Comparative Safety of Pharmacologic Treatments for Persistent Depressive Disorder: A Systematic Review and Network Meta-Analysis

Abstract

We aimed to compare the safety of antidepressants for the treatment of persistent depressive disorder (PDD) with each other and with placebo. We conducted a systematic electronic search and included randomized controlled trials that investigated antidepressants for the treatment of PDD in adults. Outcomes were the incidence of experiencing any adverse event, specific adverse events and related treatment discontinuations. We analyzed the data using traditional and network meta-analyses. Thirty-four studies that comprised 4,769 patients and examined 20 individual agents in nine substance classes were included. Almost all analyzed substance classes were associated with higher discontinuation rates than placebo including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), antipsychotics, and the serotonin antagonist and reuptake inhibitor (SARI) trazodone. The odds of experiencing any adverse event were significantly higher for TCAs and serotonin noradrenaline reuptake inhibitors (SNRIs) compared to placebo. Pairwise comparisons among the substance classes revealed that more patients receiving TCAs or SNRIs experienced any adverse event and that more patients receiving TCAs or the SARI trazodone discontinued treatment. The complementary treatment with acetyl-l-carnitine showed lower rates of experiencing any adverse event and related discontinuations than all other comparators. TCAs were primarily associated with (anti-)cholinergic and sedating adverse events. SSRIs primarily showed gastrointestinal adverse events. Patients treated with the antipsychotic amisulpride were more likely to manifest weight gain and endocrine adverse events. The comparative evidence for further agents was insufficient or lacking. The identified safety differences may be used to inform the selection among the antidepressants.

Fig 1. Study flow chart.

Fig 2. Network of eligible comparisons on discontinuations due to adverse events.

The line width is proportional to the number of studies that compare each pair of treatments, and the size of each node is proportional to the number of comparisons the treatment is included in. Plac = placebo; oAD = other antidepressant; MAOI = monoamine oxidase inhibitor; Cmpl = complementary treatment; aPS = antipsychotic; TCA = tricyclic antidepressant; SSRI = selective serotonin reuptake inhibitor; SARI = serotonin antagonist reuptake inhibitor.

Fig 3. Network of eligible comparisons on experiencing any adverse event.

The line width is proportional to the number of studies that compare each pair of treatments, and the size of each node is proportional to the number of comparisons the treatment is included in. Plac = placebo; oAD = other antidepressant; MAOI = monoamine oxidase inhibitor; Cmpl = complementary treatment; aPS = antipsychotic; TCA = tricyclic antidepressant; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin noradrenalin reuptake inhibitor; Benz = benzodiazepine.

Fig 4. Network meta-analysis estimates of discontinuation rates due to adverse events for substance classes compared with placebo.

Odds ratios higher than 1 reflect a higher discontinuation rate due to adverse events in the substance class arms, whereas odds ratios lower than 1 reflect a higher discontinuation rate due to adverse events in the placebo arms; OR = odds ratio; CI = confidence interval; aPS = antipsychotics (containing amisulpride and flupenthixol); Cmpl = complementary treatments (containing acetyl-l-carnitine); MAOI = monoamine oxidase inhibitors (containing moclobemide and phenelzine); oAD = other antidepressants (containing ritanserin and minaprine); Plac = placebo, sari = serotonin antagonist and reuptake inhibitor (containing trazodone); SSRI = selective serotonin reuptake inhibitors (containing sertraline, fluoxetine, escitalopram, and paroxetine); TCA = tricyclic antidepressants (containing imipramine, amineptine, and amitriptyline); ‘contrasts that are informed by at least one direct comparison to placebo.

Fig 5. Network meta-analysis estimates of experiencing any adverse event for substance classes compared with placebo.

Odds ratios higher than 1 reflect a higher rate of patients experiencing at least one adverse event in the substance class arms, and odds ratios lower than 1 reflect a higher rate of patients experiencing at least one adverse event in the placebo arms; OR = odds ratio; CI = confidence interval; aPS = antipsychotics (containing amisulpride and flupenthixol); Benz = benzodiazepine (containing lorazepam); Cmpl = complementary treatments (containing acetyl-l-carnitine); MAOI = monoamine oxidase inhibitors (containing moclobemide); oAD = other antidepressants (containing ritanserin and minaprine); Plac = placebo; SNRI = serotonin noradrenalin reuptake inhibitor (containing duloxetine and reboxetine); SSRI = selective serotonin reuptake inhibitors (containing sertraline, fluoxetine, escitalopram, and paroxetine); TCA = tricyclic antidepressants (containing imipramine, amineptine, and amitriptyline); ‘contrasts that are informed by at least one direct comparison to placebo.

Fig 6. Adverse event profiles for all investigated agents.