Side effects of antidepressants during long-term use in a naturalistic setting

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Abstract

Side effects of antidepressants are usually underreported in clinical trials and large scale naturalistic studies are restricted to six months of use. We examined the prevalence and nature of patient-perceived side effects and their determinants during long-term antidepressant use in a naturalistic setting. Subjects, aged 19 to 67 years, in the Netherlands Study of Depression and Anxiety were recruited from primary care and specialized mental health care covered 927 cases of single antidepressant use. In 64% of cases, on average, 2.9 side effects were reported. The number of side effects was higher when subjects had higher depression severity (OR=1.28; p=0.002), three or more psychiatric diagnoses (OR=1.97; p=0.02), higher dose (OR=1.44; p=0.006) and was lower when subjects were older (OR=0.83; p=0.02) and had longer duration of use (OR=0.94; p=0.04). Tricyclic antidepressants were associated with more side effects (OR=2.52; p=0.003) and, particularly, more anticholinergic effects, like dry mouth and constipation, as compared to selective serotonin reuptake inhibitors. Venlafaxine showed more profuse sweating (OR=1.79; p=0.007), whereas mirtazapine showed more weight gain and less sexual dysfunction (OR=0.36; p=0.03), as compared to selective serotonin reuptake inhibitors. Weight gain was associated with female gender (OR=1.76; p=0.004) and duration of use (OR=1.06; p=0.03). We show that antidepressant side effect, known from short-term studies, persist during long-term use and are associated with depression severity and antidepressant dose. A novel finding was that venlafaxine is associated with more profuse sweating and that weight gain appeared more specific in female users. Clinicians should be aware that, during long-term antidepressant use, side effects are common and persistent.

Introduction

Antidepressant use is associated with a variety of side effects (SEs). In clinical trials their prevalence is up to 27% (Trindade et al., 1998). SEs interfere with optimal treatment dosages and may be the cause of medication non-adherence and discontinuation (Lingam and Scott, 2002). Although SEs should be known before an antidepressant is introduced in daily practice, SE assessment in clinical trials concerning mental health is inadequate, particularly with respect to long-term effects (Papanikolaou et al., 2004). A recent large scale meta-analysis of 143 clinical trials on antidepressants showed that structured and systematic SE assessment strategies were used in only 21% of these trials (Rief et al., 2009). Moreover, a systematic review on 115 studies revealed that only a few trials used an objective side effect rating scale whereas adverse events were rarely pre-specified and defined (Gartlehner et al., 2008). In clinical trials often only short-term severe SEs are reported. This lack of adequate SE data is hindering the evaluation of antidepressant risk–benefit ratios (Papanikolaou et al., 2004).

Although participants of antidepressant clinical trials represent only a small highly selected minority of depressed patients in clinical practice, trial results on efficacy can be generalized to the general population (van der Lem et al., 2011, Zimmerman et al., 2002). Clinical trials have revealed differences in SE profiles among different types of antidepressants (Anderson, 2000, Trindade et al., 1998, Watanabe et al., 2010, Stahl et al., 2005, Gartlehner et al., 2008). However, it is not clear whether there is similarity between SEs reported in clinical trials and those occurring in daily practice (van der Lem et al., 2011, Zimmerman et al., 2002). Prescription Event Monitoring has provided naturalistic SE data in a primary care setting of short-term (up to 6 months) antidepressant use (Mackay et al., 1997, Mann et al., 1997, Mackay et al., 1999), but antidepressant-induced SE data in a long-term naturalistic setting is lacking.

Little is known about the persistence of patient-perceived SEs during long-term antidepressant use. In a large short-term study comparing citalopram and nortriptyline most SEs, which were assessed on a weekly basis, decreased over a 12 week study period (Uher et al., 2009). The clinical notion that SEs wear off during prolonged use over years is not substantiated with data. The mean incidence of headache and nausea in 27 antidepressant continuation- and maintenance-phase studies was 16% and 7%, respectively. Compared to acute phase studies, the relative incidence of these events was only slightly lower (Hansen et al., 2008). Finally, reports of long-term clinical trials also seldom provide differentiation between SE prevalence at the beginning of the trial and SE prevalence after 6–24 months of continued treatment (Kasper et al., 2008, Thase et al., 2011).

Patient-, disease- and treatment-related factors like age (Draper and Berman, 2008, Naranjo et al., 1995, Stone et al., 2009), depression severity (Wilting et al., 2009, Uher et al., 2009) and type and dose of antidepressant (Trindade et al., 1998, Watanabe et al., 2010, Stahl et al., 2005) influence the occurrence and severity of SEs in clinical trials. Because of unknown external validity of SE data from clinical trials to long-term daily use and the lack of systematic SE data comparing different antidepressants over an extended time course, it is important to study antidepressant-induced SEs during long-term use in a naturalistic setting. We therefore examined the prevalence, nature and determinants of SEs during long-term use of different types of antidepressants in a naturalistic setting.

Section snippets

Study sample

All subjects participating in the present study came from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing longitudinal cohort study conducted among 2981 adult subjects (18–65 years) to examine (predictors of) the long-term course of depression and anxiety disorders. The rationales, methods and recruitment strategy have been described elsewhere (Penninx et al., 2008).

The NESDA sample consists of 652 persons without depression or anxiety disorders and 2329 with a (remitted or

Results

Demographics and basic characteristics of the 846 subjects are presented in Table 1. Their mean age was 43.0 years and 67% was female. Thirty eight percent of the 927 cases had a co-morbid depression and anxiety disorder and 31% used a benzodiazepine. SSRI use (63%) mainly concerned paroxetine, fluoxetine, citalopram and escitalopram. TCA use included amitriptyline, nortriptyline and clomipramine. In 2.6% of the cases St John's wort was used.

In 64% of cases of antidepressant use, on average 2.9

Discussion

This naturalistic study shows that patient-perceived SEs are common and persist during long-term antidepressant use in a large cohort of patients with depression and/or anxiety disorders. Our structured inventory of 12 common antidepressant SEs confirms the known differences in SE profiles among different types of antidepressants. However, it also shows venlafaxine to be associated with more profuse sweating compared with SSRIs. The number of reported SEs is higher at younger patient age,

Role of the funding source

The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, Grant no. 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of

Contributors

All authors contributed to the study design, discussions and manuscript revision. P.M. Bet performed the literature search, statistical analyses and wrote the first draft.

Conflict of interest

All authors declare that they have no conflict of interest.

Acknowledgment

None.

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