Internet and telephone intervention to support patients discontinuing long-term antidepressants in primary care: the REDUCE research programme including RCT

Combining antidepressants and attention bias modification in primary health care (DEPTREAT): Protocol for a pragmatic randomized controlled trial

Introduction: The Coronavirus disease-19 (COVID-19) pandemic has generated significant impacts both economically and socially, as well as on the physical and mental health of the general population, causing an increase in depression, anxiety and stress. Depression is considered a multifactorial disorder that involves biological, psychological and social aspects and has become a relevant and growing public health problem. It is noteworthy that the pharmacological treatment for this pathology includes the use of antidepressant drugs, many of which are available in the Unified Health System (SUS). In this sense, it is worth mentioning that, in Brazil, there are still few studies evaluating the impact of the pandemic on the consumption profile of antidepressant drugs in the population. Objective: The objective of this work was to analyze the impact of the COVID-19 pandemic on the distribution of antidepressants in primary care in the municipality of Santiago, in Rio Grande do Sul. Methodology: To carry out this research, a survey of antidepressant drugs dispensed at the Basic Pharmacy of SUS in the city was carried out. Based on information contained in the Integrated Health Services Management System (SIGSS), used in the distribution management and stock control of the Basic Pharmacy, data referring to the three-year period, from March 2019 to March 2019, were analyzed. 2022. Results and Discussion: It was possible to observe an increase of 38.10% in 2020 and 115.47% in 2021 in the dispensation of antidepressant drugs, in relation to the year 2019. In addition, it was verified that the female gender presented higher rate of consumption of antidepressants, corresponding to the percentage of 77.59% in relation to males. The drug fluoxetine 20 mg was the most used drug, totaling 50.89% of dispensations during the three years, where predominantly users are aged between 46 and 60 years. Amitriptyline 25mg corresponded to 30.28% and Imipramine 25mg represented 9.33% of dispensations, both from the tricyclic antidepressant class. It is noteworthy that users of this class of medication are mostly elderly people over 61 years old. Furthermore, it was possible to observe an increase of 134.68% in the dispensations of selective serotonin reuptake inhibitors (SSRIs), 78.15% in tricyclic antidepressants and 1002.5% in atypical antidepressants during the pandemic period compared to the year 2019 , pre-pandemic period. Conclusion: It can be concluded that the pandemic had an impact on the consumption of antidepressants by the Santiaguense population served by the Basic Pharmacy. Still, the results found in this work may help in the planning of strategies that can collaborate with issues related to the mental health of the population and the consumption of antidepressants, seeking the rational use of this class of medication.

Background: Long-term treatment with antidepressants is considered effective in preventing recurrence of major depressive disorder (MDD). It is unclear whether this is true for primary care. Objectives: We investigated whether current guideline recommendations for long-term treatment with antidepressants in primary care are supported by evidence from primary care. Methods: Data sources for studies on antidepressants: PubMed, Cochrane Library, Embase, PsycInfo, Cinahl, articles from reference lists, cited reference search. Selection criteria: adults in primary care, continuation or maintenance treatment with antidepressants, with outcome relapse or recurrence, (randomized controlled) trial/naturalistic study/review. Limits: published before October 2009 in English. Results: Thirteen depression guidelines were collected. These guidelines recommend continuation treatment with antidepressants after remission for all patients including patients from primary care, and maintenance treatment for those at high risk of recurrence. Recommendations vary for duration of treatment and definitions of high risk. We screened 804 literature records (title, abstract), and considered 27 full-text articles. Only two studies performed in primary care addressed the efficacy of antidepressants in the long-term treatment of recurrent MDD. A double-blind RCT comparing mirtazapine (n = 99) and paroxetine (n = 98) prescribed for 24 weeks reported that in both groups 2 patients relapsed. An open study of 1031 patients receiving sertraline for 24 weeks, who were naturalistically followed-up for up to two years, revealed that adherent patients had a longer mean time to relapse.Conclusions: No RCTs addressing the efficacy of maintenance treatment with antidepressants as compared to placebo were performed in primary care. Recommendations on maintenance treatment with antidepressants in primary care cannot be considered evidence-based.

BackgroundDepression is a common illness, often treated in primary care. Many studies have reported undertreatment with antidepressants in primary care. Recently, some studies also reported overtreatment with antidepressants. The present study was designed to assess whether treatment with antidepressants in primary care is in accordance with current guidelines, with a special focus on overtreatment.MethodologyWe used baseline data of primary care respondents from the Netherlands Study of Depression and Anxiety (NESDA) (n = 1610). Seventy-nine patients with treatment in secondary care were excluded. We assessed justification for treatment with antidepressant according to the Dutch primary care guidelines for depression and for anxiety disorders. Use of antidepressants was based on drug-container inspection or, if unavailable, on self-report. Results were recalculated to the original population of primary care patients from which the participants in NESDA were selected (n = 10,677).Principal FindingsOf 1531 included primary care patients, 199 (13%) used an antidepressant, of whom 188 (94.5%) (possibly) justified. After recalculating these numbers to the original population (n = 10,677), we found 908 (95% CI 823 to 994) antidepressant users. Forty-nine (95% CI 20 to 78) of them (5.4%) had no current justification for an antidepressant, but 27 of them (54.5%) had a justified reason for an antidepressant at some earlier point in their life.ConclusionsWe found that overtreatment with antidepressants in primary care is not a frequent problem. Too long continuation of treatment seems to explain the largest proportion of overtreatment as opposed to inappropriate initiation of treatment.

Italy is reported to have a relatively low consumption of antidepressants. This is probably due to the fact that until 2000 antidepressants were reimbursed with some restrictions. To describe the pattern of use of antidepressants in primary care in Italy, after admission of selective serotonin reuptake inhibitors (SSRIs) for reimbursement without restrictions. We collected prescription data of antidepressants (ATC code: N06) reimbursed between January 1999 and March 2002 from three local health authorities in Emilia Romagna. Then, we calculated the prevalence of use for the different therapeutic classes of antidepressants, by age and gender. Moreover, after selecting a cohort of incident adult patients to follow for 6 months after the first prescription, we analysed the continuity, the average daily doses and the average duration of treatment. Out of 1000 subjects, 78 received at least one prescription of antidepressants in 1 year. The prevalence of use increased with age from 43 to 136/1000. Women used antidepressants more frequently than men, with a ratio varying from 1.6 to 2, depending on age. SSRIs were the most used drugs (63%), and their prevalence of use diminished with age; on the contrary, use of mianserine and trazodone increased with age, and that of the other antidepressants did not vary. About 60% of the subjects received occasional prescriptions. Continuous treatment was more frequent with SSRIs and in subjects older than 34 years. Daily doses were higher in patients receiving newer drugs (0.9-1 DDD per day), and lower in patients receiving the older agents (0.3-0.4 DDD per day). The average daily doses were usually lower than those recommended for the treatment of the major depression, especially for tricyclics, trazodone and reboxetine. Overall, doses were within the recommended range in about 75% of recipients of newer antidepressants (i.e., SSRIs, venlafaxine, mirtazapine and reboxetine), and in less than 30% of recipients of older drugs (i.e., tricyclics, trazodone and mianserine). In 59% of subjects receiving continuous treatment, the duration of the therapeutic course was at least 6 months. We found a high prevalence of use of antidepressants in primary care with a frequency of occasional use higher than in other countries. Only rarely were doses and duration of treatment consistent with recommendations for treatment of depression. Recipients of newer drugs received doses consistent with a use for major depression more frequently than others; however, rates of 6 month duration did not differ among drug classes.

Objective To examine off-label indications for antidepressants in primary care and determine the level of scientific support for off-label prescribing.Design Descriptive study of antidepressant prescriptions written by primary care physicians...

Objective: To compare the efficacy and tolerability of tricyclic antidepressants with selective serotonin reuptake inhibitors in depression in primary care.Design: Systematic review and meta-analysis of randomised controlled trials.Data sources: Register...

Primary process: why psychiatry and general practice should collaborate

Many depressed patients have negative beliefs about antidepressants, leading to poor adherence, unfavorable depression outcome, and low perceived well-being, role functioning, and quality of life. Interventions to ameliorate beliefs are therefore needed. In a cluster-randomized controlled trial conducted from September 1999 to January 2001, 2 interventions to improve management of major depressive disorder in primary care were compared: (1) a depression care program (DCP), providing enhanced patient education, stimulation of active participation of general practitioners and patients in the treatment process, discussion of benefits and costs of taking antidepressant medication, and systematic follow-up and (2) a systematic follow-up program (SFP). Thirty general practitioners were randomly assigned, and 211 patients with current major depressive disorder (diagnosed according to DSM-IV) were included. All patients were prescribed a selective serotonin reuptake inhibitor. Beliefs were assessed at baseline, at week 10, and at week 26. Differences in change of beliefs between DCP and SFP groups were analyzed. Changes in patients' beliefs were more favorable in the DCP condition at week 10 and week 26, compared with SFP only (beliefs concerning appropriate medication-taking, week 10: effect size = 0.39, p = .012; week 26: effect size = 0.55, p = .001; beliefs concerning harmfulness, week 10: effect size = 0.45, p = .011; week 26: effect size = 0.62, p = .002). The depression care program ameliorates beliefs about antidepressants in primary care patients with major depressive disorder. The study results encourage the implementation of a depression care program in order to improve beliefs about antidepressant medication in primary care patients diagnosed with major depressive disorder.

Sertraline in primary care: comments on the PANDA trial

When patients with a depressive condition first visit a general practitioner, they often get the prescription of an antidepressant1. We think that it is better to prescribe medication at a later stage, if at all. Here we explain why. It is well known that most patients in primary care have mild to moderate depression, while severe depression is an exception. For example, we found that, among primary care patients in waiting rooms, 13% had a score on the Patient Health Questionnaire-9 (PHQ-9) between 9 and 11, which is above the threshold for major depression, but only 5% had a severe depression (PHQ-9 score higher than 14)2. There is also considerable evidence that the effects of antidepressants in mild and moderate depression are small, and may not be clinically relevant. In one individual patient data meta-analysis, the risk difference (percent response to medication minus percent response to placebo) was only 6% in mild depression, which corresponds to a number needed to treat (NNT) of 163. In very severe depression, the risk difference was 25% (NNT=4); in severe depression, it was 9% (NNT=11). These results were recently confirmed in a large individual patient data meta-analysis of 232 trials with more than 73,000 patients4. Furthermore, a recent pragmatic placebo-controlled trial confirmed that antidepressants are not very effective in patients with mild depression seen in primary care: with an average PHQ-9 score of 12, the NNT was only 12.55. It is also well known that many patients in primary care who use antidepressants are not willing to stop their medication, even when it is clearly not working, because they are afraid that they will get worse. Much of the confusion about the effects of medications in depressed patients seen in primary care is due to an earlier Cochrane review6, reporting that the NNT was 8.5 for tricyclic antidepressants and 6.5 for selective serotonin reuptake inhibitors, which would be considered a reasonable clinical effect by most clinicians. However, the problem with that review was that the included trials focused on patients with severe to very severe depression, thus being not representative of the majority of patients with depression seen in primary care. The above-mentioned meta-analyses and pragmatic trial provide a much better evidence of the effects of antidepressants in this population. Even for patients with more severe depression seen in primary care, antidepressants may not be the best treatment at the first visit. Many of the few patients who initially present in primary care with a severe depression get better over time with or without medication7. Indeed, the above-mentioned Cochrane review found a median response rate of 42% with pill placebo. So, what to do at the first visit in primary care with a patient who presents with a depressive condition? Most treatment guidelines, such as those of the National Institute for Health and Care Excellence (NICE), recommend watchful waiting or a psychological intervention before medication for mild to moderate depression, unless it is the person’s preference to receive an antidepressant. Behavioural activation may be the best intervention8, but also other brief therapies specifically developed for this context, such as problem-solving therapies, may be good treatment options. It is less clear what should be done for severe depression at the first visit in primary care. The best strategy may be to reframe some of the negative cognitions of the patient and advice physical activity. In those who do not improve over the subsequent weeks, a psychotherapy or antidepressant medication should be considered. A recent meta-analysis showed that, at one-year follow-up, psychotherapies had better results than antidepressants9. This meta-analysis also found that a combination of psychotherapy and medication was better than either therapy alone. We conclude that most patients in primary care have mild to moderate depression, and that severe depression is an exception. Antidepressants should not be prescribed at the first visit if the patient has mild to moderate depression, because they have a limited efficacy and may have significant side effects. Antidepressant medication should be considered in severe depression, but not at the first visit and as an alternative to or in combination with a psychological intervention.

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. 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. 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. General practices in London, Bristol, Southampton and York. 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. 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. 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. 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 < 0.0001). By 52 weeks, relapse was experienced by 39% of those who continued antidepressants and 56% of those who discontinued antidepressants. The secondary analysis revealed that people who discontinued experienced more withdrawal symptoms than those who remained on medication, with the largest difference at 12 weeks. In the discontinuation group, 37% (95% confidence interval 28% to 45%) of participants remained on their randomised medication until the end of the trial. In total, 39% (95% confidence interval 32% to 45%) of participants in the discontinuation group returned to their original antidepressant compared with 20% (95% confidence interval 15% to 25%) of participants in maintenance group. The health economic evaluation demonstrated that participants randomised to discontinuation had worse utility scores at 3 months (-0.037, 95% confidence interval -0.059 to -0.015) and fewer quality-adjusted life-years over 12 months (-0.019, 95% confidence interval -0.035 to -0.003) than those randomised to continuation. The discontinuation pathway, besides giving worse outcomes, also cost more [extra £2.71 per patient over 12 months (95% confidence interval -£36.10 to £37.07)] than the continuation pathway, although the cost difference was not significant. 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. Current Controlled Trials ISRCTN15969819 and EudraCT 2015-004210-26. 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.

Depression is common in primary care. There are no systematic reviews of depression treatment comparing antidepressants with placebo; hence, we do not know whether these medications are effective in primary care. We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Group register of controlled trials, MEDLINE, International Pharmaceutical abstracts, PsycINFO, and EMBASE. Abstracts of potential studies were reviewed independently by 2 authors. Studies needed to include randomized controlled trials of either a tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor (SSRI), or both, and placebo in a primary care setting. The data and quality of the studies were extracted and assessed by 2 authors blind to the other's choice. Disagreements were resolved by discussion. The main outcome measures were the standardized mean difference and weighted mean difference of the final mean depression scores, the relative risk of improvement, and the number withdrawing because of side effects. Pooling of results was done using Review Manager 4.2.2. There were 10 studies in which TCAs were compared with placebo, 3 in which SSRIs were compared with placebo, and 2 with both compared with placebo. One half of the studies were of low methodological quality, and nearly all studies were of short duration, typically 6 to 8 weeks. Pooled estimates of efficacy data showed a relative risk of 1.26 (95% CI, 1.12-1.42) for improvement with TCAs compared with placebo; For SSRIs, relative risk was 1.37 (95% CI, 1.21-1.55). Most patients, 56% to 60%, responded well to active treatment compared with 42% to 47% for placebo. The number needed to treat for TCAs was about 4, and for SSRIs it was 6. The numbers needed to harm (for withdrawal caused by side effects) ranged from 5 to 11 for TCAs and 21 to 94 for SSRIs. Low-dose (100 mg or 75 mg) as well as high-dose TCAs were effective. This systematic review is the first comparing antidepressants with placebo for treatment of depression in primary care. Both TCAs and SSRIs are effective. This review is also the first to show that low-dose TCAs are effective in primary care. Prescribing antidepressants in primary care is a more effective clinical activity than prescribing placebo.

INTRODUCTION Evidence for the effectiveness of drug treatment for depression in primary care settings remains limited, with little information on newer antidepressant classes. AIM To update an earlier Cochrane review on the effectiveness of antidepressants in primary care to include newer antidepressant classes, and to examine the efficacy of individual agents. METHODS Selection criteria included antidepressant studies with a randomly assigned placebo group where half or more subjects were recruited from primary care. The Cochrane Collaboration Depression, Anxiety and Neurosis (CCDAN) group searched multiple databases to identify eligible studies. Data extraction was performed independently by two reviewers. Data were analysed using Revman version 5.3.5. RESULTS In total, 17 papers and 22 comparisons were included for analysis. Significant benefits in terms of response were found for tricyclic antidepressants (TCA) with a relative risk (RR) = 1.23 (95% CI, 1.01-1.48), and serotonin selective reuptake inhibitors (SSRI) with a RR = 1.33 (95% CI, 1.20-1.48). Mianserin was effective for continuous outcomes. Numbers needed to treat (NNT) for TCA = 8.5; SSRI = 6.5; and venlafaxine = 6. Most studies were industry-funded and of a brief duration (≤ 8 weeks). There was evidence of publication bias. There were no studies comparing newer antidepressants against placebo. CONCLUSION Antidepressants such as TCA, SSRI, SNRI (serotonin-norepinephrine reuptake inhibitor) and NaSSA (noradrenergic and specific serotonergic antidepressant) classes appear to be effective in primary care when compared with placebo. However, in view of the potential for publication bias and that only four studies were not funded by industry, caution is needed when considering their use in primary care.

Antidepressants are the third most prescribed drug class, and most prescriptions are not performed by specialists. This study aimed to evaluate primary health care (PHC) physicians' self-perceived confidence in prescribing antidepressants. This is a cross-sectional study with PHC physicians in the municipality of Salvador, Bahia State, Brazil. Psychiatrists or psychiatry residents were excluded. The self-assessment of confidence and the collection of participants' characteristics was carried out by an online questionnaire. Categorical variables were presented in absolute and relative frequencies. Continuous variables were described as means or medians according to their normality distribution. Of 447 physicians, the sample consisted of 55 participants. Their mean age was 37.2 ± 12.8 years. Most physicians (75%) claimed confidence in prescribing antidepressants. Self-perceived confidence remained predominant in scenarios with older adults (69.2%) and patients with general comorbidities (65.4%). A minority showed confidence to prescribe antidepressants to children/adolescents (19.2%) and pregnant women (26.9%). For 80.4% of participants, selective serotonin reuptake inhibitors were the most trusted pharmacological class. Referral to the Psychosocial Care Center was the most reported strategy in cases of insecure prescription (32%). To the best of our knowledge, this is the first study to address such an issue. Thus, it can contribute to more assertive health education actions for PHC physicians.