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Treatment of Depression in Children and Adolescents: A Systematic Review. Comparative Effectiveness Review No. 224

Author/s: 
Viswanathan, M, Kennedy, SM, McKeeman, J, Christian, R, Coker-Schwimmer, Cook Middleton, Bann, C, Lux, L, Randolph, Forman-Hoffman, V

Background. Depressive disorders can affect long-term mental and physical health functioning among children and adolescents, including increased risk of suicide. Despite access to several nonpharmacological, pharmacological, and combined treatment options for childhood depression, clinicians contend with sparse evidence and are concerned about harms associated with treatment.

Methods. We conducted a systematic review to evaluate the efficacy, comparative effectiveness, and moderators of benefits and harms of available nonpharmacological and pharmacological treatments for children and adolescents with a confirmed diagnosis of a depressive disorder (DD)—major depressive disorder (MDD), persistent depressive disorder (previously termed dysthymia) or DD not otherwise specified. We searched five databases and other sources for evidence available from inception to May 29, 2019, dually screened the results, and analyzed eligible studies.

Results. We included in our analyses data from 60 studies (94 articles) that met our review eligibility criteria. For adolescents (study participants’ ages range from 12 to 18 years) with MDD, cognitive behavioral therapy (CBT), fluoxetine, escitalopram, and combined fluoxetine and CBT may improve depressive symptoms (1 randomized controlled trial [RCT] each, n ranges from 212 to 311); whether the magnitude of improvement is clinically significant is unclear. Among adolescents or children with MDD, CBT plus medications (8–17 years) may be associated with lower rates of relapse (1 RCT [n = 121]). In the same population (6–17 years), selective serotonin reuptake inhibitors (SSRIs) may be associated with improved response (7 RCTs [n = 1,525]; risk difference [RD], 72/1,000 [95% confidence interval (CI), 2 to 24], I2 = 9%) and functional status (5 RCTs [n = 941]; standardized mean difference, 0.16 [95% CI, 0.03 to 0.29]; I2 = 0%). For adolescents or children with any DD (7–18 years), CBT or family therapy may be associated with improvements in symptoms, response, or functional status (1 RCT each, n ranges from 64 to 99). Among children with any DD (7–12 years), family-based interpersonal therapy may be associated with improved symptoms (1 RCT, n = 38). Psychotherapy trials did not report harms. SSRIs may be associated with a higher risk of serious adverse events among adolescents or children with MDD (7–18 years; 9 RCTs [n = 2,206]; RD, 20/1,000 [95% CI, 1 to 440]; I2, 4%) and with a higher risk of withdrawal due to adverse events among adolescents with MDD (12–18 years; 4 RCTs [n = 1,296], RD, 26/1,000 [95% CI, 6 to 45]; I2, 0%). Paroxetine (1 RCT [n = 180]) may be associated with a higher risk of suicidal ideation or behaviors among adolescents with MDD (12–18 years). Evidence was insufficient to judge the risk of suicidal ideation or behavior for other SSRIs for adolescents and children with MDD or other DD (7–18 years) (10 RCTs [n = 2,368]; relative risk, 1.14 [95% CI, 0.89 to 1.45]; I2, 8%). However, this report excluded data on inpatients and those without depressive disorders, whom the Food and Drug Administration included in finding an increased risk of suicidality for all antidepressants across all indications.

Conclusion. Efficacious treatments exist for adolescents with MDD. SSRIs may be associated with increased withdrawal and serious adverse events. No evidence on harms of psychotherapy were identified.

Keywords 
children adolescent child depression treatment cognitive behavioral therapy selective serotonin reuptake inhibitors

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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