Hyperglycemia induced by acute central fluoxetine administration: role of the central CRH system and 5-HT3 receptors

Carvalho, F.; Barros, Daniela M.; Silva, J; Rezende, Edson Campana; Soares, Maria Francisca de Paula; Fregoneze, J.B.; Silva, E De Castro e

doi:10.1016/j.npep.2004.04.004

Cited by 27 publications

(15 citation statements)

References 45 publications

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“…This may reflect a mechanism in which antidepressants increase DM risk by their own neuroendocrine traits. It is assumed that antidepressants affect the hypothalamic-pituitary-adrenal axis, which results in an increase of plasma cortisol level and insulin resistance 22,47). Some SSRIs might work as inhibitors of insulin signaling and cellular insulin resistance by activation of insulin receptor substrate 1 kinases 48).…”

Section: Discussionmentioning

confidence: 99%

Antidepressant Use and Diabetes Mellitus Risk: A Meta-Analysis

et al. 2013

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BackgroundEpidemiologic studies have reported inconsistent findings regarding the association between the use of antidepressants and type 2 diabetes mellitus (DM) risk. We performed a meta-analysis to systematically assess the association between antidepressants and type 2 DM risk.MethodsWe searched MEDLINE (PubMed), EMBASE, and the Cochrane Library (through Dec 31, 2011), including references of qualifying articles. Studies concerning the use of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or other antidepressants and the associated risk of diabetes mellitus were included.ResultsOut of 2,934 screened articles, 3 case-control studies, 9 cohort studies, and no clinical trials were included in the final analyses. When all studies were pooled, use of antidepressants was significantly associated with an increased risk of DM in a random effect model (relative risk [RR], 1.49; 95% confidence interval [CI], 1.29 to 1.71). In subgroup analyses, the risk of DM increased among both SSRI users (RR, 1.35; 95% CI, 1.15 to 1.58) and TCA users (RR, 1.57; 95% CI, 1.26 to 1.96). The subgroup analyses were consistent with overall results regardless of study type, information source, country, duration of medication, or study quality. The subgroup results considering body weight, depression severity, and physical activity also showed a positive association (RR, 1.14; 95% CI, 1.01 to 1.28). A publication bias was observed in the selected studies (Egger's test, P for bias = 0.09).ConclusionOur results suggest that the use of antidepressants is associated with an increased risk of DM.

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Section: Discussionmentioning

confidence: 99%

Antidepressant Use and Diabetes Mellitus Risk: A Meta-Analysis

et al. 2013

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“…These include forebrain (thalamus and hypothalamus) and hindbrain nuclei that are known to play important roles in regulating ANS responses during hypoglycemia. Carvalho et al (36) demonstrated that third-ventricle injections of fluoxetine in wistar rats resulted in hyperglycemia without accompanying hyperinsulinemia. Pretreatment with a selective corticotropin-releasing hormone (CRH) antagonist prevented the increase in hyperglycemia.…”

Section: Discussionmentioning

confidence: 99%

Effects of a Selective Serotonin Reuptake Inhibitor, Fluoxetine, on Counterregulatory Responses to Hypoglycemia in Healthy Individuals

et al. 2008

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OBJECTIVE-Hypoglycemia commonly occurs in intensivelytreated diabetic patients. Repeated hypoglycemia blunts counterregulatory responses, thereby increasing the risk for further hypoglycemic events. Currently, physiologic approaches to augment counterregulatory responses to hypoglycemia have not been established. Therefore, the specific aim of this study was to test the hypothesis that 6 weeks' administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine would amplify autonomic nervous system (ANS) and neuroendocrine counterregulatory mechanisms during hypoglycemia. RESEARCH DESIGN AND METHODS-A total of 20 healthy (10 male and 10 female) subjects participated in an initial single-step hyperinsulinemic (9 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 )-hypoglycemic (means Ϯ SE 2.9 Ϯ 0.1 mmol/l) clamp study and were then randomized to receive 6 weeks' administration of fluoxetine (n ϭ 14) or identical placebo (n ϭ 6) in a double-blind fashion. After 6 weeks, subjects returned for a second hypoglycemic clamp. Glucose kinetics were determined by three-tritiated glucose, and muscle sympathetic nerve activity (MSNA) was measured by microneurography.RESULTS-Despite identical hypoglycemia (2.9 Ϯ 0.1 mmol/l) and insulinemia during all clamp studies, key ANS (epinephrine, norepinephrine, and MSNA but not symptoms), neuroendocrine (cortisol), and metabolic (endogenous glucose production, glycogenolysis, and lipolysis) responses were increased (P Ͻ 0.01) following fluoxetine.CONCLUSIONS-This study demonstrated that 6 weeks' administration of the SSRI fluoxetine can amplify a wide spectrum of ANS and metabolic counterregulatory responses during hypoglycemia in healthy individuals. These data further suggest that serotonergic transmission may be an important mechanism in modulating sympathetic nervous system drive during hypoglycemia in healthy individuals. Diabetes 57:2453-2460, 2008 S everal reports have indicated that fluoxetine could have metabolic effects and influence carbohydrate metabolism (1-3). In fact, there have been three case studies reporting the occurrence of hypoglycemia related to the use of selective serotonin reuptake inhibitors (SSRIs) in depressed patients with and without diabetes (4 -6). However, although SSRIs are potent inhibitors of neuronal serotonin uptake, they also have the ability to block norepinephrine transport (7). This could increase sympathetic outflow activity (2,8). Baudrie and Chaouloff (9) have previously reported an increased hyperglycemic response to 2-deoxy-D-glycose in conscious rats following serotononergic receptor antagonists, implying increased counterregulation in these animals.A subsequent study by Perry and Fuller (2) demonstrated that systemic injection of the SSRI fluoxetine in rats resulted in threefold increases of hypothalamic norepinephrine release, thereby providing a mechanistic basis for SSRIs to modulate sympathetic nervous system activity. A later study by Bymaster et al. (3) examined the specificity of five different SSRIs (fluoxetine, citalopram, fluvoxamine, paroxe...

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“…Activation of a number of serotonergic receptors (5HT 1A , 5HT 1C , 5HT 2 , and 5HT 3 ) has been demonstrated to increase sympathetic nervous system outflow (5,6,38,39). Additionally, both systemic and central administration of SSRIs have specifically increased adrenal catecholamine and epinephrine release (7,8).…”

Section: Discussionmentioning

confidence: 99%

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Counterregulatory Responses to Hypoglycemia in Individuals With Type 1 Diabetes

et al. 2008

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OBJECTIVE-Previous work has demonstrated that chronic administration of the serotonin reuptake inhibitor (SSRI) fluoxetine augments counterregulatory responses to hypoglycemia in healthy humans. However, virtually no information exists regarding the effects of fluoxetine on integrated physiological counterregulatory responses during hypoglycemia in type 1 diabetes. Therefore, the specific aim of this study was to test the hypothesis that 6-week use of the SSRI fluoxetine would amplify autonomic nervous system (ANS) counterregulatory responses to hypoglycemia in individuals with type 1 diabetes. )-hypoglycemic clamp studies before and after 6 weeks of fluoxetine administration (n ϭ 8) or identical placebo (n ϭ 10). Glucose kinetics was determined by 3-tritiated glucose. Muscle sympathetic nerve activity (MSNA) was determined by microneurography. RESEARCH DESIGN AND METHODS-EighteenRESULTS-Hypoglycemia (2.8 Ϯ 0.1 mmol/l) and insulinemia (646 Ϯ 52 pmol/l) were similar during all clamp studies. ANS, neuroendocrine, and metabolic counterregulatory responses remained unchanged in the placebo group. However, fluoxetine administration significantly (P Ͻ 0.05) increased key ANS (epinephrine, norepinephrine, and MSNA), metabolic (endogenous glucose production and lipolysis), and cardiovascular (systolic blood pressure) counterregulatory responses during hypoglycemia.CONCLUSIONS-This study has demonstrated that 6-week administration of the SSRI fluoxetine can amplify ANS and metabolic counterregulatory mechanisms during moderate hypoglycemia in patients with type 1 diabetes. These data also suggest that the use of fluoxetine may be useful in increasing epinephrine responses during hypoglycemia in clinical practice. Diabetes 57:3315-3322, 2008 S elective serotonin reuptake inhibitors (SSRIs) are effective drugs for the treatment of depressive disorders associated with reduced serotonergic function. Serotonergic neurons play an important role in the regulation of neuroendocrine function carried out via both sympathoadrenal and hypothalamic-pituitaryadrenal (HPA) pathways.Two studies have reported increased hypoglycemia and loss of awareness to hypoglycemia related to the use of SSRIs in depressed patients with type 1 diabetes (1,2). Although SSRIs are potent inhibitors of neuronal serotonin uptake, they also have the ability to block norepinephrine transport (3,4). This would be predicted to increase sympathetic outflow activity (4 -7). Supporting this, previous studies by a number of investigators have demonstrated that SSRIs can modulate sympathetic nervous system activity and increase counterregulation in rats (8).Two recent studies in healthy humans (9) and conscious rats (10) have provided further insight into the effects of SSRIs on counterregulatory physiology during hypoglycemia. Briscoe et al. (9) investigated the effects of 6 weeks of high-dose fluoxetine administration on physiological responses to hypoglycemia in a group of healthy, nondepressed humans. Key sympathetic nervous system (epinephrine, norepinephrine,...

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Hyperglycemia induced by acute central fluoxetine administration: role of the central CRH system and 5-HT3 receptors

Cited by 27 publications

References 45 publications

Antidepressant Use and Diabetes Mellitus Risk: A Meta-Analysis

Antidepressant Use and Diabetes Mellitus Risk: A Meta-Analysis

Effects of a Selective Serotonin Reuptake Inhibitor, Fluoxetine, on Counterregulatory Responses to Hypoglycemia in Healthy Individuals

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Counterregulatory Responses to Hypoglycemia in Individuals With Type 1 Diabetes

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