Search

BACKGROUND Progressive multifocal leukoencephalopathy, (PML) a demyelinating disease of the brain, caused by the John Cunningham (JC Virus) is usually seen in patients who are immunocompromised. Here, we describe a case of an immunocompetent patient diagnosed with PML and a comprehensive literature review. CASE DESCRIPTION A 64-year-old Caucasian male presented with acute worsening of progressive neurological decline with difficulty in vision and reading. Based on history, examination, CSF markers, histopathology, and MRI Brain at the time of presentation diagnosed the patient with PML in a setting of no immunosuppression disorder. Patient was started on Pelfilgrastim with significant systematic improvement. RESULT In our literature review, it was seen that the average age of symptom presentation was 57.5 with predominance in males. Most of the patients presented with progressive neurological deficits with symptomology ranging from mild confusion, aphasia, anxiety to sensory disturbances with numbness, hemiparesis and hemianopsia. Out of the 21 cases, patients responded to mirtazapine and intravenous pulse methylprednisolone (IVMP). The mortality rate was close to 50% with 11 fatal cases and 10 non-fatal cases. CONCLUSION Our case and literature review demonstrate the possibility that PML may very rarely occur in patients that our immunocompetent. Furthermore, our review showed that patients responded well to mirtazapine and IVMP. We also want to highlight that mortality rate was lower in this review and was only compared to morality in PML associated with immunocompromised status. This article is protected by copyright. All rights reserved.

Background Receiving treatment for depression is increasingly common among young adults. Antidepressants (AD) are important in depression treatment and modification of medication is common. We examined switches and discontinuations of ADs among young Finnish adults aged 18-29 years. Methods All persons diagnosed with depression in inpatient or specialized outpatient care or having received sickness absence or disability pension due to depression at age of 18-29 years during 2004-17 were included (N = 110761). Among them, we focused on incident AD users (N = 52855, 47.7%) who were identified with a 6 month washout before AD initiation. The follow-up was 2 years. Results The majority (76.3%) initiated with selective serotonin reuptake inhibitors (SSRIs). The initial AD was switched in 17.4% of cases. Switching was most common when treatment was initiated with tricyclic antidepressants (TCA) or polytherapy, and least common when initiated with SSRIs or serotonin-noradrenaline reuptake inhibitors. Factors associated with switch included initiation with polytherapy, TCA or mirtazapine, and use of benzodiazepines or Z-drugs at baseline. During the first 3 months, 27.6% discontinued AD use, and only 14.1% used AD for 2 years. Factors associated with discontinuation included substance abuse, ADHD, previous suicide attempt and initiation with mirtazapine. SSRIs had the longest time to discontinuation (median 144 days, IQR 64-302). Limitations Our data sources lack those treated in primary care only, without receiving a sick leave of ≥2 weeks. In addition, we do not have data on severity of depression, social factors or psychotherapy. Conclusions Special emphasis should be paid to persons with increased risk of discontinuation, including those with previous self-harm/suicide attempt or substance abuse.

Objectives Laxatives are among the most prescribed medications to nursing home (NH) patients, and we evaluated the hypothesis that laxative agents could be prescribed as a result of a prescribing cascade. The aims of the study are (1) to investigate the use of laxative drugs in a large sample of Italian NHs and (2) to assess the relationship between medications that can induce constipation and laxative use. Design Retrospective cross-sectional multicenter study. Setting and Participants Individuals living in long-term care NHs. Methods Study conducted in a sample of Italian long-term care NHs distributed throughout the country. Information on drug prescriptions, diseases and sociodemographic characteristics collected 4 times during 2018 and 2019. Results Among the 2602 patients recruited from 27 NHs (mean age ± standard deviation: 88.4 ± 8.5; women: 1994, 76.6%), 1248 were receiving laxatives (48%). Parkinson disease, cerebrovascular disease, and hemiplegia were associated with laxative prescription, and diabetes was associated with a decrease. Benzodiazepines, anti-Parkinson dopaminergic agents, and antidepressants (tricyclic antidepressants and mirtazapine) were associated with laxative treatment in univariate and adjusted models. Tricyclic antidepressants users were 3 times more likely to be taking laxatives than nonusers (odds ratio 2.98, 95% confidence interval 1.31-6.77, P = .0093). A larger number of drugs that can induce constipation was associated with laxative use (P = .0003). In all, 2002 individuals had at least 2 different prescription times: from the first to the last visit laxative use rose from 46.1% to 49.9%. Time of stay was also associated with laxative use (P = .016). Conclusions and Implications Laxatives are among the most prescribed medications in Italian NHs. Medications that can induce constipation, such as antidepressants, anti-Parkinson dopaminergic agents, and benzodiazepines, are often used together with laxatives, and combinations of these drugs further increase the use of laxatives. Optimizing the prescription of psychotropic drugs could help reduce the “prescribing cascade” with laxatives. The length of stay in NHs is often proportional to laxative use and chronic treatment is very common.

У статті розглянуті сучасні аспекти патогенезу, ранньої діагностики та комплексного лікування тривожно-депресивних розладів при хворобі Паркінсона (ХП). На сьогодні науковці виділяють дві форми депресивних розладів при ХП залежно від наявності або відсутності зв’язку із флуктуаціями симптомів — депресію, що пов’язана із періодами вимикання, та депресію, що не пов’язана із періодами вимикання. Для корекції депресії при ХП застосовуються селективні інгібітори зворотного захвату серотоніну (СІЗЗС) — сертралін, пароксетин, циталопрам, міансерин, трициклічні антидепресанти (ТЦА) — амітриптилін, нортриптилін, іміпрамін, дезипрамін, селективні інгібітори зворотного захвату серотоніну та норадреналіну — дулоксетин, венлафаксин, селективний інгібітор зворотного захвату норадреналіну ребоксетин, пресинаптичний антагоніст α2-адренорецепторів міртазапін. У літературі наводяться суперечливі дані щодо ефективності тих чи інших антидепресантів. Основними препаратами для лікування депресії при ХП вважаються СІЗЗС та ТЦА. Мультидисциплінарний підхід до оптимізації лікування та догляду за пацієнтами із ХП може включати фізичну та трудотерапію, логопедичну та психологічну терапію. Все частіше у неврологічній практиці застосовуються психотерапевтичні методики на основі біоадаптивного управління, що є перспективним напрямком сучасної медицини й іменується біологічним зворотним зв’язком. Актуальним є раннє виявлення немоторних порушень при ХП, зокрема психоемоційних розладів, з метою їх своєчасної корекції для покращення якості життя пацієнтів із ХП та їх родичів. А також необхідні подальші наукові дослідження для оцінки клінічної ефективності антидепресантів при лікуванні тривожно-депресивних розладів у пацієнтів із ХП та оптимізації їх лікування з використанням у комплексній терапії сучасних немедикаментозних методів лікування, таких як когнітивно-поведінкова терапія та метод біоадаптивного управління.

Background/purpose Tricyclic antidepressants (TCAs) are still widely used and are available to purchase without prescription in some countries. Awareness of adverse cutaneous drug reactions is essential. Method We reported a case of photo-distributed hyperpigmentation due to imipramine and carried out a systematic search of the related articles using the search terms "tricyclic antidepressants" or "tricyclic antidepressive agents", and "hyperpigmentation" or "photosensitivity disorder". Fifty non-duplicate citations were identified of which 28 articles which were independently assessed in full. The review was registered in PROSPERO, CRD42018107338. Results The remaining 25 articles met our inclusion criteria. Photo-distributed hyperpigmentation tricyclic antidepressant-induced photosensitivity reactions (TIPs) was the most common presentation. In 21 cases, this presented as an asymptomatic discolouration of exposed sites. Imipramine (81%), amitriptyline (9.5%), desipramine hydrochloride (4.8%) and mirtazapine (4.8%) were reported to be the culprit drugs. Nineteen were female with a mean age at presentation of 55 years. Mean duration from commencing the culprit drug until the development of discolouration was 10.4 years. Mean daily dose was 222.7 mg for imipramine. Histology was characteristic with golden-brown or brownish granules deposited in dermis. Staining for Masson-Fontana and MEL-5 was positive in all cases. Phototesting had not been done in cases prior to ours (negative 3 months after discontinuation of imipramine). Three further reports of suspected TIP presented with non-specific and eczematous eruption. The two presentations were reported along with systemic problems (thrombocytopenia and hepatic injury). Conclusions This systematic review highlights the characteristic features of exposed site hyperpigmentation of TCA-induced photosensitivity occurring after prolonged drug exposure in many cases.

Background About one third of depression patients do not respond to the first antidepressant trial. Difficult-to-treat depression was suggested to characterize the often chronic and severe course of disease. Previous data indicate that tranylcypromine is effective in case of treatment-refractory depression. Many antidepressants are contraindicated in combination with tranylcypromine and other monoamine-oxidase inhibitors because of the risk of serotonin syndrome. The combination of tranylcypromine and amitriptyline was reported to be efficacious and safe in patients with electroconvulsive therapy-resistant major depression. Methods In this retrospective chart review, we report a series of 3 cases, in which patients with electroconvulsive therapy-resistant depression were treated with the combination of tranylcypromine and mirtazapine. There are no published clinical data on this combination yet. Disease severity and treatment response were retrospectively assessed with the Clinical Global Impression-Severity and Improvement Scales. Results All 3 patients had severe difficult-to-treat depression with chronic course of disease and several times of inpatient treatment without achieving remission. The combination treatment was tolerated well, although the patients had somatic comorbidities. One patient developed mild and self-limiting neuroleptic malignant syndrome in the long-term course after dose increase of concomitant aripiprazole. All 3 patients showed either much or very much improvement. Conclusions Under tight clinical controls in inpatient setting and after exhausting of alternatives, the combination of tranylcypromine and mirtazapine could be considered in patients, who do not achieve adequate improvement through common treatment options recommended in the guidelines. The combination has to be ceased, if symptoms of possible serotonin syndrome occur.

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.

Drug craving is the intense desire to consume drugs of abuse that promote compulsive drug use and cause drug relapse, following long-term drug withdrawal. Antidepressants like mirtazapine could be a real alternative therapy to attenuate or prevent cocaine withdrawal symptoms and drug craving. In the present study, we examined the efficacy of mirtazapine on cocaine craving in cocaine-detoxified patients during its maintenance phase. A two-arm randomized, placebo-controlled, double-blind clinical trial was scheduled for a complete 12-week period. A total of 64 cocaine-dependent individuals were randomly allocated into two groups: the placebo group (n = 32) and the mirtazapine (n = 32) groups. Both Cocaine Craving Questionnaire (CCQ-G) and the Symptom Check List 90 (SCL-90-R) were used to assess cocaine craving and the psychopathological status of patients, respectively. Assessments were performed once a week for 12 weeks during the study. Mirtazapine (30 mg/kg) was given daily during the 12 weeks of enduring drug withdrawal. A daily dosing regimen of mirtazapine (30 mg/kg) for 12 weeks significantly decrease the cocaine craving, cocaine use, and some psychiatric symptoms which included depression, anxiety, and mood-negative states along the 12 weeks that endured the study. These data suggest that mirtazapine given to cocaine-dependent patients for 12 weeks of drug withdrawal significantly decreases and controls cocaine-craving behavioral alterations. Furthermore, the present study demonstrates that mirtazapine reduces efficiently some co-morbid psychiatric symptoms that appear during cocaine withdrawal. These results argue in favor of using mirtazapine for treating cocaine addiction, reducing comorbid cocaine-withdrawal symptomology, and relieving drug craving in addicted subjects. Clinical trial number: NCT ID: NCT01949571.

Hyponatremia (HN) is the most common electrolyte imbalance (defined as a serum sodium concentration Na(S) of

BACKGROUND AND AIMS The effect of major depression and antidepressant use on patient survival in chronic liver disease is unknown. We evaluated the impact of major depressive disorder (MDD) and antidepressants on survival among patients with alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). METHODS The Health Improvement Network database, the largest medical database in the United Kingdom, was used to identify incident ALD (n = 4148) and NAFLD (n = 19 053) in patients between 1986 and 2017. Our primary outcome was development of decompensated cirrhosis or death. MDD and each class of antidepressants were assessed in multivariate Cox proportional hazards models as time-varying covariates. Models were adjusted for age, sex, socio-economic status and comorbidities. RESULTS MDD rate was higher among patients with ALD (22.8%) compared to those with NAFLD (16.1%), P

Objectives: To examine the prescribing patterns of antidepressants among a sample of psychiatrists working in Oman and to compare these practices to the current evidence for prescribing specific antidepressant in particular clinical situations. Methods: This retrospective cross sectional study. Massachusetts General Hospital Psychopharmacology Questionnaire, a 10-item questionnaire listing factors that might have influenced the choice of antidepressant medication, was sent to 83 psychiatrists working in governmental health sectors in Oman. The study was done from March to July 2019. Results: A total number of 78 psychiatrists responded to the questionnaire. Of these, 44 of the psychiatrists (56.4%) believed that one type of antidepressant is more efficacious than others, while 74 psychiatrists (94.9%) indicated that selective serotonin reuptake inhibitors (SSRIs) were their first-line treatment preference. Mirtazapine was chosen as the most likely antidepressant to cause weight gain by two-thirds of the participants. For the treatment of anxious depression and depression with melancholic feature, SSRIs were the first choice of treatment for 64.1% and 7% of respondents, respectively. For depression with atypical features, 42.3% indicated that a monoamine oxidase inhibitor would be their first option. Conclusion: There is a discrepancy between the current antidepressant prescribing practices in Oman and empirical antidepressant-prescribing evidence, and this finding is consistent with previous studies.

Introduction: Mirtazapine is an antidepressant drug that produces both noradrenergic and serotonergic activity. It is effective in treating of mild to severe depression. Proper evidence pointing to the safety of Mirtazapine is not established. The need for post-marketing surveillance (PMS) is considered most essential. This study was aimed to generate signal for unreported adverse drug reactions for Mirtazapine. Materials and Methods: Our study retrospectively analyzed the AEs reported entered in the Adverse Events Reporting System (FAERS) databases in the last 10-years during the period of Jan 2011 to June 2020. Disproportionality analysis was done using Reporting Odds Ratio, Proportional Reporting Ratio, and Information Component with 95% confidence interval. Results: A disproportionality analysis was done for 41 adverse events, out of these, signal for 11 adverse events was found. ROR values 10.17 being the highest for abulia and 2.22 being the lowest for homicidal Ideation. The PRR value was 10.17 being the highest for abulia and 2.22 being the lowest for homicidal ideation. The IC025 value was 1.87 for abulia and 0.27 for homicidal Ideation. Conclusion: The present study using the Adverse Events Reporting System (FAERS) databases maintained by the FDA suggested new safety signals for Mirtazapine. Still more cohort and epidemiological studies are recommended to validate these results. Keywords: Mirtazapine, Disproportionality analysis, Safety Signals.

BackgroundThere is growing interest in using composite individualized treatment rules (ITRs) to guide depression treatment selection, but best approaches for doing this are not widely known. We develop an ITR for depression remission based on secondary analysis of a recently published trial for second-line antidepression medication selection using a cutting-edge ensemble machine learning method.MethodsData come from the SUN(^_^)D trial, an open-label, assessor blinded pragmatic trial of previously-untreated patients with major depressive disorder from 48 clinics in Japan. Initial clinic-level randomization assigned patients to 50 or 100 mg/day sertraline. We focus on the 1549 patients who failed to remit within 3 weeks and were then rerandomized at the individual-level to continuation with sertraline, switching to mirtazapine, or combining mirtazapine with sertraline. The outcome was remission 9 weeks post-baseline. Predictors included socio-demographics, clinical characteristics, baseline symptoms, changes in symptoms between baseline and week 3, and week 3 side effects.ResultsOptimized treatment was associated with significantly increased cross-validated week 9 remission rates in both samples [5.3% (2.4%), p = 0.016 50 mg/day sample; 5.1% (2.7%), p = 0.031 100 mg/day sample] compared to randomization (30.1–30.8%). Optimization was also associated with significantly increased remission in both samples compared to continuation [24.7% in both: 11.2% (3.8%), p = 0.002 50 mg/day sample; 11.7% (3.9%), p = 0.001 100 mg/day sample]. Non-significant gains were found for optimization compared to switching or combining.ConclusionsAn ITR can be developed to improve second-line antidepressant selection, but replication in a larger study with more comprehensive baseline predictors might produce stronger and more stable results.

Objective: The aim of this review was to determine whether selective serotonin reuptake inhibitors (SSRIs) affect the ability to conceive in men and women of reproductive age, as well as to find out whether there are certain differencies between them in terms of effects on fertility. Methods: Our review was based on systematic search of literature in four online databases: Medline (PubMed), Scopus, Web of Science and SCIndex (Serbian Citation Index). Results: Several clinical studies reported that SSRIs can decrease the number and viability of sperm, and cause a disruption of their morphological structure. Regarding the effect of these antidepressants on female fertility, some experimental findings suggest that paroxetine and escitalopram may have a negative effect on the ability to conceive due to their stimulatory effect on fallopian tube motility. However, several observational studies favor the use of SSRIs in women with depression/anxiety undergoing in vitro fertilization (IVF) given their efficiency in suppressing these unpleasant symptoms without a relevant negative impact on IVF outcomes. Conclusions: SSRIs should be avoided male patients of reproductive age who wish to conceive, while the use of these antidepressants seems to be justified in women with depression or anxiety who have undergone IVF.Key pointsSSRIs could cause dose and duration-dependent reversible adverse effects on male fertility parameters.In depressed or anxious male patients of reproductive age who wish to conceive mirtazapine or bupropion should be used because of their lower potential to cause sexual side effects.The results of certain experimental studies indicate that paroxetine and escitalopram may have a negative effect on the fertility of female patients.The use of SSRIs in women with depression or anxiety who have undergone IVF seems to be justified, because these psychiatric disorders reduce the likelihood of becoming pregnant.

Background Progressive multifocal leukoencephalopathy (PML) is one of the most serious treatment-related complications that is encountered in patients with multiple sclerosis (MS). PML is a serious complication of MS treatment which is most commonly related to natalizumab. Case presentation We report clinical course of progressive multifocal leukoencephalopathy (PML) in a 40-year-old man who was on treatment for highly active relapsing-remitting multiple sclerosis with natalizumab (Nz). He was treated with steroids, cidofovir, and mirtazapine and went on to develop long-term disability. The case describes the evolution of PML from diagnosis up till 5 months with changes on sequential brain scans and clinical symptoms in our patient. Conclusion Patients who are on natalizumab should be aware and consented for the risk of PML. They should be periodically re-assessed for their relative PML risk. There is a growing body of evidence that suggests switching patients from natalizumab who have a higher risk of PML to other safer treatment options.

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder with limited approved pharmacological treatment options and high symptom burden. Therefore, real-life prescription patterns may differ from guideline recommendations, especially in psychiatric inpatient settings. The European Drug Safety Program in Psychiatry (“Arzneimittelsicherheit in der Psychiatrie”, AMSP) collects inpatients’ prescription rates cross-sectionally twice a year in German-speaking psychiatric hospitals. For this study, the AMSP database was screened for psychiatric inpatients with a primary diagnosis of PTSD between 2001 and 2017. N = 1,044 patients with a primary diagnosis of PTSD were identified with 89.9% taking psychotropics. The average prescription rate was 2.4 (standard deviation: 1.5) psychotropics per patient with high rates of antidepressant drugs (72.0%), antipsychotics drugs (58.4%) and tranquilizing drugs (29.3%). The presence of psychiatric comorbidities was associated with higher rates of psychotropic drug use. The most often prescribed substances were quetiapine (24.1% of all patients), lorazepam (18.1%) and mirtazapine (15.0%). The use of drugs approved for PTSD was low (sertraline 11.1%; paroxetine 3.7%). Prescription rates of second-generation antipsychotic drugs increased, while the use of tranquilizing drugs declined over the years. High prescription rates and extensive use of sedative medication suggest a symptom-driven prescription (e.g., hyperarousal, insomnia) that can only be explained to a minor extent by existing comorbidities. The observed discrepancy with existing guidelines underlines the need for effective pharmacological and psychological treatment options in psychiatric inpatient settings.

Antipsychotic-induced akathisia (AIA) is a common and distressing adverse effect associated with many first- and second-generation antipsychotics. The risk of developing AIA can be minimized by administering the minimal effective dosage of an antipsychotic, avoiding rapid dose escalation and avoiding antipsychotic polypharmacy. Once AIA is diagnosed, patients should first receive an adjustment in their antipsychotic drug regimen (i.e. stop antipsychotic polypharmacy if applicable, lower the dosage of the antipsychotic medication or switch to an antipsychotic with lower AIA potential). If further intervention is needed, propranolol is considered as the first-choice anti-akathisia agent. Alternatively, low-dose mirtazapine, anticholinergics and benzodiazepines can also be considered.

Background Partial response to antidepressant medication as well as relapse and treatment resistance are common in major depressive disorder (MDD). Therefore, for most patients with MDD, there will be a need to consider changing antidepressant medication at some stage during the course of the illness. The PREDDICT study investigates the efficacy of augmenting vortioxetine with celecoxib. Methods We describe the method used in the PREDDICT study to change participants, who were already taking antidepressant medication at the time of the screening visit, to vortioxetine. We used a cross-titration to change study participants to vortioxetine. Results Of a total of 122 study participants who were randomized to receive vortioxetine plus celecoxib or vortioxetine plus placebo at the study baseline visit, 82 were taking antidepressant medication (other than vortioxetine) prior to randomization. These medications were selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants, mirtazapine, or agomelatine. Eighty of these 82 participants completed the changeover to vortioxetine as well as the study baseline visit. We found side effects were generally mild during this changeover period. In addition, there was a reduction in mean total Montgomery-Åsberg Depression Rating Scale score of 2.5 (SD 6.0) from study baseline to week 2 and a further reduction in mean total Montgomery-Åsberg Depression Rating Scale of 2.5 (SD 5.9) from week 2 to week 4. Conclusion Changing other antidepressants to vortioxetine can be done safely and was generally well-tolerated. However, there are some antidepressant classes, in particular monoamine oxidase inhibitors that require a washout period, which were not represented in this study. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR); ID number 12617000527369p; http://www.anzctr.org.au/ACTRN12617000527369p.aspx

This article outlines current guidelines for the pharmacological treatment of depression. For acute treatment of moderate to severe depression in the absence of specific factors, the recommendation is treatment with a selective serotonin reuptake inhibitor or mirtazapine. Other options for acute antidepressant treatment are discussed, and advantages and disadvantages of specific drugs are outlined. Recommendations for next-step treatment for patients with an inadequate response include increasing the dose, switching to another antidepressant, augmentation with another agent or using a combination of antidepressants. Again, recommendations for specific drugs are outlined, and the common advantages and disadvantages of specific drugs are listed in a table format. The options for non-pharmacological treatments are briefly explored in regards to symptom severity and other clinical features, and a list of non-pharmacological treatment options is provided.

AIM:To estimate the extent of off-label prescribing of antidepressants in older adults and to characterize patients with off-label vs on-label prescriptions of antidepressants using a large German health claims database. METHODS:Using data from the German Pharmacoepidemiological Research Database (GePaRD), we conducted a cross-sectional study in adults aged 65 years or older with a dispensation of an antidepressant between 1 January 2009 and 31 December 2015 after a period of 365 days without such a dispensation. We assessed the overall and annual proportion of off-label prescriptions of antidepressants by class and individual substance. RESULTS: Among 263 276 incident users of antidepressants, the proportion of off-label prescribing was 43.6% (95% CI 43.4-43.8%) with little variation between 2009 and 2015 (42.2-44.4%). The proportion of off-label use was higher in men (49%) than women (41%). While the proportion of off-label prescriptions was highest for tri- and tetracyclic antidepressants with 56.2% (amitriptyline 54.6%, maximum 65.9% for trimipramine), it amounted to 41.8% for selective serotonin reuptake inhibitors (citalopram 41.6%, maximum 46.0% for escitalopram) and was 51.2% for mirtazapine. Indicators of overall morbidity were similar in both groups, eg, pain was coded in 72% of off-label users vs 77% of on-label users (insomnia 20% vs 24%). CONCLUSION: Our study suggests a high prevalence of off-label antidepressant use among older adults in Germany, which was not restricted to certain classes of antidepressants or individual antidepressants. Given the unclear risk-benefit ratio, studies investigating the safety of off-label use among older adults for individual antidepressants are urgently needed.

Background: There is a lack of evidence to guide treatment of comorbid depression and anxiety. Preliminary evidence suggests mirtazapine may be effective in treating patients with both depression and anxiety symptoms. Methods: We undertook a secondary analysis of mirtazapine (MIR): a placebo-controlled trial of the addition of mirtazapine to a selective serotonin reuptake inhibitor or serotonin–norepinephrine reuptake inhibitor in treatment-resistant depression (TRD) in primary care. We subdivided participants into three groups by baseline generalized anxiety disorder score (GAD-7): severe (GAD-7 ⩾ 16), moderate (GAD-7 = 11–15), no/mild (GAD-7 ⩽ 10). We used linear regression including likelihood-ratio testing of interaction terms to assess how baseline anxiety altered the response of participants to mirtazapine as measured by 12-week GAD-7 and Beck Depression Inventory II (BDI-II) scores. Results: Baseline generalized anxiety moderated mirtazapine’s effect as measured by GAD-7 ( p = 0.041) and BDI-II ( p = 0.088) at 12 weeks. Participants with severe generalized anxiety receiving mirtazapine had lower 12-week GAD-7 score (adjusted difference between means (ADM) −2.82, 95% confidence interval (CI) −0.69 to −4.95) and larger decreases in BDI-II score (ADM −6.36, 95% CI −1.60 to −10.84) than placebo. Conversely, there was no anxiolytic benefit (ADM 0.28, 95% CI −1.05 to 1.60) or antidepressant benefit (ADM −0.17, 95% CI −3.02 to 2.68) compared with placebo in those with no/mild generalized anxiety. Conclusions: These findings extend the evidence for the effectiveness of mirtazapine to reduce generalized anxiety in TRD in primary care. These results may inform targeted prescribing in depression based on concurrent anxiety symptoms, although these conclusions are constrained by the post-hoc nature of this analysis.

To determine the relative variability and magnitude of symptomatic improvement in antidepressant-treated individuals compared to placebo-treated individuals, and to investigate moderating factors.Multiple databases and previous publications were searched through February 2019 to identify all randomized controlled trials comparing placebo and antidepressants in acute treatment of depression. Primary outcome was relative variability of change in symptom severity in antidepressant-treated individuals compared to placebo-treated patients quantified using the coefficient of variation ratio (CVR).Of 9389 identified records, 134 were found to be eligible (total n = 46,646). Antidepressant-treated patients showed a significantly greater magnitude (g = 0.28, 95% CI 0.25-0.30, p.0001) and lower variability (CVR = 0.94, 95% CI 0.93-0.95, p.0001) of change in symptom severity relative to placebo-treated patients. Compared to placebo antidepressant-related improvement was more uniform in older studies (z = 3.01, p = .003) and in studies where antidepressants showed greater efficacy (z = -7.21, p.0001). | Imipramine, moclobemide, amitriptyline and mirtazapine showed significantly lower CVR than several other antidepressants. However, no difference in CVR exists between multiple and single-neurotransmitter profile antidepressants (z = -0.01, p = .99).There is lower variability and greater magnitude of change in symptom severity with antidepressant treatment relative to placebo. This is not consistent with our hypothesis that there are distinct sub-groups of treatment-responsive and treatment-resistant patients with major depression. Our results in-stead suggest that antidepressants show a relatively uniform effect.

Managing treatment-resistant obsessive-compulsive disorder (TR-OCD) is often a challenge for clinicians, especially when adolescents and children are the patients. Approximately one-quarter to one-third of children with OCD do not respond to first-line treatments. Studies on the combination of venlafaxine and mirtazapine in children and adolescents are promising, but there is insufficient information about the use of this combination in TR-OCD. As far as we know, this is the first report of an adolescent patient with TR-OCD who responded favorably to a combination of a serotonin-norepinephrine reuptake inhibitor (venlafaxine), an alpha-2 adrenergic receptor antagonist (mirtazapine), and an atypical antipsychotic (aripiprazole). This case provides an example of the effective and safe use of the venlafaxine, mirtazapine, and aripiprazole given in combination in an adolescent with TR-OCD. [ Psychiatr Ann . 2020;50(11):509–512.]

Depression is common in older adults and those with cardiovascular disease. Although selective serotonin reuptake inhibitors generally have been shown to be safe to treat depression in these patients, it is important to identify additional antidepressants when selective serotonin reuptake inhibitors are not effective. This qualitative narrative review summarizes what is known about the cardiovascular side effects of some of the newer antidepressants. Twelve novel non-selective serotonin reuptake inhibitor antidepressants were identified from the literature: venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, mirtazapine, bupropion, vilazodone, vortioxetine, agomelatine, moclobemide, and ketamine-esketamine. A search restricted to publications written in English was conducted in PubMed and Google Scholar with the following search criteria: the specific antidepressant AND (QT OR QTc OR "heart rate" OR "heart rate variability" OR "hypertension" OR "orthostatic hypotension" OR "cardiovascular outcomes" OR "arrhythmia" OR "myocardial infarction" OR "cardiovascular mortality") AND (geriatric OR "older adults" OR "late life depression" OR "cardiovascular disease" OR "hospitalized" OR "hospitalized"). The recommended use, dosing ranges, cardiovascular effects, and general advantages and disadvantages of each of the drugs are discussed. Levomilnacipran and vilazodone have not received enough study to judge their safety in older patients or in those with, or at high risk for, cardiovascular disease. There is at least some evidence for possible adverse events with each of the other newer antidepressants that could be of concern in these patients. Nevertheless, with careful administration and attention to the potential adverse reactions for each drug, these may provide safe effective alternatives for older adults and patients with cardiovascular disease who do not respond to selective serotonin reuptake inhibitor antidepressants. However, more research on the safety and efficacy of these drugs in these specific patient populations is urgently needed.

Background/Aims A strong correlation between depression and irritable bowel syndrome with diarrhea (IBS-D) has been identified. The aim of this study is to identify the correlations among depression, structural factors, gastrointestinal (GI) and extra-GI symptoms, and efficacy of neuromodulators in patients with IBS-D. Methods Patients meeting the Rome III Diagnostic Criteria for IBS-D were enrolled. The intestinal symptoms and psychological states were evaluated using IBS-specific symptom questionnaires and Hamilton Depression Rating Scale. Results In total, 410 patients with IBS-D were enrolled, 28.8% (118/410) had comorbid depression. Patients with depression did not readily experience improvement in abdominal pain/discomfort after defecation, and had a higher prevalence of passing mucus, overlapping functional dyspepsia, and extra-GI symptoms. The structural factor “mental disorders” significantly correlated with main bowel symptom score and degree of pre-defecation abdominal pain/discomfort. No structural factor significantly correlated with bowel movements or stool form. Patients who had passing mucus, overlapping functional dyspepsia and extra-GI painful symptoms have higher score of “anxiety/somatization.” Patients with sexual dysfunction have higher score of “retardation symptoms.” In total, 28.3% of patients with IBS-D were prescribed neuromodulators. Baseline scores of “anxiety/somatization” and “retardation symptoms” positively correlated with improvement of diarrhea after paroxetine, and “sleep disturbances” positively correlated with improvement of abdominal pain/discomfort and diarrhea after mirtazapine. Conclusions Comorbid depression and higher scores of structural factors might aggravate GI and extra-GI symptoms other than bowel movements and stool form. Structural factors of Hamilton Depression Rating Scale correlated with efficacy of paroxetine and mirtazapine in patients with IBS-D. (J Neurogastroenterol Motil 2020;26:505-513)

Introduction Burns patients with psychiatric comorbidities may be at increased risk of harm from drug interactions. We aimed to identify the most common classes of drug involved, the potential clinical effects and any clinical evidence for their occurrence. Methods The International Burn Injury Database was used to identify all admission episodes for patients with a psychiatric comorbidity over a 5-year period at an adult regional burns unit. For this group, all drugs administered were categorised as either a new or continuing medication. Following this, an established online tool was used to screen for potential interactions between drugs. Where one was identified, a retrospective notes review was used to investigate whether it had occurred clinically. Results Ninety-one admission episodes were identified and records were available for 60 of these. In total, 145 incidences of severe potential interactions were identified (89 between a new drug and a continuing drug and 56 between two new drugs). The most frequently involved continuing drugs with the potential for interaction were neurotransmitter reuptake-inhibiting antidepressants and mirtazapine, while the most common new drugs identified were ondansetron, fentanyl and tramadol. The most frequently identified potential consequence of interactions were serotonin syndrome, arrhythmias and hypokalaemia. Clinically, there was minimal evidence for any interaction. Conclusion We have found many potential severe interactions in this patient group and psychotropic drugs were more commonly implicated than other drug classes. However, there was little evidence of the clinical manifestations of interaction. Serious drug interactions in burns patients are likely rare, but clinicians should be aware of the most likely drugs involved and the possible sequelae.

Background According to previous studies, older patients frequently have serum concentrations of antidepressant medication above the recommended reference range. Objective The aim of this study was to investigate whether prescribed doses of antidepressants and the proportion of individuals with serum concentrations above the recommended reference range in older individuals (≥ 65 years) have changed over a 10-year period in Norway. Methods Serum concentration measurements and prescribed daily doses of antidepressants in 2007 and 2017 were extracted from a therapeutic drug monitoring (TDM) database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. The database contains routine follow-up serum concentration measurements of psychotropic drugs for patients from all parts of the country. For citalopram, escitalopram, sertraline, mirtazapine and venlafaxine, the differences between 2007 and 2017 in mean prescribed doses and the proportion of patients with at least one serum concentration above the reference range, according to the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) guidelines, were compared. For the proportion of patients with serum concentrations above the recommended reference range, differences between individuals aged 65–79 and ≥ 80 years were also examined. Results The analyses of prescribed doses included 806 patients from 2007 and 1932 patients from 2017, with 972 and 2441 TDM samples, respectively. Between 2007 and 2017, modest reductions in prescribed daily doses were observed for citalopram (20 vs. 17 mg/day) and escitalopram (11 vs. 10 mg/day), but the proportion of patients with serum concentrations above the recommended reference range was unchanged for both drugs, i.e. 11.5% vs. 12.4% for citalopram and 3.6% vs. 2.9% for escitalopram. For mirtazapine and venlafaxine, prescribed doses were reduced from 28 to 25 mg/day and 150 to 125 mg/day, respectively. A significant reduction in the proportion of individuals with serum concentrations above the recommended reference range was observed for mirtazapine (27.1% vs. 11.5%) and for individuals aged ≥ 80 years using venlafaxine (60.0% vs. 30.0%). For sertraline, no differences in prescribed doses or serum concentrations above the recommended reference range were observed. Conclusions Over a 10-year period, prescribed doses of antidepressants have been slightly reduced in older Norwegian patients, but a considerable proportion is still exposed to high serum concentrations of antidepressants. Electronic supplementary material The online version of this article (10.1007/s40266-020-00784-9) contains supplementary material, which is available to authorized users.

Background Generic antidepressants are approved on the market based on evidence of bioequivalence to their brand-name versions. We aimed to assess whether generic antidepressants exert equal effectiveness as their brand-name counterparts for treating patients with depressive disorders. Methods In a nationwide, population-based cohort in Taiwan from 1997 through 2013, patients with a diagnosis of a depressive disorder aged between 18 and 65 years who were new users of antidepressant drugs were classified into either the brand-name group or the generic group. All patients were followed up until medication discontinuation or the end of the study period. We assessed the risk for hospitalization as a primary outcome and augmentation therapy, daily dose, medication discontinuation, or switching to another antidepressant as secondary outcomes. Results A total of 277 651 brand-name users (35.8% male; mean age: 41.2 years) and 270 583 generic users (35.8% male; mean age: 41.0 years) were divided into 10 different antidepressant groups (fluoxetine, sertraline, paroxetine, escitalopram, citalopram, venlafaxine, mirtazapine, moclobemide, imipramine, and bupropion). We found that patients treated with the generic form of sertraline, paroxetine, escitalopram, venlafaxine, mirtazapine, and bupropion demonstrated significantly higher risks of psychiatric hospitalization (adjusted hazard ratios ranged from 1.20–2.34), compared to their brand-name counterparts. The differences between brand-name antidepressants and their generic counterparts in secondary outcomes varied across different drugs. Conclusions Compared to most generic antidepressants, brand-name drugs exhibited more protective effects on psychiatric hospitalization for depressive patients. These findings could serve as an important reference for clinicians when encountering patients with depressive disorder.

Elderly individuals, particularly those with cognitive impairment, are oftentimes restless during the night, and this increases the distress of relatives, professional carers and themselves. A number of conditions other than dementia need to be considered from nyctophobia and insomnophobia, to pain, specific motor disorders during sleep, parasomnias as REM-sleep behaviour disorder, dipping, hypoglycemia, withdrawal or excessive tea, coffee and alcohol consumption. A clear-cut differential diagnosis between dementia and delirium is not always possible, as dementia is the major risk factor for confusional states decreasing the vulnerability by anticholinergic medication and any other disruptive factor, biological or psychological. Treatment of nocturnal agitation usually requires (1) reassurance and re-orientation; (2a) the discontinuation of anticholinergic substances; (2b) symptomatic psychotropic intervention; and (3) causal treatment of underlying problems. Benzodiazepines should only be used at the lowest necessary dosage for the shortest possible time, particularly in individuals who are already benzodiazepine-dependent. Quetiapine or mirtazapine at low dosages can be employed in patients with psychotic or depressive symptoms. Melatonin and its derivatives hold promise for chronic circadian rhythm disorders. There is no “one fits all” recipe for this notorious problem and each case needs to be examined individually.

STUDY OBJECTIVES: Angelman syndrome (AS) is a rare neurodevelopmental disorder that is characterized by developmental delay, intellectual disability, seizures, a characteristic happy personality, gait ataxia, tremulousness of the limbs, microcephaly, and anxiety. Severe sleep disturbances with the diminished need for sleep and abnormal sleep-wake cycles are seen in up to 90% of patients with AS. AS is caused by absent maternal expression of the gene UBE3A located in the 15q11.2-q13 locus. We hypothesized that selective antagonism of 5-HT(2) and 5-HT(3) serotonin receptors with mirtazapine would benefit sleep disturbances in patients with AS. METHODS: Institutional Review Board approval was obtained at Vanderbilt University Medical Center. Medical records of individuals seen in the Comprehensive Angelman Syndrome clinic were retrospectively reviewed to determine the use of mirtazapine for disordered sleep. Parents were asked to respond to a survey to assess the phenotypic features of sleep and behavioral disturbances in AS. They were asked about the use of medications for sleep, focusing on the benefits and risks of mirtazapine. RESULTS: A cohort of 8 individuals with AS, ranging in age from 3 to 16 years old with histories of sleep challenges, were treated with 3.75 to 30 mg of mirtazapine at bedtime for 0 to 36 weeks. Nocturnal awakenings were the most common sleep challenge reported. Seven of eight patients reported benefits from mirtazapine, including increased total sleep time, decreased nocturnal awakenings, and decreased time to fall asleep. The most significant side effects of mirtazapine were hyperphagia and weight gain. CONCLUSIONS: Individuals with AS have abnormal sleep-wake cycles and a high unmet medical need. Mirtazapine helped with sleep onset and nighttime awakenings in 7 of 8 patients, with 2 patients reporting a positive benefit with respect to behavior. These data suggest that mirtazapine may be considered for the treatment of sleep difficulties in patients with AS who remain refractory to more conventional therapies. Weight gain was a common side-effect and led to discontinuation of treatment in 1 patient. CITATION: Hanzlik E, Klinger SA, Carson R, Duis J. Mirtazapine for sleep disturbances in Angelman syndrome: a retrospective chart review of 8 pediatric cases. J Clin Sleep Med. 2020;16(4):591–595.

Background Stimulant drugs are second only to cannabis as the most widely used class of illicit drug globally, accounting for 68 million past-year consumers. Dependence on amphetamines (AMPH) or methamphetamine (MA) is a growing global concern. Yet, there is no established pharmacotherapy for AMPH/MA dependence. A comprehensive assessment of the research literature on pharmacotherapy for AMPH/MA dependence may inform treatment guidelines and future research directions. Methods We systematically reviewed the peer-reviewed literature via the electronic databases PubMed, EMBASE, CINAHL and SCOPUS for randomised controlled trials reported in the English language examining a pharmacological treatment for AMPH/MA dependence or use disorder. We included all studies published to 19 June 2019. The selected studies were evaluated for design; methodology; inclusion and exclusion criteria; sample size; pharmacological and (if included) psychosocial interventions; length of follow-up and follow-up schedules; outcome variables and measures; results; overall conclusions and risk of bias. Outcome measures were any reported impact of treatment related to AMPH/MA use. Results Our search returned 43 studies that met our criteria, collectively enrolling 4065 participants and reporting on 23 individual pharmacotherapies, alone or in combination. Disparate outcomes and measures (n = 55 for the primary outcomes) across studies did not allow for meta-analyses. Some studies demonstrated mixed or weak positive signals (often in defined populations, e.g. men who have sex with men), with some variation in efficacy signals dependent on baseline frequency of AMPH/MA use. The most consistent positive findings have been demonstrated with stimulant agonist treatment (dexamphetamine and methylphenidate), naltrexone and topiramate. Less consistent benefits have been shown with the antidepressants bupropion and mirtazapine, the glutamatergic agent riluzole and the corticotropin releasing factor (CRF-1) antagonist pexacerfont; whilst in general, antidepressant medications (e.g. selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs]) have not been effective in reducing AMPH/MA use. Conclusions No pharmacotherapy yielded convincing results for the treatment of AMPH/MA dependence; mostly studies were underpowered and had low treatment completion rates. However, there were positive signals from several agents that warrant further investigation in larger scale studies; agonist therapies show promise. Common outcome measures should include change in use days. Future research must address the heterogeneity of AMPH/MA dependence (e.g. coexisting conditions, severity of disorder, differences between MA and AMPH dependence) and the role of psychosocial intervention. Electronic supplementary material The online version of this article (10.1007/s40263-020-00711-x) contains supplementary material, which is available to authorized users.

Background: Clozapine has been used in treatment-resistant patients with schizophrenia. However, only 40% of patients with treatment-resistant schizophrenia have response to clozapine. Many augmentation strategies have been proposed to treat those clozapine-resistant patients, but the results are inconclusive. In this review, we intended to review papers dealing with the augmentation strategies in the treatment of clozapineresistant patients with schizophrenia. Method: We reviewed randomized, double-blind, placebo- or sham-controlled trials (RCT) for clozapine-resistant patients with schizophrenia in Embase, PsycINFO, Cochrane, and PubMed database from January 1990 to June 2019. Results: Antipsychotics, antidepressants, mood stabilizers, brain stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation, and other strategies, were used as an augmentation in clozapine-resistant patients with schizophrenia. Except for better evidence in memantine with 2 RCTs and cognitive behavior therapy in 2 studies to support its effectiveness, we found that all the other effective augmentations, including sulpiride, ziprasidone, duloxetine, mirtazapine, ECT, sodium benzoate, ginkgo biloba, and minocycline, had only one RCT with limited sample size. Conclusion: In this review, no definite effective augmentation strategy was found for clozapine-resistant patients. Some potential strategies with beneficial effects on psychopathology need further studies with a larger sample size to support their efficacy.

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).

espanolLa depresion es un trastorno psiquiatrico que representa un problema de salud mundial. Afecta a cerca de 350 millones de personas, predominantemente mujeres. Sin embargo, algunos reportes indican que su incidencia en hombres esta aumentando, por lo que es necesario buscar opciones de tratamiento que sean igualmente efectivas en ambos sexos. Objetivo Analizar si existen diferencias relacionadas con el sexo en el efecto de tipo antidepresivo de la mirtazapina y la venlafaxina, y considerar los posibles mecanismos neuroquimicos involucrados. Metodo se administraron mirtazapina (40 mg/kg) o venlafaxina (60 mg/kg) en esquema subcronico a grupos independientes de ratas macho y hembra ovariectomizadas tratadas con estradiol y progesterona. Se evaluaron el efecto tipo antidepresivo y las conductas activas (nado y escalamiento) utilizando la prueba de nado forzado (PNF). Resultados a) tanto la mirtazapina como la venlafaxina redujeron la inmovilidad en la PNF en machos y hembras; b) ambos antidepresivos incrementaron las conductas activas en machos; c) en hembras, la mirtazapina y la venlafaxina produjeron un aumento del nado, pero no modificaron el escalamiento. Discusion y conclusion En machos, los efectos de la mirtazapina y la venlafaxina en la PNF se deben a su accion sobre los sistemas serotonergico y noradrenergico; en cambio, en hembras solo se modifica la conducta de nado, lo que sugiere que el estradiol modula las acciones de ambos antidepresivos sobre el sistema serotoninergico. EnglishIntroduction: depression is a global health problem with nearly 350 million people affected, mainly women. However, nowadays a rising amount of men are being diagnosed. This makes necessary the screening of new treatment options that are effective in women as well as in men. Objective: to analyze if the administration of mirtazapine and venlafaxine to male and female rats shows a sex-related antidepressant-like effect, and the possible associated neurochemical mechanisms. Method: mirtazapine (40 mg/kg) or venlafaxine (60 mg/kg) were administered subchronically to young adult male and female (ovariectomized and steroid-primed) rats, and their antidepressant-like effects were evaluated using the forced swim test (FST). The active behaviors, swimming and climbing, were also analyzed. Results: a) mirtazapine and venlafaxine reduced immobility in the FST in males and females; b) both antidepressants increased climbing and swimming in male rats; c) in female rats, mirtazapine and venlafaxine only increased swimming. Discussion and conclusion: in males, the effects of mirtazapine and venlafaxine seem to be produced by the activation of the serotonergic and noradrenergic systems. Conversely, estradiol might be modulating the mechanisms of action of both antidepressants in females producing only an increased swimming and suggesting the participation of the serotonergic system.

BACKGROUND In fixed dose antidepressant trials, the lower range of the licensed dose achieves the optimal balance between efficacy and tolerability. Whether flexible upward titration while side effects permit provides additional benefits is unknown. METHODS We did a systematic review of placebo-controlled randomised trials that examined selective serotonin reuptake inhibitors (SSRIs), venlafaxine or mirtazapine in the acute treatment of major depression. Our primary outcome was response, defined as 50% or greater reduction in depression severity. Secondary outcomes included dropouts due to adverse effects and dropouts for any reason. We conducted random effects meta-analyses to calculate the ratios of odds ratios (RORs) between trials comparing the flexible dose titrating above the minimum licensed dose against placebo and those comparing the fixed minimum licensed dose against placebo. RESULTS We included 123 published and unpublished randomized controlled trials (29,420 participants). There was no evidence supporting efficacy of the flexible dosing over the fixed low dose of SSRIs (ROR 0.96, 95%CI: 0.73 to 1.25), venlafaxine (1.24, 0.96 to 1.60) or mirtazapine (0.77, 0.33 to 1.78). No important differences were noted for tolerability or for any subgroup analyses except the superior efficacy of venlafaxine flexible dosing between 75-150 mg over the fixed 75 mg (1.30, 1.02 to 1.65). CONCLUSION There was no evidence to support added value in terms of efficacy, tolerability or acceptability of flexibly titrating up the dosage over the minimum licensed dose of SSRIs or mirtazapine. For venlafaxine, increased efficacy can be expected by flexibly titrating up to 150 mg.

BackgroundThis study aimed to examine the efficacy of combining paroxetine and mirtazapine v. switching to mirtazapine, for patients with major depressive disorder (MDD) who have had an insufficient response to SSRI monotherapy (paroxetine) after the first 2 weeks of treatment.MethodsThis double-blind, randomized, placebo-controlled, three-arm study recruited participants from five hospitals in China. Eligible participants were aged 18–60 years with MDD of at least moderate severity. Participants received paroxetine during a 2-week open-label phase and patients who had not achieved early improvement were randomized to paroxetine, mirtazapine or paroxetine combined with mirtazapine for 6 weeks. The primary outcome was improvement on the Hamilton Rating Scale for Depression 17-item (HAMD-17) scores 6 weeks after randomization.ResultsA total of 204 patients who showed early non-response to paroxetine monotherapy were randomly assigned to receive either mirtazapine and placebo (n = 68), paroxetine and placebo (n = 68) or mirtazapine and paroxetine (n = 68), with 164 patients completing the outcome assessment. At week 8, the least squares (LS) mean change of HAMD-17 scores did not significantly differ among the three groups, (12.98 points) in the mirtazapine group, (12.50 points) in the paroxetine group and (13.27 points) in the mirtazapine plus paroxetine combination group. Participants in the paroxetine monotherapy group were least likely to experience adverse effects.ConclusionsAfter 8 weeks follow-up, paroxetine monotherapy, mirtazapine monotherapy and paroxetine/mirtazapine combination therapy were equally effective in non-improvers at 2 weeks. The results of this trial do not support a recommendation to routinely offer additional treatment or a switch in treatment strategies for MDD patients who do not show early improvement after 2 weeks of antidepressant treatment.

A 2-year-old male neutered domestic shorthair cat from Florida, USA, presented with a one-month history of multiple subcutaneous nodules affecting the entire body. Dermatohistopathology revealed nodular to diffuse, eosinophilic, histiocytic, and mastocytic dermatitis and panniculitis with collagen flame figures, and many nematode larvae and adults within nodules and migration tracts. The worms were morphologically consistent with Dirofilaria striata. The serum antibody test was positive for D. immitis with a negative antigen assay result (both with and without heat treatment), and microfilariae were not recovered by a modified Knott's test. PCR and sequencing of 18S rRNA and mitochondrial 12S rRNA and cytochrome oxidase subunit I genes confirmed the presence of a Dirofilaria spp. Unfortunately, there is no available reference sequence or material for D. striata for comparison. The cat was treated with monthly topical 10% imidacloprid/1% moxidectin. Lesions clinically resolved within one month, but new lesions appeared on different locations despite the monthly treatment. Resolution occurred without changing the treatment regimen, as no additional nodules were noted after 1 year. This Dirofilaria sp. may cause subcutaneous nodules in the domestic cat and should be included in the differential diagnosis for felines with nodular dermatitis, and is present in Florida.

Mirtazapine (MTZ) is an atypical antidepressant frequently prescribed for the management of major depressive disorder. It has multiple mechanisms of action, which probably contribute to the several side effects encountered with this medication. Hyperkinetic movement disorders induced by MTZ have been rarely reported in the literature. To the best of authors’ knowledge, there are five cases of dystonia (DTN) secondary to MTZ use, but this study reports the youngest individual in a nonpsychiatric MTZ indication. We report a case of an adult woman who presented with axial and cervical DTN-type laterocollis after 5 days of MTZ use, which was indicated for hot flashes. A comprehensive review of the cases and a mechanism assumption are performed.

Importance Hyperemesis gravidarum (HEG) affects 0.3% to 3% of pregnancies and requires additional therapies beyond those commonly used for less severe instances of nausea and vomiting of pregnancy (NVP). Differentiating between NVP and HEG is a vital yet challenging function for any obstetrician. The literature for management of HEG is lacking compared with that of NVP. Objective Review etiology of NVP/HEG highlights key considerations in the workup of HEG as they compare to NVP and explore management options for recalcitrant HEG focusing principally on how they affect maternal and fetal outcomes and secondarily on where data are nonprescriptive. Evidence acquisition This was a literature review primarily using PubMed and Google Scholar. Results Short-course corticosteroids and treatment for Helicobacter pylori have the most favorable risk-reward profiles of the 4 pharmacologic therapies evaluated. Mirtazapine and diazepam may have a place in highly selected patients. If nutritional supplementation is required, enteral nutrition is strictly preferred to parenteral nutrition. Postpyloric feeding approaches are less likely to induce vomiting. Surgically placed feeding tubes are less likely to be dislodged and may be worth the invasive insertion procedure if nasogastric or nasojejunal tubes are not tolerated. Conclusions and relevance Hyperemesis gravidarum is a diagnosis reserved for refractory cases of NVP and therefore by definition poses treatment challenges. Any clinical presentation that lent itself to prescriptive, algorithmic management would likely fall short of the diagnostic criteria for HEG. However, data can inform management on a patient-by-patient basis or at least help patient and provider understand risks and benefits of therapies reserved for refractory cases.

Extending from the ‘triple wave epidemic’ of opioid-related overdose deaths, a ‘fourth wave’ of high mortality involving methamphetamine and cocaine use has been gathering force. This paper provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, and medical and behavioral treatments

Background There has been a steady increase in the number of primary care patients receiving long-term maintenance antidepressant treatment, despite limited evidence of a benefit of this treatment beyond 8 months. Objective The ANTidepressants to prevent reLapse in dEpRession (ANTLER) trial investigated the clinical effectiveness and cost-effectiveness of antidepressant medication in preventing relapse in UK primary care. Design This was a Phase IV, double-blind, pragmatic, multisite, individually randomised parallel-group controlled trial, with follow-up at 6, 12, 26, 39 and 52 weeks. Participants were randomised using minimisation on centre, type of antidepressant and baseline depressive symptom score above or below the median using Clinical Interview Schedule – Revised (two categories). Statisticians were blind to allocation for the outcome analyses. Setting General practices in London, Bristol, Southampton and York. Participants Individuals aged 18–74 years who had experienced at least two episodes of depression and had been taking antidepressants for ≥ 9 months but felt well enough to consider stopping their medication. Those who met an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of depression or with other psychiatric conditions were excluded. Intervention At baseline, participants were taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg. They were randomised to either remain on their current medication or discontinue medication after a tapering period. Main outcome measures The primary outcome was the time, in weeks, to the beginning of the first depressive episode after randomisation. This was measured by a retrospective Clinical Interview Schedule – Revised that assessed the onset of a depressive episode in the previous 12 weeks, and was conducted at 12, 26, 39 and 52 weeks. The depression-related resource use was collected over 12 months from medical records and patient-completed questionnaires. Quality-adjusted life-years were calculated using the EuroQol-5 Dimensions, five-level version. Results Between 9 March 2017 and 1 March 2019, we randomised 238 participants to antidepressant continuation (the maintenance group) and 240 participants to antidepressant discontinuation (the discontinuation group). The time to relapse of depression was shorter in the discontinuation group, with a hazard ratio of 2.06 (95% confidence interval 1.56 to 2.70; p Conclusions Patients who discontinue long-term maintenance antidepressants in primary care are at increased risk of relapse and withdrawal symptoms. However, a substantial proportion of patients can discontinue antidepressants without relapse. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants and improve shared decision-making. The participants may not have been representative of all people on long-term maintenance treatment and we could study only a restricted range of antidepressants and doses. Identifying patients who will not relapse if they discontinued antidepressants would be clinically important. Trial registration Current Controlled Trials ISRCTN15969819 and EudraCT 2015-004210-26. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 69. See the NIHR Journals Library website for further project information.

Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha- and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha- and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebo- controlled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and larger-scale studies of promising agents with positive results from smaller trials.

Background\ud 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.\ud \ud Methods\ud 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.\ud \ud Findings\ud 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).\ud \ud Interpretation\ud 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.\ud \ud Funding\ud UK National Institute for Health Research Health Technology Assessment Programme.

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.

Syncope associated with bradycardia and ventricular arrhythmia is an indication of cardiac intervention. However, in adolescent patients with anorexia nervosa, the management of syncope and arrhythmia can be different. We present a case of a 17-year-old boy who was admitted to the hospital because of syncope during exercise. Electrocardiographic monitoring showed that his mean heart rate was 41 beats/minute, with many long pauses and frequent premature ventricular contractions. These results suggested that the syncope was probably caused by arrythmia. He had been on a diet and had lost 20 kg in the past 6 months, with a body mass index of only 15.3 kg/m2. He was diagnosed with anorexia nervosa. Pacemaker implantation or ablation was not performed. Refeeding therapy was performed with mirtazapine. A follow-up showed a stepwise increase in his heart rate and a stepwise decrease in premature ventricular contractions, with an increase in his body weight. The findings from this case show that vagal hyperactivity associated with anorexia nervosa might lead to multiple premature ventricular contractions and bradycardia.

BACKGROUNDPatients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting.METHODSWe conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings.RESULTSA total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; PCONCLUSIONSAmong patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819. opens in new tab.)

Post-fundoplication dyspepsia is a common complication of gastric fundoplication surgeries. This can be attributable to the loss of fundal relaxation, decreased gastric accommodation, and/or alterations in gastric motility and sensitivity following fundoplication. The role of neuromodulators in the management of such symptoms is unknown. We retrospectively assessed the efficacy of neuromodulators such as tricyclic antidepressants, buspirone, and mirtazapine for the management of post-fundoplication dyspepsia.