Selective serotonin reuptake inhibitors in the treatment of affective disorders—III. Tolerability, safety and pharmacoeconomics

Abstract

The clinical use of tricyclic antidepressants (TCAs) is often complicated by toxicity and safety problems due to their effects on multiple mechanisms of action, many of which are unnecessary for therapeutic effect. The development of the selective serotonin reuptake inhibitors (SSRIs), with their selective mode of action, has resulted in a class of antidepressant drugs possessing an improved side-effect profile, while retaining good clinical efficacy. Their introduction into clinical practice has led to enhanced patient compliance with antidepressant therapy and the ability to maintain treatment over longer periods of time at an adequate therapeutic dose. Although, as a result of their selective action, side-effects associated with SSRI therapy are minimised, distinct variations between individual SSRIs in terms of their tolerability profiles have been observed. The wealth of clinical data now available has revealed differences in their potential to cause psychiatric and neurological side-effects, dermatological reactions, anticholinergic side-effects, changes in body weight, sexual dysfunction, cognitive impairment, discontinuation reactions and drug-drug interactions. Patients who suffer from concomitant depression and physical illness may experience different tolerability profiles, in addition to the greater likelihood that they will be receiving concomitant medications with the potential for pharmacokinetic drug-drug interactions with coadministered SSRI therapy. In addition, the safety margin of SSRIs in overdose may vary within the group. Knowledge of the differences that exist among the SSRIs in respect of tolerability and safety will aid physicians in the selection of the most beneficial treatment strategy for their patients. A successful clinical outcome leads to a reduced economic burden for the patient, their family and the healthcare services. Thus, pharmacoeconomic considerations are also important in choosing antidepressant therapy. The SSRIs, despite relatively higher prescription costs, have been demonstrated to be a more cost-effective option than the TCAs. Furthermore, there is evidence that the emerging clinical differences between SSRIs may translate into significantly different economic outcomes within the group.

Panic Disorder and Serotonin Reuptake Inhibitors Predict Coupling of Cortical and Cardiac Activity

“…Thus, it would be incorrect to assume that individuals who are taking SRIs are characterized by reduced symptoms and should therefore also have reduced N300H. Moreover, consistent with the wide-spread localization of 5-HT signaling in the human brain (Cools et al, 2008), SRIs are known to have both anxiolytic and anxiogenic effects, with the anxiogenic effects being more pronounced at the beginning of treatment (Goldstein and Goodnick, 1998;Stahl, 1998;Trindade et al, 1998) often causing treatment discontinuation (Zanardi et al, 1996). In light of the positive relationship between anxiety and N300H , we hypothesize that SRIs by increasing brain-heart coupling produce anxiety-like side effects, which manifest at the beginning of treatment when anxiolytic effects of SRIs are not yet established (Stahl, 1998).…”

Cardiovascular Safety Profile of Dapoxetine during the Premarketing Evaluation

“…Dapoxetine is an SSRI and, as a new compound in this class, it merited special attention, given that other SSRI medications approved for the treatment of depression, anxiety, and other psychiatric conditions have infrequently been associated with reports of cardiovascular adverse events. [14][15][16] It was also important to assess the cardiovascular safety profile of dapoxetine because the proposed indication (i.e. PE) is not a life-threatening condition, and so syncope, albeit rare, might offset the clinical benefit.…”

“…The most common adverse events were those associated with the gastrointestinal and nervous system organ classes, and reflected acute symptomatic events that were generally self-limiting and temporally related to dosing, reflecting tolerability rather than serious safety concerns. [26][27][28][29][30] Special attention was given to cardiovascularrelated safety issues since syncope has been reported with marketed SSRIs [14][15][16] and there were five cases of vasovagal syncope during dapoxetine phase I studies. During the initial two phase III clinical studies of dapoxetine, further cases of syncope were reported although, at the time, the occurrence appeared balanced among the placebo, 30 mg, and 60 mg treatment groups (2 of 872 [0.2%], 3 of 876 [0.3%], and 2 of 870 [0.2%] episodes, respectively).…”

“…arrhythmias, orthostatic hypotension, syncope). [14][15][16] During premarketing clinical studies for these medications, adverse events, such as hypertension, tachycardia, and palpitations, were reported as more frequent events. [17][18][19] Here, we describe the evaluation of the cardiovascular safety of dapoxetine by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., [5] including the background and rationale for studies at each phase of development.…”

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

“…Inhibition of SERT is a common feature that TCAs, SSRIs and SNRIs possess to elicit an antidepressant response; however, selective NE reuptake inhibitors (NRIs): reboxetine, atomoxetine and viloxazine have also been developed for depression and are prescribed for attentiondeficit/hyperactivity disorder (ADHD) [52][53][54]. SSRIs and SNRIs by virtue of their selective interactions at the SERT and NET exhibited an improved adverse effect profile; however, they were not without shortcomings [55,56]. These agents have failed to improve the efficacy and exhibit delayed onset, typically 4-6 weeks, of antidepressant response [57].…”