The main study purposes were to determine: whether antidepressant (AD) use increases the risk of type 2 diabetes mellitus; and whether results differ when using different methodological designs: retrospective cohort design and nested case-control design. A retrospective Texas Medicaid database analysis of new AD (exposed cohort) and benzodiazepine (unexposed cohort [BZ]) users from January 1, 2002 to December 31, 2009 was conducted. Patients aged 18-64 years without diabetes at cohort entry were included. The primary outcome was incident diabetes and the main independent variable was AD vs. BZ use. Covariates included age, gender, race/ethnicity, medication adherence, persistence, number of concomitant diabetogenic medications, Chronic Disease Score, treatment duration, year of cohort entry, and use of both AD and BZ at index. Regression analyses (adjusted) were used to address the study purposes. Of the study cohort (N=44,715), 35,552 (79.5%) were AD users and 9,163 (20.5%) were BZ users. Patients were followed for an average of 2.3±1.9 years (Median=1.8 years), were on average 38.6±14.2 years old, and 69.3% were female. Using the retrospective cohort design, AD use was associated with a 48.9% increase (logistic regression) and 60.0% increase (Cox regression) in the risk of diabetes compared to BZ use (logistic regression analysis: RR[subscript adj]. =1.489; 95% CI: 1.331-1.667; Cox regression analysis: HR[subscript adj]. =1.600; 95% CI: 1.437 - 1.783). Using a nested case-control design within the entire study cohort, AD use was associated with a 54.1% increase in the risk of diabetes compared to BZ use (OR[subscript adj]. =1.541; 95% CI: 1.368 - 1.735). Using a nested case-control design within the exposed cohort, current AD use was associated with a two-fold higher risk of diabetes compared to former AD use (OR[subscript adj]. =1.995; 95% CI: 1.759 - 2.264). Among antidepressant classes, TCAs, SSRIs, SNRIs, and Other ADs were associated with a higher diabetes risk compared with BZs. The results from the present study suggest that AD use is associated with an increased risk of diabetes. Clinicians may need to take this into account when choosing treatment for depression in patients at high risk of diabetes. / text

Contexte: À date, il existe peu de données sur l’adhésion, la persistance et les coûts associés aux antidépresseurs selon le type d’assurance médicament (privé ou public). Objectif: Comparer selon le régime d’assurance médicament (privé ou public), l'adhésion, la persistance et les coûts des antidépresseurs. Méthodes de recherche: Une étude de cohorte appariée a été réalisée en utilisant des bases de données du Québec. Sujets: Nous avons sélectionné 194 patients assurés par un régime privé et 1923 patients assurés par le régime public de la Régie de l’assurance maladie du Québec (RAMQ) (18-64 ans) qui ont rempli au moins une ordonnance pour un antidépresseur entre décembre 2007 et septembre 2009. Mesures: L’adhésion, mesurée sur une période d’un an, a été estimée en utilisant le proportion of prescribed days covered (PPDC). Un modèle de régression linéaire a été utilisé afin d’estimer la différence moyenne en PPDC entre les patients assurés par un régime privé et ceux assurés par le régime public de la RAMQ. La persistance a été comparé entre ces deux groupes avec un modèle de régression de survie Cox, et le coût mensuel d'antidépresseurs ($ CAN) a été comparé entre ces deux groupes en utilisant un modèle de régression linéaire. Résultats: Le PPDC parmi les patients assurés par un régime privé était de 86,4% (intervalle de confiance (IC) 95%: 83,3%-89,5%) versus 81,3% (IC 95%: 80,1%-82,5%) pour les patients assurés par le régime public de la RAMQ, pour une différence moyenne ajustée de 6,7% (IC 95%: 3,0%-10,4%). La persistance après un an parmi les patients assurés par un régime privé était de 49,5% versus 18,9% pour les patients assurés par le régime public de la RAMQ (p <0,001), et le rapport de risque ajusté était de 0,48 (IC 95%: 0,30-0,76). Comparativement aux patients assurés par le régime public de la RAMQ, les patients ayant une assurance privée ont payé 14,94 $ CAD (95% CI: $12,30-$17,58) de plus par mois en moyenne pour leurs antidépresseurs. Conclusion: Les patients assurés par un régime privé avaient une meilleure adhésion, persistance, mais avaient aussi un plus haut coût pour leurs antidépresseurs que ceux assurés par le régime public de la RAMQ. Cette différence de coûts peut être due aux différentes exigences de paiement en pharmacie entre les deux régimes ainsi qu’aux limites des honoraires des pharmaciens imposés par le régime public. / Background: The influence of the type of drug insurance on adherence, persistence and cost of antidepressants is not well known. Objective: To compare adherence, persistence and cost of antidepressants in patients with private and public drug insurance. Research Design: A matched cohort study was conducted using prescription claims databases from Quebec, Canada. Subjects: 194 privately and 1923 publicly insured patients (18-64 years) who filled at least one prescription for an antidepressant between December 2007 and September 2009. Measures: Adherence over one year was estimated using the proportion of prescribed days covered (PPDC). The difference in mean PPDC between patients with private and public drug insurance was estimated with a linear regression model. Persistence was compared between the groups with a Cox regression model, and the monthly cost of antidepressants (CAD$) was compared between the two groups using linear regression. Results: The PPDC was 86.4% (95% CI: 83.3-89.5) in patients with private and 81.3% (95%CI: 80.1-82.5) in patients with public drug insurance and the adjusted mean difference was 6.7% (95% CI: 3.0-10.4). Persistence was 49.5% in patients with private and 18.9% in patients with public drug insurance at one year (p<0.001), and the adjusted hazard ratio was 0.48 (95%CI: 0.30-0.76). Patients privately insured paid 14.94$ CAD (95% CI: 12.30; 17.58) more per month on average for their antidepressants. Conclusion: Better adherence and persistence and higher costs were observed in privately insured patients. Cost difference might be due to different pharmacy payment requirements and pharmacists’ honorary restrictions under the public plan.

O transtorno obsessivo-compulsivo (TOC) é um transtorno psiquiátrico freqüentemente crônico caracterizado pela presença de obsessões e/ou compulsões. Tratamentos de primeira linha, que incluem os inibidores seletivos da recaptura de serotonina (ISRS) e a terapia cognitivocomportamental com técnicas de exposição e prevenção de respostas não conseguem melhora satisfatória em até 40% dos pacientes. Para estes casos, existem evidências que apóiam o uso de antipsicóticos como a quetiapina, na potencialização dos ISRS. No entanto, os antipsicóticos são eficazes para apenas um terço dos pacientes e estão associados a eventos adversos preocupantes no longo prazo. Este estudo tem como objetivo comparar a eficácia da potencialização do ISRS fluoxetina com a clomipramina, um inibidor de recaptura da serotonina não-seletivo, ou quetiapina, versus placebo. Para inclusão neste estudo, os pacientes precisavam: relatar os sintomas de TOC como sendo seu problema principal; estar em uso da dose máxima tolerada ou recomendada de fluoxetina por pelo menos oito semanas; ter um escore total na escala Yale Brown Obsessive-Compulsive Disorder Scale (YBOCS) de pelo menos 16; e ter tido uma redução do escore inicial da YBOCS menor do que 35% após tratamento com fluoxetina. Os pacientes (N=54) foram alocados por meio de um método de minimização em três grupos: quetiapina (até 200mg/dia) com fluoxetina (até 40mg/dia) (QTP/FLX) (N=18); clomipramina (até 75mg/dia) com fluoxetina (até 40mg/dia) (CMI/FLX) (N=18); e placebo com dose máxima de fluoxetina (até 80mg/dia) (PLC/FLX) (N=18). Avaliadores cegos obtiveram os escores da YBOCS nas semanas 0 e 12. As análises foram realizadas por intenção de tratar, com imputação do tipo hot-deck para os dados faltantes. Teste de Wald por ANCOVA não paramétrico para medidas ordinais repetidas foi utilizado para avaliar efeitos de grupo, tempo e interação para os resultados da YBOCS e desfechos secundários, tendo as medidas iniciais como co-variáveis. Os resultados da impressão clínica global de melhora (ICG-M) foram utilizados para classificar os pacientes como respondedores ou não-respondedores. O teste qui-quadrado foi utilizado para avaliar a freqüência de respondedores em cada grupo. Foram feitos gráficos de percentis e análises de sensibilidade. Quarenta pacientes (74%) completaram o seguimento. Não foram observados efeitos adversos graves. Pacientes dos grupos PLC/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=49%, DP=0.49) e CMI/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=46%, DP=0.51) melhoraram significativamente e tiveram uma melhor resposta quando comparados aos do grupo QTP/FLX (YBOCS final: média=13, DP=3; redução em relação ao inicial: média=18%, DP=0.20; p=0.001). Não foram encontradas diferenças significativas para as medidas secundárias. Os gráficos de percentis confirmaram que os pacientes do grupo QTP/FLX pioraram com maior freqüência e melhoraram menos do que os pacientes dos outros dois grupos. Análises de sensibilidade demonstraram que outros métodos de análise não modificaram significativamente os resultados. Este é o primeiro estudo duplo-cego controlado de potencialização de ISRS com clomipramina em TOC e também o primeiro a comparar a eficácia de potencialização com quetiapina à de outro potencializador. Limitações deste estudo incluem o uso de doses baixas dos potencializadores, taxas de abandono diferentes para os três grupos e período curto de seguimento. Apesar dessas limitações, nossos resultados apóiam o uso da clomipramina como potencializador (principalmente para aqueles que não toleram doses altas de fluoxetina) e o aumento do período de seguimento com fluoxetina em dose máxima antes de uma potencialização medicamentosa ser tentada / Obsessive-compulsive disorder (OCD) manifests often as a chronic illness and is characterized by the presence of obsessions and compulsions. Firstline treatment options, which include selective serotonin reuptake inhibitors (SSRI) and cognitive-behavior therapy with exposure and response prevention techniques, fail to achieve a satisfactory response in up to 40% of patients. Current evidence supports the augmentation of SSRI with antipsychotics, such as quetiapine. However, anti-psychotics are effective for only one-third of the patients and have been associated with severe long term side effects. This study aimed to compare clomipramine and quetiapine augmentation of the SSRI fluoxetine. Previously to the beginning of this trial all patients had to: report OCD as they primary diagnosis, be taking the highest tolerated or recommended dose of fluoxetine for at least eight weeks, have a current Yale Brown Obsessive-Compulsive Scale (YBOCS) total of at least 16, and have had a reduction of less than 35% of the initial total YBOCS score with fluoxetine treatment. Fifty-four patients were allocated trough a minimization procedure in one of three arms: quetiapine (up to 200 mg/day) plus fluoxetine (up to 40 mg/day) (QTP/FLX) (N=18), clomipramine (up to 75 mg/day) plus fluoxetine (up to 40 mg/day) (CMI/FLX) (N=18) and 18 placebo plus sustained maximum dose fluoxetine (up to 80 mg/day) (PLC/FLX) (N=18). Blinded raters collected YBOCS scores at weeks 0 and 12. Analyses were made with intention-to-treat and hot-deck imputation of missing data. Wald statistics from non-parametric ANCOVA for ordinal categorical repeated measures were used to evaluate group, time and interaction effects for YBOCS scores and secondary outcome measures considering initial measures as covariates. Clinical Global Impression scores of improvement (CGI-I) were used to classify individuals in responders or non-responders. Chi-square was used to evaluate frequency of responders in each group. Percentile-plots were built and sensitivity analyses were performed. Completion rate was 74% (N=40). No severe adverse events occurred during the trial. Patients from the PLC/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=49%, SD=0.49) and CMI/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=46%, SD=0.51) groups improved significantly and also had a significantly better response than the ones from the QTP/FLX group (final YBOCS score: mean=13, SD=3; reduction from initial YBOCS score: mean=18%, SD=0.20; p=0.001). No significant differences were evident for secondary outcome measures. Percentile plots confirmed that patients in the QTP/FLX group got worse more often or improved less than in the other two groups. Sensitivity analyses showed that other analytical methods did not significantly change results. This is the first double-blind placebo-controlled trial of clomipramine augmentation and the first to compare quetiapine augmentation with another active augmenter. Limitations of our trial include the use of low dose of augmenters, differential drop-out rates for each treatment arm and short period of follow-up. Despite these limitations, our results support the use of clomipramine as an augmentation strategy (mainly for those who do not tolerate higher doses of fluoxetine) and the prorogation of the period of maximum dose of fluoxetine before an augmentation is tried

O transtorno obsessivo-compulsivo (TOC) é um transtorno psiquiátrico freqüentemente crônico caracterizado pela presença de obsessões e/ou compulsões. Tratamentos de primeira linha, que incluem os inibidores seletivos da recaptura de serotonina (ISRS) e a terapia cognitivocomportamental com técnicas de exposição e prevenção de respostas não conseguem melhora satisfatória em até 40% dos pacientes. Para estes casos, existem evidências que apóiam o uso de antipsicóticos como a quetiapina, na potencialização dos ISRS. No entanto, os antipsicóticos são eficazes para apenas um terço dos pacientes e estão associados a eventos adversos preocupantes no longo prazo. Este estudo tem como objetivo comparar a eficácia da potencialização do ISRS fluoxetina com a clomipramina, um inibidor de recaptura da serotonina não-seletivo, ou quetiapina, versus placebo. Para inclusão neste estudo, os pacientes precisavam: relatar os sintomas de TOC como sendo seu problema principal; estar em uso da dose máxima tolerada ou recomendada de fluoxetina por pelo menos oito semanas; ter um escore total na escala Yale Brown Obsessive-Compulsive Disorder Scale (YBOCS) de pelo menos 16; e ter tido uma redução do escore inicial da YBOCS menor do que 35% após tratamento com fluoxetina. Os pacientes (N=54) foram alocados por meio de um método de minimização em três grupos: quetiapina (até 200mg/dia) com fluoxetina (até 40mg/dia) (QTP/FLX) (N=18); clomipramina (até 75mg/dia) com fluoxetina (até 40mg/dia) (CMI/FLX) (N=18); e placebo com dose máxima de fluoxetina (até 80mg/dia) (PLC/FLX) (N=18). Avaliadores cegos obtiveram os escores da YBOCS nas semanas 0 e 12. As análises foram realizadas por intenção de tratar, com imputação do tipo hot-deck para os dados faltantes. Teste de Wald por ANCOVA não paramétrico para medidas ordinais repetidas foi utilizado para avaliar efeitos de grupo, tempo e interação para os resultados da YBOCS e desfechos secundários, tendo as medidas iniciais como co-variáveis. Os resultados da impressão clínica global de melhora (ICG-M) foram utilizados para classificar os pacientes como respondedores ou não-respondedores. O teste qui-quadrado foi utilizado para avaliar a freqüência de respondedores em cada grupo. Foram feitos gráficos de percentis e análises de sensibilidade. Quarenta pacientes (74%) completaram o seguimento. Não foram observados efeitos adversos graves. Pacientes dos grupos PLC/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=49%, DP=0.49) e CMI/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=46%, DP=0.51) melhoraram significativamente e tiveram uma melhor resposta quando comparados aos do grupo QTP/FLX (YBOCS final: média=13, DP=3; redução em relação ao inicial: média=18%, DP=0.20; p=0.001). Não foram encontradas diferenças significativas para as medidas secundárias. Os gráficos de percentis confirmaram que os pacientes do grupo QTP/FLX pioraram com maior freqüência e melhoraram menos do que os pacientes dos outros dois grupos. Análises de sensibilidade demonstraram que outros métodos de análise não modificaram significativamente os resultados. Este é o primeiro estudo duplo-cego controlado de potencialização de ISRS com clomipramina em TOC e também o primeiro a comparar a eficácia de potencialização com quetiapina à de outro potencializador. Limitações deste estudo incluem o uso de doses baixas dos potencializadores, taxas de abandono diferentes para os três grupos e período curto de seguimento. Apesar dessas limitações, nossos resultados apóiam o uso da clomipramina como potencializador (principalmente para aqueles que não toleram doses altas de fluoxetina) e o aumento do período de seguimento com fluoxetina em dose máxima antes de uma potencialização medicamentosa ser tentada / Obsessive-compulsive disorder (OCD) manifests often as a chronic illness and is characterized by the presence of obsessions and compulsions. Firstline treatment options, which include selective serotonin reuptake inhibitors (SSRI) and cognitive-behavior therapy with exposure and response prevention techniques, fail to achieve a satisfactory response in up to 40% of patients. Current evidence supports the augmentation of SSRI with antipsychotics, such as quetiapine. However, anti-psychotics are effective for only one-third of the patients and have been associated with severe long term side effects. This study aimed to compare clomipramine and quetiapine augmentation of the SSRI fluoxetine. Previously to the beginning of this trial all patients had to: report OCD as they primary diagnosis, be taking the highest tolerated or recommended dose of fluoxetine for at least eight weeks, have a current Yale Brown Obsessive-Compulsive Scale (YBOCS) total of at least 16, and have had a reduction of less than 35% of the initial total YBOCS score with fluoxetine treatment. Fifty-four patients were allocated trough a minimization procedure in one of three arms: quetiapine (up to 200 mg/day) plus fluoxetine (up to 40 mg/day) (QTP/FLX) (N=18), clomipramine (up to 75 mg/day) plus fluoxetine (up to 40 mg/day) (CMI/FLX) (N=18) and 18 placebo plus sustained maximum dose fluoxetine (up to 80 mg/day) (PLC/FLX) (N=18). Blinded raters collected YBOCS scores at weeks 0 and 12. Analyses were made with intention-to-treat and hot-deck imputation of missing data. Wald statistics from non-parametric ANCOVA for ordinal categorical repeated measures were used to evaluate group, time and interaction effects for YBOCS scores and secondary outcome measures considering initial measures as covariates. Clinical Global Impression scores of improvement (CGI-I) were used to classify individuals in responders or non-responders. Chi-square was used to evaluate frequency of responders in each group. Percentile-plots were built and sensitivity analyses were performed. Completion rate was 74% (N=40). No severe adverse events occurred during the trial. Patients from the PLC/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=49%, SD=0.49) and CMI/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=46%, SD=0.51) groups improved significantly and also had a significantly better response than the ones from the QTP/FLX group (final YBOCS score: mean=13, SD=3; reduction from initial YBOCS score: mean=18%, SD=0.20; p=0.001). No significant differences were evident for secondary outcome measures. Percentile plots confirmed that patients in the QTP/FLX group got worse more often or improved less than in the other two groups. Sensitivity analyses showed that other analytical methods did not significantly change results. This is the first double-blind placebo-controlled trial of clomipramine augmentation and the first to compare quetiapine augmentation with another active augmenter. Limitations of our trial include the use of low dose of augmenters, differential drop-out rates for each treatment arm and short period of follow-up. Despite these limitations, our results support the use of clomipramine as an augmentation strategy (mainly for those who do not tolerate higher doses of fluoxetine) and the prorogation of the period of maximum dose of fluoxetine before an augmentation is tried

Contexte: À date, il existe peu de données sur l’adhésion, la persistance et les coûts associés aux antidépresseurs selon le type d’assurance médicament (privé ou public). Objectif: Comparer selon le régime d’assurance médicament (privé ou public), l'adhésion, la persistance et les coûts des antidépresseurs. Méthodes de recherche: Une étude de cohorte appariée a été réalisée en utilisant des bases de données du Québec. Sujets: Nous avons sélectionné 194 patients assurés par un régime privé et 1923 patients assurés par le régime public de la Régie de l’assurance maladie du Québec (RAMQ) (18-64 ans) qui ont rempli au moins une ordonnance pour un antidépresseur entre décembre 2007 et septembre 2009. Mesures: L’adhésion, mesurée sur une période d’un an, a été estimée en utilisant le proportion of prescribed days covered (PPDC). Un modèle de régression linéaire a été utilisé afin d’estimer la différence moyenne en PPDC entre les patients assurés par un régime privé et ceux assurés par le régime public de la RAMQ. La persistance a été comparé entre ces deux groupes avec un modèle de régression de survie Cox, et le coût mensuel d'antidépresseurs ($ CAN) a été comparé entre ces deux groupes en utilisant un modèle de régression linéaire. Résultats: Le PPDC parmi les patients assurés par un régime privé était de 86,4% (intervalle de confiance (IC) 95%: 83,3%-89,5%) versus 81,3% (IC 95%: 80,1%-82,5%) pour les patients assurés par le régime public de la RAMQ, pour une différence moyenne ajustée de 6,7% (IC 95%: 3,0%-10,4%). La persistance après un an parmi les patients assurés par un régime privé était de 49,5% versus 18,9% pour les patients assurés par le régime public de la RAMQ (p <0,001), et le rapport de risque ajusté était de 0,48 (IC 95%: 0,30-0,76). Comparativement aux patients assurés par le régime public de la RAMQ, les patients ayant une assurance privée ont payé 14,94 $ CAD (95% CI: $12,30-$17,58) de plus par mois en moyenne pour leurs antidépresseurs. Conclusion: Les patients assurés par un régime privé avaient une meilleure adhésion, persistance, mais avaient aussi un plus haut coût pour leurs antidépresseurs que ceux assurés par le régime public de la RAMQ. Cette différence de coûts peut être due aux différentes exigences de paiement en pharmacie entre les deux régimes ainsi qu’aux limites des honoraires des pharmaciens imposés par le régime public. / Background: The influence of the type of drug insurance on adherence, persistence and cost of antidepressants is not well known. Objective: To compare adherence, persistence and cost of antidepressants in patients with private and public drug insurance. Research Design: A matched cohort study was conducted using prescription claims databases from Quebec, Canada. Subjects: 194 privately and 1923 publicly insured patients (18-64 years) who filled at least one prescription for an antidepressant between December 2007 and September 2009. Measures: Adherence over one year was estimated using the proportion of prescribed days covered (PPDC). The difference in mean PPDC between patients with private and public drug insurance was estimated with a linear regression model. Persistence was compared between the groups with a Cox regression model, and the monthly cost of antidepressants (CAD$) was compared between the two groups using linear regression. Results: The PPDC was 86.4% (95% CI: 83.3-89.5) in patients with private and 81.3% (95%CI: 80.1-82.5) in patients with public drug insurance and the adjusted mean difference was 6.7% (95% CI: 3.0-10.4). Persistence was 49.5% in patients with private and 18.9% in patients with public drug insurance at one year (p<0.001), and the adjusted hazard ratio was 0.48 (95%CI: 0.30-0.76). Patients privately insured paid 14.94$ CAD (95% CI: 12.30; 17.58) more per month on average for their antidepressants. Conclusion: Better adherence and persistence and higher costs were observed in privately insured patients. Cost difference might be due to different pharmacy payment requirements and pharmacists’ honorary restrictions under the public plan.