treatment of depression in aged with of tricyclic and second generalation antidepressants

O objetivo deste artigo é rever a literatura no que se refere à eficácia, efeitos colaterais e uso de antidepressivos tricíclicos e de segunda geraçäo em geriatria. Os vários ensaios clínicos duplo-cegos com esses psicofármacos aplicados a idosos, relatados na literatura de língua inglesa até 1989, foram resenhados

Hemodiálise: depressäo e uso de antidepressivo / Hemodialysis: depression and antidepressive agents use

Foram estudados quatorze pacientes através de entrevistas clínicas, do Inventário Multifásico Minesota de Personalidade - MMPI -, da Escala de Depressäo de Hamilton, além de exames laboratoriais. O perfil psicológico médio realizado com treze pacientes que se submeteram ao inventário foi: 28 "I" 3 4 5 6 9 - 70/F" L? K/ ou seja uma elevaçäo mais acentuada nas escalas de depressäo, esquizofrenia e hipocondria. A primeira aplicaçäo da escala de Hamilton apresentou um resultado de 32.5. Os sintomas encontrados em todos os pacientes foram tendência a inatividade, desânimo, diminuiçäo da capacidade de trabalho, distúrbio do sono, anorexia, hipersensibilidade emocional, mal ajustamento sexual e familiar, fraqueza, indecisäo e sentimento de inutilidade. Em seis pacientes administrou-se um antidepressivo durante dezoito meses. Houve melhora dos sintomas avaliados através de entrevistas clínicas, da aplicaçäo mensal da escala de depressäo de Hamilton e da reaplicaçäo do MMPI no final do estudo

Estudo clínico aberto com mianserina nas depressöes / An open clinical study with mianserin in depressions

Este é um trabalho clínico aberto com 48 pacientes, idades variando de 20 a 80 anos, quanto ao uso de mianserina para síndrome ou doença depressiva. A duraçäo do tratamento foi de dois meses. Após a apresentaçäo dos resultados, discute-se a baixa incidência de efeitos colaterais, a eficácia terapêutica comprovada e o espectro de indicaçöes desse novo antidepressivo no Brasil