Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression.

Few reliable predictors indicate which depressed individuals respond to antidepressants. Several studies suggest that a history of early-life trauma predicts poorer response to antidepressant therapy but results are variable and limited in adults. The major goal of the present study was to evaluate the role of early-life trauma in predicting acute response outcomes to antidepressants in a large sample of well-characterized patients with major depressive disorder (MDD). The international Study to Predict Optimized Treatment for Depression (iSPOT-D) is a randomized clinical trial with enrollment from December 2008 to January 2012 at eight academic and nine private clinical settings in five countries. Patients (n=1008) meeting DSM-IV criteria for MDD and 336 matched healthy controls comprised the study sample. Six participants withdrew due to serious adverse events. Randomization was to 8 weeks of treatment with escitalopram, sertraline or venlafaxine with dosage adjusted by the participant's treating clinician per routine clinical practice. Exposure to 18 types of traumatic events before the age of 18 was assessed using the Early-Life Stress Questionnaire. Impact of early-life stressors-overall trauma 'load' and specific type of abuse-on treatment outcomes measures: response: (⩾50% improvement on the 17-item Hamilton Rating Scale for Depression, HRSD17 or on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated, QIDS_SR16) and remission (score ⩽7 on the HRSD17 and ⩽5 on the QIDS_SR16). Trauma prevalence in MDD was compared with controls. Depressed participants were significantly more likely to report early-life stress than controls; 62.5% of MDD participants reported more than two traumatic events compared with 28.4% of controls. The higher rate of early-life trauma was most apparent for experiences of interpersonal violation (emotional, sexual and physical abuses). Abuse and notably abuse occurring at ⩽7 years of age predicted poorer outcomes after 8 weeks of antidepressants, across the three treatment arms. In addition, the abuses occurring between ages 4 and 7 years differentially predicted the poorest outcome following the treatment with sertraline. Specific types of early-life trauma, particularly physical, emotional and sexual abuse, especially when occurring at ⩽7 years of age are important moderators of subsequent response to antidepressant therapy for MDD.

CRMPs: critical molecules for neurite morphogenesis and neuropsychiatric diseases.

Neuronal polarity and spatial rearrangement of neuronal processes are central to the development of all mature nervous systems. Recent studies have highlighted the dynamic expression of Collapsin-Response-Mediator Proteins (CRMPs) in neuronal dendritic/axonal compartments, described their interaction with cytoskeleton proteins, identified their ability to activate L- and N-type voltage-gated calcium channels (VGCCs) and delineated their crucial role as signaling molecules essential for neuron differentiation and neural network development and maintenance. In addition, evidence obtained from genome-wide/genetic linkage/proteomic/translational approaches revealed that CRMP expression is altered in human pathologies including mental (schizophrenia and mood disorders) and neurological (Alzheimer's, prion encephalopathy, epilepsy and others) disorders. Changes in CRMPs levels have been observed after psychotropic treatments, and disrupting CRMP2 binding to calcium channels blocked neuropathic pain. These observations, altogether with those obtained from genetically modified mice targeting individual CRMPs and RNA interference approaches, pave the way for considering CRMPs as potential early disease markers and modulation of their activity as therapeutic strategy for disorders associated with neurite abnormalities.

Nicotine-induced changes of brain ß-endorphin.

A consensus has emerged that endogenous opioid peptides and their receptors play an important role in the psychoactive properties of nicotine. Although behavioral studies have shown that ß-endorphin contributes to the rewarding and emotional effects of nicotine, whether the drug alters the function of brain endorphinergic neurons is not fully explored. These studies investigated the effect of acute, 1mg/kg, sc, and chronic, daily injection of 1mg/kg, sc, for 14 days, administration of free base nicotine on brain ß-endorphin and its precursor proopiomelanocortin (POMC). Acute and chronic treatment with nicotine decreased ß-endorphin content in hypothalamus, the principal site of ß-endorphin producing neurons in the brain, and in the endorphinergic terminal fields in striatum and hippocampus. The acute effect of nicotine on ß-endorphin was reversed by the nicotinic antagonist mecamylamine and the dopamine antagonist haloperidol, indicating pharmacological specificity and involvement of dopamine D2-like receptors. Similar observations were made in prefrontal cortex. POMC mRNA in hypothalamus and prefrontal cortex was unchanged following acute nicotine, but it decreased moderately with chronic treatment. The nicotine treatments had no effect on pituitary and plasma ß-endorphin. Taken together, these results could be interpreted to indicate that nicotine alters the synthesis and release of ß-endorphin in the limbic brain in vivo. Altered endorphinergic function may contribute to the behavioral effects of acute and chronic nicotine treatment and play a role in nicotine addiction.

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.

OBJECTIVE: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. METHODS: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. RESULTS: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert-Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. INTERPRETATION: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

Changes in plasma nerve growth factor levels in older adults associated with chronic stress.

Evidence indicates that the actions of nerve growth factor (NGF) reach beyond the nervous system and might modulate immune function. Based on reports that blood NGF rises following the acute stress of parachute jumping, we investigated whether exposure to a chronic stressor, caregiving for a cognitively impaired spouse, could alter the levels of blood NGF. High perceived stress and depression in caregivers (vs. well-matched controls) were associated with elevated blood NGF. These data suggest that exposure to this chronic stressor can alter the concentrations of circulating NGF, and that psychological stress can induce changes in NGF concentrations in older adults.

Nerve growth factor (NGF) and NGF mRNA change in rat uterus during pregnancy.

During pregnancy, the uterus undergoes a profound sympathetic denervation. To explore whether this is associated with changes in neurotrophic factors, we assayed nerve growth factor (NGF) and NGF mRNA in the uterus of non-pregnant and pregnant rats. In the uterine horn, the concentration of NGF and its mRNA decreased during middle and late pregnancy. However, when values were corrected for the increase of uterine weight and total RNA yield during pregnancy, NGF content and mRNA per horn increased during middle and late pregnancy. Similar, but less pronounced, changes were observed in the cervix. By seven days postpartum, both parameters returned to near normal.

Glutamate receptors participate in the nicotine-induced changes of met-enkephalin in striatum.

A single dose of nicotine given to mice induces first a rapid decrease (presumed release/enhanced degradation) and then a rise (presumed synthesis/enhanced accumulation) of met-enkephalin (Met-Enk) in dorsal and ventral striatum observed at 30 and 60 min post-treatment, respectively. These studies investigated whether the nicotine effect on Met-Enk was mediated indirectly, in part, via other neurotransmitters known to be released by nicotine. Based on the ability of selective antagonists of dopamine (Sch 23390, D1; Sulpiride, D2), glutamate (CPP, competitive NMDA; dizocilpine, non-competitive NMDA; NBQX, AMPA) and GABA (bicuculline, GABA(A); Sch 50911, GABA(B)) receptors, to inhibit or enhance the response to nicotine, we conclude that nicotine alters striatal Met-Enk, in part, via glutamate NMDA and AMPA receptors. These findings further support the notion that glutamate might play a role in the pharmacology of nicotine.

Phosphorylation and activation of brain aromatic L-amino acid decarboxylase by cyclic AMP-dependent protein kinase.

Aromatic L-amino acid decarboxylase (AAAD), an enzyme required for the synthesis of catecholamines, indoleamines, and trace amines, is rapidly activated by cyclic AMP-dependent pathways in striatum and midbrain in vivo, suggesting enzyme phosphorylation. We now report that the catalytic subunit of cyclic AMP-dependent protein kinase (PKA) directly phosphorylated AAAD immunoprecipitated from homogenates prepared from the mouse striatum and midbrain in vitro. Under the same phosphorylation conditions, the catalytic subunit of PKA also phosphorylated a recombinant AAAD protein expressed in Escherichia coli transfected with an AAAD cDNA isolated from the bovine adrenal gland. The PKA-induced AAAD phosphorylation of immunoprecipitates from striatum and midbrain was time and concentration dependent and blocked by a specific PKA peptide inhibitor. Incubation of the catalytic subunit of PKA with striatal homogenates increased enzyme activity by approximately 20% in a time- and concentration-dependent manner. Moreover, incubation of the catalytic subunit of PKA with recombinant AAAD increased activity by approximately 70%. A direct phosphorylation of AAAD protein by PKA might underlie the cyclic AMP-induced rapid and transient activation of AAAD in vivo.

GM1 ganglioside restores dopaminergic neurochemical and morphological markers in aged rats.

The monosialoganglioside GM1 exerts neurotrophic-like activity in vitro and in vivo. In particular, it improves cholinergic neuron morphology and chemistry and learning abilities of cognitively impaired aged rats and young animals with cholinergic lesions, and restores neurochemical, pharmacological, morphological and behavioral parameters in animal models of Parkinson's disease. Our studies present evidence that GM1 reverses dopaminergic deficits in the nigrostriatal neurons of aged rats. GM1 administered to aged Sprague-Dawley rats for 30 days reversed the decreased activity of tyrosine hydroxylase in the midbrain and striatum, elevated the reduced protein content and mRNA levels of the enzyme in the midbrain, and reversed the decrements of dopamine and 3,4-dihydroxyphenylacetic acid content in both the midbrain and striatum. Tyrosine hydroxylase activity of the midbrain, but not of the striatum, remained elevated for 15 days after discontinuing GM1. The count profiles of tyrosine hydroxylase-immunopositive neurons, the size of tyrosine hydroxylase-immunopositive neurons and the number of tyrosine hydroxylase-immunopositive fibers were decreased in the substantia nigra pars compacta and the ventral tegmental area of aged rats. GM1 corrected the morphology of dopaminergic neurons in the substantia nigra pars compacta and partially improved it in the ventral tegmental area. These findings support the notion that the aged striatal dopaminergic neurons respond to GM1, and strengthen the utility of using this compound for combating age-associated neuronal deficits.

Tyrosine hydroxylase, aromatic L-amino acid decarboxylase and dopamine metabolism after chronic treatment with dopaminergic drugs.

Mice were treated with dopamine (DA) receptor agonist and antagonist drugs: Agonists: (+/-)-SKF 38393 ((+/-)-1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol) [DA D1-like]; bromocriptine, [DA D2 selective]; quinpirole, [DA D2/D3 preferring]; (+/-)-7-hydroxy-dipropylamino-tetralin (7-OH-DPAT), [DA D3/D2 preferring], Antagonists: R(+)-SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine), [DA D1-like]; and haloperidol, [DA D2-like]. All drugs were administered intraperitoneally, two injections daily 8 h apart for 30 days. Aromatic L-amino acid decarboxylase (AAAD) and tyrosine hydroxylase (TH) activity, protein and mRNA, as well as DA metabolism were followed with time thereafter in the nigrostriatal neurons. We observed that chronic administration of D1-like agonists had no effect on TH or AAAD activity, while D2-like agonists decreased AAAD, but not TH activity. Additionally, chronic blockade of DA D2-like receptors resulted in prolonged induction of TH and AAAD, while chronic blockade of DA D1-like receptors induced changes of AAAD only. Compared to TH the induction of AAAD was longer lasting. DA metabolism was altered by chronic administration of drugs acting on DA D2-like, but not DA D1-like receptors, and in general the patterns of change did not follow those for TH or AAAD. When studied 48 h after the last dose of the chronic haloperidol schedule TH displayed tolerance to acute drug challenge. At the same time interval, there was tolerance to the enhancing effects of haloperidol and SCH 23390 on DA metabolism. The induction of AAAD by haloperidol or SCH 23990 did not appear to develop tolerance after chronic administration. These observations complement existing knowledge, and provide novel information about AAAD that may have practical importance for Parkinson's patients on L-DOPA therapy.

Parallel modulation of striatal dopamine synthetic enzymes by second messenger pathways.

The activity of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the striatum and their mRNA content in the midbrain were assayed in mice following the intracerebroventricular injection of forskolin or phorbol-12,13-myristic acid (PMA). Control and 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals were studied. Both forskolin and PMA induced a rapid and transient increase of tyrosine hydroxylase and aromatic L-amino acid decarboxylase activity in the striatum that lasted less than 45 and 60 min, respectively. A second belated increase of striatal tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities was seen only after forskolin, and it was accompanied by a rise of tyrosine hydroxylase and aromatic L-amino acid decarboxylase mRNA in the midbrain. In the MPTP-lesioned mouse, the rise of tyrosine hydroxylase and aromatic L-amino acid decarboxylase following forskolin appeared exaggerated, while the response to PMA was not. These studies suggest that tyrosine hydroxylase and aromatic L-amino acid decarboxylase of striatum can be modulated in parallel by protein kinase A and protein kinase C, and that exaggerated responsiveness to protein kinase A is observed in the partially denervated striatum.

Chimeric receptors composed of phosphoinositide 3-kinase domains and FCgamma receptor ligand-binding domains mediate phagocytosis in COS fibroblasts.

Receptors for the Fc portion of IgG (FcgammaR) initiate phagocytosis of IgG-opsonized particles by a process involving the assembly of a multi-molecular signaling complex. Several members of this complex have been identified, including Src family kinases, Syk/ZAP 70 family kinases, and phosphoinositide 3-kinase (PI3-K). To test directly the role of PI3-K in mediating phagocytosis, we assessed the phagocytic ability of chimeric receptors composed of FcgammaR extracellular and transmembrane domains fused to regions of the p85 subunit of PI3-K. We found that chimeric receptors with cytoplasmic tails composed of the entire p85 subunit of PI3-K or the inter-Src homology 2 portion of p85 triggered phagocytosis in transfected COS fibroblasts. These two chimeras also showed phosphoinositide kinase activity in vitro when immunoadsorbed. In contrast, a chimera containing only the carboxyl-terminal Src homology 2 domain of p85 that does not interact with the catalytic p110 subunit of PI3-K did not trigger phagocytosis, nor did it show kinase activity in vitro. These data suggest that localization and direct activation of PI3-K at the site of particle attachment is sufficient to trigger the process of phagocytosis.

Functional separation of pseudopod extension and particle internalization during Fc gamma receptor-mediated phagocytosis.

Receptors for the Fc portion of immunoglobulin (Ig)G (Fc gamma R) mediate phagocytosis of IgG-opsonized particles by a process that can be divided into four major steps: receptor-ligand binding, pseudopod extension, internalization, and lysosomal fusion. We have expressed single classes of Fc gamma R in COS fibroblasts to examine the structural determinants necessary to complete the four steps of phagocytosis. Using phase contrast, fluorescence, confocal, and electron microscopy we have demonstrated that Fc gamma R-expressing COS cells can phagocytose in a manner similar to that of professional phagocytes. We have further analyzed the capacity of the three classes of Fc gamma R to phagocytose, placing special emphasis on the Fc gamma RIA-gamma chain complex, which allowed us to examine independently the roles of the ligand-binding unit (Fc gamma RIA) and the signaling unit (gamma chain). We found that receptor complexes containing a conserved tyrosine activation motif (ITAM), as found in the cytoplasmic domain of Fc gamma RIIA and in the gamma chain associated with Fc gamma RIA and Fc gamma RIIIA, readily internalized target particles. In contrast, Fc gamma RIA alone, having no ITAM, was unable to internalize target particles efficiently, but did mediate pseudopod extension. Cotransfection of gamma chain with Fc gamma RIA restored the ability of the receptor to internalize target particles. A mutant Fc gamma RIA in which the cytoplasmic domain had been deleted was also capable of mediating pseudopod extension, showing that neither the gamma chain nor the cytoplasmic domain of Fc gamma RIA were required for this step. Cytochalasin D, an inhibitor of actin polymerization, blocked particle internalization by all Fc gamma R, but did not block pseudopod extension. Staining the Fc gamma RIA COS cells for F-actin and for tyrosine phosphoproteins, we found that actin did not polymerize during Fc gamma RIA-mediated pseudopod extension, nor were tyrosine kinases activated. Our data suggest that pseudopod extension and internalization are functionally distinct steps mediated through different pathways.

Molecular characterization of six variant Fcgamma receptor class I (CD64) transcripts.

In humans, three distinct but closely related classes of receptors that bind the Fc portion of IgG (FcgammaRI, II and III) have been identified. FcgammaRI can bind monomeric IgG with high affinity and has a unique third extracellular domain (EC3). Three very similar genes have been characterized for FcgammaRI (A, B, C). Although the sequences are remarkably similar, a number of coding-region differences discriminate between the genes and amongst their transcripts. Six distinct FcgammaRI transcripts were analysed. Three transcripts, one from each gene, contain all six exons. Only the gene A transcript appears to encode a bona fide high affinity receptor, a three Ig-domain membrane spanning receptor that can bind monomeric IgG. Stop codons in the EC3 domains of the gene B and gene C isoforms would be predicted to generate secreted receptors. Three transcripts are alternatively spliced isoforms, one from gene A and two from gene B. One gene B transcript encodes a two Ig-domain transmembrane receptor which has structural characteristics of a low affinity FcgammaR.

Molecular cloning of a new unc-33-like cDNA from rat brain and its relation to paraneoplastic neurological syndromes.

Anti-CV2-autoantibodies from patients with paraneoplastic neurological syndromes were used to purify protein(s) related to this disease. A novel cDNA, c-22, was obtained by PCR with primers based on amino-acid sequence of peptides obtained from this protein and rat brain cDNA as template. The deduced amino-acid sequence of c-22 shows homology to the Unc-33 gene from C. elegans in which mutations lead to defects in neuritic outgrowth and axonal guidance and cause uncoordinated movements of the nematode. Several consensus sites for putative protein kinase C phosphorylation were found, suggesting that the c-22 gene product may be a phosphoprotein. Northern hybridizations show that the apparently unique 3.8-kb mRNA of c-22 is present in rat brain tissue and its expression is developmentally regulated: the levels of C-22 mRNA, detectable in brain at embryonic day 17 (E17), increase up to post-natal day 7 (P7) and decline rapidly to an almost undetectable level in adult.

Association of non-receptor protein tyrosine kinases with the Fc gamma RI/gamma-chain complex in monocytic cells.

To characterize the functional macromolecular complex of the high affinity receptor for IgG (Fc gamma RI), we have undertaken the identification of the molecules associated with the ligand binding unit and its associated subunit, gamma-chain, in a monocyte cell line, U937. Comparison of the pattern of tyrosine-phosphorylated proteins that coprecipitate with anti-Fc gamma RI or anti-gamma-chain Abs after Fc gamma RI clustering suggests that, like other receptor systems, the different units of the receptor associate or recruit different elements of the signaling pathway. Syk associates preferentially with the gamma-chain subunit and not with Fc gamma RI itself. This association is dependent on receptor clustering and correlates with gamma-chain phosphorylation. The Src kinase Lyn is also part of the receptor complex. Lyn associates with both units of the receptor, and this association is independent of receptor engagement; however, the level of tyrosine phosphorylation of the kinase increases after Fc gamma RI clustering. Association of a 35-kDa phosphoprotein with the binding unit was also observed after receptor clustering. We further found that after Fc gamma RI clustering, tyrosine-phosphorylated Syk associates with Lyn. These data suggest that several levels of interaction occur between these molecules or that different pools of tyrosine kinases become activated after Fc gamma RI clustering.