Evaluation of central serotonergic function in affective and related disorders by the fenfluramine challenge test: a critical review

Abstract

Plasma prolactin levels following oral administration of the serotonin (5-HT) releasing agent, fenfluramine hydrochloride, have been extensively used to evaluate central serotonergic function in affective and related disorders. Cortisol responses to fenfluramine have generally been a less informative measure. In healthy subjects, prolactin release by fenfluramine is dose-dependent, blocked by antagonists of serotonin receptors of the 5-HT-2a/2c type, negatively correlated with age and increased in young females. In major depression, a preponderance of studies have found blunted prolactin responses compared to matched normal controls. Although a significant minority of studies have not found blunting, increased prolactin release has not been observed. The blunted prolactin release is not due to a deficient secretory capacity of pituitary lactotrophs and is congruent with other evidence for reduced central serotonergic function in major depression. Blunting of the prolactin response may be associated with severity of depression and with elevated baseline cortisol levels. Treatment with antidepressant drugs and electroconvulsive therapy has been reported to increase the prolactin response but this has not been replicated in all studies. Blunted prolactin responses to fenfluramine have been fairly consistently associated with impulsive aggression in different personality disorders and with severity of suicide attempts in depressed patients. A number of studies employing the fenfluramine challenge test (FCT) have been conducted in obsessive compulsive disorder but their results have been variable. Prolactin responses to fenfluramine may be enhanced in panic disorder and chronic fatigue syndrome but the number of studies in these conditions is small as is the case for seasonal affective disorder. Since the therapeutic administration of fenfluramine as an appetite suppressant has been suspended because of reports of cardiac complications, further use of this compound as a challenge agent is not anticipated. Future studies are likely to employ agents acting on specific serotonin receptors and should apply methodological insights from the use of the FCT, which are considered in this review. Use of concomitant brain imaging to evaluate the central effects of challenge agents directly is likely to become more prevalent and may supplant neuroendocrine challenge paradigms such as the FCT which have been remarkably heuristic but are limited in scope and methodologically complex.

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

“…[337][338][339] Administration of D-fenfluramine results in a dosedependent rise in prolactin levels, 340 which has been used as an index of central 5-HT responsivity. [341][342][343] The prolactin response to fenfluramine in depression has been studied extensively, with mixed results (for review see Kavoussi et al 340 ). Studies that compare prolactin response to fenfluramine in depressed patients before and after antidepressant treatment have yielded mixed results.…”

From Galactorrhea to Osteopenia: Rethinking Serotonin–Prolactin Interactions

“…In humans, the observation that oral administration of fenfluramine to healthy volunteers induced a dose-related increase in PRL secretion provided an index of central serotonergic function (Quattrone et al, 1983), a phenomenon that has been reliably reproduced many times over. Fenfluramine, a serotonin-releasing agent, which also inhibits the reuptake of synaptic 5-HT and stimulates postsynaptic 5-HT 2A and 2C receptors (Newman et al, 1998) induces a rapid surge of PRL in laboratory animals and humans (Lu and Meites, 1973;Pinder et al, 1975;Slater et al, 1976). In contrast to healthy controls, a blunted PRL response occurs in some depressed patients when challenged with fenfluramine (Siever et al, 1984;Cleare et al, 1995;Coccaro et al, 1989;Mann et al, 1995;O'Keane and Dinan, 1991;Lopez-Ibor et al, 1988;Mitchell and Smythe, 1990), suggesting abnormal central serotonergic transmission in this condition.…”

“…However, many studies have failed to show similar results (Asnis et al, 1988;Abel et al, 1997;Maes et al, 1991;Weizman et al, 1988;Kavoussi et al, 1998). The main criticism of studies documenting a positive correlation between a blunted PRL response and depression is the use of heterogeneous patient populations with other psychiatric comorbidities (Newman et al, 1998). More recent studies indicate that blunted PRL response to fenfluramine is associated with impulsive aggression and suicidal behavior, traits associated with depression (Coccaro et al, 1989(Coccaro et al, , 1997aFava et al, 2000;New and Siever, 2002;Placidi et al, 2001).…”

Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder

“…26 Neuroendocrine challenge studies with d and dl fenfluramine have consistently shown blunted release of prolactin in depressed patients and it has been reported that this blunting is a trait phenomenon which is also observed in the well state. 27 Fenfluramine-induced prolactin release has been shown to be mediated by 5-HT2C receptors. 28 The HT2CR cys23ser polymorphism examined in this study may have functional effects on mCPP binding in vitro.…”