Mirtazapine versus megestrol acetate in treatment of anorexia-cachexia in advanced cancer patients: a randomized, double-blind trial.

OBJECTIVE: Cancer-related anorexia-cachexia comprises one of the most common syndromes of advanced cancer patients. The management of cancer-related anorexia-cachexia is a great challenge in clinical practice. There are no definite practice guidelines yet for the prevention and treatment of cancer-related anorexia-cachexia. This study is considered to find out whether there is any role of mirtazapine in the improvement of anorexia in cancer patients. METHODS: A total of 80 cancer-anorexia patients were enrolled. Patients in the trial arm received the standard chemotherapy medication plus one tablet of mirtazapine 15 mg daily at night orally for 8 weeks starting from the day of an initial assessment. The control arm received the standard chemotherapy medication plus one tablet of megestrol acetate 160 mg daily orally for 8 weeks starting from the day of an initial assessment. Each patient was assessed by validated versions of Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale v 4 questionnaires. RESULTS: After 4 and 8 weeks each patient was evaluated again using the Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale tool. The quality of life of each patient was assessed by European Organization for Research and Treatment QLQ-C30 v 3.0. After 4 to 8 weeks of treatment, the Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale score in cancer anorexia patients in the mirtazapine improved anorexia significantly. However, the improvement after 4 to 8 weeks was not statistically significant when it was compared with the megestrol acetate (P > 0.05). CONCLUSIONS: Therefore, the findings of this study reveal that mirtazapine might be a potential alternative to megestrol acetate, as it has shown potential efficacy as like as megestrol acetate.

Prediction of Human Disproportionate and Biliary Excreted Metabolites Using Chimeric Mice with Humanized Liver.

The PXB-mouse is potentially a useful in vivo model to predict human hepatic metabolism and clearance. Four model compounds, [14C]desloratadine, [3H]mianserin, cyproheptadine, and [3H]carbazeran, all reported with disproportionate human metabolites, were orally administered to PXB- or control SCID mice to elucidate the biotransformation of each of them. For [14C]desloratadine in PXB-mice, O-glucuronide of 3-hydroxydesloratadine was observed as the predominant metabolite in both the plasma and urine. Both 3-hydroxydesloratadine and its O-glucuronide were detected as major drug-related materials in the bile, whereas only 3-hydroxydesloratadine was detected in the feces, suggesting that a fraction of 3-hydroxydesloratadine in feces was derived from deconjugation of its O-glucuronide by gut microflora. This information can help understand the biliary clearance mechanism of a drug and may fill the gap in a human absorption, distribution, metabolism, and excretion study, in which the bile samples are typically not available. The metabolic profiles in PXB-mice were qualitatively similar to those reported in humans in a clinical study in which 3-hydroxydesloratadine and its O-glucuronide were major and disproportionate metabolites compared with rat, mouse, and monkey. In the control SCID mice, neither of the metabolites was detected in any matrix. Similarly, for the other three compounds, all human specific or disproportionate metabolites were detected at a high level in PXB-mice, but they were either minimally observed or not observed in the control mice. Data from these four compounds indicate that studies in PXB-mice can help predict the potential for the presence of human disproportionate metabolites (relative to preclinical species) prior to conducting clinical studies and understand the biliary clearance mechanism of a drug. SIGNIFICANCE STATEMENT: Studies in PXB-mice have successfully predicted the human major and disproportionate metabolites compared with preclinical safety species for desloratadine, mianserin, cyproheptadine, and carbazeran. In addition, biliary excretion data from PXB-mice can help illustrate the human biliary clearance mechanism of a drug.

[Two patients with progressive multifocal leukoencephalopathy with immune response against JC virus showing good long-term outcome by combination therapy of mefloquine, mirtazapine, and risperidone].

Patient 1 was a 59-year-old woman receiving prednisolone for idiopathic hypereosinophilia. Brain MRI of patient 1 disclosed slight gadolinium enhancement at lesions, indicating inflammation. Patient 2 was a 32-year-old woman with systemic lupus erythematosus under immunosuppressive therapy. Brain biopsy of patient 2 showed balanced infiltration of CD8+ and CD4+ T lymphocytes at the sites of lesions. Both subjects were diagnosed as having progressive multifocal leukoencephalopathy (PML) shortly after the onset of neurological symptoms and were treated with a combination of mefloquine, mirtazapine, and risperidone. Both patients remain alive with improved neurological symptoms even after long-term follow-up (24 months in patient 1 and 45 months in patient 2). Although the prognosis of PML is very poor, our findings suggest that pharmacotherapy may be effective for patients with well-controlled immune reactions against the JC virus.

Tachyphylaxis to the Sedative Action of Mirtazapine.

BACKGROUND The pharmacological term tachyphylaxis is used to describe rapidly occurring response desensitization, a situation where the biological response to a given drug dose diminishes when it is given continuously. This pharmacological phenomenon is well observed in some drug categories such as ephedrine, nitrates, beta blockers and H2 antagonists. Mirtazapine is a widely-used antidepressant with a multimodal mechanism of action. CASE REPORT In the present case, we report rapid onset and consistent tachyphylaxis regarding the sedative action of mirtazapine in a 30-year-old female. CONCLUSIONS To our knowledge this is the first reported case of rapid onset and consistent tachyphylaxis to the sedative effect of mirtazapine confirming the complexity of the pharmacological profile of the drug.

Development and evaluation of orally disintegrating tablets comprising taste-masked mirtazapine granules.

INTRODUCTION: Orally disintegrating tablets (ODTs) provide an important treatment option for pediatric, geriatric and psychiatric patients. In our previous study, we have performed the initial studies for the formulation development and characterization of new ODT formulations containing a bitter taste drug, mirtazapine, coated with 6% (w/w) Eudragit® E-100 (first group of formulations, FGF) without taste evaluation. In present study, coating ratio of the drug was increased to 8% (w/w) (second group of formulations, SGF) to examine the effect of increased coating ratio of drug on in vitro characterization of the formulations including in vitro taste masking study. MATERIALS AND METHODS: Coacervation technique using Eudragit® E-100 was employed to obtain taste-masked mirtazapine granules. FGF and SGF were compared to original product (Remeron SolTab, an antidepressant drug which produced by pellet technology) in terms of in vitro permeability, in vitro taste masking efficiency which was performed by dissolution studies in salivary medium and dissolution stability. Also, the other tablet characteristics (such as diameter, thickness) of SGF were examined. RESULTS AND DISCUSSION: The disintegration time of the SGF were found as A1 < A2 < A3 < A5 < A4 (8% Eudragit® E-100), but all of the formulations dissolved under 30 seconds and friability values were less than 1%. In vitro taste masking efficiency studies demonstrated that C2 formulation (in FGF) had the most similar dissolution profile to Remeron SolTab. CONCLUSIONS: According to these findings, B2 or C2 (with citric acid or sodium bicarbonate, respectively, with 6% Eudragit® E-100) formulations could be promising alternatives to Remeron SolTab.

Intractable hyperemesis gravidarum in a patient with type 1 diabetes.

Hyperemesis gravidarum is not uncommon. Its pathogenies is multifactorial but not fully understood. We present a case of a middle class, Caucasian pregnant woman aged 24 years with coexisting type 1 diabetes, who had severe hyperemesis gravidarum from the sixth week of pregnancy and was resistant to all standard and off-the-label treatments raising questions about the pathogenesis of hyperemesis gravidarum. She was managed with a multidisciplinary approach and was supported with total parenteral nutrition till she had an emergency caesarean section in the 29th week of pregnancy. Her vomiting stopped as soon as a small for gestational age but otherwise healthy male baby was delivered.

Chronic dosing with mirtazapine does not produce sedation in rats

Objective: Sedation/somnolence are major side effects of pharmacotherapies for depression, and negatively affect long-term treatment compliance in depressed patients. Use of mirtazapine (MIR), an atypical antidepressant approved for the treatment of moderate to severe depression with comorbid anxiety disorders, is associated with significant sedation/somnolence, especially in short-term therapy. Nonetheless, studies with human subjects suggest that MIR-induced sedation is transient, especially when high and repeated doses are used. The purpose of this study was to explore the effects of acute and chronic administration of different doses of MIR on sedation in the rat. Methods: Assessment of sedation was carried out behaviorally using the rotarod, spontaneous locomotor activity, and fixed-bar tests. Results: A 15-mg/kg dose of MIR induced sedative effects for up to 60 minutes, whereas 30 mg/kg or more produced sedation within minutes and only in the first few days of administration. Conclusion: These results suggest that 30 mg/kg is a safe, well-tolerated dose of MIR which generates only temporary sedative effects.

Synergistic interactions between mirtazapine and prazosin prevent the induction and expression of behavioral sensitization to cocaine in rats.

Cocaine abuse and dependence are a global public health problem. To date, no effective therapy has been established to treat cocaine dependence but mirtazapine-as well as prazosin used in preclinical and clinical trials-has been shown to decrease cocaine behavioral effects. Therefore, our hypothesis was that the effectiveness of mirtazapine might improve when used in combination with prazosin. This study investigated the combined effect of mirtazapine and prazosin on cocaine-induced locomotor activity impairment in rats subjected to locomotor sensitization testing. We found that chronic treatment with the mirtazapine-prazosin combination significantly improved the effect of single mirtazapine dosing on cocaine-induced locomotor activity and on the induction and expression of cocaine sensitization. These results suggest that the combined use of mirtazapine and prazosin may be a potentially effective treatment to attenuate induction and expression of locomotor sensitization to cocaine.

The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study.

RATIONALE: The purpose of this study is to evaluate the single dose effect of intranasal esketamine (84 mg) compared to placebo on on-road driving performance. Mirtazapine (oral, 30 mg) was used as a positive control, as this antidepressant drug is known to negatively affect driving performance. METHODS: Twenty-six healthy volunteers aged 21 to 60 years were enrolled in this study. In the evening, 8 h after treatment administration, participants conducted the standardized 100-km on-road driving test. Primary outcome measure was the standard deviation of lateral position (SDLP), i.e., the weaving of the car. Mean lateral position, mean speed, and standard deviation of speed were secondary outcome measures. For SDLP, non-inferiority analyses were conducted, using +2.4 cm (relative to placebo) as a predefined non-inferiority margin for clinical relevant impairment. RESULTS: Twenty-four participants completed the study. No significant SDLP difference was found between esketamine and placebo (p = 0.7638), whereas the SDLP after mirtazapine was significantly higher when compared to placebo (p = 0.0001). The upper limit of the two-sided 95% confidence interval (CI) of the mean difference between esketamine and placebo was +0.86 cm, i.e., <+2.4 cm, thus demonstrating that esketamine was non-inferior to placebo. Non-inferiority could not be concluded for mirtazapine (+3.15 cm SDLP relative to placebo). No significant differences in mean speed, standard deviation of speed, and mean lateral position were observed between the active treatments and placebo. CONCLUSIONS: No significant difference in driving performance was observed 8 h after administering intranasal esketamine (84 mg) or placebo. In contrast, oral mirtazapine (30 mg) significantly impaired on road driving performance.

Repeated co-treatment with antidepressants and risperidone increases BDNF mRNA and protein levels in rats.

BACKGROUND: Recently, several clinical studies have suggested a beneficial effect of a combination of antidepressants (ADs) with antipsychotic drugs in drug-resistant depression. Moreover, preclinical and clinical studies indicated a role of brain-derived neurotrophic factor (BDNF) in the pathology of depression, as well as in the mechanism of action of ADs. METHODS: In the present study, we investigated the effect of repeated administration of ADs, escitalopram, fluoxetine or mirtazapine and a low dose of risperidone (an atypical antipsychotic drug) given separately or in combination, on the mRNA and protein levels of BDNF or cAMP response element binding (p-CREB) in the hippocampus and frontal cortex of male Wistar rats. ADs were given repeatedly (once daily for 14 days), separately or in combination with a low dose of risperidone. The tissue for biochemical assays was dissected 24h after the last dose of ADs. RESULTS: The obtained results showed that repeated co-treatment with an inactive dose of risperidone and escitalopram or mirtazapine but not fluoxetine increased the BDNF mRNA expression in the hippocampus and frontal cortex. Moreover, combined treatment with an inactive dose risperidone and escitalopram elevated the protein levels of p-CREB in the frontal cortex. While, co-treatment with risperidone and fluoxetine or mirtazapine increased the protein levels of BDNF and p-CREB in both examined regions of the brain. CONCLUSIONS: Our present findings suggest that enhancement levels of BDNF may be essential for the therapeutic effect of co-treatment with ADs and a low dose risperidone in patients with drug-resistant depression.

Dose- and time-dependent effects of mirtazapine on the expression of cocaine-induced behavioral sensitization in rats.

Relapse to cocaine use is a major problem in the clinical treatment of cocaine dependence. Antidepressant medications have been studied as potential therapeutic drugs to relieve a cocaine dependence disorder. Mirtazapine is an antidepressant implicated in reducing behavioral alterations induced by drugs of abuse. We have reported elsewhere that 30mg/kg mirtazapine administered for 30 days during cocaine extinction significantly attenuated the induction and expression of cocaine-induced locomotor sensitization and decreased the duration of the cocaine-induced locomotor effect. This study focused on exploring whether different mirtazapine dosing regimens could optimize and/or improve the effect of 30mg/kg mirtazapine administered for 30 days on cocaine-induced locomotor activity during the expression phase of behavioral sensitization. Our study revealed that the daily dosing regimen with a fixed dose of mirtazapine (30mg/kg ip) over 60 days improved the decrease in cocaine-induced locomotor activity and behavioral sensitization obtained by dosing of 30mg mirtazapine for 30 days. In addition, it showed that a dosing regimen of 30mg/Kg mirtazapine for 30 days managed to reduce cocaine toxicity. These results suggested that dosage of mirtazapine for 30 consecutive days may be an effective therapy.

Mirtazapine for symptom control in refractory gastroparesis.

INTRODUCTION: Gastroparesis symptoms can be severe and debilitating. Many patients do not respond to currently available treatments. Mirtazapine has been shown in case reports to reduce symptoms in gastroparesis. AIM: To assess the efficacy and safety of mirtazapine in gastroparetic patients. METHODS: Adults with gastroparesis and poorly controlled symptoms were eligible. Participants were prescribed mirtazapine 15 mg PO qhs. Questionnaires containing the gastrointestinal cardinal symptom index (GCSI) and the clinical patient grading assessment scale (CPGAS) were completed by patients' pretreatment, at 2 weeks, and at 4 weeks. Primary end point was nausea and vomiting response to mirtazapine using the GCSI. Secondary end point was nausea and vomiting severity assessment using the CPGAS. P-values were calculated using the paired two-tailed Student's t-test. Intention to treat analysis was used. RESULTS: A total of 30 patients aged 19-86 years were enrolled. Of those, 24 patients (80%) completed 4 weeks of therapy. There were statistically significant improvements in nausea, vomiting, retching, and perceived loss of appetite at 2 and 4 weeks (all P-values <0.05) compared with pretreatment. There was a statistically significant improvement in the CPGAS score at week 2 (P=0.003) and week 4 (P<0.001). Of the total patients, 14 (46.7%) experienced adverse effects from mirtazapine and due to this, 6 patients stopped therapy. CONCLUSION: Mirtazapine significantly improved both nausea and vomiting in gastroparetics after 2 and 4 weeks of treatment. Side effects led to treatment self-cessation in a fifth of patients. From these data, we conclude that mirtazapine improves nausea and vomiting, among other symptoms, in patients with gastroparesis and might be useful in select patients.

Single dose of mirtazapine modulates whole-brain functional connectivity during emotional narrative processing.

The link between neurotransmitter-level effects of antidepressants and their clinical effect remain poorly understood. A single dose of mirtazapine decreases limbic responses to fearful faces in healthy subjects, but it is unknown whether this effect applies to complex emotional situations and dynamic connectivity between brain regions. Thirty healthy volunteers listened to spoken emotional narratives during functional magnetic resonance imaging (fMRI). In an open-label design, 15 subjects received 15mg of mirtazapine two hours prior to fMRI while 15 subjects served as a control group. We assessed the effects of mirtazapine on regional neural responses and dynamic functional connectivity associated with valence and arousal. Mirtazapine attenuated responses to unpleasant events in the right fronto-insular cortex, while modulating responses to arousing events in the core limbic regions and the cortical midline structures (CMS). Mirtazapine decreased responses to unpleasant and arousing events in sensorimotor areas and the anterior CMS implicated in self-referential processing and formation of subjective feelings. Mirtazapine increased functional connectivity associated with positive valence in the CMS and limbic regions. Mirtazapine triggers large-scale changes in regional responses and functional connectivity during naturalistic, emotional stimuli. These span limbic, sensorimotor, and midline brain structures, and may be relevant to the clinical effectiveness of mirtazapine.

Endothelial nitric oxide synthase in rat brain is downregulated by sub-chronic antidepressant treatment.

BACKGROUND: Nitric oxide (NO) is a neurotransmitter that may be related to major depressive disorder (MDD) because the selective neuronal NO synthase (NOS) inhibitor, 7-nitroindazole, induces a dose-dependent antidepressant-like effect. NO modulates major neurotransmitters involved in the neurobiology of MDD, such as norepinephrine, serotonin, dopamine, and glutamate. In this study, we investigated the effects of antidepressants as NO modulators in acute and sub-chronic treatments. METHODS: Rats were injected with the SSRI paroxetine (PAR, 10 mg/kg), the SNRI milnacipran (MIL, 30 mg/kg), or the NaSSA mirtazapine (MIR, 10 mg/kg) for acute (1 h) or sub-chronic (3 weeks) treatment prior to analysis of nine brain regions (frontal cortex, temporal cortex, striatum, thalamus, hippocampus, midbrain, pons, cerebellum, and olfactory bulb). The mRNA expression levels of three NOS subtypes (neuronal: nNOS, inducible: iNOS, and endothelial: eNOS) were analyzed using real-time PCR with Taqman probes. RESULTS: Acute MIR treatment significantly increased nNOS mRNA expression in the hippocampus, midbrain, cerebellum and olfactory bulb, and iNOS mRNA expression in the frontal cortex and midbrain. Acute PAR and MIR treatments significantly increased eNOS mRNA expression in most brain regions. Conversely, sub-chronic treatment with all types of antidepressants resulted in significant decreases of eNOS mRNA expression in most brain regions. CONCLUSIONS: Sub-chronic treatment with the three types of antidepressants consistently decreased eNOS mRNA expression levels in the rat brain. These effects may be associated with the involvement of the NO system in the mechanism of action of antidepressants.

Chronic dosing with mirtazapine does not produce sedation in rats.

OBJECTIVE:: Sedation/somnolence are major side effects of pharmacotherapies for depression, and negatively affect long-term treatment compliance in depressed patients. Use of mirtazapine (MIR), an atypical antidepressant approved for the treatment of moderate to severe depression with comorbid anxiety disorders, is associated with significant sedation/somnolence, especially in short-term therapy. Nonetheless, studies with human subjects suggest that MIR-induced sedation is transient, especially when high and repeated doses are used. The purpose of this study was to explore the effects of acute and chronic administration of different doses of MIR on sedation in the rat. METHODS:: Assessment of sedation was carried out behaviorally using the rotarod, spontaneous locomotor activity, and fixed-bar tests. RESULTS:: A 15-mg/kg dose of MIR induced sedative effects for up to 60 minutes, whereas 30 mg/kg or more produced sedation within minutes and only in the first few days of administration. CONCLUSION:: These results suggest that 30 mg/kg is a safe, well-tolerated dose of MIR which generates only temporary sedative effects.

Add-on mirtazapine improves orgasmic functioning in patients with schizophrenia treated with first-generation antipsychotics.

AIM: Sexual dysfunction, common in schizophrenia, may be further exaggerated by antipsychotics, especially those of First Generation (FGAs), and antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRs). Mirtazapine, an antidepressant characterized by its different action mechanism compared with that of the majority of other antidepressants, may improve SSRI-induced sexual dysfunction in patients with depression. It is unknown, however, whether mirtazapine improves sexual functioning in schizophrenia. METHODS: This study randomly assigned FGA-treated patients with schizophrenia to receive either an add-on mirtazapine (n = 20) or a placebo (n = 19) for 6 weeks. Sexual functioning was prospectively measured using five relevant items from the Udvalg for Kliniske Undersogelser side-effect rating scale (UKU-SERS). RESULTS: Orgasmic function improved with statistical significance in the mirtazapine group (p = .03), with no changes in any other sexual functions in either group. CONCLUSION: Add-on mirtazapine appears to relieve orgasmic dysfunction in FGA-treated patients with schizophrenia.

Drug exposure and clinical effect of transdermal mirtazapine in healthy young cats: a pilot study.

Objectives The objective of this study was to measure drug exposure and clinical effects after administration of transdermal mirtazapine (TMZ) in healthy cats. Methods Phase I: seven healthy research cats received (1) 3.75 mg and 7.5 mg TMZ once aurally with 48 h serum sampling (serum samples were obtained via the jugular catheter at 0, 0.5, 1, 2, 5, 9, 12, 24, 36 and 48 h); (2) 7.5 mg TMZ and placebo daily aurally for 6 days then 48 h serum sampling; (3) 1.88 mg mirtazapine orally once with serum sampling at 1, 4 and 8 h. Phase II: 20 client-owned cats were enrolled in a randomized, double-blind, placebo-controlled, three-way crossover clinical effect study. Treatments consisted of 6 days of aural 7.5 mg TMZ or placebo gel at home, and 1.88 mg mirtazapine orally once in the clinic. Owners documented appetite, rate of food ingestion, begging activity and vocalization daily at home. On day 6, food consumed, activity and vocalization were documented in hospital, and trough and peak serum mirtazapine levels were obtained. Serum mirtazapine and gel concentrations were measured using liquid chromatography/tandem mass spectrometry. Results Phase I: administration of TMZ achieved measureable serum mirtazapine concentrations. Area under the curve0-48 of multidose 7.5 mg TMZ was significantly higher than single-dose 1.88 mg oral mirtazapine (OMZ) ( P = 0.02). Phase II: client-owned cats administered TMZ had a significant increase in appetite ( P = 0.003), rate of food ingestion ( P = 0.002), activity ( P = 0.002), begging ( P = 0.002) and vocalization ( P = 0.002) at home. In hospital there was a significant increase in food ingested with both TMZ and OMZ compared with placebo ( P <0.05). Gel concentrations ranged from 87%-119% of target dose. Conclusions and relevance TMZ 7.5 mg daily achieves measureable serum concentrations and produces significant appetite stimulation despite variance in compounded gel concentrations, but side effects denote a lower dose is indicated.

A case of progressive multifocal leukoencephalopathy with chronic renal failure, whose JC virus in cerebrospinal fluid disappeared after mefloquine-mirtazapine dual therapy.

An 83-year-old man with chronic renal failure was referred to our hospital because of subacute progressive right hemiparesis. A brain MRI showed high-intensity lesions in bilateral middle cerebellar peduncles and white matter of the left frontal lobe on T2-weighted images. The lesions increased gradually, so we suspected a brain tumor because 1H-MRS images showed elevated Cho and decreased NAA, and also pathologic findings of the brain biopsy suggested glioblastoma. However, JC virus (JCV) in cerebrospinal fluid was revealed highly positive by PCR. So we reconsidered pathologically and finally found bizarre astrocytes which were infected with JCV in immunohistochemical studies and we diagnosed progressive multifocal leukoencephalopathy at last. Then we medicated with mefloquine and mirtazapine, and the JCV in cerebrospinal fluid disappeared, without new MRI lesions. This is a rare case in respect of the background of the patient and the clinical course.

A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia.

The antidepressant mirtazapine is an alternative to classical hypnotics, and this study investigated the efficacy and safety of esmirtazapine (Org 50081, the maleic acid salt of S-mirtazapine) in patients given a diagnosis of primary insomnia after acute (2-day) treatment. Patients aged 18 to 65 years with primary insomnia were randomized to receive placebo or 1.5-, 3.0-, or 4.5-mg esmirtazapine in a balanced 4-way crossover study; 2 sleep laboratory nights with polysomnography were separated by 5-day, single-blind placebo washout periods. Polysomnography-determined total sleep time (primary end point) and patient-reported total sleep time improved by at least 25 minutes with all 3 doses of esmirtazapine (P ≤ 0.001 vs placebo). Polysomnography-measured wake time after sleep onset (P ≤ 0.0001) and latency to persistent sleep also improved vs placebo (P ≤ 0.01, 3.0 and 4.5 mg). Patient-reported sleep quality improved with 3.0- and 4.5-mg esmirtazapine (P ≤ 0.01 and P ≤ 0.05, respectively, vs placebo). Morning alertness and contentment were not altered after esmirtazapine, and calmness increased with 4.5-mg esmirtazapine vs placebo. Evening questionnaires showed no difference in duration of daytime naps but reduced energy and ability to work/function after esmirtazapine treatment periods vs placebo (P < 0.05), although this effect was limited to the first night of each 2-night period. There were few adverse events, no serious adverse events, or clinically relevant treatment differences in vital signs, laboratory values, or electrocardiogram. Esmirtazapine doses of 1.5 to 4.5 mg/day significantly improved quantity and quality of sleep and were generally well tolerated, with no evidence of safety concerns or consistent pattern of residual effects.

An open-label pilot study of quetiapine plus mirtazapine for heavy drinkers with alcohol use disorder.

Animal research suggests that medications that produce a weak dopamine D2 receptor blockade and potentiate noradrenergic activity may decrease alcohol drinking. In an open-label pilot study of subjects with alcohol dependence, we tested whether the combination of quetiapine, a weak dopamine D2 receptor antagonist, whose primary metabolite, desalkylquetiapine, is a norepinephrine reuptake inhibitor, and mirtazapine, a potent α2 norepinephrine receptor antagonist, would decrease alcohol drinking and craving. Twenty very heavy drinkers with alcohol dependence entered a trial of 8 weeks of treatment with quetiapine followed by 8 weeks of treatment with a combination of quetiapine plus mirtazapine. Alcohol use was assessed weekly with a Timeline Follow-Back interview and craving with the Penn Alcohol Craving Scale. Among the 11 completers, subjects reported improved outcomes in the quetiapine plus mirtazapine period compared to the quetiapine alone period: fewer very heavy drinking days per week (1.3 [SD = 2.4] vs. 2.1 [SD = 2.8]; t = 2.3, df = 10, p = 0.04); fewer total number of drinks per week (39.7 [SD = 61.6] vs. 53.4 [SD = 65.0]; t = 2.8, df = 10, p = 0.02); and lower craving scores (2.5 [SD = 1.4] vs. 3.2 [SD = 1.2]; t = 2.4, df = 10, p = 0.04). All subjects reported at least one adverse event; 72.7% reported somnolence. In this open-label pilot study, treatment with quetiapine plus mirtazapine was associated with a decrease in alcohol drinking and craving. These findings are consistent with our previous work in animal models of alcohol use disorders and suggest that further study of medications or combinations of medications with this pharmacologic profile is warranted.