Safe Discontinuation of Antidepressants in Individuals With Clinically Remitted Depressive Disorders
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 150
- 主要终点
- Proportion of Participants Who Do Not Successfully Discontinue Antidepressant Treatment Within 16 Weeks
研究概览
简要总结
Overprescribing and long-term use of antidepressants (ADs) are common and may increase the risk of adverse effects and withdrawal symptoms when discontinuation is attempted. Although several discontinuation strategies have been proposed, empirical evidence comparing different tapering approaches is limited. In particular, hyperbolic tapering has been suggested as a potentially safer and more effective alternative to standard linear tapering, but no randomized trials have directly compared these strategies.
This study is a pragmatic, multicentre, open-label, parallel-group, superiority randomized trial designed to compare two antidepressant discontinuation strategies-linear tapering and hyperbolic tapering-in adults with remitted depressive disorders. Eligible participants are adults aged 18 years or older with currently remitted depressive disorders who have been taking antidepressants for at least six months and are considered clinically appropriate candidates for discontinuation.
Participants will be recruited in outpatient psychiatric settings, with the involvement of general practitioners and other medical specialists. After baseline assessment, participants will be randomized to either a linear tapering strategy, consisting of dose reductions of 50% of the minimal effective dose every two weeks until discontinuation, or a hyperbolic tapering strategy, consisting of proportional dose reductions of approximately 20-25% every two weeks until discontinuation. Follow-up assessments will be conducted regularly over a 36-week period.
The primary outcome is the proportion of participants who fail to discontinue the antidepressant within the predefined tapering schedule (allowing a limited tolerance period) or who re-initiate antidepressant treatment during the 16 weeks following discontinuation. Secondary outcomes include measures of safety, tolerability, acceptability, clinical effectiveness, and cost-effectiveness, as well as withdrawal symptoms, relapse of depressive or anxiety symptoms, and adherence to the tapering schedule.
Participants and recruiting clinicians will not be blinded to treatment allocation, while outcome assessors and the biostatistician will remain blinded until completion of the study to minimize detection bias. The study aims to provide pragmatic evidence to inform clinical practice and guideline development regarding optimal strategies for antidepressant discontinuation.
详细描述
Antidepressants (ADs) are effective in the treatment of moderate-to-severe depression and anxiety disorders and are recommended by national and international clinical guidelines, although concerns about over-prescribing persist. In Italy, AD consumption increased by over 10% between 2014 and 2020. Selective serotonin reuptake inhibitors (SSRIs) account for approximately 70% of AD prescriptions and around half of total AD-related expenditure. Across most countries, AD prescribing has increased steadily, largely driven by use in general practice and by longer treatment duration.
For individuals experiencing a first depressive episode, evidence-based guidelines recommend continuing AD treatment for 6-9 months after clinical response. Meta-analytic evidence suggests a similar risk of relapse for maintenance periods ranging from six months to over one year. Treatment duration may vary according to illness severity and recurrence, with at least two years commonly recommended in cases of multiple episodes with functional impairment. In Italy, approximately one in three individuals continue AD treatment beyond 12 months, raising concerns about potentially inappropriate long-term or indefinite prescribing.
Prolonged AD use is associated with an increased risk of long-term adverse effects, including sexual dysfunction, weight gain, emotional blunting, and cardiovascular conditions. Discontinuation of ADs may also lead to withdrawal symptoms, which can be clinically relevant in a substantial proportion of patients. Several clinical factors appear to increase the risk of withdrawal, and it has been suggested that, for some individuals, disabling withdrawal symptoms rather than relapse may be the primary reason for unsuccessful discontinuation.
Randomized controlled trials indicate that discontinuing ADs is associated with a higher risk of relapse compared with continuation. However, discontinuation schedules used in many trials are rapid or abrupt, potentially increasing withdrawal symptoms that may be misclassified as relapse and thereby inflating relapse estimates. There is broad agreement that gradual tapering may reduce withdrawal symptoms, but most clinical guidelines provide only generic recommendations, often implying a linear dose reduction approach that remains standard in routine practice.
Alternative tapering strategies have been proposed, most notably hyperbolic tapering, which involves proportional dose reductions over longer periods. This approach is based on the nonlinear relationship between dose and receptor occupancy and may require tapering periods ranging from several months to over one year. Hyperbolic tapering often necessitates very low doses that are not readily achievable with standard marketed formulations, raising feasibility, regulatory, and policy challenges. To date, no randomized trials have directly compared different tapering strategies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
The outcome assessor and the statistician will be blinded to treatment allocation.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18 years old or above;
- •diagnosed with a depressive disorder, single episode (ICD-11, 6A70) or recurrent (ICD-11, 6A71);
- •currently taking a selective serotonin reuptake inhibitor (SSRI), serotonin and norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), or vortioxetine for the treatment of depression;
- •the current AD has been taken for at least 6 months;
- •the current AD has been on a stable dose over the last 2 months;
- •a score ≤9 on the PHQ-9 and ≤5 on the GAD-7 at study enrolment;
- •DSM-5-TR criteria for a depressive episode are not met at the time of recruitment;
- •no clinical evidence of moderate-to-severe symptoms in the last 6 months, as assessed by the recruiting clinician;
- •discontinuing the AD is clinically indicated by the recruiting clinician, and agreed to by the participant in a shared decision-making process;
- •uncertainty about which discontinuation strategy would be best for the participant;
- •the participant is willing to sign the informed consent to participate to the study.
排除标准
- •comorbid schizophrenia-spectrum disorders, bipolar disorder, or dementia, as formally diagnosed by a psychiatrist, neurologist, geriatrician, or other specialists;
- •current treatment with more than one AD at therapeutic doses;
- •current treatment with ADs of other classes (e.g., mirtazapine, agomelatine, bupropion, for which the evidence on the risk of withdrawal is unclear), alone or in combination with other ADs;
- •conditions or medications that contraindicate the use of any AD according to the Summary of Product Characteristics of included ADs (synthetically reported in Table 1) (e.g., current symptoms of mania);
- •current treatment with benzodiazepines above the dose of 2.5 mg equivalents of lorazepam per day (corresponding to clonazepam 1.2 mg/day; alprazolam 1.2 mg/day; diazepam 19 mg/day);
- •pregnancy or willingness to become pregnant.
研究组 & 干预措施
Linear tapering
Antidepressant (AD) dose will be reduced by fixed amounts (generally 50% of the minimum effective dose) every 2 weeks, according to pre-defined schedules, with the aim of reaching 50% of the minimum effective dose (as defined in the AIFA Summary of Product Characteristics), and finally discontinuing the AD after 4 to 10 weeks (depending on the initial dose). This approach is similar to the tapering schedules commonly used in current clinical practice. Any SSRI, SNRI, tricyclic antidepressant, and vortioxetine will be allowed.
干预措施: Linear tapering (Drug)
Hyperbolic tapering
Antidepressant (AD) dose will be reduced by 20-25% every 2 weeks, according to pre-defined schedules adapted from the Maudsley Hospital Guidelines (Taylor, 2021), with the aim of reaching at least 20% of the minimum effective dose (as defined in the AIFA Summary of Product Characteristics), and finally discontinuing the AD after 12 to 20 weeks (depending on the initial dose). Any SSRI, SNRI, tricyclic antidepressant, and vortioxetine will be allowed.
干预措施: Hyperbolic tapering (Drug)
结局指标
主要结局
Proportion of Participants Who Do Not Successfully Discontinue Antidepressant Treatment Within 16 Weeks
时间窗: 16 weeks
Proportion of participants who fail to successfully discontinue the antidepressant treatment, defined as either: 1. continued use of the antidepressant beyond the predefined tapering schedule (allowing a tolerance period of up to 15% of the total tapering duration), or 2. re-initiation of any antidepressant medication for any reason (e.g., withdrawal symptoms, recurrence of depressive or anxiety symptoms).
次要结局
- Proportion of Participants Who Fail to Discontinue Antidepressant Treatment by the End of the Predefined Tapering Schedule(Up to the end of the predefined tapering period)
- Proportion of Participants Who Re-initiate Antidepressant Treatment Within 16 Weeks After Discontinuation(Up to 16 weeks after complete antidepressant discontinuation)
- Proportion of Participants Non-adherent to the Predefined Antidepressant Tapering Schedule(Up to the end of the predefined tapering period)
- Mean of DESS highest overall scores(Up to the end of the 16-weeks follow-up period)
- Proportion of participants leaving the study early due to any reason without meeting criteria for the primary outcome(Up to the end of the 16-weeks follow-up period)
研究者
Giovanni Ostuzzi
Principal Investigator; Assistant Professor; MD; PhD
Universita di Verona