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Individualized antidepressant therapy in patients with major depressive disorder: Novel evidence-informed decision support tool

Author/s: 
Chin, T., Huyghebaert, T., Svrcek, C., Oluboka, O.

Objective: To introduce a visual clinical decision support tool to assist with individualizing first-line antidepressant pharmacotherapy for adults with major depressive disorder (MDD) in a Canadian context.

Sources of information: A literature review was conducted with Google Scholar, PubMed, the Cochrane Database of Systematic Reviews, and Trip Pro using the MeSH headings depression, antidepressive agents, primary care, practice patterns, medication adherence, and decision making, shared.

Main message: Major depressive disorder affects about 4.7% of Canadians annually and is a prevalent condition encountered and diagnosed in primary care. Untreated depression is associated with decreased quality of life, increased risk of suicide, and worsening physical health outcomes when depression co-occurs with other chronic medical conditions. In a network meta-analysis, antidepressant medications (such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, bupropion, and vortioxetine) reduced depressive symptoms by 50% or more when compared with placebo in acute treatment of adults with moderate to severe MDD. Poor treatment adherence and high discontinuation rates limit MDD treatment success. Factors such as strong therapeutic alliances between patients and prescribers, collaborative care, patient education, and supportive self-management have been shown to enhance treatment adherence. The most recent Canadian Network for Mood and Anxiety Treatments depression treatment guidelines (published in 2016) suggest 15 different first-line antidepressant medication options for the treatment of MDD. There is a need for evidence-informed decision support aids to individualize antidepressant therapy to treat patients diagnosed with MDD.

Conclusion: Recent studies on antidepressants have indicated no single antidepressant is superior to others in treating patients with MDD. This suggests there may be opportunities to enhance treatment adherence and success by tailoring antidepressant therapy to align with each patient's preferences. The Antidepressant Decision Support Tool was developed to help prescribers and adult patients engage in shared decision making to select an individualized and optimal first-line antidepressant for the treatment of acute MDD.

Keywords 
Systematic Reviews as Topic antidepressive agents Serotonin Uptake Inhibitors Major Depressive Disorder SSRI

Adverse Effects of First-line Pharmacologic Treatments of Major Depression in Older Adults

Author/s: 
Sobieraj, D.M., Baker, W.L., Martinez, B.K., Hernandez, A.V., Coleman, C.I., Ross, J.S., Berg, K.M., Steffens, D.C.

Objective. To assess selected adverse events of antidepressants in the treatment of major depressive disorder (MDD) in adults 65 years old or older. Antidepressants included in this review, as determined by expert opinion, are selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine.

Data sources. MEDLINE®, Embase®, Cochrane Central, and PsycINFO® bibliographic databases from earliest date through May 15, 2018; hand searches of references of relevant studies; www.clinicaltrials.gov; and the International Controlled Trials Registry Platform.

Review methods. Two investigators screened abstracts and subsequently reviewed full-text files. We abstracted data, performed meta-analyses when appropriate, assessed the risk of bias of each individual study, and graded the strength of evidence (SOE) for each comparison and selected outcomes. Number needed to harm (NNH) is reported for graded outcomes with statistically significant findings.

Results. Nineteen randomized controlled trials (RCTs) and two observational studies reported in 41 articles were included. Studies mostly evaluated treatment of the acute phase (<12 weeks) of MDD that was of moderate severity in patients 65 years and older, required subjects to be free from uncontrolled medical comorbidities or psychological conditions, and relied on spontaneous reporting of adverse events. Evidence was scarce and conclusions (based on statistical significance) for a given comparison and outcome are based often on a single study, particularly for specific adverse events. None of the RCTs were powered or designed to capture adverse events and most RCTs studied low doses of antidepressants. Observational data were limited by residual confounding.

SSRIs (escitalopram and fluoxetine, moderate SOE), vortioxetine (high SOE), and bupropion extended release (moderate SOE) had a statistically similar frequency of adverse events compared with placebo, whereas SNRIs (duloxetine and venlafaxine) were found to cause a greater number of adverse events (high SOE, NNH 10) compared with placebo during treatment of the acute phase of MDD. Both SSRIs (citalopram, escitalopram, and fluoxetine) and SNRIs caused a greater number of withdrawals due to adverse events than placebo (SSRIs, low SOE, NNH 11; SNRIs, moderate SOE, NNH 17). Duloxetine led to a greater number of falls compared with placebo (moderate SOE, NNH 10) over 24 weeks of treatment. A single observational study provided evidence on long-term use of antidepressants (low SOE) and suggested increased risk of adverse events (SSRIs), falls (SSRIs, SNRI venlafaxine, mirtazapine, trazadone), fractures (SSRIs, SNRI venlafaxine, mirtazapine), and mortality (SSRIs, SNRI venlafaxine, mirtazapine, trazadone) compared to no antidepressant.

Evidence for the comparative harms of different antidepressants was limited to single RCTs, mostly studying treatment of the acute phase of MDD (<12 weeks). Comparing SSRIs to each other or SSRIs to SNRIs showed statistically similar rates of adverse events (moderate SOE). SSRIs (paroxetine, citalopram, sertraline) had fewer withdrawals due to adverse events than tricyclic antidepressants (amitriptyline or nortriptyline) (low SOE, number needed to treat [NNT] 13), as did mirtazapine compared with paroxetine (low SOE, NNT 9). Vortioxetine had fewer adverse events than with duloxetine (high SOE, NNT 6).

Increasing age was associated with greater incidence of serious adverse events with escitalopram (low SOE). The increased risk of falls on duloxetine may be associated with the presence of cardiopulmonary conditions (low SOE).

Conclusions. In patients 65 years of age or older, treatment of the acute phase of MDD with SNRIs (duloxetine and venlafaxine) led to a greater number of adverse events compared with placebo, while adverse events were statistically similar to placebo with SSRIs (escitalopram, fluoxetine), vortioxetine, and bupropion. SSRIs (citalopram, escitalopram, and fluoxetine) and SNRIs (duloxetine and venlafaxine) led to a greater number of study withdrawals due to adverse events than placebo, and duloxetine increased the risk of falls. Further characterization of the comparative safety of antidepressants is difficult because few studies were identified, comparisons were based on statistical significance, trials were not powered to identify small differences in adverse events, and observational studies may be confounded. Comparative, long-term, well-designed studies that report specific adverse events are needed to better inform decision making in this population.

Keywords 
SSRI SNRI

Pharmacotherapy for social anxiety disorder (SAnD)

Author/s: 
Williams, Taryn, Hattingh, Coenie J., Kariuki, Catherine M., Tromp, Sean A., van Balkom, Anton J., Ipser, Jonathan C., Stein, Dan J.

Background

Recognition is growing that social anxiety disorder (SAnD) is a chronic and disabling disorder, and data from early trials demonstrate that medication may be effective in its treatment. This systematic review is an update of an earlier review of pharmacotherapy of SAnD.

Objectives

To assess the effects of pharmacotherapy for social anxiety disorder in adults and identify which factors (methodological or clinical) predict response to treatment.

Search methods

We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR‐Studies and CCMDCTR‐References) to 17 August 2015. The CCMDCTR contains reports of relevant RCTs from MEDLINE (1950‐), Embase (1974‐), PsycINFO (1967‐) and CENTRAL (all years). We scanned the reference lists of articles for additional studies. We updated the search in August 2017 and placed additional studies in Awaiting Classification, these will be incorporated in the next version of the review, as appropriate.

Selection criteria

We restricted studies to randomised controlled trials (RCTs) of pharmacotherapy versus placebo in the treatment of SAnD in adults.

Data collection and analysis

Two authors (TW and JI) assessed trials for eligibility and inclusion for this review update. We extracted descriptive, methodological and outcome information from each trial, contacting investigators for missing information where necessary. We calculated summary statistics for continuous and dichotomous variables (if provided) and undertook subgroup and sensitivity analyses.

Main results

We included 66 RCTs in the review (> 24 weeks; 11,597 participants; age range 18 to 70 years) and 63 in the meta‐analysis. For the primary outcome of treatment response, we found very low‐quality evidence of treatment response for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (number of studies (k) = 24, risk ratio (RR) 1.65; 95% confidence interval (CI) 1.48 to 1.85, N = 4984). On this outcome there was also evidence of benefit for monoamine oxidase inhibitors (MAOIs) (k = 4, RR 2.36; 95% CI 1.48 to 3.75, N = 235), reversible inhibitors of monoamine oxidase A (RIMAs) (k = 8, RR 1.83; 95% CI 1.32 to 2.55, N = 1270), and the benzodiazepines (k = 2, RR 4.03; 95% CI 2.45 to 6.65, N = 132), although the evidence was low quality. We also found clinical response for the anticonvulsants with gamma‐amino butyric acid (GABA) analogues (k = 3, RR 1.60; 95% CI 1.16 to 2.20, N = 532; moderate‐quality evidence). The SSRIs were the only medication proving effective in reducing relapse based on moderate‐quality evidence. We assessed the SSRIs and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine on the basis of treatment withdrawal; this was higher for medication than placebo (SSRIs: k = 24, RR 2.59; 95% CI 1.97 to 3.39, N = 5131, low‐quality evidence; venlafaxine: k = 4, RR 3.23; 95% CI 2.15 to 4.86, N = 1213, moderate‐quality evidence), but there were low absolute rates of withdrawal for both these medications classes compared to placebo. We did not find evidence of a benefit for the rest of the medications compared to placebo.

For the secondary outcome of SAnD symptom severity, there was benefit for the SSRIs, the SNRI venlafaxine, MAOIs, RIMAs, benzodiazepines, the antipsychotic olanzapine, and the noradrenergic and specific serotonergic antidepressant (NaSSA) atomoxetine in the reduction of SAnD symptoms, but most of the evidence was of very low quality. Treatment with SSRIs and RIMAs was also associated with a reduction in depression symptoms. The SSRIs were the only medication class that demonstrated evidence of reduction in disability across a number of domains.

We observed a response to long‐term treatment with medication for the SSRIs (low‐quality evidence), for the MAOIs (very low‐quality evidence) and for the RIMAs (moderate‐quality evidence).

Authors' conclusions

We found evidence of treatment efficacy for the SSRIs, but it is based on very low‐ to moderate‐quality evidence. Tolerability of SSRIs was lower than placebo, but absolute withdrawal rates were low.

While a small number of trials did report treatment efficacy for benzodiazepines, anticonvulsants, MAOIs, and RIMAs, readers should consider this finding in the context of potential for abuse or unfavourable side effects.

Keywords 
SSRI
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