Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases

Certain selective serotonin reuptake inhibitors (SSRIs) induce the clinical and biochemical manifestations of a metabolic syndrome by as yet unknown mechanism. Here we demonstrate that incubation (1 h) of rat hepatoma Fao cells with the SSRIs paroxetine and sertraline, but not with the atypical antipsychotic drug olanzapine, inhibited the insulin-stimulated Tyr phosphorylation of the insulin receptor substrate-1 (IRS-1) with half-maximal effects at approximately 10 microM. This inhibition correlated with a rapid phosphorylation and activation of a number of Ser/Thr IRS-1 kinases including JNK, S6K1, ERK and p38 MAPK, but not PKB (Akt). JNK appears as a key player activated by SSRIs because specific JNK inhibitors partially eliminated the effects of these drugs. The SSRIs induced the phosphorylation of IRS-1 on S307 and S408, which inhibits IRS-1 function and insulin signaling. These results implicate selected SSRIs as inhibitors of insulin signaling and as potential inducers of cellular insulin resistance.     

The neuroanatomical basis of affective mentalizing in schizophrenia: comparison of patients with schizophrenia and patients with localized prefrontal lesions

Patients with schizophrenia show impaired emotional and social behavior, such as misinterpretation of social situations and lack of Theory of Mind (ToM). However, the neuroanatomical basis of impaired ToM and its nature in schizophrenia is still largely unknown. Based on previous findings, the present study suggests that impaired social cognition observed in schizophrenic patients may be similar to that observed in patients with prefrontal (PFC) damage due to impaired ‘affective ToM’ abilities, rather than to a general impairment in ToM. We examined the behavioral and neural mechanisms that underlie the social and communicative impairments observed in patients with schizophrenia and with PFC damage, by looking at differential patterns of ToM impairment in these individuals. The performance of 24 patients with schizophrenia was compared to the responses of patients with localized lesions in the ventromedial (VM) or dorsolateral PFC, patients with non-frontal lesions, and healthy control subjects. Patients with schizophrenia and those with VM lesions were impaired on ‘affective ToM’ tasks but not in cognitive ToM conditions. It was concluded that the pattern of mentalizing impairments in schizophrenia resembled those seen in patients with lesions of the frontal lobe, particularly with VM damage, providing support for the notion of a disturbance of the fronto-limbic circuits in schizophrenia.     

Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs: the role of the aromatic ring.

OBJECTIVE: Antiepileptic drugs (AEDs) can cause various 'idiosyncratic' hypersensitivity reactions, i.e. the mechanism by which AEDs induce hypersensitivity is unknown. The aim of this study was to assess whether the presence of an aromatic ring as a commonality in chemical structures of AEDs can explain symptoms of hypersensitivity. METHODS: Between January 1985 and January 2007, all adverse drug reactions (ADRs) reported to the Netherlands Pharmacovigilance Centre Lareb related to AEDs as suspected drugs were included in this study. ADRs were analysed using a case/non-case design. Cases were defined as those patients with ADRs involving symptoms of hypersensitivity. Non-cases were patients with all other ADR reports. Symptoms of hypersensitivity were classified according to the Gell and Coombs classification (type I-IV) and the organ involved (e.g. cutaneous, hepatic). AEDs were classified as aromatic anticonvulsant if their chemical structure contained at least one aromatic ring. All other AEDs were classified as non-aromatic. We assessed the strength of the association between aromatic AEDs versus non-aromatic AEDs and reported hypersensitivity reactions with logistic regression analysis and expressed these as reporting odds ratios (RORs). RESULTS: In total, 303 cases of hypersensitivity associated with the use of AEDs were reported. Aromatic AEDs were suspected in 64.4% of these reports versus 41.3% (574/1389) of the non-hypersensitivity reports. A significant ROR of 2.15 (95% CI 1.63, 2.82) was found for aromatic AEDs and all hypersensitivity reactions. Aromatic AEDs were significantly associated with immunoglobin E-mediated type I hypersensitivity reactions (ROR 2.15; 95% CI 1.23, 3.78) and T-cell-mediated type IV reactions (ROR 6.06; 95% CI 3.41, 10.75). Type II and III reactions did not show an association. Cutaneous symptoms represented 39.9% of the hypersensitivity-related ADRs. Aromatic AEDs were significantly associated with cutaneous hypersensitivity reactions (ROR 5.81; 95% CI 3.38, 9.99). CONCLUSION: This study confirms that the presence of an aromatic ring as a common feature in chemical structures of AEDs partly explains apparent 'idiosyncratic' hypersensitivity reactions. Symptoms of hypersensitivity were reported twice as frequently with aromatic AEDs than with non-aromatic AEDs. Strong associations for aromatic AEDs versus non-aromatic AEDs were found for T-cell-mediated (type IV) reactions, as well as for cutaneous reactions.     

Association of tumour necrosis factor and haemodynamic shock in a newborn undergoing surgery for sacrococcygeal teratoma

A newborn who was operated upon for a benign sacrococcygeal teratoma at the age of 2 weeks developed haemodynamic instability with a shock episode at the time of operation. The serum level of tumour necrosis factor alpha (TNF-Alpha) during this event rose to 158 pg/ml (normal <15 pg/ml). Preoperatively TNF-Alpha was undetectable, while post-operatively the level was 23 pg/ml. Serum levels of the cytokine interleukin-1 beta (IL-1 beta) were undetectable throughout the study. The baby was treated successfully by fluid challenge and dopamine. This case represents a temporal association between haemodynamic instability during surgical intervention and a high serum level of TNF-Alpha, which is an important mediator in the pathogenesis of septic shock.     

Learned irrelevance is disrupted in first-episode but not chronic schizophrenia patients

Learned irrelevance (LIrr) is a pre-exposure effect in which uncorrelated presentations of a conditioned stimulus (CS) and an unconditioned stimulus (US) retard subsequent CS-US association. LIrr is closely related to the phenomenon of latent inhibition (LI). LI refers to the retarding effects of inconsequential stimulus pre-exposure on subsequent conditioning to that stimulus, and is considered to reflect the organism's capacity to ignore irrelevant stimuli. LI is disrupted in schizophrenia patients, due to faster learning of the association between the preexposed CS and the US. A new within-subject target-recognition LIrr procedure was applied. The target was either cued by a priming signal or appeared at random, and priming signals were novel or preexposed cues. Schizophrenia patients were compared to age- and sex-matched control subjects. Normal subjects (n = 24) have shown robust LIrr, namely, faster cue-target associations of novel compared to preexposed cues. Schizophrenia patients at the early stages of their first episode (n = 7) showed LIrr disruption, namely, cue-target associations to preexposed cues were as fast as for novel cues. Chronic patients during an acute phase (n = 18) did not show LIrr as they failed to learn the cue-target association. In addition to the LIrr paradigm the same subjects were tested in a covert-orientation task. No differences were observed between the groups on this task. The possible advantages of the new LIrr paradigm are discussed.     

Birthweight of offspring and mortality of parents: the Jerusalem perinatal study cohort

PURPOSE: We sought to examine the association between birthweight in offspring and mortality in their parents. Distinguishing between risks of outcomes in mothers from fathers potentially provides clues as to the relative roles of genetic versus nongenetic mechanisms underlying these associations. METHODS: We studied total and cause-specific mortality in a population-based cohort of 37,718 mothers and 38,002 fathers whose offspring were delivered in West Jerusalem during 1964-1976, after an average follow-up of 34.12 years. RESULTS: Hazard models controlling for sociodemographic and lifestyle characteristics indicated a U-shaped relationship between offspring's birthweight and overall mortality, deaths from coronary heart disease, circulatory and other non-neoplastic causes in their mothers. Greater rates of mortality from coronary heart disease were observed among mothers who gave birth to babies with low (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.40-3.25) and high birthweight (HR, 1.98; 95% CI, 1.36-2.88), as compared with mothers whose offspring weighed 2500-3999 g at birth. Adjustment for maternal pre-eclampsia slightly attenuated these results. Multivariate models indicated a negative linear relationship (HR, 0.95; 95% CI, 0.91-0.99) between offspring's birthweight and overall mortality in their fathers. Unlike the association in mothers, the relation was noted primarily with deaths from "other causes." CONCLUSIONS: Birthweight of offspring is associated with parental mortality although the relation differs for fathers and mothers. These findings broaden previous observations that intra-uterine events have long-term consequences for adult health and support the need to explore genetic and/or environmental mechanisms underlying these associations.