Therapeutic Effects, Side Effects, and Adverse Effects of Neuropsychiatric Drugs in the Context of Treating Cancer-Related Anorexia With Olanzapine and Mirtazapine.

Drugs have actions that may be classified as therapeutic effects and side effects; side effects are actions that do not contribute to therapeutic benefit. Some side effects are neutral; others, experienced as undesirable or unpleasant, are recorded as adverse effects. Some drug actions are therapeutic for some disorders and adverse for others; or therapeutic during acute illness and adverse during maintenance treatment. As an example, anticholinergic action may be adverse when a tricyclic antidepressant is used to treat depression but therapeutic when the drug is used to treat irritable bowel syndrome with diarrhea. In clinical practice, side or adverse effects of a drug may be leveraged to manage troublesome symptoms. As an example, the sedative effect of a low dose of trazodone may be useful for some patients with insomnia. With this background, studies have examined whether the increase in appetite and weight associated with olanzapine and mirtazapine may be effective against anorexia and cachexia associated with cancer and cancer chemotherapy. The subject is important because cachexia may be present in 30%-50% of patients with cancer (with higher prevalence in patients with more advanced cancer) and because the presence of cachexia is associated with a higher risk of disease progression and mortality. Many randomized controlled trials (RCTs) have examined pharmacologic interventions such as progestins, corticosteroids, anamorelin, and medical cannabis for cancer related cachexia; most results have been disappointing. A recent RCT found that olanzapine (2.5 mg/d for 12 weeks) improved appetite, weight, other nutritional parameters, and quality of life in patients with locally advanced or metastatic cancer treated with chemotherapy. Another RCT, however, found that mirtazapine (30 mg/d for 8 weeks) brought no nutritional or anthropometric gain in patients with cancer and anorexia. It is concluded that olanzapine but not mirtazapine merits further investigation in patients with cancer who have anorexia and cachexia.

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.

Association of Antidepressant Use With Drug-Related Extrapyramidal Symptoms: A Pharmacoepidemiological Study.

BACKGROUND: Antidepressants are one of the most prescribed classes of medications. A number of case reports have linked these drugs to extrapyramidal symptoms (EPSs), but no large epidemiologic study to date has examined this association. We sought to quantify the association of EPSs with different antidepressants by undertaking a large pharmacoepidemiologic study. METHODS: A nested case-control study was conducted using a large health claims database in the United States from June 2006 to December 2015. Subjects with a diagnosis of primary Parkinson disease and those who received prescriptions of levodopa, ropinirole, pramipexole, domperidone, metoclopramide, entacapone, benztropine, selegiline, rasagiline, diphenhydramine, trihexyphenidyl, typical and atypical antipsychotics, and tricyclic antidepressants were excluded. Cases were followed to the first billing code for an extrapyramidal event or last date of enrollment in the cohort. For each case, 10 control subjects were matched by follow-up time, calendar time, and age through density-based sampling. Rate ratios were computed using conditional logistic regression adjusting for other covariates. RESULTS: We identified 3,838 subjects with EPSs compared with 38,380 age-matched control subjects. Rate ratios with respect to EPSs were as follows: duloxetine, 5.68 (95% confidence interval [CI], 4.29-7.53); mirtazapine, 3.78 (95% CI, 1.71-8.32); citalopram, 3.47 (95% CI, 2.68-4.50); escitalopram, 3.23 (95% CI, 2.44-4.26); paroxetine, 3.07 (95% CI, 2.15-4.40); sertraline, 2.57 (95% CI, 2.02-3.28); venlafaxine, 2.37 (95% CI, 1.71-3.29); bupropion, 2.31 (95% CI, 1.67-3.21); and fluoxetine, 2.03 (95% CI, 1.48-2.78). CONCLUSIONS: This observational study demonstrates a harmful association between the incidence of Parkinson disease or associated EPSs and use of the antidepressants duloxetine, mirtazapine, citalopram, escitalopram, paroxetine, sertraline, venlafaxine, bupropion, and fluoxetine.

Risk of Diabetes Hospitalization or Diabetes Drug Intensification in Patients With Depression and Diabetes Using Second-Generation Antipsychotics Compared to Other Depression Therapies.

OBJECTIVE: Use of second-generation antipsychotics (SGAs) for treatment of depression has increased, and patients with depression and comorbid diabetes or cardiovascular disease are more likely to use SGAs than those without these conditions. We compared SGA and non-SGA depression pharmacotherapies on the risk of diabetes hospitalization or treatment intensification in adults with depression and preexisting diabetes. METHODS: This was a retrospective cohort study of US commercially insured adults (2009-2015 Truven MarketScan Commercial Claims and Encounters Database) aged 18-64 years old with type 2 diabetes mellitus and unipolar depression previously treated with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor. New users of SGAs versus non-SGAs, as well as specific treatments (aripiprazole, quetiapine, bupropion, mirtazapine, and tricyclic antidepressants [TCAs]) were matched on class/medication-specific high-dimensional propensity score. Cox proportional hazard models were used to compare the risk of diabetes-related hospitalization or treatment intensification. RESULTS: We identified 6,625 SGA (aripiprazole = 3,461; quetiapine = 1,977; other = 1,187) and 23,921 non-SGA patients for inclusion (bupropion = 15,511; mirtazapine = 1,837; TCAs = 5,989; other = 584) with a mean age of 51 years. In the matched cohort, the rate of diabetes-related hospitalization or drug intensification was 47.9 per 100 person-years in the SGA group and 43.5 per 100 person-years in the non-SGA group (adjusted hazard ratio [aHR] = 1.03; 95% CI, 0.96-1.11). When comparing treatment subgroups, the risk of events was lower for bupropion versus TCAs (aHR = 0.85; 95% CI, 0.76-0.98), quetiapine versus mirtazapine (aHR = 0.82; 95% CI, 0.67-0.99), and quetiapine versus TCAs (aHR = 0.84; 95% CI, 0.72-0.98). For other comparisons, differences were small and not statistically significant. CONCLUSIONS: While drug-specific effects on risk of diabetes hospitalization or treatment intensification most likely guide clinical decision making, we observed only modest differences in risk. The overall impact of SGAs on diabetes control depends not only on direct effects on glucose metabolism but also on effectiveness of depression symptom relief. Future studies evaluating other diabetes outcomes (glycosylated hemoglobin, diabetes complications) are needed.

Can we recommend mirtazapine and bupropion for patients at risk for bleeding?: A systematic review and meta-analysis.

BACKGROUND: Many studies have reported that selective serotonin reuptake inhibitors (SSRI) are associated with an increased risk of bleeding. Mirtazapine and bupropion, which commonly lack serotonin reuptake inhibition, have been recommended as alternatives for patients who are at risk for bleeding. However, the evidence for these recommendations is insufficient. METHODS: We conducted a systematic search, systematic review, and meta-analysis to investigate an evidence-based approach for the bleeding risks of mirtazapine and bupropion. From 1946 to May 2017, a total of 3981 studies were searched from PubMed, Embase, and the Cochrane Library. Among the studies, two independent reviewers selected studies per predefined eligibility criteria. RESULTS: A total of five meta-analyses were conducted. Patients taking mirtazapine were at a greater risk of gastrointestinal bleeding (OR = 1.17, 95% CI = 1.01-1.38) than those who did not take antidepressants. No differences were observed in the bleeding risk between mirtazapine and SSRI or between bupropion and SSRI. LIMITATIONS: The number of studies included in the meta-analysis was small. CONCLUSION: Our results suggest that it is premature to recommend mirtazapine and bupropion for patients who have a bleeding risk. More studies with larger sample sizes and longitudinal follow-ups are warranted.

Mirtazapine-induced steatosis
.

Mirtazapine is a commonly used drug indicated for the treatment of severe depression. It works as a presynaptic α2-adrenoreceptor antagonist that increases central noradrenergic and serotonergic neurotransmission, and it is metabolized by the p450 cytochrome oxidase system. There is evidence within the literature to suggest a link between antidepressants and increased liver enzymes, although case reports demonstrating a link between mirtazapine specifically and steatosis are sparse. Here, we present a case of mirtazapine-induced steatosis in a 48-year-old office worker. She presented with painless jaundice of 2 days duration and generalized lethargy and peripheral edema present for 3 weeks beforehand. Extensive investigations were undertaken to identify the cause of her jaundice but no biochemical, blood-borne, or anatomical cause could be found. Mirtazapine was subsequently stopped, and her liver function, both clinically and biochemically, improved rapidly. She made a full recovery after discontinuation of her mirtazapine.
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Reevaluating the Efficacy and Predictability of Antidepressant Treatments: A Symptom Clustering Approach.

IMPORTANCE: Depressive severity is typically measured according to total scores on questionnaires that include a diverse range of symptoms despite convincing evidence that depression is not a unitary construct. When evaluated according to aggregate measurements, treatment efficacy is generally modest and differences in efficacy between antidepressant therapies are small. OBJECTIVES: To determine the efficacy of antidepressant treatments on empirically defined groups of symptoms and examine the replicability of these groups. DESIGN, SETTING, AND PARTICIPANTS: Patient-reported data on patients with depression from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (n = 4039) were used to identify clusters of symptoms in a depressive symptom checklist. The findings were then replicated using the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (n = 640). Mixed-effects regression analysis was then performed to determine whether observed symptom clusters have differential response trajectories using intent-to-treat data from both trials (n = 4706) along with 7 additional placebo and active-comparator phase 3 trials of duloxetine (n = 2515). Finally, outcomes for each cluster were estimated separately using machine-learning approaches. The study was conducted from October 28, 2014, to May 19, 2016. MAIN OUTCOMES AND MEASURES: Twelve items from the self-reported Quick Inventory of Depressive Symptomatology (QIDS-SR) scale and 14 items from the clinician-rated Hamilton Depression (HAM-D) rating scale. Higher scores on the measures indicate greater severity of the symptoms. RESULTS: Of the 4706 patients included in the first analysis, 1722 (36.6%) were male; mean (SD) age was 41.2 (13.3) years. Of the 2515 patients included in the second analysis, 855 (34.0%) were male; mean age was 42.65 (12.17) years. Three symptom clusters in the QIDS-SR scale were identified at baseline in STAR*D. This 3-cluster solution was replicated in CO-MED and was similar for the HAM-D scale. Antidepressants in general (8 of 9 treatments) were more effective for core emotional symptoms than for sleep or atypical symptoms. Differences in efficacy between drugs were often greater than the difference in efficacy between treatments and placebo. For example, high-dose duloxetine outperformed escitalopram in treating core emotional symptoms (effect size, 2.3 HAM-D points during 8 weeks, 95% CI, 1.6 to 3.1; P < .001), but escitalopram was not significantly different from placebo (effect size, 0.03 HAM-D points; 95% CI, -0.7 to 0.8; P = .94). CONCLUSIONS AND RELEVANCE: Two common checklists used to measure depressive severity can produce statistically reliable clusters of symptoms. These clusters differ in their responsiveness to treatment both within and across different antidepressant medications. Selecting the best drug for a given cluster may have a bigger benefit than that gained by use of an active compound vs a placebo.

Non-tricyclic and Non-selective Serotonin Reuptake Inhibitor Antidepressants and Recurrent Falls in Frail Older Women.

OBJECTIVE: To determine the risk of recurrent falls associated with antidepressants other than tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs) among frail older women. METHODS: This is a secondary analysis of the Zoledronic acid in frail Elders to STrengthen bone, or ZEST, trial data treated as a longitudinal cohort in 181 frail, osteoporotic women aged ≥65 years in long-term care. The primary exposure was individual non-TCA/non-SSRI antidepressants (i.e., serotonin norepinephrine reuptake inhibitors, mirtazapine, trazodone, and bupropion) at baseline and 6 months. The main outcome was recurrent (at least two) falls within 6 months after antidepressant exposure. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were derived using a generalized estimating equations model. RESULTS: At least 15% of women experienced recurrent falls between 0-6 and 6-12 months. At baseline and 6 months, 18.2% and 6.9% had a non-TCA/non-SSRI antidepressant, respectively. Adjusting for demographics, health status, and other drugs that increase risk of falls, non-TCA/non-SSRI antidepressant exposure significantly increased the risk of recurrent falls (AOR: 2.14; 95% CI: 1.01-4.54). Fall risk further increased after removing bupropion from the non-TCA/non-SSRI antidepressant group in sensitivity analyses (AOR: 2.73; 95% CI: 1.24-6.01). CONCLUSIONS: Other antidepressant classes may not be safer than TCAs/SSRIs with respect to recurrent falls in frail older women.

Serotonin Syndrome Following an Uncomplicated Orthopedic Surgery in a Patient With Post-Traumatic Stress Disorder.

Serotonin syndrome (SS) is a potentially life-threatening adverse drug reaction that may occur in patients treated with serotonin agonist medications. Medications responsible for serotonin syndrome include commonly prescribed antidepressants, anxiolytics, analgesics, and antiemetics. Veterans with post-traumatic stress disorder (PTSD) are at risk for polypharmacy with serotoninergic medications, given their psychological comorbidities and service-related musculoskeletal injuries. The perioperative period is a particularly vulnerable time owing to the use of high-dose anxiolytics and antiemetics frequently administered in this period, and places PTSD patients at higher risk of SS. Herein, we present the first case of SS in a young veteran with combat-related PTSD following an uncomplicated L5-S1 revision discectomy that highlights the unique set of clinical challenges and dilemmas faced when treating SS in a patient with severe postsurgical pain. As we are likely to encounter increasing numbers of veterans treated for PTSD who require multiple surgical procedures to treat their service-related injuries, health care providers need to be familiar with prevention, recognition, and the clinical challenges in the management of SS in the postoperative period.

Mirtazapine, in orodispersible form, for patients with preoperative psychological distress: A pilot study.

BACKGROUND: Perioperative psychological distress is associated with preoperative anxiety, depression, and postoperative pain. Mirtazapine is effective as an antidepressant, anxiolytic agent, and sleep enhancer. Moreover, mirtazapine can be made as orodispersible tablets with a fast onset for patients in nil per os status. This study is to determine whether mirtazapine can help psychologically distressed patients reduce perioperative anxiety, depression, and postoperative pain. MATERIALS AND METHODS: Patients with preoperative psychological distress, undergoing major abdominal surgery, were inquired and assigned to two groups according to their own choice. In the treatment group, patients could choose to take orodispersible mirtazapine 30 mg at each night from Preoperative Day 0 to Postoperative Day 3. There was no other intervention in the nontreatment group. Hospital Anxiety and Depression Scale (HADS), Athens Insomnia Scale (AIS), and pain scores were accessed on the day before operation (Day 0), and on the 1(st) day (Day 2) and 3(rd) day (Day 4) after operation. We compared the HADS, AIS, and pain scores, and morphine consumptions between the two groups on a daily basis. Marginal regression models were fitted to our correlated longitudinal data alone with the generalized estimating equations method to estimate the population average effects of time-varying mirtazapine usage on the mean values of HADS, AIS, and pain scores, and daily morphine consumptions. RESULTS: From September 2007 to December 2008, 86 patients agreed to be enrolled and 79 of them completed the study. Propensity scores and multivariate analysis showed that mirtazapine reduced HADS scores of patients in 2 days. Trial results indicated that mirtazapine lowered the AIS day index and tended to decrease night index as well. Mirtazapine may reduce patients' morphine consumption, but this effect was not statistically significant (p = 0.2). CONCLUSION: Mirtazapine helps reduce anxiety, depression, and insomnia scores for patients with perioperative psychological distress.

Transcranial magnetic stimulation as an antidepressant alternative in a patient with Brugada syndrome and recurrent syncope.

Brugada syndrome (BrS) is a common occult cause of sudden cardiac arrest in otherwise healthy-appearing adults. The pathognomonic electrocardiographic pattern may be unmasked only by certain medications, many of which are unknown. We report a case of a depressed but otherwise healthy man with an asymptomatic right bundle branch block on electrocardiography who experienced antidepressant-induced BrS and ultimately recovered with transcranial magnetic stimulation (TMS). After an initial trial of nortriptyline, the patient's depressive symptoms improved; however, he experienced a syncopal event and was subsequently diagnosed as having BrS. Cross titration to bupropion, which had not previously been known to exacerbate BrS, was followed by another cardiac event. As a result, the patient was referred for TMS as a substitute for pharmacotherapy. After 31 TMS sessions over 8 weeks, the patient demonstrated significant improvement by subjective report and objective reduction in his Patient Health Questionnaire-9 scores from 10 (moderate) to 1 (minimal). Transcranial magnetic stimulation is a Food and Drug Administration-approved nonpharmacologic treatment for depression. Given the potential lethality of BrS with known and unknown psychopharmacologic agents, providers should consider TMS as first-line therapy in this patient population. Bupropion should be added to the list of agents known to exacerbate this disease.

[Electroconvulsion therapy for neuroleptic malignant syndrome]. / Elektroconvulsietherapie in de behandeling van maligne antipsychoticasyndroom.

A 64-year-old man, diagnosed with recurrent depression, developed a neuroleptic malignant syndrome (nms) during treatment with olanzapine and mirtazapine. Psychotropic drugs were discontinued. Supportive therapy in an intensive care setting was initiated and electroconvulsive therapy (ect) was administered, after which the patient recovered. This case report discusses the place of ect in the treatment of nms.

Acute hepatitis after starting pinaverium bromide in a patient taking mirtazapine.

A 56-year-old man presented with chronic abdominal pain. He had been evaluated extensively in the recent past undergoing upper gastrointestinal endoscopy, colonoscopy and CT scan of the abdomen with normal results. The provisional diagnosis of irritable bowel syndrome was performed and pinaverium bromide was started. The patient had pre-existing hypertension, a major depressive disorder and gastro-oesophageal reflux disease. He had been taking nebivolol and pantoprazole for several years and mirtazapine for the last 1 year. The patient developed nausea, vomiting and anorexia after 5 days of starting pinaverium bromide. Investigations revealed marked elevation of liver enzymes and bilirubin. He was negative for HIV, HBSAg, anti-hepatitis C virus, IgM for hepatitis A virus, hepatitis E virus, antinuclear antibody and antimitochondrial antibody. An ultrasound showed mild hepatomegaly with hypoechoic echo texture; the rest of scan was normal. Pinaverium and mirtazapine were stopped immediately. The patient was treated symptomatically and his liver profile returned to normal after 4 weeks.

Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: a four-week, randomized, double-blinded, placebo-controlled study.

This is a 4 week, randomized, double-blind, placebo-controlled study to examine the effects of methylphenidate as add-on therapy to mirtazapine compared to placebo for treatment of depression in terminally ill cancer patients. It involved 88 terminally ill cancer patients from University of Malaya Medical Centre, Kuala Lumpur, Malaysia. They were randomized and treated with either methylphenidate or placebo as add on to mirtazapine. The change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 3 was analyzed by linear regression. Changes of MADRS and Clinical Global Impression-Severity Scale (CGI-S) over 28 days were analyzed using mixed model repeated measures (MMRM). Secondary analysis of MADRS response rates, defined as 50% or more reduction from baseline score. A significantly larger reduction of Montgomery-Åsberg Depression Rating Scale (MADRS) score in the methylphenidate group was observed from day 3 (B=4.14; 95% CI=1.83-6.45). Response rate (defined as 50% or more reduction from baseline MADRS score) in the methylphenidate treated group was superior from day 14. Improvement in Clinical Global Impression-Severity Scale (CGI-S) was greater in the methylphenidate treated group from day 3 until day 28. The drop-out rates were 52.3% in the methylphenidate group and 59.1% in the placebo group (relative risk=0.86, 95%CI=0.54-1.37) due to cancer progression. Nervous system adverse events were more common in methylphenidate treated subjects (20.5% vs 9.1%, p=0.13). In conclusions, methylphenidate as add on therapy to mirtazapine demonstrated an earlier antidepressant response in terminally ill cancer patients, although at an increased risk of the nervous system side effects.

Impact of antidepressants on cytokine production of depressed patients in vitro.

The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1ß, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively. Citalopram increased production of IL-1ß, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1ß, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1ß, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1ß, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.

Efficacy and safety of mirtazapine in fibromyalgia syndrome patients: a randomized placebo-controlled pilot study.

BACKGROUND: Data from an open-label trial suggest that mirtazapine might prove useful in treatment of fibromyalgia syndrome (FMS). OBJECTIVE: To obtain preliminary efficacy data of mirtazapine for estimation of sample size requirements for a Phase 2 clinical trial in FMS. METHODS: This 13-week randomized controlled trial compared the effects of mirtazapine 15 mg/day, mirtazapine 30 mg/day, and placebo in 40 patients with FMS. The primary outcomes were change in Pain Visual Analog Scale (PVAS) and proportion of pain responders (≥30% PVAS reduction). Secondary outcomes included scores from the Jenkins Sleep Scale (JSS), Patient Global Impression of Change (PGIC), Fibromyalgia Impact Questionnaire (FIQ), Hamilton Depression Rating Scale (HAM-D), Patient Global Assessment, and self-reported adverse events. RESULTS: Significant within-group PVAS reductions from baseline were observed in all 3 groups, with the greatest improvement in the mirtazapine 30-mg group (p < 0.005); between-group difference was not significant. The proportion of pain responders did not meet significance criteria (66.67% for mirtazapine 30 mg, 50% for mirtazapine 15 mg, 41.67% for placebo). Significant within-group improvement in JSS scores was seen for mirtazapine 30 mg (p < 0.01) and mirtazapine 15 mg (p < 0.05). Between-group comparison achieved significance for JSS item 3, waking several times per night (p < 0.05). On the PGIC, 72.73% felt better with both mirtazapine dosages compared with 50% for placebo. Within-group FIQ responses indicated improvement in only mirtazapine-treated groups, whereas within-group improvement for HAM-D and Patient Global Assessment was observed in all groups. Based on our findings, the sample size requirement (80% power, 5% type I error) should be 83 per group to detect PVAS change difference between mirtazapine 30 mg and placebo. Common mirtazapine-related adverse events were increased appetite and weight gain. CONCLUSIONS: Patients with FMS taking mirtazapine exhibited within-group significant improvement in most of the measured outcomes. Between-group analysis was predictably compromised by the small sample size. Mirtazapine was well tolerated. Further study with a larger sample size is likely to be useful.

The impact of chronic depression on acute and long-term outcomes in a randomized trial comparing selective serotonin reuptake inhibitor monotherapy versus each of 2 different antidepressant medication combinations.

OBJECTIVE: To compare sociodemographic and clinical features, acute and continuation treatment outcomes, and adverse events/side effect burden between outpatients with chronic (current episode > 2 years) versus nonchronic major depressive disorder (MDD) who were treated with combination antidepressant therapy or selective serotonin reuptake inhibitor (SSRI) monotherapy. METHOD: 663 outpatients with chronic (n = 368) or nonchronic (n = 295) moderate to severe DSM-IV-TR MDD (17-item Hamilton Depression Rating Scale score ≥ 16) were enrolled from March 2008 through September 2009 in a single-blind 7-month prospective randomized trial conducted at 6 primary and 9 psychiatric care sites across the United States. Participants were treated with escitalopram monotherapy plus placebo or 1 of 2 combination treatments (bupropion sustained-release [SR] + escitalopram or venlafaxine extended-release [XR] + mirtazapine). Analyses compared baseline sociodemographic and clinical characteristics, rates of remission (at least 1 of the last 2 consecutive scores on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR16] < 6, with the other < 8), and adverse events/side effect burden (Frequency, Intensity, and Burden of Side Effects Ratings) obtained at 12 and 28 weeks. RESULTS: Participants with chronic MDD were at greater socioeconomic disadvantage and had greater medical and psychiatric disease burden. The chronic and nonchronic groups did not differ in rates of remission at 12 weeks (35.9% vs 42.0%, respectively; odds ratio [OR] = 0.778, P = .1500; adjusted OR [AOR] = 0.956, P = .8130) or at 28 weeks (41.0% vs 49.8%, respectively; OR = 0.706, P = .0416; AOR = 0.837, P = .3448). Participants with chronic MDD had higher final QIDS-SR(16) scores and smaller overall percent changes in QIDS-SR(16) from baseline to exit, but these differences did not remain after adjusting for covariates. There were no significant differences in adverse events or side effect burden. No significant interactions were found between chronicity and type of treatment at 12 or 28 weeks. CONCLUSION: Chronicity of illness does not appear to differentially impact acute or longer-term outcomes with SSRI monotherapy or combination antidepressant medication treatment in patients with moderate to severe nonpsychotic MDD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00590863.

Mirtazapine and mefloquine therapy for progressive multifocal leukoencephalopathy in a patient infected with human immunodeficiency virus.

PURPOSE: A case of progressive multifocal leukoencephalopathy (PML) in a patient infected with human immunodeficiency virus (HIV) treated with mirtazapine and mefloquine is reported. SUMMARY: A 49-year-old African-American man who was recently diagnosed with HIV infection was admitted to the hospital for progressive ataxia, dysarthria, and unsteady gait. Upon initial examination, the patient was fully oriented but appeared drowsy and uncooperative and was observed to be unsteady on his feet. Magnetic resonance imaging of the patient's brain revealed marked cerebellar and mild cerebral atrophy and moderate, nonspecific white matter disease. The results of a lumbar puncture revealed the presence of JC virus, and PML was diagnosed. As the patient's cognitive function began to worsen, mirtazapine and mefloquine were initiated. Treatment with mirtazapine 30 mg orally daily and mefloquine hydrochloride 250 mg orally for three days, then 250 mg weekly, was initiated. The dosing regimen was derived from a study currently underway at Washington University in St. Louis, Missouri. The patient also had pneumonia and, on day 7 of hospitalization, required intubation. The patient was extubated on day 11 and showed significant cognitive improvement; he was able to communicate his wish to enact a "Do Not Intubate" order. At this time, the patient began refusing all medications and ultimately died on hospital day 16 due to respiratory failure. CONCLUSION: A patient with HIV infection and PML was treated with mirtazapine and mefloquine. He tolerated the drugs well and exhibited functional and cognitive improvement, but the specific effects of mirtazapine and mefloquine were difficult to discern.