Here we report a case showing the opposite effects of fluvoxamine and sertraline in a female patient with psychotic major depression that was non-respondent to antipsychotics. In this case, fluvoxamine monotherapy was effective in the treatment of psychotic major depression, and the switch to sertraline worsened the psychotic symptoms in the patient. The mechanisms underlying the opposite effects of these two SSRIs on the symptoms of a patient with psychotic major depression are currently unclear. This case suggests that fluvoxamine is clinically effective in the treatment of psychotic major depression, but sertraline may not be clinically useful for psychotic major depression although a further detailed study is necessary. It is thus likely that doctors should treat very carefully for the treatment of psychotic major depression using SSRI monotherapy.
One possible mechanism may be due to the difference in the action of these SSRIs at the endoplasmic reticulum protein sigma-1 receptors. Several pieces of evidence suggest that sigma-1 receptors play a role in the pathophysiology of major depression and in the active mechanisms of some antidepressants [
16‐
20]. The inhibition constants (Ki) of fluvoxamine and sertraline at sigma-1 receptors are 36 nM and 57 nM, respectively [
21]. Some recent studies have suggested that fluvoxamine is a potent agonist at sigma-1 receptors, whereas sertraline may be a sigma-1 receptor antagonist [
18,
19,
22‐
24]. A positron emission tomography study demonstrated that fluvoxamine binds to sigma-1 receptors in the intact human brain at therapeutic doses [
25], suggesting that sigma-1 receptors are involved in the active mechanisms of fluvoxamine [
19]. Interestingly, the addition of haloperidol (a potent sigma-1 receptor antagonist) has been found to reduce the response rate to fluvoxamine from 69% to 45%, suggesting that haloperidol might antagonize the sigma-1 receptor activity of fluvoxamine [
26]. Based on all these findings, it has been hypothesized that the sigma-1 receptors may be implicated in the efficacy of fluvoxamine for psychotic depression [
7,
8,
10‐
12]. It seems that serotonin reuptake inhibition as well as sigma-1 receptor agonism may be involved in the active mechanism of fluvoxamine, since paroxetine (no affinity at sigma-1 receptors) has a lesser effect in psychotic major depression [
27]. Although this case study does not clarify whether sigma-1 receptors are involved in the active mechanism of fluvoxamine, it is likely that the difference in the pharmacological actions (agonist or antagonist) of the two SSRIs at the sigma-1 receptors may have been related to the mechanisms of the opposite effects of the two SSRIs in this case. Thus, it seems that the antagonism of sigma-1 receptors by sertraline may be involved in the recurrence of psychotic symptoms in this case, although a further detailed study is necessary.
Another possibility is due to the potent inhibition (Ki = 22 nM for sertraline, Ki = 16,790 nM for fluvoxamine) of dopamine transporter by sertraline [
28]. It is suggested that the relative potency of sertraline for dopamine transporter inhibition might differentiate its psychopharmacology from that of other SSRIs [
29]. It is therefore possible that activation of the dopaminergic system by the inhibition of dopamine transporter may be involved in the mechanism of unwanted effects (deterioration of psychosis) of sertarline in this case, although further study is necessary.