European Neuropsychopharmacology (v.19, #10)

Contents (OBC).

SSRIs, bone mineral density, and risk of fractures — a review by Sofie Schwan; Pär Hallberg (683-692).
A possibility for selective serotonin reuptake inhibitors (SSRIs) to increase the risk of bone fracture has been debated during recent years. Proposed causes include an ability for the drugs to reduce bone mineral density (BMD). Experimental data have identified a functional 5-HT system in bone, although its role is unclear. Results from numerous epidemiological studies are heterogeneous and several different associations have been suggested; between depression and low BMD, SSRIs and low BMD, depression and falls, SSRIs and falls, depression and fractures, and SSRIs and fractures. In this paper, we review the available data and discuss the various study results. Based on the current available data, we conclude that it is not possible to determine whether SSRIs may negatively influence bone regulation or are innocent bystanders. It is likely that only a large, prospective, long-term study designed to investigate changes in BMD will be able to answer the question.
Keywords: Selective serotonin reuptake inhibitor; Antidepressive drug; Osteoporosis; Fracture; Bone;

Intranasal application of dopamine reduces activity and improves attention in Naples High Excitability rats that feature the mesocortical variant of ADHD by Lucia A. Ruocco; Maria A. de Souza Silva; Bianca Topic; Claudia Mattern; Joseph P. Huston; Adolfo G. Sadile (693-701).
Based on findings of a profound action of intranasally applied dopamine (DA) on dopamine release in the striatum, we examined the possibility that intranasal application of DA would influence indices of attention and activity in juvenile male rats of the Naples High Excitability line. This rat model features the main aspects of Attention Deficit/Hyperactivity Disorder (ADHD). Juvenile NHE rats received an intranasal application of either DA (0.075 mg/kg, 0.15 mg/kg and 0.3 mg/kg) or vehicle into both nostrils daily for 15 days. On day 14, 1 h after treatment, they were tested in the Làt maze, and one day later, in the eight arm radial maze. Activity in the Làt maze: The highest dose of DA (0.3 mg/kg) decreased horizontal (HA) and vertical (VA) activity during the first 10 min of the test. No effect was found for rearing duration (RD), which indexes non-selective attention (NSA). Activity in the radial maze: No treatment effects were found for HA and VA components, and for RD. Attention indices: The intermediate dose of DA (0.15 mg/kg) significantly improved the number of arms visited before the first repetitive arm entry in the radial maze, an index of selective spatial attention (SSA). In conclusion, intranasal application of DA reduced hyperactivity at the highest dose used, whereas the intermediate dose improved attention in an animal model of ADHD. These results suggest the potential of employing intranasal DA for therapeutic purposes.
Keywords: Intranasal route; NHE rats; ADHD; Làt maze; Olton maze; Dopamine; Attention; Hyperactivity;

Sertindole causes distinct electrocardiographic T-wave morphology changes by Jimmi Nielsen; Claus Graff; Thomas Hardahl; Mads P. Andersen; Jens Kristoffersen; Johannes J. Struijk; Egon Toft; Jonathan M. Meyer (702-707).
Sertindole's propensity to prolong the QT interval relates to blockade of the KCNH2 (HERG) encoded Ikr potassium channel, but there has been limited detailed data on T-wave morphology changes. Digital 12-lead ECG was recorded at baseline and at steady-state in 37 patients switched to sertindole. ECG was analyzed for quantitative T-wave morphology changes and Fridericia-corrected QT duration (QTcF). Prominent T-wave morphology changes occurred during sertindole treatment and in some cases without concomitant prolongation of the QTcF interval. Four patients developed notched T-waves during sertindole treatment. Mean QTc prolongation was 19 ms. The mean effect size was higher for T-wave morphology combination score (MCS) (ES = 1.92; 95% CI: 1.35–2.49) compared to the mean effect size for QTcF (ES = 0.88; 95% CI: 0.52–1.24). The use of T-wave morphology analysis may become clinically relevant, particularly if shown to be associated with drug-induced arrhythmia risk.
Keywords: T-wave; Sertindole; Antipsychotics; QTc; Sudden death; Torsade de pointes;

Characteristics and consequences of muscarinic receptor activation by tau protein by Alberto Gómez-Ramos; Miguel Díaz-Hernández; Alicia Rubio; Juan Ignacio Díaz-Hernández; Maria Teresa Miras-Portugal; Jesus Avila (708-717).
It was recently suggested that tau protein released as a result of neuronal death is toxic to neighbouring cells, an effect that is mediated through the activation of muscarinic M1 and/or M3 receptors. Nevertheless, why tau protein and not other native muscarinic agonists, like ACh, can induce this neurotoxicity remains unknown. To clarify this issue, we analysed the different responses and properties of muscarinic receptors in response to stimulation by tau or ACh. The results revealed that the tau protein has an affinity for muscarinic receptors of around one order of magnitude higher than that of ACh. Furthermore, while the repeated stimulation with ACh induces desensitization of the muscarinic receptors, reiterate stimulation with tau failed to produce this phenomenon. Finally, we found the tau protein to be very stable in the extracellular milieu. These studies provide valuable information to help understand tau toxicity on neural cells bearing M1 or M3 muscarinic receptors and its contribution to neurodegenerative progression in tauopathies.
Keywords: Tau protein; Alzheimer; Muscarinic receptors;

Effect of basic fibroblast growth factor (FGF2) gene polymorphisms on SSRIs treatment response and side effects by Masaki Kato; Gaku Okugawa; Masataka Wakeno; Yoshiteru Takekita; Shinpei Nonen; Shinji Tetsuo; Keiichiro Nishida; Junichi Azuma; Toshihiko Kinoshita; Alessandro Serretti (718-725).
Antidepressant response usually appears in 2 to 4 weeks and 30–40% of patients do not show a significant response although biochemical changes of monoaminergic system occur within hours after administration. Genetic factors could play a role in this process and genes involved in synaptic plasticity and neurogenesis are possible candidates. In fact, antidepressants and electroconvulsive therapy increase basic fibroblast growth factor (FGF2) and the rs1449683C/T polymorphism within this gene has been found to be a predictor for both an elevated mRNA and protein level of FGF2. Therefore we examined the possible association of rs1449683C/T and a panel of tagging SNPs in SSRI efficacy and side effects in 144 Japanese major depressive subjects followed for 6 weeks. We observed a significant association of rs1449683T (p  = 0.010) and rs308393C (p  = 0.029) variant carriers toward a better response to SSRI and of rs1048201 with higher frequency of drop out due to side effects (p  = 0.010), independently from clinical variables. Furthermore the rs308447T–rs308393C–rs1449683T haplotype was associated with higher response rate (p  = 0.012) while the rs1048201T–rs3747676T haplotype was significantly associated with higher dropped out rate (p  = 0.015). In conclusion, this is the first study investigating the association of antidepressant response and intolerance with FGF2 variants. This finding adds an important piece of information for the pathway of detecting the genetics of antidepressant response.
Keywords: Basic fibroblast growth factor; Depression; Pharmacogenetics; Antidepressants; Treatment response; Side effects;

Proapoptotic and chemosensitizing effects of selective serotonin reuptake inhibitors on T cell lymphoma/leukemia (Jurkat) in vitro by Ben Hayman Amit; Irit Gil-Ad; Michal Taler; Meytal Bar; Amichai Zolokov; Abraham Weizman (726-734).
While selective serotonin reuptake inhibitors (SSRIs) are commonly used for psychiatric indications, evidence implies them to possess anti-cancerous properties as well. We evaluated such in vitro effects in malignant T cells (Jurkat), finding that exposure to high concentrations of sertraline (IC50  = 9.5 µM) or paroxetine (IC50  = 18 µM) yielded a considerable reduction in cellular viability, exceeding equimolar doses of the chemotherapeutics vincristine and cyclophosphamide (P  < 0.015). The cytotoxic effects included both inhibition of proliferation and induction of apoptosis, demonstrated by decreased [3H] thymidine incorporation and increased activity of the caspase-3 enzyme, as well as a decrease in the expression of the Bcl-2 proto-oncogene. No effect on c-Jun or ERK was observed, rendering the complete mechanism yet to be fully elucidated. When combined with chemotherapy, sertraline (7.5 µM) markedly enhanced the effects of both vincristine and doxorubicin, suggesting SSRI antidepressants as potential new chemosensitizers in chemotherapeutic regimens, pending further in vivo research.
Keywords: Sertraline; Antidepressants; Chemosensitizers; Jurkat; T cell lymphoma; T cell leukemia;

The antinociceptive properties of reboxetine in acute pain by Shaul Schreiber; Ruthi Frishtick; Ina Volis; Vardit Rubovitch; Chaim G. Pick; Ronit Weizman (735-739).
The antinociceptive effects of the selective noradrenaline reuptake inhibitor antidepressant reboxetine and its interaction with various opioid and noradrenaline receptor subtypes were evaluated. Reboxetine (i.p.) induced a weak dose-dependent antinociceptive effect in acute pain, using the hotplate model. The reboxetine-induced antinociception was significantly inhibited by the opioid receptor antagonists naloxone, nor-BNI, naltrindole and b-FNA, implying a non-selective role for the opioid receptors in the reboxetine's antinociceptive effect. The adrenergic antagonists yohimbine and phentolamine attenuated to some extent the reboxetine-induced antinociception, implying a minor adrenergic mechanism of antinociception. The addition of opioid or α2 agonists, did not potentiate the antinociception effect of reboxetine. Thus, it seems that reboxetine possesses a weak antinociceptive effect, mediated by non-selective opioid receptors and influenced somewhat by noradrenaline α2 receptors. These results suggest that reboxetine as monotherapy does not have sufficient efficacy in the management of acute pain. However, further research is needed in order to establish its possible use alone or in combination with other antidepressants or analgesics in the amelioration of chronic pain disorders.
Keywords: Antidepressants; Antinociception; Hotplate; Noradrenaline; Opioid receptor subtypes; Pain; Reboxetine;

Brain opioid receptor binding in early abstinence from alcohol dependence and relationship to craving: An [11C]diprenorphine PET study by Tim M. Williams; Simon J.C. Davies; Lindsay G. Taylor; Mark R.C. Daglish; Alexander Hammers; David J. Brooks; David J. Nutt; Anne Lingford-Hughes (740-748).
The importance of the opioid receptor system in substance dependence is increasingly recognised. We used PET with the non-selective tracer [11C]diprenorphine to examine opioid receptor binding in early abstinence from alcohol dependence and the relationship to craving. We recruited 11 alcohol dependent patients and 13 controls. Subjects underwent one [11C]diprenorphine PET scan in early abstinence from dependent alcohol use (∼ 2 weeks) and 2 months later if continuously abstinent. Global and regional [11C]diprenorphine volumes of distribution (VD) were increased in alcohol dependent patients compared with controls but did not reach significance. We demonstrated a correlation between global and regional [11C]diprenorphine VD and craving in alcohol dependent patients which persisted in the anterior cingulate cortex into extended abstinence. This confirms previous work showing increased opioid receptor availability in early abstinence from substances of abuse and correlation with craving suggesting that the opioid system plays a fundamental role in this phase of addiction.
Keywords: Addiction; Alcohol; Opioid receptor; Abstinence; PET; Craving;

Safflower, the dry flower of Carthamus tinctorius L., has long been applied for empirically treating cerebral ischemia and depression in traditional Chinese medicine. Pathogenesis of major depression involves monoaminergic transmission. The present study assessed whether safflower or its isolate would be effective in functionally regulating monoamine transporter using in vitro screening cell lines. We discovered that safflower insoluble fraction significantly inhibited serotonin uptake in Chinese hamster ovary cells stably expressing serotonin transporter (i.e. S6 cells). This fraction went through an activity-guided isolation and an active ingredient was obtained, which was subsequently elucidated as a novel coumaroylspermidine analog N 1,N 5-(Z)-N 10-(E)-tri-p-coumaroylspermidine using NMR techniques. Pharmacologically, this compound potently and selectively inhibited serotonin uptake in S6 cells or in synaptosomes, with IC50 of 0.74 ± 0.15 µM for S6 cells or 1.07 ± 0.23 µM for synaptosomes and with a reversible competitive property for the 5HT-uptake inhibition. The potency of it for 5HT uptake was weaker than that of fluoxetine whereas efficacy generally similar for both. Animals treated with this testing compound showed a significant decrease in synaptosomal 5HT uptake capacity. Thus, N 1,N 5-(Z)-N 10-(E)-tri-p-coumaroylspermidine is a novel serotonin transporter inhibitor, which could improve neuropsychological disorders through regulating serotoninergic transmission.
Keywords: Safflower; N 1,N 5-(Z)-N 10-(E)-tri-p-coumaroylspermidine; Serotonin transporter; Reuptake; Inhibitor;