Influence Of Selective Serotonin Reuptake Inhibitors Research Articles

Abstract PS7-51: The impact of SSRI use on overall survival in breast cancer patients in northern Israel

Abstract Background: It is estimated that 12.7% of the US population had been prescribed an antidepressant in the past month and that women are twice as likely to be on an antidepressant than men. Therefore, it is especially important to understand how SSRIs interact with female hormones and influence risk and progression of female cancers, especially breast cancer, being the most common. Up to a third of women use selective serotonin reuptake inhibitors (SSRIs) after breast cancer diagnosis. Recent investigation has demonstrated serotonin receptor (5-HTR2B) expression in the breast and identified serotonin production in breast tumor cells as an indicator of poor prognosis. This paper presents a unique comparative assessment between the influence of prior SSRI use, continuous and after use relative to breast cancer diagnosis on overall mortality among breast cancer patients. This analysis is expected to provide a clearer understanding of the influence of SSRIs based on period of use relative to time of diagnosis on overall mortality. Methods: The present study includes a population-based sample of consecutively diagnosed breast cancer cases identified as part of the Breast Cancer in Northern Israel study. Patients were recruited and followed from January 1st, 2000 to July, 2019. Participants completed risk factor questionnaires regarding medical, reproductive, family and personal history of cancer, medication use and health habits. Additionally full prescription data was available through the Israeli national CLALIT medical database. An analysis of 5976 newly diagnosed women with breast cancer was performed. K-M survival analysis and time-dependent and time-independent COX proportional hazard models were performed to determine overall survival based on interval of SSRI use. Results: Use of SSRIs in the 5 years prior to breast cancer diagnosis was associated with a 66% increase in overall mortality (HRadj.=1.66; CI: 1.05-2.63). Use of SSRIs with use that initiated after breast cancer diagnosis was associated with an 81% increase in mortality (HRadj.=1.81; CI: 1.58-2.06). Use of SSRIs in the 5 years post-diagnosis was associated with a significant (P<0.001) dose-response increase in long-term mortality (>5 years). For 24 months of SSRI use after diagnosis, there was a 99% increase in mortality (HR=1.99; CI: 1.39-2.83). Conclusion: SSRIs used both prior to and after breast cancer diagnosis are associated with reduced overall survival in breast cancer patients. The effect of SSRIs on mortality persisted even after adjustment for tamoxifen and factors thought to mediate the relationship behind depression and increased mortality including increased age at diagnosis, comorbidities and stage at diagnosis pointing toward other mechanisms mediating the association between SSRIs and impaired survival in breast cancer patients. Additional research is needed to better understand who is susceptible to the adverse effects of SSRIs on breast cancer overall mortality. Treating depressive symptomatology is of high importance. The results presented here indicate that risks and benefits of SSRI use after breast cancer diagnosis should be weighed when initiating pharmachotherapy and additional research is needed to better understand why SSRIs are associated with worse outcomes in breast cancer patients. Citation Format: Avital Fischer, Hedy Rennert, Ofra Barnett, Gad Rennert. The impact of SSRI use on overall survival in breast cancer patients in northern Israel [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-51.

Perioperative use of selective serotonin reuptake inhibitors is associated to poor postoperative outcome in patients undergoing liver resection

Presenter: Patrick Starlinger MD | Mayo Clinic, Rochester Background: Recently, modification of intra-platelet serotonin levels as therapeutic intervention to promote postoperative liver regeneration was proposed. In this context, we previously showed a bivalent effect of serotonin on liver regeneration and early tumour recurrence. We were able to provide exploratory data on the use of selective serotonin reuptake inhibitors (SSRI) within the previous publications. Yet, this data has to be considered exploratory, as the number of patients under SSRI treatment was extremely low. Accordingly, we aimed to evaluate the use of selective serotonin reuptake inhibitors (SSRI) in a large cohort of patients undergoing liver resection. Methods: In total, 755 patients undergoing liver resection were retrospectively included from our prospectively maintained institutional database. Perioperative intake of SSRI was evaluated and patients were followed up for postoperative liver dysfunction (LD) and morbidity. Results: Within this cohort 75 patients (9.9%) with perioperative SSRI therapy could be identified. Of note, patients treated with SSRI showed a higher incidence of severe morbidity (22.9% - no SSRI vs 31.6% - SSRI, p<0.05) and a significantly increased incidence of liver dysfunction (10.7% - no SSRI vs 23.4% - SSRI, p<0.05). On the other hand, patients receiving SSRI therapy were found to suffer from significantly reduced early tumor recurrences at 6 and 12 months after surgery (6 months: 13.0% - no SSRI vs 22.7% - SSRI, p<0.05; 12 months: 26.3% - no SSRI vs 42.1% - SSRI, p<0.05). Conclusion: Within the present study we present solid data on the influence of SSRI on postoperative clinical outcome. Indeed, perioperative SSRI treatment seems to be associated to development of LD most likely via downregulation of intra-platelet serotonin, which was shown to be central for postoperative liver regeneration. However, SSRI therapy also seems to supressearly tumor recurrences and might therefore reflect an attractive adjuvant therapy in patients after liver resection.

Acute escitalopram but not contextual conditioning exerts a stronger "anxiogenic" effect in rats with high baseline "anxiety" in the acoustic startle paradigm.

Acute administration of selective serotonin reuptake inhibitors (SSRIs) may enhance anxiety in humans, those with anxiety disorders being more susceptible than others. Fear-conditioned or unconditioned acoustic startle and freezing are common measures of fear and/or "anxiety" in rodents that may be used to study this effect of SSRIs preclinically. Our aim was to shed further light on the effect of acute administration of an SSRI, escitalopram (10mg/kg), on startle and freezing in the absence or presence of prior contextual conditioning. Repeated testing also enabled us to evaluate (i) if there are stable inter-animal variations with respect to these parameters in a batch of outbred Wistar rats, (ii) the possible relationship between the two and (iii) if baseline behaviour predicts the response to escitalopram. Inter-animal test-retest correlations were found for both startle and freezing at baseline, and the two parameters also correlated with each other. Both escitalopram and contextual conditioning increased freezing and startle but without exerting any synergistic effect. While animals displaying high startle at baseline showed higher susceptibility to respond to escitalopram, the effect of conditioning was more pronounced in those with low baseline startle. The results support the usefulness of both conditioned and non-conditioned startle and freezing to capture an "anxiogenic" influence of SSRIs. Also, they suggest that baseline non-conditioned startle may predict this response in a manner reflecting the clinical situation in the sense that subjects with high baseline "anxiety" are particularly prone to respond with enhanced "anxiety" following acute SSRI administration.

Evaluation of serotonin, noradrenaline and dopamine reuptake inhibitors on light-induced phase advances in hamster circadian activity rhythms

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for the treatment of anxiodepressive states that are often associated with perturbed circadian rhythms including, in certain patients, phase advances. Surprisingly, the influence of SSRIs upon circadian activity rhythms has been little studied in experimental models. Accordingly, this study examined the ability of SSRIs to modulate the phase-setting properties of light on circadian activity rhythms in hamsters. Their actions were compared to those of the mixed serotonin/noradrenaline reuptake inhibitor (SNRI), venlafaxine, the selective noradrenaline reuptake inhibitor, reboxetine, and the dopamine reuptake inhibitor, bupropion. Wheel-running activity rhythms were recorded in male Syrian hamsters. Drugs were administered systemically before a light stimulus that was used to advance the timing of the hamster running rhythms. Four chemically diverse SSRIs, citalopram (1-10 mg/kg, intraperitoneally), fluvoxamine (1-10), paroxetine (1-10), and fluoxetine (10 and 20), all robustly and significantly inhibited the ability of light to phase advance hamster circadian wheel-running activity rhythms. Their actions were mimicked by venlafaxine (1-10) that likewise elicited a marked reduction in phase advances. Conversely, reboxetine (1-20) and bupropion (1-20) did not exert significant effects. These data suggest that suppression of serotonin (but not noradrenaline or dopamine) reuptake by SSRIs and SNRIs modifies circadian locomotor activity rhythms in hamsters. Further, they support the notion that an inhibitory influence upon the early-morning light-induced advance in circadian activity contributes to the therapeutic effects of serotonin uptake inhibitors in certain depressed patients.

Effect of selective serotonin reuptake inhibitors on the oxidative metabolism of propafenone: in vitro studies using human liver microsomes.

Propafenone is mainly metabolized by CYP2D6 to form 5-hydroxypropafenone (5-OHP) and to a minor extent by CYP1A2 and CYP3A4 to form N-depropylpropafenone (N-DPP). The in vitro inhibitory effect of selective serotonin reuptake inhibitors (SSRIs) on the formation of both metabolites was studied, using human liver microsomes. The 5-OHP formation from racemic propafenone and from its individual enantiomers followed one-enzyme Michaelis-Menten kinetics. Incubation with the racemate yielded a mean Vmax of 64 pmol x min(-1) x mg(-1) and a mean Km of 0.12 microM (N = 3). Stereoselectivity in Vmax and Km values was observed, with (S)-propafenone displaying higher Km and Vmax values. N-DPP formation from racemic propafenone followed one-enzyme Michaelis-Menten kinetics and yielded a mean Vmax of 403 pmol x min(-1) x mg(-1) and a mean Km of 116 microM (N = 3). No stereoselectivity in propafenone N-dealkylation was observed. The influence of SSRIs and quinidine, a prototypical CYP2D6 inhbitor, on propafenone 5-hydroxylation was investigated. Quinidine was the most potent inhibitor, followed by fluoxetine, norfluoxetine, and paroxetine. Sertraline, desmethylsertraline, and fluvoxamine had only a moderate inhibitory effect, whereas citalopram displayed slight or no inhibition when racemic propafenone was used as substrate. Mean Ki values of quinidine, fluoxetine, norfluoxetine, and paroxetine were 0.13, 0.33, 0.55, and 0.54 microM, respectively (N = 3). Quinidine and paroxetine were also tested as inhibitors using the individual enantiomers, but no stereoselectivity was observed. Among the SSRIs tested, only fluvoxamine substantially inhbited propafenone N-dealkylation with a mean IC50 of 7.0 microM (N = 3). There was a more pronounced inhibitory effect of fluvoxamine on (R)-propafenone than on (S)-propafenone N-dealkylation. In conclusion, these in vitro data suggest that an in vivo interaction between propafenone and the SSRIs, fluoxetine and paroxetine, can be expected, which can lead to clinically relevant beta-blockade and an increased risk of side effects in the central nervous system. An interaction with fluvoxamine may be of importance in poor metabolizers for CYP2D6.

Subchronic administration of fluoxetine impairs estrous behavior in intact female rats.

Treatment with serotonin reuptake inhibitors (SRIs) has been shown to cause reduced libido and anorgasmia in women. A large body of evidence suggests that serotonin may influence sexual behavior in estradiol + progesterone primed, gonadectomized female rats; however, the influence of selective SRIs on the estrous behavior of intact female rats has not been described previously. In the present study, the effect of 1 to 3 weeks of fluoxetine administration (10 mg/kg daily) on vaginal and behavioral estrus in intact female rats was studied; in addition, the effect of fluoxetine (same dose, 1-8 weeks) on copulatory behavior and on sexual motivation in hormone-primed gonadectomized rats was investigated. Subchronic administration of fluoxetine did not influence cyclicity as judged by the examination of vaginal smears but significantly reduced the percentage of rats displaying receptive behavior in the estrous phase. In addition, fluoxetine significantly reduced receptive behavior, including lordosis, in ovariectomized female rats primed with estradiol (6.25 micrograms/rat; -48 hr) plus progesterone (1.0 mg/rat, -4 hr); in contrast, sexual motivation--as reflected by the amount of time these rats elected to spend in the vicinity of a male rather than in the vicinity of a female or elsewhere--was little affected by the treatment.