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.

Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Imagery rehearsal therapy and/or mianserin in treatment of refugees diagnosed with PTSD: Results from a randomized controlled trial.

Sleep disturbances are frequently part of the symptomatology in refugees with post-traumatic stress disorder (PTSD). It has been suggested that targeting sleep disturbances may enhance the outcome of PTSD treatment. However, randomized studies on the effect of treatment focusing on sleep disturbances in refugees with PTSD are lacking. The aim of this study was to examine add-on treatment with imagery rehearsal therapy (IRT) and/or mianserin against treatment as usual (TAU) alone in a sample of trauma-affected refugees with PTSD at 8-12 months follow-up. In a randomized controlled trial, 219 adult refugees diagnosed with PTSD and suffering from sleep disturbances were randomized to four groups (1:1:1:1) receiving, respectively, TAU, TAU + mianserin, TAU + IRT, and TAU + IRT + mianserin. The primary outcome was subjective sleep quality (Pittsburgh Sleep Quality Index) and the secondary outcomes included PTSD and depression symptoms, level of functioning and subjective well-being. The data were analysed using mixed models. The only significant effect of IRT was on level of functioning (p = .040, ES 0.44), whereas there was no significant effect of mianserin on any of the measured outcomes. Low adherence to both IRT (39%) and mianserin (20%) was observed. Contrary to our hypothesis, we did not find IRT or mianserin to be superior to TAU. The low adherence may potentially cause an underestimation of the effect of IRT and mianserin and indicates a necessity to further analyse the complex factors that may impact the motivation and ability of trauma-affected refugees to participate in and profit from available treatment options.

Pharmacological interventions for treatment-resistant depression in adults.

BACKGROUND: Although antidepressants are often a first-line treatment for adults with moderate to severe depression, many people do not respond adequately to medication, and are said to have treatment-resistant depression (TRD). Little evidence exists to inform the most appropriate 'next step' treatment for these people. OBJECTIVES: To assess the effectiveness of standard pharmacological treatments for adults with TRD. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (March 2016), CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science (31 December 2018), the World Health Organization trials portal and ClinicalTrials.gov for unpublished and ongoing studies, and screened bibliographies of included studies and relevant systematic reviews without date or language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) with participants aged 18 to 74 years with unipolar depression (based on criteria from DSM-IV-TR or earlier versions, International Classification of Diseases (ICD)-10, Feighner criteria or Research Diagnostic Criteria) who had not responded to a minimum of four weeks of antidepressant treatment at a recommended dose. Interventions were: (1) increasing the dose of antidepressant monotherapy; (2) switching to a different antidepressant monotherapy; (3) augmenting treatment with another antidepressant; (4) augmenting treatment with a non-antidepressant. All were compared with continuing antidepressant monotherapy. We excluded studies of non-standard pharmacological treatments (e.g. sex hormones, vitamins, herbal medicines and food supplements). DATA COLLECTION AND ANALYSIS: Two reviewers used standard Cochrane methods to extract data, assess risk of bias, and resolve disagreements. We analysed continuous outcomes with mean difference (MD) or standardised mean difference (SMD) and 95% confidence interval (CI). For dichotomous outcomes, we calculated a relative risk (RR) and 95% CI. Where sufficient data existed, we conducted meta-analyses using random-effects models. MAIN RESULTS: We included 10 RCTs (2731 participants). Nine were conducted in outpatient settings and one in both in- and outpatients. Mean age of participants ranged from 42 - 50.2 years, and most were female. One study investigated switching to, or augmenting current antidepressant treatment with, another antidepressant (mianserin). Another augmented current antidepressant treatment with the antidepressant mirtazapine. Eight studies augmented current antidepressant treatment with a non-antidepressant (either an anxiolytic (buspirone) or an antipsychotic (cariprazine; olanzapine; quetiapine (3 studies); or ziprasidone (2 studies)). We judged most studies to be at a low or unclear risk of bias. Only one of the included studies was not industry-sponsored. There was no evidence of a difference in depression severity when current treatment was switched to mianserin (MD on Hamilton Rating Scale for Depression (HAM-D) = -1.8, 95% CI -5.22 to 1.62, low-quality evidence)) compared with continuing on antidepressant monotherapy. Nor was there evidence of a difference in numbers dropping out of treatment (RR 2.08, 95% CI 0.94 to 4.59, low-quality evidence; dropouts 38% in the mianserin switch group; 18% in the control). Augmenting current antidepressant treatment with mianserin was associated with an improvement in depression symptoms severity scores from baseline (MD on HAM-D -4.8, 95% CI -8.18 to -1.42; moderate-quality evidence). There was no evidence of a difference in numbers dropping out (RR 1.02, 95% CI 0.38 to 2.72; low-quality evidence; 19% dropouts in the mianserin-augmented group; 38% in the control). When current antidepressant treatment was augmented with mirtazapine, there was little difference in depressive symptoms (MD on Beck Depression Inventory (BDI-II) -1.7, 95% CI -4.03 to 0.63; high-quality evidence) and no evidence of a difference in dropout numbers (RR 0.50, 95% CI 0.15 to 1.62; dropouts 2% in mirtazapine-augmented group; 3% in the control). Augmentation with buspirone provided no evidence of a benefit in terms of a reduction in depressive symptoms (MD on Montgomery and Asberg Depression Rating Scale (MADRS) -0.30, 95% CI -9.48 to 8.88; low-quality evidence) or numbers of drop-outs (RR 0.60, 95% CI 0.23 to 1.53; low-quality evidence; dropouts 11% in buspirone-augmented group; 19% in the control). Severity of depressive symptoms reduced when current treatment was augmented with cariprazine (MD on MADRS -1.50, 95% CI -2.74 to -0.25; high-quality evidence), olanzapine (MD on HAM-D -7.9, 95% CI -16.76 to 0.96; low-quality evidence; MD on MADRS -12.4, 95% CI -22.44 to -2.36; low-quality evidence), quetiapine (SMD -0.32, 95% CI -0.46 to -0.18; I2 = 6%, high-quality evidence), or ziprasidone (MD on HAM-D -2.73, 95% CI -4.53 to -0.93; I2 = 0, moderate-quality evidence) compared with continuing on antidepressant monotherapy. However, a greater number of participants dropped out when antidepressant monotherapy was augmented with an antipsychotic (cariprazine RR 1.68, 95% CI 1.16 to 2.41; quetiapine RR 1.57, 95% CI: 1.14 to 2.17; ziprasidone RR 1.60, 95% CI 1.01 to 2.55) compared with antidepressant monotherapy, although estimates for olanzapine augmentation were imprecise (RR 0.33, 95% CI 0.04 to 2.69). Dropout rates ranged from 10% to 39% in the groups augmented with an antipsychotic, and from 12% to 23% in the comparison groups. The most common reasons for dropping out were side effects or adverse events. We also summarised data about response and remission rates (based on changes in depressive symptoms) for included studies, along with data on social adjustment and social functioning, quality of life, economic outcomes and adverse events. AUTHORS' CONCLUSIONS: A small body of evidence shows that augmenting current antidepressant therapy with mianserin or with an antipsychotic (cariprazine, olanzapine, quetiapine or ziprasidone) improves depressive symptoms over the short-term (8 to 12 weeks). However, this evidence is mostly of low or moderate quality due to imprecision of the estimates of effects. Improvements with antipsychotics need to be balanced against the increased likelihood of dropping out of treatment or experiencing an adverse event. Augmentation of current antidepressant therapy with a second antidepressant, mirtazapine, does not produce a clinically important benefit in reduction of depressive symptoms (high-quality evidence). The evidence regarding the effects of augmenting current antidepressant therapy with buspirone or switching current antidepressant treatment to mianserin is currently insufficient. Further trials are needed to increase the certainty of these findings and to examine long-term effects of treatment, as well as the effectiveness of other pharmacological treatment strategies.

Mirtazapine for fibromyalgia in adults.

BACKGROUND: Fibromyalgia is a clinically defined chronic condition of unknown etiology characterised by chronic widespread pain, sleep disturbance, cognitive dysfunction, and fatigue. Many patients report high disability levels and poor quality of life. Drug therapy aims to reduce key symptoms, especially pain, and improve quality of life. The tetracyclic antidepressant, mirtazapine, may help by increasing serotonin and noradrenaline in the central nervous system (CNS). OBJECTIVES: To assess the efficacy, tolerability and safety of the tetracyclic antidepressant, mirtazapine, compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, SCOPUS, the US National Institutes of Health, and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials, and examined reference lists of reviewed articles, to 9 July 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any formulation of mirtazapine against placebo, or any other active treatment of fibromyalgia, in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study characteristics, outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias, resolving discrepancies by discussion. Primary outcomes were participant-reported pain relief (at least 50% or 30% pain reduction), Patient Global Impression of Change (PGIC; much or very much improved), safety (serious adverse events), and tolerability (adverse event withdrawal). Other outcomes were health-related quality of life (HRQoL) improved by 20% or more, fatigue, sleep problems, mean pain intensity, negative mood and particular adverse events. We used a random-effects model to calculate risk difference (RD), standardised mean difference (SMD), and numbers needed to treat. We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Three studies with 606 participants compared mirtazapine with placebo (but not other drugs) over seven to 13 weeks. Two studies were at unclear or high risk of bias in six or seven of eight domains. We judged the evidence for all outcomes to be low- or very low-quality because of poor study quality, indirectness, imprecision, risk of publication bias, and sometimes low numbers of events.There was no difference between mirtazapine and placebo for any primary outcome: participant-reported pain relief of 50% or greater (22% versus 16%; RD 0.05, 95% confidence interval (CI) -0.01 to 0.12; three studies with 591 participants; low-quality evidence); no data available for PGIC; only a single serious adverse event for evaluation of safety (RD -0.00, 95% CI -0.01 to 0.02; three studies with 606 participants; very low-quality evidence); and tolerability as frequency of dropouts due to adverse events (3% versus 2%; RD 0.00, 95% CI -0.02 to 0.03; three studies with 606 participants; low-quality evidence).Mirtazapine showed a clinically-relevant benefit compared to placebo for some secondary outcomes: participant-reported pain relief of 30% or greater (47% versus 34%; RD 0.13, 95% CI 0.05 to 0.21; number needed to treat for an additional beneficial outcome (NNTB) 8, 95% CI 5 to 20; three studies with 591 participants; low-quality evidence); participant-reported mean pain intensity (SMD -0.29, 95% CI -0.46 to -0.13; three studies with 591 participants; low-quality evidence); and participant-reported sleep problems (SMD -0.23, 95% CI -0.39 to -0.06; three studies with 573 participants; low-quality evidence). There was no benefit for improvement of participant-reported improvement of HRQoL of 20% or greater (58% versus 50%; RD 0.08, 95% CI -0.01 to 0.16; three studies with 586 participants; low-quality evidence); participant-reported fatigue (SMD -0.02, 95% CI -0.19 to 0.16; two studies with 533 participants; low-quality evidence); participant-reported negative mood (SMD -0.67, 95% CI -1.44 to 0.10; three studies with 588 participants; low-quality evidence); or withdrawals due to lack of efficacy (1.5% versus 0.1%; RD 0.01, 95% CI -0.01 to 0.02; three studies with 605 participants; very low-quality evidence).There was no difference between mirtazapine and placebo for participants reporting any adverse event (76% versus 59%; RD 0.12, 95 CI -0.01 to 0.26; three studies with 606 participants; low-quality evidence). There was a clinically-relevant harm with mirtazapine compared to placebo: in the number of participants with somnolence (42% versus 14%; RD 0.24, 95% CI 0.18 to 0.30; number needed to treat for an additional harmful outcome (NNTH) 5, 95% CI 3 to 6; three studies with 606 participants; low-quality evidence); weight gain (19% versus 1%; RD 0.17, 95% CI 0.11 to 0.23; NNTH 6, 95% CI 5 to 10; three studies with 606 participants; low-quality evidence); and elevated alanine aminotransferase (13% versus 2%; RD 0.13, 95% CI 0.04 to 0.22; NNTH 8, 95% CI 5 to 25; two studies with 566 participants; low-quality evidence). AUTHORS' CONCLUSIONS: Studies demonstrated no benefit of mirtazapine over placebo for pain relief of 50% or greater, PGIC, improvement of HRQoL of 20% or greater, or reduction of fatigue or negative mood. Clinically-relevant benefits were shown for pain relief of 30% or greater, reduction of mean pain intensity, and sleep problems. Somnolence, weight gain, and elevated alanine aminotransferase were more frequent with mirtazapine than placebo. The quality of evidence was low or very low, with two of three studies of questionable quality and issues over indirectness and risk of publication bias. On balance, any potential benefits of mirtazapine in fibromyalgia were outweighed by its potential harms, though, a small minority of people with fibromyalgia might experience substantial symptom relief without clinically-relevant adverse events.

Mirtazapine adjunct for people with schizophrenia.

BACKGROUND: Many individuals who have a diagnosis of schizophrenia experience a range of distressing and debilitating symptoms. These can include positive symptoms (such as delusions, hallucinations, disorganised speech), cognitive symptoms (such as trouble focusing or paying attention or using information to make decisions), and negative symptoms (such as diminished emotional expression, avolition, alogia, and anhedonia). Antipsychotic drugs are often only partially effective, particularly in treating negative symptoms, indicating the need for additional treatment. Mirtazapine is an antidepressant drug that when taken in addition to an antipsychotic may offer some benefit for negative symptoms. OBJECTIVES: To systematically assess the effects of mirtazapine as adjunct treatment for people with schizophrenia. SEARCH METHODS: The Information Specialist of Cochrane Schizophrenia searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including registries of clinical trials) up to May 2018. SELECTION CRITERIA: All randomised-controlled trials (RCTs) with useable data focusing on mirtazapine adjunct for people with schizophrenia. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat (ITT) basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. For included studies we assessed risk of bias and created 'Summary of findings' table using GRADE. MAIN RESULTS: We included nine RCTs with a total of 310 participants. All studies compared mirtazapine adjunct with placebo adjunct and were of short-term duration. We considered five studies to have a high risk of bias for either incomplete outcome data, selective reporting, or other bias.Our main outcomes of interest were clinically important change in mental state (negative and positive symptoms), leaving the study early for any reason, clinically important change in global state, clinically important change in quality of life, number of days in hospital and incidence of serious adverse events.One trial defined a reduction in the Scale for the Assessment of Negative Symptoms (SANS) overall score from baseline of at least 20% as no important response for negative symptoms. There was no evidence of a clear difference between the two treatments with similar numbers of participants from each group showing no important response to treatment (RR 0.81, 95% CI 0.57 to 1.14, 1 RCT, n = 20, very low-quality evidence).Clinically important change in positive symptoms was not reported, however, clinically important change in overall mental state was reported by two trials and data for this outcome showed a favourable effect for mirtazapine (RR 0.69, 95% CI 0.51 to 0.92; I2 = 75%, 2 RCTs, n = 77, very low-quality evidence). There was no evidence of a clear difference for numbers of participants leaving the study early (RR 1.03, 95% CI 0.64 to 1.66, 9 RCTs, n = 310, moderate-quality evidence), and no evidence of a clear difference in global state Clinical Global Impressions Scale (CGI) severity scores (MD -0.10, 95% CI -0.68 to 0.48, 1 RCT, n = 39, very low-quality evidence). A favourable effect for mirtazapine adjunct was found for the outcome clinically important change in akathisia (RR 0.33, 95% CI 0.20 to 0.52, 2 RCTs, n = 86, low-quality evidence; I2 = 61%I). No data were reported for quality life or number of days in hospital.In addition to the main outcomes of interest, there was evidence relating to adverse events that the mirtazapine adjunct groups were associated with an increased risk of weight gain (RR 3.19, 95% CI 1.17 to 8.65, 4 RCTs, n = 127) and sedation/drowsiness (RR 1.64, 95% CI 1.01 to 2.68, 7 RCTs, n = 223). AUTHORS' CONCLUSIONS: The available evidence is primarily of very low quality and indicates that mirtazapine adjunct is not clearly associated with an effect for negative symptoms, but there is some indication of a positive effect on overall mental state and akathisia. No effect was found for global state or leaving the study early and data were not available for quality of life or service use. Due to limitations of the quality and applicability of the evidence it is not possible to make any firm conclusions, the role of mirtazapine adjunct in routine clinical practice remains unclear. This underscores the need for new high-quality evidence to further evaluate mirtazapine adjunct for schizophrenia.

Antidepressants for insomnia in adults.

BACKGROUND: Insomnia disorder is a subjective condition of unsatisfactory sleep (e.g. sleep onset, maintenance, early waking, impairment of daytime functioning). Insomnia disorder impairs quality of life and is associated with an increased risk of physical and mental health problems including anxiety, depression, drug and alcohol abuse, and increased health service use. hypnotic medications (e.g. benzodiazepines and 'Z' drugs) are licensed for sleep promotion, but can induce tolerance and dependence, although many people remain on long-term treatment. Antidepressant use for insomnia is widespread, but none is licensed for insomnia and the evidence for their efficacy is unclear. This use of unlicensed medications may be driven by concern over longer-term use of hypnotics and the limited availability of psychological treatments. OBJECTIVES: To assess the effectiveness, safety and tolerability of antidepressants for insomnia in adults. SEARCH METHODS: This review incorporated the results of searches to July 2015 conducted on electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 6), MEDLINE (1950 to 2015), Embase (1980 to 2015) and PsycINFO (1806 to 2015). We updated the searches to December 2017, but these results have not yet been incorporated into the review. SELECTION CRITERIA: Randomised controlled trials (RCTs) of adults (aged 18 years or older) with a primary diagnosis of insomnia and all participant types including people with comorbidities. Any antidepressant as monotherapy at any dose whether compared with placebo, other medications for insomnia (e.g. benzodiazepines and 'Z' drugs), a different antidepressant, waiting list control or treatment as usual. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and extracted data using a data extraction form. A third review author resolved disagreements on inclusion or data extraction. MAIN RESULTS: The search identified 23 RCTs (2806 participants).Selective serotonin reuptake inhibitors (SSRIs) compared with placebo: three studies (135 participants) compared SSRIs with placebo. Combining results was not possible. Two paroxetine studies showed significant improvements in subjective sleep measures at six (60 participants, P = 0.03) and 12 weeks (27 participants, P < 0.001). There was no difference in the fluoxetine study (low quality evidence).There were either no adverse events or they were not reported (very low quality evidence).Tricyclic antidepressants (TCA) compared with placebo: six studies (812 participants) compared TCA with placebo; five used doxepin and one used trimipramine. We found no studies of amitriptyline. Four studies (518 participants) could be pooled, showing a moderate improvement in subjective sleep quality over placebo (standardised mean difference (SMD) -0.39, 95% confidence interval (CI) -0.56 to -0.21) (moderate quality evidence). Moderate quality evidence suggested that TCAs possibly improved sleep efficiency (mean difference (MD) 6.29 percentage points, 95% CI 3.17 to 9.41; 4 studies; 510 participants) and increased sleep time (MD 22.88 minutes, 95% CI 13.17 to 32.59; 4 studies; 510 participants). There may have been little or no impact on sleep latency (MD -4.27 minutes, 95% CI -9.01 to 0.48; 4 studies; 510 participants).There may have been little or no difference in adverse events between TCAs and placebo (risk ratio (RR) 1.02, 95% CI 0.86 to 1.21; 6 studies; 812 participants) (low quality evidence).'Other' antidepressants with placebo: eight studies compared other antidepressants with placebo (one used mianserin and seven used trazodone). Three studies (370 participants) of trazodone could be pooled, indicating a moderate improvement in subjective sleep outcomes over placebo (SMD -0.34, 95% CI -0.66 to -0.02). Two studies of trazodone measured polysomnography and found little or no difference in sleep efficiency (MD 1.38 percentage points, 95% CI -2.87 to 5.63; 169 participants) (low quality evidence).There was low quality evidence from two studies of more adverse effects with trazodone than placebo (i.e. morning grogginess, increased dry mouth and thirst). AUTHORS' CONCLUSIONS: We identified relatively few, mostly small studies with short-term follow-up and design limitations. The effects of SSRIs compared with placebo are uncertain with too few studies to draw clear conclusions. There may be a small improvement in sleep quality with short-term use of low-dose doxepin and trazodone compared with placebo. The tolerability and safety of antidepressants for insomnia is uncertain due to limited reporting of adverse events. There was no evidence for amitriptyline (despite common use in clinical practice) or for long-term antidepressant use for insomnia. High-quality trials of antidepressants for insomnia are needed.

JC virus granule cell neuronopathy in the setting of chronic lymphopenia treated with recombinant interleukin-7.

JC virus (JCV) is a human polyomavirus that infects the central nervous system (CNS) of immunocompromised patients. JCV granule cell neuronopathy (JCV-GCN) is caused by infection of cerebellar granule cells, causing ataxia. A 77-year-old man with iatrogenic lymphopenia presented with severe ataxia and was diagnosed with JCV-GCN. His ataxia and cerebrospinal fluid (CSF) improved with intravenous immunoglobulin, high-dose intravenous methylprednisolone, mirtazapine, and mefloquine. Interleukin-7 (IL-7) therapy reconstituted his lymphocytes and reduced his CSF JCV load. One month after IL-7 therapy, he developed worsening ataxia and CSF inflammation, which raised suspicion for immune reconstitution inflammatory syndrome. Steroids were restarted and his ataxia stabilized.

Interleukin 17 selectively predicts better outcomes with bupropion-SSRI combination: Novel T cell biomarker for antidepressant medication selection.

BACKGROUND: Interleukin 17 (IL-17) is produced by highly inflammatory Th17 cells and has been implicated in pathophysiology of depression. IL-17 putatively disrupts the blood brain barrier and affects dopamine synthesis whereas dopamine has been shown to decrease Th17 cell-mediated immune response. Nevertheless, whether IL-17 can predict differential treatment outcome with antidepressants modulating dopaminergic transmission is unknown. METHODS: IL-17 and other T cell and non-T cell markers (Th1, Th2 and non-T cell markers) were measured with the Bioplex Pro™ human cytokine 27-plex kit in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants who provided baseline plasma and were treated with either bupropion plus escitalopram (bupropion-SSRI), escitalopram plus placebo (SSRI monotherapy), or venlafaxine plus mirtazapine (n=166). Differential changes in symptom severity and side-effects based on levels of IL-17 and other T and non-T cell markers were tested using a treatment-arm-by-biomarker interaction in separate repeated measures mixed model analyses. Subsequent analyses stratified by treatment arm were conducted for those markers with a significant interaction. RESULTS: There was a significant treatment-arm-by-IL-17 interaction for depression severity (p=0.037) but not for side-effects (p=0.28). Higher baseline IL-17 level was associated with greater reduction in depression severity (effect size=0.78, p=0.008) in the bupropion-SSRI but not the other two treatment arms. Other T and non-T cell markers were not associated with differential treatment outcomes. CONCLUSION: Higher baseline levels of IL-17 are selectively associated with greater symptomatic reduction in depressed patients treated with bupropion-SSRI combination.

Treatment options for hyperemesis gravidarum.

Hyperemesis gravidarum (HG) is a severe and prolonged form of nausea and/or vomiting during pregnancy. HG affects 0.3-2% of pregnancies and is defined by dehydration, ketonuria, and more than 5% body weight loss. Initial pharmacologic treatment for HG includes a combination of doxylamine and pyridoxine. Additional interventions include ondansetron or dopamine antagonists such as metoclopramide or promethazine. The options are limited for women who are not adequately treated with these medications. We suggest that mirtazapine is a useful drug in this context and its efficacy has been described in case studies. Mirtazapine acts on noradrenergic, serotonergic, histaminergic, and muscarinic receptors to produce antidepressant, anxiolytic, antiemetic, sedative, and appetite-stimulating effects. Mirtazapine is not associated with an independent increased risk of birth defects. Further investigation of mirtazapine as a treatment for HG holds promise to expand treatment options for women suffering from HG.

New antidepressant use in older adults: a Canadian population-based study (1997-2013).

OBJECTIVE: There has been much attention on appropriate prescribing in older adults in recent years. Recent guidelines favor the use of newer antidepressants over older agents based on their safety profile in this population. This study aimed to examine whether there has been a decline in older antidepressants and an increase in newer antidepressants used by older adults. METHOD: A retrospective cross-sectional study using administrative databases examined the annual incidence of antidepressant use (per 1000) of community-dwelling adults ≥60 years old between 1997/1998 and 2012/2013 in Manitoba, Canada. RESULTS: The population of Manitoba ≥60 years increased by 25.6% from 188,296 to 236,569 from 1997/1998 to 2012/2013. New antidepressant use peaked to 45.9 per 1000 in 1999/2000, and then decreased steadily to 30.5 per 1000 in 2012/2013 (p < 0.0001). Incident amitriptyline use was high but declined from 15.5 to 7.4 per 1000 (p < 0.001). An increase in incident trazodone, mirtazapine, and venlafaxine use was observed (p < 0.001). CONCLUSIONS: There has been an overall decrease in the annual incidence of antidepressant users in older adults over the last 16 years, with a marked decline in new amitriptyline use and an increase in the incidence of newer agents.

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.

Navigating Undiagnosed Dissociative Identity Disorder in the Inpatient Setting: A Case Report.

BACKGROUND: This case illustrates previously undiagnosed dissociative identity disorder (DID) in a middle-aged female with extensive childhood trauma, who was high functioning prior to a trigger that caused a reemergence of her symptoms. The trigger sparked a dissociative state, attempted suicide, and subsequent inpatient psychiatric hospitalization. OBJECTIVE: Practitioners should include in their differential and screen for undiagnosed DID in patients with episodic psychiatric hospitalizations refractory to the standard treatments for previously diagnosed mental illnesses. DESIGN: Case study. RESULTS: During hospitalization, the diagnosis of DID became apparent and treatment included low-dose risperidone, mirtazapine, sertraline, unconditional positive regard, normalization of her dissociative states in an attempt to decrease her anxiety during treatment, and documentation for the patient via written notes following interviews. CONCLUSION: These methods helped her come to terms with the diagnosis and allowed the treatment team to teach her coping skills to lessen the impact of dissociative states following discharge.

Mirtazapine for Symptomatic Relief on a Psychiatric Consultation Service: A Case Series.

BACKGROUND: With a complex pharmacologic profile, mirtazapine may promote sleep, stimulate appetite, improve nausea, and reduce pain. Some practitioners working on the Mayo Clinic inpatient psychiatric consultation/liaison service have recommended mirtazapine in medically ill patients with or without formal psychiatric comorbidity to target these symptoms. OBJECTIVE: To assess the success of this practice, we conducted a retrospective chart review covering a 4.5-year period. METHODS: For patients recommended to start mirtazapine, global improvement in specific symptoms and suspected side effects were recorded. RESULTS: During the study period, 528 medically ill patients started mirtazapine following a recommendation from the psychiatric consultation service. In total, 475 patients were provided mirtazapine to specifically target sleep, nausea, pain, or appetite. There was documented improvement in these symptoms for 37.7%, 37.0%, 36.4%, and 23.5% of the patients, respectively. These rates of improvement are conservative for the 229 patients without documented response, i.e., 48% of the patients who were given the medication for a somatic symptom were counted as having no improvement. Commonly documented adverse effects were daytime sedation (5.3%), worsening mental status (2.3%), and nightmares (1%). CONCLUSIONS: Despite the limitations of this retrospective, qualitative study, these data confirm that mirtazapine is generally well tolerated and can provide at least short-term relief of certain symptoms in medically ill patients. Controlled trials are needed to assess these benefits more systematically, and it is not clear how long mirtazapine should be used for these symptoms.

Effect of Mirtazapine Treatment on Serum Levels of Brain-Derived Neurotrophic Factor and Tumor Necrosis Factor-α in Patients of Major Depressive Disorder with Severe Depression.

BACKGROUND: This study evaluated the clinical efficacy of mirtazapine and its effect on serum brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-α (TNF-α) levels in patients of major-depressive disorder (MDD) with severe depression. METHODS: Patients (aged 18-60) with MDD diagnosed by DSM-IV criteria, and Hamilton Rating Scale for Depression (HAM-D) score ≥25 were included (n = 30). Mirtazapine was given in the doses of 30 mg/day. All patients were followed up for 12 weeks for the evaluation of clinical efficacy, safety along with serum BDNF and TNF-α levels. RESULTS: HAM-D score at the start of treatment was 30.1 ± 1.92, which significantly (p < 0.05) reduced to 13.47 ± 1.77 at 12 weeks of treatment. In responders, mean serum BDNF levels at the start of treatment were 2.32 ± 0.3 ng/ml, which significantly (p < 0.05) increased to 2.79 ± 0.33 ng/ml at 12 weeks of treatment and mean serum TNF-α levels at the start were 5.18 ± 0.67 pg/ml, which significantly decreased to 4.36 ± 0.72 pg/ml (p < 0.05) at 12 weeks of treatment. CONCLUSION: Our results suggest that mirtazapine is effective and well tolerated in severely depressed patients and treatment response is associated with an increase in serum BDNF and a decrease in serum TNF-α levels.

Treatment Options for Central Sleep Apnea: Comparison of Ventilator, Oxygen, and Drug Therapies.

Central sleep apnea (CSA) is a sleep-related disorder characterized by pauses in breathing during sleep when the brain respiratory network momentarily interrupts transmission of impulses to the respiratory musculature. CSA presents significant problems being an independent risk factor for cardiovascular events and death. There are several available treatment options according to CSA severity. Currently, adaptive servo-ventilation is considered best for CSA patients. The goal of the present study was to retrospectively investigate different treatment methods employed for CSA, such as different modes of ventilation, oxygen therapy, and drugs to determine the most effective one. Data were obtained from hospital records during 2010-2015. The diagnosis of CSA and the optimal treatment method were supported by polysomnography examinations. Devices used during sleep to support breathing included continuous positive airway pressure, bi-level positive airway pressure, or adaptive servo-ventilation. We classified 71 (2.9 %) patients as having CSA from 2,463 patients with sleep-disordered breathing. Of those 71 patients, 54 (76.1 %, 95 % CI 66.2-86.0 %) were male and 17 (23.9 %, 95 % CI 14.0-33.8 %) were female, and they had a mean age of 67.1 ± 14.1. Four (5.6 %) patients underwent a combination therapy, 39 (54.9 %) received a ventilator in proper ventilation mode, 25 (35.2 %) received oxygen therapy, 7 (9.9 %) received medication, and 4 (5.6 %) received no treatment. We conclude that although the majority of patients needed treatment for central sleep apnea, a clear advantage in using ventilators when compared to oxygen therapy or drug therapy could not be found.

Progressive multifocal leukoencephalopathy in common variable immunodeficiency: mitigated course under mirtazapine and mefloquine.

Demonstration of survival and outcome of progressive multifocal leukoencephalopathy (PML) in a 56-year-old patient with common variable immunodeficiency, consisting of severe hypogammaglobulinemia and CD4+ T lymphocytopenia, during continuous treatment with mirtazapine (30 mg/day) and mefloquine (250 mg/week) over 23 months. Regular clinical examinations including Rankin scale and Barthel index, nine-hole peg and box and block tests, Berg balance, 10-m walking tests, and Montreal Cognitive Assessment (MoCA) were done. Laboratory diagnostics included complete blood count and JC virus (JCV) concentration in cerebrospinal fluid (CSF). The noncoding control region (NCCR) of JCV, important for neurotropism and neurovirulence, was sequenced. Repetitive MRI investigated the course of brain lesions. JCV was detected in increasing concentrations (peak 2568 copies/ml CSF), and its NCCR was genetically rearranged. Under treatment, the rearrangement changed toward the archetype sequence, and later JCV DNA became undetectable. Total brain lesion volume decreased (8.54 to 3.97 cm(3)) and atrophy increased. Barthel (60 to 100 to 80 points) and Rankin (4 to 2 to 3) scores, gait stability, and box and block (7, 35, 25 pieces) and nine-hole peg (300, 50, 300 s) test performances first improved but subsequently worsened. Cognition and walking speed remained stable. Despite initial rapid deterioration, the patient survived under continuous treatment with mirtazapine and mefloquine even though he belongs to a PML subgroup that is usually fatal within a few months. This course was paralleled by JCV clones with presumably lower replication capability before JCV became undetectable. Neurological deficits were due to PML lesions and progressive brain atrophy.

The effects of mirtazapine versus placebo on alcohol consumption in male high consumers of alcohol: a randomized, controlled trial.

BACKGROUND: The number of therapeutic drugs available for the treatment of alcohol use disorders (AUDs) is limited, and a well-tolerated, self-administrable drug is much needed. Subgroups of alcohol-dependent individuals, for example, individuals with heredity for AUD, may respond differently to pharmacological treatments, particularly to drugs affecting the serotonergic system in the brain. RATIONALE: Clinical observations and case reports indicate that mirtazapine, a widely used and well-tolerated antidepressant drug, which increases both noradrenaline and serotonin release but simultaneously blocks serotonergic (5-hydroxytryptamine)3 receptors, reduces alcohol consumption. Moreover, drugs affecting serotonergic (5-hydroxytryptamine)3 receptors have been shown to work differently in individuals with heredity for AUD. METHODS: This double-blind, randomized, placebo-controlled, 2-armed clinical trial aimed to establish whether mirtazapine lowers alcohol consumption in male high consumers. The study population was also subgrouped in accordance with heredity for AUD. After 2 lead-in weeks of single-blind placebo, 59 males were randomly assigned to receive 8 weeks of treatment with 30-mg mirtazapine daily (n = 29) or placebo (n = 30). The main outcome was self-reported alcohol consumption (drinks per day) measured by an alcohol diary. The alcohol consumption was calculated as weekly mean during the study period compared with baseline. The data were analyzed in accordance with intention to treat and per protocol. RESULTS: The results suggest that high consumers of alcohol with a heredity for AUD benefit from treatment with mirtazapine. CONCLUSIONS: The results of this study did not support an advantage of mirtazapine over placebo on alcohol consumption in the intention-to-treat analysis. However, mirtazapine could be an alternative to available treatments for alcohol dependence in patients with heredity for AUD.

Mirtazapine in pregnancy and lactation: data from a case series.

Depression is a common disorder in pregnancy and associated with adverse effects for both mother and neonate. Pharmacological treatment and prevention options include mirtazapine. In a series of 56 cases, we investigated neonatal outcome after intrauterine exposure to mirtazapine and exposure through lactation in the first days postpartum.No increase in any neonatal complication was observed. None of the infants exposed to mirtazapine in the first trimester were born with a major malformation. Of the 54 infants exposed to mirtazapine in the third trimester, 14 were diagnosed with poor neonatal adaptation syndrome (PNAS). This incidence (25.9%) is similar to the incidence of PNAS after intrauterine exposure to other antidepressants. The incidence of PNAS after exposure to mirtazapine was significantly diminished in children who were partially or fully breastfed (18.6% versus 54.5%, P = 0.024).