Failing Memory in Nonaffective Psychosis and Prolactin Response to 12.5 µg i.v. TRH

Dear EditorThe increase in plasma prolactin at 15 min following administration of 12.5 µg TRH i. v. (∆prol) was introduced in Pharmacopsychiatry as an inverse estimate of tuberoinfundibular dopamine (TIDA) activity 1. We used the unpublished data set in 20 participants with nonaffective psychosis from our 1991 study utilizing ∆prol 2 and here report new results with its association with memory.

MON-LB60 Prolactin Response to Metformin in Cabergoline-Resistant Prolactinomas: A Prospective Study

Introduction: Prolactinomas are the most frequent pituitary-secreting tumors. Medical therapy with cabergoline (CAB), a dopamine agonist (DA), is the first line treatment, but 10% of prolactinomas are resistant to CAB. Recently, in vitro studies have shown anti-tumoral activity of metformin and other biguanids in human prolactinomas1, which prompted us to investigate that possibility in vivo. Aim: To evaluate the effect of metformin (MET) on Prolactin (PRL) secretion in patients with CAB resistant prolactinomas. Design and Setting: Prospective interventional study in a single referral center. Subjects: Ten patients (7 M; mean age: 44 ± 12y) with CAB resistant (PRL: 148 ± 125ng/ml; range: 38 - 386) prolactinomas (all macroadenomas) and metabolic syndrome on maximally tolerated CAB doses (4.3 ± 1.2 mg/week; range: 2.0-7.0) for ≥ 6 months (45 ± 39mo; range: 6-120). Intervention: Oral extended release metformin (p.o.) was prescribed according to patient’s tolerance (mean dose: 1.3 ± 0.4 g; range: 1.0-2.0). Main Outcome Measurements: Serum PRL (Elecsys, Roche, Indianapolis, USA), body weight (BW), fasting glycemia (FG) and HbA1C were evaluated before and at two time points during metformin treatment (30-60 and 120-180 days). Results: BW, FG, and/or HbA1C reductions were observed in 9/10 patients and mean FG decreased significantly (P=0.04). No significant changes were observed in serum PRL levels during metformin treatment [134 ± 124 ng/ml vs 138 ± 132 ng/ml vs 144 ± 129 ng/ml, before, at 30-60 days and at 120-180 days, respectively (P=0.499, mixed-effects analysis with the Geisser-Greenhouse correction)]. Individually, two patients exhibited a ≥ 50% decrease in PRL levels at a single timepoint (one at 30-60 days, with a further increase at 120-180 days and the other at 120-180 days). Conclusion: Metformin, at usual doses, did not inhibit prolactin secretion in patients with cabergoline-resistant prolactinomas. The discrepancy between our results and in vitro studies is not clear, but may be related to the much higher concentrations of metformin used in vitro1 as compared to the serum concentrations observed in patients during metformin treatment2. References: 1Gao J et al. Metformin inhibits growth and prolactin secretion of pituitary prolactinoma cells and xenografts. J Cell Mol Med. 2018 22:6368-79; 2 Frid A et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care 2010 33:1291-3.

Neurobiological Functioning and the Personality-Trait Hierarchy: Central Serotonergic Responsivity and the Stability Metatrait

Trait domains of the five-factor model are not orthogonal, and two metatraits have often been estimated from their covariation. Here, we focus on the stability metatrait, which reflects shared variance in conscientiousness, agreeableness, and (inversely) neuroticism. It has been hypothesized that stability manifests, in part, because of individual differences in central serotonergic functioning. We explored this possibility in a community sample ( N = 441) using a multiverse analysis of (a) multi-informant five-factor-model traits and (b) stability as a predictor of individual differences in central serotonergic functioning. Differences in serotonergic functioning were assessed by indexing change in serum prolactin concentration following intravenous infusion of citalopram, a selective serotonin reuptake inhibitor. Results were mixed, showing that trait neuroticism, agreeableness, and conscientiousness, as well as the stability metatrait, were significantly associated with prolactin response but that these findings were contingent on a number of modeling decisions. Specifically, these effects were nonlinear, emerging most strongly for participants with the highest levels (or lowest, for neuroticism) of the component traits.

Kisspeptin Stimulation of Prolactin Secretion Requires Kiss1 Receptor but Not in Tuberoinfundibular Dopaminergic Neurons

Kisspeptin has been shown to stimulate prolactin secretion. We investigated whether kisspeptin acts through the Kiss1 receptor (Kiss1r) to regulate dopamine and prolactin. Initially, we evaluated prolactin response in a Kiss1r-deficient mouse line, in which Kiss1r had been knocked into GnRH neurons (Kiss1r−/−R). Intracerebroventricular kisspeptin-10 (Kp-10) increased prolactin release in wild-type but not in Kiss1r−/−R female mice. In ovariectomized, estradiol-treated rats, the Kiss1r antagonist kisspeptin-234 abolished the Kp-10–induced increase in prolactin release but failed to prevent the concomitant reduction in the activity of tuberoinfundibular dopaminergic (TIDA) neurons, as determined by the 3,4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence. Using whole-cell patch clamp recordings in juvenile male rats, we found no direct effect of Kp-10 on the electrical activity of TIDA neurons. In addition, dual-label in situ hybridization in the hypothalamus of female rats showed that Kiss1r is expressed in the periventricular nucleus of the hypothalamus (Pe) and arcuate nucleus of the hypothalamus (ARC) but not in tyrosine hydroxylase (Th)–expressing neurons. Kisspeptin also has affinity for the neuropeptide FF receptor 1 (Npffr1), which was expressed in the majority of Pe dopaminergic neurons but only in a low proportion of TIDA neurons in the ARC. Our findings demonstrate that Kiss1r is necessary to the effect of kisspeptin on prolactin secretion, although TIDA neurons lack Kiss1r and are electrically unresponsive to kisspeptin. Thus, kisspeptin is likely to stimulate prolactin secretion via Kiss1r in nondopaminergic neurons, whereas the colocalization of Npffr1 and Th suggests that Pe dopaminergic neurons may play a role in the kisspeptin-induced inhibition of dopamine release.

Neurobiological Functioning and the Personality Trait Hierarchy: Central Serotonergic Responsivity and the Stability Meta-trait

Trait domains of the five-factor model (FFM) are not orthogonal, and two meta-traits have often been estimated from their covariation. Here we focus on the Stability meta-trait, which reflects shared variance in conscientiousness, agreeableness, and neuroticism (inversely). It has been hypothesized that Stability manifests, in part, due to individual differences in central serotonergic functioning. We explore this possibility in a community sample (N=441) using a multiverse analysis of multi-informant FFM traits and Stability predicting individual differences in central serotonergic functioning, as assessed by change in serum prolactin concentration following intravenous infusion of the selective serotonin reuptake inhibitor, citalopram. Results were mixed, showing that trait neuroticism, agreeableness, and conscientiousness, as well as the Stability meta-trait, are significantly associated with prolactin response, but that these findings are contingent on a number of modeling decisions. Specifically, these effects were non-linear, emerging most strongly for those highest (lowest for neuroticism) on the component traits.