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Pattern of treatment of behavioural and psychological symptoms of dementia and pain: evidence on pharmacoutilization from a large real-world sample and from a centre for cognitive disturbances and dementia.
Scuteri, D, Vulnera, M, Piro, B, Bossio, RB, Morrone, LA, Sandrini, G, Tamburin, S, Tonin, P, Bagetta, G, Corasaniti, MT
European journal of clinical pharmacology. 2021;(2):241-249
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Abstract
PURPOSE Data concerning the number of diagnoses and of the drugs prescribed to patients affected by dementia are still scarce. Here we test whether or not (1) prescription of symptomatic drugs against Alzheimer's disease (AD) may approximate the number of patients affected by dementia in Italy and (2) adherence to this treatment affects the pattern of prescription of drugs (i.e. antipsychotics and antidepressants) for behavioural and psychological symptoms of dementia (BPSD) and the previously reported limited prescription of analgesics. METHODS This retrospective observational study concerns 84,235 subjects older than 60 years and registered in the provincial prescription database of the health district of Cosenza accounting for a population of 298,000 inhabitants. The prescribing pattern of antipsychotics, antidepressants, and analgesics has been investigated in patients receiving concurrent prescriptions of acetylcholinesterase inhibitors (AChEI) and/or memantine. Data from a single centre for cognitive disturbances and dementia (CDCD) in the same health district were used to explore at which stage dementia was diagnosed. The study was approved by Calabria Region Ethical Committee no. 31/2017 and registered on October 31, 2017. RESULTS The data show that 859 patients are treated with AChEI and/or memantine; 420 patients (48.89%) receive at least 80% of the recommended medications. CDCD data indicate a delay in dementia diagnosis, which often was made when the patients were moderately to severely demented (Mini Mental State Examination, MMSE ≤ 20). Adherence did not influence prescription of most of the drugs explored, but use of non-steroidal anti-inflammatory drugs was higher in non-adherent patients. Antipsychotics and antidepressants are frequently used (20.61-20.71% and 42.37-51.43%, respectively), and this, at least in part, might stem from the observed under-treatment of chronic pain (opioids are prescribed in the 4.76% and 12.46% of adherent and non-adherent patients and gabapentin and pregabalin are used in the 4.29% and 4.07% of adherent and non-adherent patients respectively), resulting in more frequent BPSD. 16.43% of patients receive antipsychotics for longer than 6-12 weeks. CONCLUSION This 2-year period study, including a wide cohort of community demented patients, shows that dementia is diagnosed late and that prevalence of BPSD prescriptions is high and not impacted by adherence to anti-dementia drugs. The rate of prescription of potentially harmful antipsychotics and antidepressants appears to be high though whether the concomitantly observed limited prescription of analgesics might be a contributing factor needs to be further investigated. Our data support the development of strategies to improve the management of BPSD.
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Serotonin Transporter Gene Promoter Hypomethylation as a Predictor of Antidepressant Treatment Response in Major Depression: A Replication Study.
Schiele, MA, Zwanzger, P, Schwarte, K, Arolt, V, Baune, BT, Domschke, K
The international journal of neuropsychopharmacology. 2021;(3):191-199
Abstract
BACKGROUND The serotonin transporter gene (SLC6A4; 5-HTT; SERT) is considered a prime candidate in pharmacogenetic research in major depressive disorder (MDD). Besides genetic variation, recent advances have spotlighted the involvement of epigenetic mechanisms such as DNA methylation in predicting antidepressant treatment response in "pharmaco-epigenetic" approaches. In MDD, lower SLC6A4 promoter methylation has been suggested to predict impaired response to serotonergic antidepressants. The present study sought to replicate and extend this finding in a large, independent sample of MDD patients. METHODS The sample comprised n = 236 Caucasian patients with MDD receiving antidepressant medication in a naturalistic treatment setting. Functional DNA methylation of 9 CpG sites located in the SLC6A4 promoter region was analyzed via direct sequencing of sodium bisulfite- treated DNA extracted from blood cells. Patients were assessed over the course of a 6-week in-patient treatment using the Hamilton Depression Scale (HAM-D). RESULTS Results confirm relative SLC6A4 hypomethylation to predict impaired antidepressant response both dimensionally and categorically (HAM-D reductions < 50%) and to furthermore be indicative of nonremission (HAM-D > 7). This also held true in a homogenous subgroup of patients continuously treated with selective serotonin reuptake inhibitors or serotonin/noradrenaline reuptake inhibitors (n = 110). CONCLUSIONS Impaired response to serotonergic antidepressants via SLC6A4 hypomethylation may be conveyed by increased gene expression and consequently decreased serotonin availability, which may counteract the effects of serotonergic antidepressants. The present results could in the future inform clinical decision-making towards a more personalized treatment of MDD.
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Treatment with montelukast and antidepressive medication-a symmetry analysis.
Winkel, JS, Damkier, P, Hallas, J, Henriksen, DP
Pharmacoepidemiology and drug safety. 2018;(12):1409-1415
Abstract
PURPOSE Leukotriene receptor antagonists are used in asthma and rhinitis treatment. Pharmacovigilance data have suggested an association between montelukast and depression, but the association has not been established in controlled study designs. We described the association between initiation of montelukast and depression, using prescriptions of antidepressants as a surrogate marker, and assessed whether the association was related to the underlying asthma disease. METHODS We performed a symmetry analysis, with a study period from January 1, 2000 to December 31, 2016, using 3 nationwide Danish registers. We included all adults, who filled their first prescription of montelukast and antidepressants within an interval of 1 year. In the absence of an association between montelukast and antidepressant use, a symmetrical distribution of prescriptions is expected before and after montelukast initiation (ie, a sequence ratio [rc ] of 1.0). We subcategorized the subjects after the severity of underlying asthma disease. RESULTS In total, 4450 subjects filled their first prescriptions of both montelukast and antidepressants within a 1-year interval: 2434 redeemed their first prescription of montelukast before antidepressants, and 2016 redeemed the medications in the opposite order (rc 1.21 [95% CI 1.14-1.28]). We found rc above unity in groups with long-acting asthma treatment, but no increase in antidepressant prescription, when stratifying by the asthma severity. CONCLUSION We found a weak association between the use of montelukast and the risk of being prescribed an antidepressant, unlikely to be of clinical relevance. Stratified analyses suggest that this association may relate to asthma, rather than to montelukast.
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Predictors of Depressive Relapse in Women Undergoing Infertility Treatment.
Freeman, MP, Lee, H, Savella, GM, Sosinsky, AZ, Marfurt, SP, Murphy, SK, Cohen, LS
Journal of women's health (2002). 2018;(11):1408-1414
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BACKGROUND Despite high prevalence rates among women of mood disorders and of infertility, there is a paucity of systematic data to inform the treatment of women at risk for psychiatric morbidity in the context of assisted reproductive technologies (ART). The objective was to delineate predictors of depressive relapse in women with histories of mood disorders during ART, including the role of psychotropic medication continuation. METHODS This was a prospective observational study of women undergoing ART with past diagnoses of major depressive disorder (MDD) or bipolar depression. For 6-months, follow-up included assessments of mood, perceived stress, and partner support. A subsample participated in biomarker collection. Depressive relapse was confirmed using Mini-International Neuropsychiatric Interview. RESULTS N = 38 were evaluable. Participants with MDD (N = 25) experienced a depressive relapse rate of 44.0%. Relapse rates among antidepressant maintainers (N = 15; relapse rate = 40.0%) and antidepressant discontinuers (N = 10; relapse rate = 50.0%) were not significantly different. Among participants with bipolar disorder (N = 13), the overall relapse rate was 30.8%. Among psychotropic medication maintainers (N = 10), 40.0% relapsed, and among discontinuers (N = 3), none relapsed. Scores on the Perceived Stress Scale correlated with relapse risk (odds ratio [OR] = 1.17, 95% confidence interval [CI]: 1.08-1.26, p = 0.0065). C-reactive protein was associated with relapse (OR = 1.92, 95% CI: 1.43-2.55, p < 0.0001); blood cortisol and interleukin-6 were not. CONCLUSIONS Risk of depressive relapse among women undergoing ART is considerable. Medication continuation does not adequately confer relapse prevention. Stress and inflammation appear to contribute to risk of relapse. Additional strategies to mitigate depressive relapse in at-risk women undergoing ART are needed.
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Impact of antidepressant treatment during pregnancy on obstetric outcomes among women previously treated for depression: an observational cohort study.
Venkatesh, KK, Castro, VM, Perlis, RH, Kaimal, AJ
Journal of perinatology : official journal of the California Perinatal Association. 2017;(9):1003-1009
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OBJECTIVE To examine the impact of pharmacologic treatment for depression on obstetric outcomes in women treated for depression during the 2 years prior to pregnancy. STUDY DESIGN Observational cohort study among 2859 women treated for depression during the 2 years prior to pregnancy. The primary exposure was any antidepressant treatment during pregnancy. Secondary analyses examined the impact of treatment by period of antidepressant exposure. Multivariable logistic regression models as well as propensity score analysis was utilized. RESULTS Among 2859 women, 1648 (58%) were treated with antidepressant medication during pregnancy. Women who received antidepressants had no difference in preterm and early-term deliveries, Apgar scores, and small for gestational age (SGA); they had a lower likelihood of breastfeeding (adjusted odds ratio (AOR) 0.69, (95% confidence interval (CI): 0.51 to 0.94)). In secondary analysis, women who used antidepressants all three trimesters who delivered at term were more likely to deliver early term (AOR 1.36, (95% CI: 1.09 to 1.72)). Women who were treated with antidepressants only during the first and second trimesters had a reduced likelihood of SGA (AOR: 0.51 (95% CI: 0.32 to 0.83)). Generally similar results were observed with propensity score analysis. CONCLUSION Antidepressant exposure during pregnancy does not confer an increased risk of preterm birth nor growth restriction in women recently treated for depression, but also does not appear to markedly improve these outcomes.
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Investigating incretin-based therapies as a novel treatment for depression in type 2 diabetes: Findings from the South London Diabetes (SOUL-D) Study.
Moulton, CD, Pickup, JC, Amiel, SA, Winkley, K, Ismail, K
Primary care diabetes. 2016;(2):156-9
Abstract
We aimed to investigate the association between incretin-based therapies and 1-year change in depressive symptoms in a cohort of 1735 patients with newly diagnosed type 2 diabetes. The incretin group experienced significant reduction in depressive symptoms compared to controls. This was independent of HbA1c and may be mediated by an anti-inflammatory mechanism.
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Quantifying midbrain serotonin transporter in depression: a preliminary study of diagnosis and naturalistic treatment outcome.
Tsai, HC, Lin, SH, Chen, PS, Chang, HH, Lee, IH, Yeh, TL, Chen, KC, Chiu, NT, Yao, WJ, Liao, MH, et al
Pharmacopsychiatry. 2015;(2):58-64
Abstract
INTRODUCTION Serotonin may play an important role in the pathology of major depressive disorder (MDD). However, the relationship between serotonin transporter (SERT) availability and the medical outcome of antidepressant treatment is uncertain. METHODS In this naturalistic study, SERT availability (expressed as the specific uptake ratio, SUR) in the midbrain of 17 drug-free patients with MDD and 17 controls matched for age and gender was measured using SPECT with [(123)I]ADAM. The severity of MDD was measured by the Hamilton Depression Rating Scale before, and after 6 weeks of non-standardized antidepressant treatment. RESULTS A total of 12 patients completed the study. The SUR of the patients with MDD was significantly lower than that of the healthy controls. The SUR of SERT was not found to have a linear relationship with the treatment outcome; however, supplemental analysis found a curvilinear relationship between treatment outcome and the SUR of SERT. DISCUSSION The findings indicate that the SUR of SERT is lower in patients with MDD; however it did not predict treatment outcome in a linear fashion. Studies with larger sample sizes are required.
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Antidepressant medication use and trajectories of fasting plasma glucose, glycated haemoglobin, β-cell function and insulin sensitivity: a 9-year longitudinal study of the D.E.S.I.R. cohort.
Azevedo Da Silva, M, Dugravot, A, Balkau, B, Roussel, R, Fumeron, F, Elbaz, A, Canonico, M, Singh-Manoux, A, Nabi, H, ,
International journal of epidemiology. 2015;(6):1927-40
Abstract
BACKGROUND Use of antidepressants is seen to be a risk factor for type 2 diabetes, even though the underlying mechanisms remain unclear. We examined whether antidepressant use was associated with change in fasting plasma glucose, glycated haemoglobin (HbA1c), β-cell function (HOMA2-%B) and insulin sensitivity (HOMA2-%S) over time. METHODS Participants in the French D.E.S.I.R. cohort study included over 4700 men (48.1%) and women, free of diabetes, aged 30-65 years at baseline in 1994-96 (D.E.S.I.R. 0), who were followed for 9 years at 3-yearly intervals (D.E.S.I.R. 3, 1997-99; 6, 2000-02; 9, 2003-05). Antidepressant use, fasting plasma glucose, HbA1c, HOMA2-%B and HOMA2-%S were assessed concurrently at four medical examinations. Linear mixed models were used to examine the cross-sectional and longitudinal associations of time-dependent antidepressant use with changes in these four biological parameters. RESULTS Mean fasting plasma glucose and HbA1c increased whereas HOMA2-%B and HOMA2-%S decreased over the follow-up. In a fully adjusted model, there were no differences in: mean fasting plasma glucose (β = 0.01 mmol/l, P = 0.702); HbA1c (β = 0.01 %, P = 0.738); HOMA2-%B (β = 0.00, P = 0.812); or HOMA2-%S (β =-0.01, P = 0.791) at baseline (1994-96) between antidepressant users and non-users. The interaction term with time also suggested no differences in the annual change in: fasting plasma glucose (β = 0.00 mmol/l, P = 0.322); HbA1c (β = 0.00 %, P = 0.496); HOMA2-%B (β = 0.00, P = 0.609); or HOMA2-%S (β = 0.00, P = 0.332) between antidepressant users and non-users. Similar associations were observed in analyses of type and cumulative use of antidepressants over follow-up. CONCLUSION Our longitudinal data show that use of antidepressants is not associated with altered glucose metabolism, suggesting that the association between antidepressant use and diabetes reported by previous studies may not be causal. Detection bias or clinical ascertainment bias may account for much of this apparent association.
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Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment.
Saunders, EF, Reider, A, Singh, G, Gelenberg, AJ, Rapoport, SI
Bipolar disorders. 2015;(7):729-42
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OBJECTIVES Omega (n)-3 and n-6 polyunsaturated fatty acids (PUFAs) are molecular modulators of neurotransmission and inflammation. We hypothesized that plasma concentrations of n-3 PUFAs would be lower and those of n-6 PUFAs higher in subjects with bipolar disorder (BD) compared to healthy controls (HCs), and would correlate with symptom severity in subjects with BD, and that effective treatment would correlate with increased n-3 but lower n-6 PUFA levels. Additionally, we explored clinical correlations and group differences in plasma levels of saturated and monounsaturated fatty acids. METHODS This observational, parallel group study compared biomarkers between HCs (n = 31) and symptomatic subjects with BD (n = 27) when ill and after symptomatic recovery (follow-up). Plasma concentrations of five PUFAs [linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)], two saturated fatty acids (palmitic acid and stearic acid) and two monounsaturated fatty acids (palmitoleic acid and oleic acid) were measured in esterified (E) and unesterified (UE) forms. Calculated ratios included UE:E for the five PUFAs, ratios of n-3 PUFAs (DHA:ALA, EPA:ALA and EPA:DHA), and the ratio of n-6:n-3 AA:EPA. Comparisons of plasma fatty acid levels and ratios between BD and HC groups were made with Student t-tests, and between the BD group at baseline and follow-up using paired t-tests. Comparison of categorical variables was performed using chi-square tests. Pearson's r was used for bivariate correlations with clinical variables, including depressive and manic symptoms, current panic attacks, and psychosis. RESULTS UE EPA was lower in subjects with BD than in HCs, with a large effect size (Cohen's d = 0.86, p < 0.002); however, it was not statistically significant after correction for multiple comparisons. No statistically significant difference was seen in any plasma PUFA concentration between the BD and HC groups after Bonferroni correction for 40 comparisons, at p < 0.001. Neither depressive severity nor mania severity was correlated significantly with any PUFA concentration. Exploratory comparison showed lower UE:E EPA in the BD than the HC group (p < 0.0001). At follow-up in the BD group, UE, E DHAALA, and UE EPAALA were decreased (p < 0.002). Exploratory correlations of clinical variables revealed that mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. No plasma fatty acid level or ratio correlated with self-reported n-3 PUFA intake or use of medication by class. CONCLUSIONS A large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state may be important factors in vulnerability to a mood state. Altered n-3 PUFA ratios could indicate changes in PUFA metabolism concurrent with symptom improvement. Our findings are consistent with preclinical and postmortem data and suggest testing interventions that increase n-3 and decrease n-6 dietary PUFA intake.
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Depression in multiple sclerosis: a long-term longitudinal study.
Koch, MW, Patten, S, Berzins, S, Zhornitsky, S, Greenfield, J, Wall, W, Metz, LM
Multiple sclerosis (Houndmills, Basingstoke, England). 2015;(1):76-82
Abstract
BACKGROUND Depression is a common comorbidity in multiple sclerosis (MS), but little is known about its long-term prognosis. Depression in the general population is usually episodic with relatively short-lasting depressive episodes. In this study we investigate the long-term prognosis of depression in MS. METHODS Using data from a large longitudinal observational study and from the Calgary MS clinic database, we investigated changes in Center for Epidemiological Studies Depression Scale (CESD) scores in MS patients over four years of follow-up. We used logistic regression to investigate the association of the factors sex, age, disease duration, Expanded Disability Status Scale (EDSS), depression at baseline, and antidepressant use with depression at each year of follow-up. RESULTS CESD scores remained largely stable, or decreased slightly over four years of follow-up, whereas EDSS scores steadily increased. Depression at baseline was the strongest predictor of depression at follow-up; the other factors were not or not consistently associated with depression at follow-up. As expected, antidepressant use was associated with a greater risk of depression at follow-up. Starting and stopping antidepressant treatment during follow-up was not associated with the risk of depression at follow-up or with significant change in CESD scores. CONCLUSION In contrast to depression in the general population, depression in MS is largely chronic, which suggests a different pathophysiology.