Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. METHODS: This parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. FINDINGS: Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). INTERPRETATION: This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Mirtazapine use may increase the risk of hypothyroxinaemia in patients affected by major depressive disorder.

AIMS: Hypothyroxinaemia could be easily neglected if attention is paid only to patients with elevated thyroid-stimulating hormone. We aimed to assess the association between mirtazapine use and hypothyroxinaemia in patients affected by major depressive disorder. METHODS: We conducted a retrospective cohort study in the Second Affiliated Hospital of Xinxiang Medical University between January 2016 and December 2018. Patients affected by major depression disorder and admitted to the hospital for treatment during the study period and who had thyroid tests at admission and after treatment were included. Mirtazapine use during hospitalization was the exposure measure and newly developed hypothyroxinaemia was as the primary outcome and structure parameters of thyroid homeostasis were the secondary outcomes of this study. Log-binomial model was used to estimate the association between mirtazapine use and hypothyroxinaemia, after adjusting for potential confounding factors. RESULTS: A total of 220 eligible patients were included in the final analysis. The incidence of hypothyroxinaemia in patients who used mirtazapine was higher (37.5%) than those patients who did not use (19.7%). The relative risk of developing hypothyroxinaemia was 1.70 (95% confidence interval: 1.21-2.43) for mirtazapine use, after adjusting for confounding factors. The degree of reduction in thyroid feedback quantile-based index in mirtazapine group was significantly greater than that in nonmirtazapine group. CONCLUSION: Mirtazapine use was associated with the increased risk of developing hypothyroxinaemia. The underlying mechanism may be involved the changed central set point of thyroid homeostasis, in which pituitary was in a possibly impaired sensitivity to the lower level of thyroid hormones.

Risk of out-of-hospital cardiac arrest in antidepressant drug users.

Conflicting results have been reported regarding the association between antidepressant use and out-of-hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA. METHODS: We conducted a nationwide nested case-control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time-dependent exposure and time-dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately. RESULTS: During the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high-dose citalopram (>20 mg) and high-dose escitalopram (>10 mg; HR:1.46 [95% CI:1.27-1.69], HR:1.43 [95% CI:1.16-1.75], respectively) among selective serotonin reuptake inhibitors (reference drug sertraline), and for high-dose mirtazapine (>30; HR:1.59 [95% CI:1.18-2.14]) among the serotonin-norepinephrine reuptake inhibitors or noradrenergic and specific serotonergic antidepressants (reference drug duloxetine). Among tricyclic antidepressants (reference drug amitriptyline), no drug was associated with significantly increased OHCA rate. Increased OHCA rate was found for antidepressants with known potassium channel blocking properties (HR:1.14 [95% CI:1.05-1.23]), but for not those with sodium channel blocking properties. Citalopram, although not statistically significant, and mirtazapine were associated with increased OHCA rate in patients without cardiac disease and cardiovascular risk factors. CONCLUSION: Our findings indicate that careful titration of citalopram, escitalopram and mirtazapine dose may have to be considered due to drug safety issues.

Mirtazapine exposure in pregnancy and fetal safety: A nationwide cohort study.

OBJECTIVE: To investigate the association between mirtazapine exposure in pregnancy and risk of specific adverse pregnancy outcomes. METHODS: A register-based nationwide cohort study was conducted including all registered pregnancies in Denmark from 1997 to 2016. Mirtazapine-exposed pregnancies were compared with mirtazapine unexposed pregnancies in a 1:4 ratio matched according to propensity scores. Outcomes were major congenital malformations analyzed using log binomial models, and spontaneous abortion, stillbirth and neonatal death analyzed using Cox proportional hazard regression. RESULTS: From a source population of 1,650,649 pregnancies, the propensity score-matched cohort included 4475 pregnancies (895 mirtazapine exposed) in the analysis of major congenital malformations. The analyses of spontaneous abortion included 9 500 pregnancies (1900 mirtazapine exposed), and for the analyses of stillbirths and neonatal deaths 9725 (1 945 mirtazapine-exposed) and 4485 pregnancies (897 mirtazapine-exposed) were included, respectively. Thirty-one (3.5%) children were diagnosed with major congenital malformation among the mirtazapine exposed compared with 152 (4.3%) among the unexposed pregnancies (OR=0.81, 95% CI 0.55-1.20). Spontaneous abortion occurred in 237 (12.5%) of the mirtazapine exposed compared with 931 (12.3%) of the unexposed pregnancies (HR = 1.04%, 95% CI 0.91-1.20). The analyses revealed no increased risk of stillbirth (HR = 0.88%, 95% CI 0.34-2.29) or neonatal death (HR = 0.60%, 95% CI 0.18-2.02). CONCLUSIONS: In this nationwide Danish register study, mirtazapine exposure in pregnancy was not associated with major congenital malformations, spontaneous abortion, stillbirth, or neonatal death. Clinicians and patients can be reassured that mirtazapine is safe in pregnancy.

Effectiveness and adverse effects of the use of mirtazapine as compared to duloxetine for fibromyalgia: real-life data from a retrospective cohort.

On the background of a restricted armamentarium of drugs available for the management of fibromyalgia (FM), we aimed to compare the real-world effectiveness of two serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine (MTZ) and duloxetine (DLX) in FM. A medical records review was done to identify patients diagnosed with FM and prescribed a stable dose of either MTZ or DLX for more than 6 months. Their present status was determined by a telephonic interview which included a subjective assessment of improvement (Likert scale), FIQR (Revised Fibromyalgia Impact Questionnaire), adverse drug effects and compliance. One-fifty-eight patients were screened to include 81 patients [mean age 46.7 (± 13.0) years, 64 (79%) females]. Sixty (79%) had primary fibromyalgia and 66 (81.5%) were on DLX (20-40 mg) while 15(18.5%) were on MTZ (7.5 mg). In addition to the drugs, lifestyle modification was followed by 57 (70.3%). A moderate-to-good improvement was seen in 66 (81.5%), while 15 (18.5%) reported poor to no improvement overall. In the DLX group, a majority (59, 89.4%) showed moderate-to-good improvement compared to 7(46.7%) on MTZ [p = 0.001, 9.6(2.6-34)]. However, FIQR was similar for those on DLX (3.6 ± 0.9) and MTZ (3.8 ± 0.7). Adverse effects were reported for 51 (77%) of patients on DLX and all (100%) on MTZ with a poorer compliance with MTZ 5 (33.3%) compared to DLX 47 (71.2%) [p = 0.008, OR 0.1(0.03-0.4)]. On multivariate analysis, DLX use [OR 16.7 (95% CI 2.7-100); p = 0.008] and lifestyle modification [p = 0.002; OR 11.2(1.5-83.3)] were associated with better subjective outcomes. Low-dose MTZ appears to be inferior to DLX in the management of FM in this real-world cohort.

What is the effectiveness and safety of mirtazapine versus escitalopram in alleviating cancer-associated poly-symptomatology (the MIR-P study)? A mixed-method randomized controlled trial protocol.

BACKGROUND: Advanced cancer patients often experience multiple symptoms at a same time. This might lead to polypharmacy and increase adverse events representing major threats to the quality of health care, especially in palliative care situations. Mirtazapine, an antidepressant agent, has been suggested as a potential relevant drug to alleviate multiple cancer-related symptoms at a same time. Therefore, the present study aims to assess the effectiveness of mirtazapine in alleviating multiple symptoms at a same time in advanced cancer patients suffering from a major depressive episode compared to a group receiving escitalopram, another antidepressant agent. METHODS: Multicentre, prospective, randomized, controlled trial in 12 palliative care services in France. The study will be based on a mixed-method methodology using parallel groups, of oral mirtazapine compared with oral escitalopram, with a 56 day follow-up. The primary outcome will be an improvement of the Global health Status (issued from the EORTC-QLQ-C30) on day 56. 418 participants will be clinically followed-up on day 7 and 56 and will have a telephonic assessment on days 14 and 28. A sub-sample of participants will be invited to take part in semi-structured qualitative interviews at baseline and day 56. For the qualitative part, purposeful sampling will be used. DISCUSSION: This study will provide evidence for the pharmaceutics management of poly-symptomatology in advanced cancer patients. This could lead to important changes in the management of those patients by using a single molecule to alleviate multiple symptoms at a same time, potentially improving medication adherence, symptoms' control, and reducing the risk of medications adverse events. TRIAL REGISTRATION: Trial registration: NCT04763135 . Registered 18 March 2021.

Antiplatelet Effect of Mirtazapine via Co-blocking of the 5-HT2A and α2-Adrenergic Receptors on Platelets.

Mirtazapine (MTZ) is a noradrenergic and specific serotonergic antidepressant. MTZ is reportedly associated with an increased risk of bleeding. However, the underlying mechanism remains unclear. In this study, we investigated the antiplatelet effect of MTZ in mice via light transmission aggregometry to elucidate the mechanism of MTZ-induced bleeding. The results of the ex vivo study showed that the oral administration of MTZ (20 or 100 mg/kg) significantly suppressed platelet aggregation mediated by the synergic interaction of 5-hydroxytryptamine (5-HT) and adrenaline. Additionally, MTZ significantly suppressed platelet aggregation, mediated by the synergic interaction of ADP and 5-HT or adrenaline. Similar results were obtained in vitro, under the condition of 5-HT- and adrenaline-induced platelet aggregation. Overall, the results suggest that MTZ exerts antiplatelet effect by co-blocking 5-HT2A and α2-adrenergic receptors on platelets and suppresses platelet aggregation mediated by ADP, increased by either 5-HT or adrenaline. Thus, a detailed monitoring of bleeding is recommended for patients taking MTZ.

Mirtazapine, a dopamine receptor inhibitor, as a secondary prophylactic for delayed nausea and vomiting following highly emetogenic chemotherapy: an open label, randomized, multicenter phase III trial.

Background We examined the efficacy of mirtazapine in preventing delayed nausea and vomiting following highly emetogenic chemotherapy (HEC). Patients and methods Patients who had experienced delayed emesis and would be subsequently scheduled for at least three more cycles of the same chemotherapy were randomly assigned to either a mirtazapine (15 mg daily on days 2-4) or a control group. In addition, both groups received a standard triplet regimen comprising aprepitant, a 5-HT3 receptor antagonist, and dexamethasone (7.5 mg on days 2-4). The chemotherapy regimens were either an epirubicin plus cyclophosphamide regimen or cisplatin-containing regimens. The primary end point was a complete response (no emesis and no rescue treatment) to the delayed phase (25-120 h post-chemotherapy) during Cycle 1. The impact on quality of life (QOL) was assessed using the Functional Living Index-Emesis (FLIE) questionnaire. Results Of 95 enrolled patients, 46 were assigned to the mirtazapine group and 49 to the control group. The complete response rate in the delayed phase during Cycle 1 was significantly higher with mirtazapine than in the control group (78.3% versus 49.0%, P = 0.003). The main adverse effects of mirtazapine were mild to moderate somnolence and weight gain. Mean total FLIE scores were similar between the two arms. Conclusions This is the first randomized prospective study to show that adding mirtazapine has a substantial and statistically significant benefit with good tolerance in patients with breast cancer who have experienced delayed emesis following the same prior HEC. (Trial registration: ClinicalTrials.gov NCT02336750).

What is the evidence for mirtazapine in treating cancer-related symptomatology? A systematic review.

PURPOSE: Cancer patients often experience multiple distressing symptoms which are challenging to manage. It would therefore be helpful to find a treatment that alleviates more than one symptom, to avoid polypharmacy: mirtazapine has been used in several studies for this purpose. The objective of this study was to assess the effectiveness and safety of mirtazapine in alleviating one or more frequently encountered cancer-related symptoms. METHODS: Systematic review of clinical trials in English or French. Eight databases were searched. Included studies assessed the effectiveness of mirtazapine in alleviating one or more frequently encountered cancer-related symptoms. Comparator and validated assessment tools were required. Studies were independently appraised by two investigators before data synthesis. RESULTS: The search yielded 1898 references, from which we identified 12 relevant articles evaluating highly heterogeneous outcomes. These were two randomised-controlled (RCTs), three non-randomised controlled, and seven non-randomised non-controlled trials. In total, 392 participants were included and 185 were in RCTs. No study assessed the effectiveness of mirtazapine in alleviating symptoms at the same time, but some considered more than one symptom. Overall, the data was of poor quality, limited by small sample size and bias. However, mirtazapine showed effectiveness in treating depression, anxiety, sleep disorders, emesis and neuropathic pain. Across all studies, mirtazapine is safe to use, with drowsiness and dizziness the most common side-effects. CONCLUSION: Study design and small sample sizes limit the ability to interpret results. Trials to assess the impact of mirtazapine or other medicines in alleviating multiple symptoms would be valuable.

Clinical Management of Bleeding Risk With Antidepressants.

OBJECTIVE: This nonsystematic review describes risk of bleeding in treatment with serotonin reuptake inhibitors (SRIs) and provide recommendations for the management of patients at risk of bleeding. DATA SOURCES: Articles were identified by English-language MEDLINE search published prior to June 2018 using the terms SRI, serotonin and noradrenaline reuptake inhibitors, OR antidepressive agents, AND hemorrhage OR stroke. STUDY SELECTION AND DATA EXTRACTION: Meta-analyses were utilized to identify information regarding risk of bleeding with antidepressants. Individual studies were included if they had information regarding bleeding risk with specific SRIs, timing of risk, or risk with medications of interest. DATA SYNTHESIS: SRIs increase risk of bleeding by 1.16- to 2.36-fold. The risk is synergistic between SRIs and nonsteroidal anti-inflammatory drugs (NSAIDs; odds ratio [OR] range between studies 3.17-10.9). Acid-reducing medications may mitigate risk of gastrointestinal bleeds in chronic NSAIDs and SRI users (OR range between studies 0.98-1.1). Antidepressants with low or no affinity for the serotonin transporter, such as bupropion or mirtazapine, may be appropriate alternatives for patients at risk of bleeding. Relevance to Patient Care and Clinical Practice: This review includes data regarding bleeding risk for specific antidepressants, concomitant medications, and risk related to duration of SRI use. Considerations and evidence-based recommendations are provided for management of SRI users at high bleeding risk. CONCLUSIONS: Clinicians must be aware of the risk of bleeding with SRI use, especially for patients taking NSAIDs. Patient education is prudent for those prescribed NSAIDs and SRIs concurrently.

Esmirtazapine treatment of postmenopausal vasomotor symptoms: two randomized controlled trials.

OBJECTIVES: Two identical 12-week, randomized, double-blind, placebo-controlled, multi-arm, parallel-group Phase III studies (Study P012, NCT00560833; Study P013, NCT00535288) evaluated the efficacy and safety of esmirtazapine, an investigational medicine, for the treatment of moderate to severe vasomotor symptoms (VMS) in postmenopausal women. METHODS: Participants were randomized to placebo or esmirtazapine (2.25, 4.5, 9.0, or 18.0 mg). Co-primary efficacy endpoints (daily frequency and severity of moderate to severe VMS, both at weeks 4 and 12) were based on participative LogPad daily diaries. Adverse events (AEs) were recorded. RESULTS: In Studies P012 and P013, 942 and 946 participants were randomized, respectively. Compared with placebo, esmirtazapine significantly reduced the mean daily frequency by 1.4-2.2 moderate to severe VMS at weeks 4 and 12 (both ≥4.5 mg) and mean daily severity by 0.06-0.08 symptoms at weeks 4 (≥4.5 mg) and 12 (9.0 mg P012; 18.0 mg P013 only). Esmirtazapine was generally well tolerated with a more favorable safety profile at lower doses. Somnolence and fatigue were the most frequently reported AEs. CONCLUSIONS: Esmirtazapine reduced the frequency and severity of moderate to severe VMS associated with menopause and was generally well tolerated in the study population.

Effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder.

The objective of the study was to investigate the effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder who received mirtazapine. The study included 109 Russian patients who received mirtazapine at a dose of 30.0 [15.0; 45.0] mg per day. Genotyping of CYP2D6*4 (1846G > A, rs3892097) was performed using real-time polymerase chain reaction with allele-specific hybridization. The activity of CYP2D6 was evaluated by determining the concentration of endogenous substrate of the enzyme and its urinary metabolite - pinoline to 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline ratio, using high-performance liquid chromatography - mass spectrometry. The statistically significant differences between the scores on the Hamilton Depression Rating Scale (HAMD) in patients with different genotypes were revealed by day 16: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.2] (p < 0.001), and for the The UKU Side Effects Rating Scale (UKU): (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p < 0.001). The calculation of correlation coefficients between the differences in scale scores and metabolic rate showed the presence of statistically significant weak inverse correlation with the efficacy indicator evaluated by HAMD (r = -0.278, p < 0.05), but not by UKU (r = 0.274, p > 0.05). This study demonstrated that an increased CYP2D6 activity reduces the efficacy of treatment with mirtazapine.

Combination of mirtazapine and paroxetine: possible clinically demonstrated interaction?

We currently have a wide range of antidepressants available. However, the mechanisms of action are different, giving a theoretical justification for their combination in the failure of monotherapy. However, the combination of drugs entails, in addition to benefits, an increase in the risk of, for example, drug interactions. Many drug interactions in psychiatry are due to the pharmacokinetic interactions between drugs, where their plasma concentrations are altered by inhibiting or inducing cytochrome P450 isoenzymes, especially CYP2D6 and CYP3A4 and P-glycoprotein. When treating depression, we should consider the risks and benefits of combination therapy in individual patients and take measures to minimize the side effects of medicines. The case report describes a case of a patient who reported significant depression after adding paroxetine and mirtazapine to psychiatric medication. As a theoretical cause, it discusses the possible clinically demonstrated interaction between paroxetine and mirtazapine, which has been clinically manifested by fatigue and pronounced daytime sleepiness.

The role of mirtazapine in patients with fibromyalgia: a systematic review.

Mirtazapine is commonly used to treat major depressive disorder. Due to its effects on multiple neurotransmitters, it has been investigated for possible benefits in patients with fibromyalgia. The objective of this systematic review is to assess the efficacy and safety of mirtazapine in the treatment of patients with fibromyalgia. Pubmed (1946-May 2018), Embase (1947-May 2018), CENTRAL, and ClinicalTrials.gov were queried using the search term combination: fibromyalgia, pain, chronic pain, neuralgia, neuropathic pain, chronic widespread pain, or chronic pain syndrome and mirtazapine. Studies appropriate to the objective were evaluated, including three randomized, placebo-controlled trials and one open-label trial, investigating the effect of mirtazapine in patients with fibromyalgia. In patients with fibromyalgia, treatment with mirtazapine resulted in improvements in pain, sleep, and quality of life. Study durations ranged from 6 to 13 weeks and studies used varying dosing strategies for mirtazapine. Minor occurrences of somnolence, weight gain, nasopharyngitis, dry mouth, and increased appetite were reported with mirtazapine use. Based on the reviewed literature, mirtazapine appears to be a promising therapy to improve pain, sleep, and quality of life in patients with fibromyalgia. These benefits were demonstrated in patients that were treatment naïve and those that had failed previous therapies. Additional clinical evidence through larger and longer length trials would be of benefit to further define the role of mirtazapine for patients with fibromyalgia.

The risk of antidepressant-induced hyponatremia: A meta-analysis of antidepressant classes and compounds.

BACKGROUND: Hyponatremia (hypoNa) is a potentially serious adverse event of antidepressant treatment. Previous research suggests the risk of drug-induced hyponatremia differs between antidepressants. This meta-analysis sought to determine the risk of antidepressant-induced hypoNa, stratified by different compounds and classes. METHODS: A PRISMA-compliant systematic search of Web of Science and PubMed databases was performed from inception until Jan 5, 2023, for original studies reporting incidences or risks of hypoNa in adults using antidepressants. We modelled random-effects meta-analyses to compute overall event rates and odds ratios of any and clinically relevant hypoNa for each compound and class, and ran head-to-head comparisons based on hypoNa event rates. We conducted subgroup analyses for geriatric populations and sodium cut-off value. The study is registered with PROSPERO, CRD42021269801. RESULTS: We included 39 studies (n = 8,175,111). Exposure to antidepressants was associated with significantly increased odds of hypoNa (k = 7 studies, OR = 3.160 (95%CI 1.911-5.225)). The highest event rates were found for SNRIs (7.44%), SSRIs (5.59%), and TCAs (2.66%); the lowest for mirtazapine (1.02%) and trazodone (0.89%). Compared to SSRIs, SNRIs were significantly more likely (k = 10, OR = 1.292 (1.120 - 1.491), p < 0.001) and mirtazapine significantly less likely (k = 9, OR = 0.607 (0.385 - 0.957), p = 0.032) to be associated with hypoNa. CONCLUSION: Our meta-analysis demonstrated that, while no antidepressant can be considered completely risk-free, for hypoNa-prone patients mirtazapine should be considered the treatment of choice and SNRIs should be prescribed more cautiously than SSRIs and TCAs.