Article
Clinical outcome and tolerability of sertraline in major depression: A study with plasma levels

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Abstract

Sertraline (SRT) has been shown to be an effective antidepressant in extensive clinical trial programs but data on plasma concentrations regarding clinical outcome and tolerability are lacking. Twenty-one out-patients of both sexes, with mean age of 50.23 years (S.D.=17.37), affected by major depressive disorder, recurrent (Diagnostic and Statistical Manual of Mental Disorder—IV, DSM-IV), were treated with 25–150 mg of SRT once a day (mean=66.26 mg, S.D.=30.50) for 30 days. Clinical evaluation was assessed at baseline (T0), after 15 days (T15), and then after 30 days (T30). Plasma samples for SRT level determination were collected at T30. Brief Psychiatric Rating Scale (BPRS), Hamilton Rating Scale for Depression (HRS-D), and Hamilton Rating Scale for Anxiety (HRS-A) showed a significant improvement during the study (P<.01 vs. T0). The most commonly reported side effects were nausea (19%), cephalalgia (9.5%), dry mouth (9.5%), decreased libido (9.5%), tremor (4.7%), and tachycardia (4.7%). SRT plasma levels ranged from 2.82 to 112.20 ng/ml (mean=40.42 ng/ml, S.D.=26.93). No correlation between SRT plasma levels and clinical improvement or side effects were observed. Drug plasma level determination does not seem be strictly necessary from a clinical point of view but further research seems advisable in patients at risk like elderly and during long-term studies.

Introduction

Sertraline (SRT) has been shown to be an effective antidepressant in extensive clinical trial programs. Available evidences from short-term studies (6-week duration) suggest that SRT has similar efficacy to tricyclic antidepressants in patients with major depression. In particular, the antidepressant activity of SRT is similar to amitriptyline, imipramine, nefazodone, nortriptyline, and dothiepin, and significantly greater than that of placebo Lydiard et al., 1997, Olie et al., 1997, Miller et al., 1998, Rush et al., 1998 also during maintenance therapy Doogan and Caillard, 1992, Keller et al., 1998. On the other hand, SRT showed efficacy similar to fluoxetine and fluvoxamine in patients with major depression Lane et al., 1995, Davis and Wilde, 1996.

SRT has shown its efficacy in dysthymic patients and it was recommended as the first choice in the treatment of affective disorders, so that psychotherapeutic approaches could be facilitated (Thase et al., 1996).

Efficacy of SRT was also recently supported by a PET study (Buchsbaum et al., 1997).

The dose regimen in the treatment of depression has been well established: A starting dose of 50 mg/day is also usually considered the effective therapeutic dose, and the optimal dose when both efficacy and tolerability for most patients were considered Preskorn and Lane, 1995, Van Houdenhove et al., 1997.

SRT has been very well tolerated by patients with major depression in clinical trials. Adverse events associated with SRT therapy were usually dose-related, mild, and transient. The most common side effects, gastrointestinal reactions (nausea, diarrhea), headache, dry mouth, insomnia, dizziness, tremor, fatigue, agitation, and somnolence, occurred in about 10–20% of patients and caused treatment withdrawal in approximately 1–4% of the cases. In any case, SRT has demonstrated a better tolerability profile than amitriptyline as indicated by a significantly lower incidence of anticholinergic, cardiovascular, and sedative effects and a lower adverse effect burden Doogan and Caillard, 1992, Murdoch and McTavish, 1992.

SRT, like other serotonin selective reuptake inhibitors (SSRIs), is slowly but completely absorbed from the gut with a time to peak plasma concentrations of 6–8 h. SRT elimination half-life is 26 h, thus making the drug suitable for once-daily administration. Steady-state plasma levels are achieved within 7 days. SRT has been reported to have a linear pharmacokinetics at a dosage of 50–200 mg/day. Peak plasma concentrations and area under the curve (AUC) values were reported to be increased in elderly (≥65 years) volunteers (Warrington, 1991). Age–gender interaction for SRT was described: plasma concentrations were 35–40% lower in young men than in young women, elderly men, and elderly women (Ronfeld et al., 1997). Other studies in elderly volunteers reported a prolonged elimination half-life (about 36 h), although this difference was not statistically significant (Warrington, 1991). SRT, similar to other SSRIs, is eliminated mainly by oxidative metabolism. The determinant metabolite is N-demethyl sertraline (DMSRT). Different from citalopram, paroxetine, and probably fluoxetine, CYP enzymes (CYP 2D6) do not seem to have a major role in the metabolism of SRT Preskorn, 1996, Preskorn, 1997, Solai et al., 1997. In terms of serotonin uptake inhibition, DMSRT is up to 25 times weaker than SRT in vitro, producing only 6–15% of the total serotonin uptake inhibition achieved with maternal drug, DMSRT being considered substantially less active than the parent compound playing a negligible role in its clinical activity Sprouse et al., 1996, Davis and Wilde, 1996, Preskorn, 1997.

Nevertheless, data on plasma concentrations regarding clinical outcome and tolerability profile are lacking. The aim of this naturalistic study was to evaluate SRT plasma concentrations in relation to clinical variables in a short-term treatment at low dosage.

Section snippets

Patient population

Twenty-one out-patients of both sexes (7 males and 14 females), affected by major depressive disorder, recurrent, according to Diagnostic and Statistical Manual of Mental Disorder—IV (DSM-IV, American Psychiatric Association, 1994) criteria, were included in the study. They were aged between 26 and 79 years (mean=50.23 years, S.D.=17.37).

After complete description of the study to the patients, written informed consent was obtained.

Drug treatment

After a washout period of approximately 1 week, the patients

Clinical outcome

BPRS and HRS-D total score (mean values) showed a significant improvement at T15 and T30 vs. T0 (P=.002 and P<.001, respectively). HRS-A total score (mean values) showed a significant improvement at T30 vs. T0 (P<.001) (Fig. 1). Mean percent of improvement was 25.71 (S.D.=15.22) for BPRS, 56.02% (S.D.=19.21) for HRS-D, and 44.04% (S.D.=29.23) for HRS-A. Eleven (52.38%) patients showed more than 50% reduction on HRS-A and 15 (71.42%) patients showed more than 50% reduction on HRS-D.

Side effects

The most

Discussion

Even if our study is a not controlled one and it has been conducted with a small number of patients, our data suggests that SRT seems to be effective and well tolerated at low dosage (mean=60 mg/day) in the treatment of major depression. Regarding antidepressant and anxiolytic effect, SRT showed its efficacy in both situations even if the significant amelioration of HRS-A was reported only at T30, which could indicate that SRT at this dosage should not have peculiar anxiolytic or sedative

Conclusion

Our study is limited because of the small number of patients and also because it is an open one. However, it confirms, in a naturalistic setting, the good efficacy and tolerability of SRT at the dose range studied. According to our data, drug plasma level determination seems not to be strictly necessary from a clinical point of view but further research is needed to determine the utility of plasma level monitoring in patients at risk such as elderly or renal- and liver-impaired patients and

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