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Genes belonging to neuroplasticity, monoamine, circadian rhythm, and transcription factor pathways were investigated as modulators of antidepressant efficacy. The present study aimed (1) to replicate previous findings in an independent sample with treatment-resistant depression (TRD), and (2) to perform a pathway analysis to investigate the possible molecular mechanisms involved. 220 patients with major depressive disorder who were non-responders to a previous antidepressant were treated with venlafaxine for 4-6 weeks and in case of non-response with escitalopram for 4-6 weeks. Symptoms were assessed using the Montgomery Asberg Depression Rating Scale. The phenotypes were response and remission to venlafaxine, non-response (TRDA) and non-remission (TRDB) to neither venlafaxine nor escitalopram. 50 tag SNPs in 14 genes belonging to the pathways of interest were tested for association with phenotypes. Molecular pathways (KEGG database) that included one or more of the genes associated with the phenotypes were investigated also in the STAR*D sample. The associations between ZNF804A rs7603001 and response, CREB1 rs2254137 and remission were replicated, as well as CHL1 rs2133402 and lower risk of TRD. Other CHL1 SNPs were potential predictors of TRD (rs1516340, rs2272522, rs1516338, rs2133402). The MAPK1 rs6928 SNP was consistently associated with all the phenotypes. The protein processing in endoplasmic reticulum pathway (hsa04141) was the best pathway that may explain the mechanisms of MAPK1 involvement in antidepressant response. Signals in genes previously associated with antidepressant efficacy were confirmed for CREB1, ZNF804A and CHL1. These genes play pivotal roles in synaptic plasticity, neural activity and connectivity. [ABSTRACT FROM AUTHOR]

Little is known about guideline adherence of naturalistic antidepressant drug therapy in outpatients with major depressive disorder (MDD). The aim of the study was to analyze guideline adherence, especially regarding treatment length, treatment evaluation and medication change strategies. We investigated 889 patients with MDD who had been admitted for inpatient treatment and were enrolled in the early medication change trial (ClinicalTrials.gov NCT00974155). We investigated all patients at screening visit regarding previous outpatient drug treatment in the index episode, which was assessed by structured interviews. Demographic variables were obtained from patients and patients' records. 51.0% of the patients had received previous drug treatment in the index episode, 56.6% were females, and their mean age was 40.0 years. In the 153 patients who were pharmacologically treated at least 8 weeks, medication was not changed in 129 (84.3%) patients. Patients who had a medication change in their index episode ( n = 24, 15.7%) waited 71.1 weeks (±110.4) for their treatment optimization. Only 5 of those 153 patients (3.3%) had a dose increase, whereas 132 patients (86.3%) had no dose adaption at all. Antidepressant blood levels were measured in 46 patients (30.1%). We conclude that a large proportion of patients with MDD is not treated in adherence to treatment guidelines recommending treatment evaluation (e.g. therapeutic drug monitoring) and treatment change after 4 to 8 weeks in non-responders. Earlier treatment optimization may prevent long-term suffering of patients and may avoid inpatient treatment. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review considers the contribution of monoamine neurotransmitters to anhedonia, substance abuse, and sexual dysfunction and the relationship between antidepressant efficacy and abuse liability. Recent Findings: The use of drugs with known abuse potential to treat depression, the addition of psychostimulants with antidepressants, and the development of novel antidepressants with preclinical evidence for abuse liability have increased in recent years. This is in contrast to the general lack of abuse potential reported for traditional antidepressants such as selective serotonin reuptake inhibitors. While these new strategies might have the benefit of reduced sexual dysfunction, it is at the expense of increased abuse liability. Summary: Increasing extracellular dopamine may both increase antidepressant efficacy and reduce sexual dysfunction, but it increases abuse potential. Preclinical researchers should incorporate behavioral economics to assess both antidepressant efficacy and abuse liability while clinicians need to be aware of this relationship in considering novel treatments. [ABSTRACT FROM AUTHOR]

Lettuce is an edible crop that is well known for dietary and antioxidant benefits. The present study was conducted to investigate the effects of rol ABC genes on antioxidant and medicinal potential of lettuce by Agrobacterium-mediated transformation. Transgene integration and expression was confirmed through PCR and real-time RT-PCR, respectively. The transformed plants showed 91-102 % increase in total phenolic contents and 53-65 % increase in total flavonoid contents compared to untransformed plants. Total antioxidant capacity and total reducing power increased up to 112 and 133 % in transformed plants, respectively. Results of DPPH assay showed maximum 51 % increase, and lipid peroxidation assay exhibited 20 % increase in antioxidant activity of transformed plants compared to controls. Different in vivo assays were carried out in rats. The transgenic plants showed up to 80 % inhibition in both hot plate analgesic assay and carrageenan-induced hind paw edema test, while untransformed plants showed only 45 % inhibition. Antidepressant and anticoagulant potential of transformed plants was also significantly enhanced compared to untransformed plants. Taken together, the present work highlights the use of rol genes to enhance the secondary metabolite production in lettuce and improve its analgesic, anti-inflammatory, antidepressant, and anticoagulatory properties. [ABSTRACT FROM AUTHOR]

Rationale: It has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl]-methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model. Objective: In the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression. Results: We observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC. The mechanism of antidepressant and glioprotective effects of Lu AA33810 has not been studied, so far. We demonstrated the contribution of the noradrenergic rather than the serotonergic pathway to the antidepressant-like action of Lu AA33810 in the FST. Moreover, we found that antidepressant-like effect of Lu AA33810 was connected with the influence on brain-derived neurotrophic factor (BDNF) protein expression. We also demonstrated the antidepressant-like effect of Lu AA33810 in the FST in rats which did not receive the gliotoxin. We found that intracerebroventricular injection of the selective MAPK/ERK inhibitor U0126 (5 μg/2 μl) and the selective PI3K inhibitor LY294002 (10 nmol/2 μl) significantly inhibited the anti-immobility effect of Lu AA33810 in the FST in rats, suggesting that MAPK/ERK and PI3K signaling pathways could be involved in the antidepressant-like effect of Lu AA33810. Conclusion: Our results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy. [ABSTRACT FROM AUTHOR]

Antidepressant medications represent the most common treatment option for major depressive disorder (MDD), but the neuro-psychological mechanisms by which antidepressants act to improve depressive symptoms remain under-specified. We designed this study to assess the effects of escitalopram treatment on spontaneous brain activity of MDD patients using functional magnetic resonance imaging (fMRI). Twenty first-episode drug-naive MDD patients received resting-state fMRI scans before and after 8 weeks of treatment with a selective serotonin reuptake inhibitor - escitalopram. Twenty age- and gender-matched healthy controls were also scanned twice with an 8-week interval. The fractional amplitude of low-frequency fluctuation (fALFF) was used to characterize the spontaneous brain activity. The analysis of covariance (ANCOVA) was performed to determine treatment-related changes in fALFF. The symptoms were significantly improved in MDD patients after treatment. We observed significant group-by-time interaction on fALFF in the left dorsomedial prefrontal cortex, the right middle frontal gyrus, and the left putamen. Post-hoc analyses showed that the fALFF values in these regions were significantly higher in the MDD patients compared to healthy controls at baseline and were reduced after treatment. The findings suggest that abnormalities in the brain areas involved in emotional processing and regulation could be normalized by effective antidepressant treatment with escitalopram in the MDD patients and free of a task situation. [ABSTRACT FROM AUTHOR]

Exposure to human antidepressants has been shown to disrupt locomotion and other foot-mediated mechanisms in aquatic snails. We tested the effect of three selective serotonin reuptake inhibitor (SSRI)- and one selective serotonin-norepinephrine reuptake inhibitor (SNRI)-type antidepressants on the righting response in the marine snail, Ilyanassa obsoleta. All four antidepressants (fluoxetine, sertraline, paroxetine, venlafaxine) significantly increased righting time compared with controls with an exposure time as short as 1 h. Dose responses were nonmonotonic with effects seen mainly at the lowest exposure concentrations and shortest duration. The lowest concentration to show an effect was 3.45 μg/L fluoxetine with a 2-h exposure period and is about 3.71 times higher than environmental concentrations. Our results highlight rapid disruption of another foot-mediated behavior in aquatic snails by SSRI-type antidepressants. We discuss these and other reported nonmonotonic dose responses caused by antidepressants in terms of the various possible physiological mechanisms of action in nontarget aquatic species. [ABSTRACT FROM AUTHOR]

Rationale: Affective biases seemingly play a crucial role for the onset and development of depression. Acute treatment with monoamine-based antidepressants positively influences emotional processing, and an early correction of biases likely results in repeated positive experiences that ultimately lead to improved mood. Objectives: Using two conventional antidepressants, sertraline and duloxetine, we aimed to forward the characterization of a newly developed affective bias test (ABT) for rats. Further, we examined the effect of vortioxetine, a recently approved antidepressant, and the α adrenoceptor antagonist idazoxan on affective biases. Methods: Sprague Dawley rats were tested in an affective bias test using a fully balanced within-subject study design. Rats learned to associate two different digging substrates with a reward during six reward-pairing days. The absolute value of the rewards was identical, but the affective state at the time of learning induces a positive or negative bias towards the treatment-paired digging substrate at recall. The choice bias between the two digging substrates at recall represents the affective bias. Sertraline (1, 3 and 10 mg/kg), duloxetine (1, 3 and 10 mg/kg), vortioxetine (1, 3 and 10 mg/kg) and idazoxan (3 and 10 mg/kg) were tested in the ABT. Results and conclusions: All four drugs, regardless of their mechanism of action, induced a positive affective bias in the ABT, although the overall effect of treatment was not statistically significant for sertraline and duloxetine. The largest effects were induced by vortioxetine and idazoxan, both of which caused significant positive biases at all tested doses. [ABSTRACT FROM AUTHOR]

Creatine has been proposed to exert beneficial effects in the management of depression, but the cell signaling pathways implicated in its antidepressant effects are not well established. This study investigated the involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. The acute treatment of mice with creatine (1 mg/kg, po) increased the Akt and P70S6K phosphorylation, and HO-1, GPx and PSD95 immunocontents. The pretreatment of mice with LY294002 (10 nmol/mouse, icv, PI3K inhibitor), wortmannin (0.1 μg/mouse, icv, PI3K inhibitor), ZnPP (10 μg/mouse, icv, HO-1 inhibitor), or rapamycin (0.2 nmol/mouse, icv, mTOR inhibitor) prevented the antidepressant-like effect of creatine (1 mg/kg, po) in the TST. In addition, the administration of subeffective dose of either the selective GSK3 inhibitor AR-A014418 (0.01 μg/mouse, icv), the nonselective GSK3 inhibitor lithium chloride (10 mg/kg, po), or the HO-1 inductor CoPP (0.01 μg/mouse, icv), in combination with a subeffective dose of creatine (0.01 mg/kg, po) reduced the immobility time in the TST as compared with either drug alone. No treatment caused significant changes in the locomotor activity of mice. These results indicate that the antidepressant-like effect of creatine in the TST depends on the activation of Akt, Nrf2/HO-1, GPx, and mTOR, and GSK3 inhibition. [ABSTRACT FROM AUTHOR]

The co-morbidity of neuropsychiatric disorders, particularly major depressive disorder (MDD) with neurodegenerative diseases, in particular Parkinson's disease (PD) is now well recognized. Indeed, it is suggested that depressive disorders, especially in late life, may be an indication of latent neurodegeneration. Thus, it is not unreasonable to expect that deterrents of MDD may also deter the onset and/or progression of the neurodegenerative diseases including PD. In this review, examples of neuroprotective efficacy of established as well as prospective antidepressants are provided. Conversely, mood-regulating effects of some neuroprotective drugs are also presented. Thus, in addition to currently used antidepressants, ketamine, nicotine, curcumin, and resveratrol are discussed for their dual efficacy. In addition, potential neurobiological substrates for their actions are presented. It is concluded that pharmacological developments of mood-regulating or neuroprotective drugs can have cross benefit in co-morbid conditions of neuropsychiatric and neurodegenerative disorders and that inflammatory and neurotrophic factors play important roles in both conditions. [ABSTRACT FROM AUTHOR]

In 2004 the Food and Drug Administration issued a warning on the risk of suicidality in children and adolescents receiving antidepressants. This was followed by reports of changes in antidepressant prescription patterns, suicidality and other aggressive behaviors, but debate is continuing regarding the nature and magnitude of these changes. We examined a large physician database for impact of the warning on antidepressant prescriptions, suicidality and other aggressive behaviors in major depressive disorder (MDD) and anxiety disorders in adult and pediatric patients. We analyzed electronic database covering over 100,000 patients, treated in Pre- (before 2003) and Post- (after 2004) warning periods. We compared strength of the association between the measures and the time period with two tests. Multivariate logistic regression analyses were performed to ascertain the unique effect of each parameter. Of 10,089 MDD (61.0 %) and anxiety disorders (39.0 %) patients, 65.2 % received antidepressant prescription and 16.1 % were pediatric patients. In post-warning period, there was a greater reduction in adult versus pediatric antidepressant prescription rates. Logistic modeling showed greater likelihood of antidepressant prescription in MDD as compared with anxiety disorders in post-warning period. Pediatric patients were more likely than adults to receive fluoxetine during the post-warning period. There was an overall reduction in suicidality and other aggressive behaviors in the post-warning period. Regulatory warnings may have had an impact on antidepressant benefit/risk assessment and consequent utilization, therapeutic effects, and adverse events. Our observations suggest that psychiatrists may heed regulatory warnings, but may also exert professional independence and discrimination in their application. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) of dementia including agitation, depression, and psychosis are common and debilitating facets of the disease process. Despite the significant impact of these symptoms on both individuals with dementia and their caregivers, safe and effective treatment options are lacking. From a pharmacological approach, antipsychotics have historically been the treatment of choice, but these medications are only modestly effective with significant adverse effects. Behavioral and psychosocial interventions have been shown to be effective but are difficult to implement in routine clinical practice. SSRI medications have been investigated as an alternative psychopharmacological approach based on evidence that the serotoninergic system is involved in the etiology of NPS in dementia. The evidence base for using SSRI medications in the treatment of NPS is growing, but the applicability of research findings to the utility of SSRIs in general in routine clinical practice is not entirely clear at this point. Further studies of a variety of SSRI medications in targeting NPS are needed to make a more definitive assessment of the efficacy of these medications in the relief of NPS. [ABSTRACT FROM AUTHOR]

Rationale: Metabolic syndrome (MetS) is common in patients with bipolar disorder, with a relative risk of 1.6-2 compared to the general population. The increased risk is believed to be due to unhealthy lifestyles and use of medications. Although antipsychotics and mood stabilizers have been associated with weight gain and MetS, the impact of antidepressants has not been comprehensively evaluated. Objective: The objective of the study is to assess the risk of MetS in patients exposed to different types of antidepressants. Methods: In this cross-sectional study, 294 patients with bipolar disorder were consecutively recruited. MetS was diagnosed according to NCEP ATP-III modified criteria. Antidepressants used by the patients were classified according to the usual nomenclature (SSRI, TCA, SNRI, and other antidepressants) and a pharmacodynamic classification taking into account histamine 1-receptor (H1-R) affinity. Results: Use of antidepressants in general was not associated with MetS (prevalence ratio [PR], 1.08; 95% confidence interval, 0.73 to 1.62; p = 0.70). However, subjects using H1-R high-affinity antidepressants ( N = 15) showed a substantial increase in the prevalence of MetS (PR, 2.17; 95 % confidence interval, 1.24 to 3.80; p = 0.007). When we included the inhibition constant (Ki) as a continuous covariate in the models, we found an inverse association between Ki and prevalence of MetS ( p = 0.004). Conclusion: We observed for the first time in a clinical setting that a pharmacodynamic-based classification of antidepressants could be more useful than the traditional one to predict the risk of MetS in patients with bipolar disorder. Clinical consequences may be relevant. However larger studies are warranted to generalize these results. [ABSTRACT FROM AUTHOR]

A series of novel 4-(substituted-phenyl) tetrazolo[1,5- a]quinazolin-5(4 H)-ones ( 6a- x) and their derivatives with tetrazole and other heterocyclic substituents ( 7- 14) were designed, synthesized, and evaluated for antidepressant activities in mice. Pharmacological tests showed that three compounds ( 6l, 6u, and 6v) at a dose of 50 mg/kg significantly reduced the immobility time in the forced swimming test. The most active compound was 4-( p-tolyl)tetrazolo[1,5- a]quinazolin-5(4 H)-one ( 6v), which decreased the immobility time by 82.69 % at 50 mg/kg. Moreover, 6v did not affect spontaneous activity in the open-field test, and this effect was comparable to the antidepressant effect of fluoxetine. Noradrenaline (NE) and 5-hydroxytryptamine (5-HT) levels in the brains of mice in the test sample groups significantly increased at a dose of 50 mg/kg compared with that in the control group. The monoamine oxidase (MAO) level of all test groups was reduced, but this result was not significantly different between the groups. Therefore, we can infer that their underlying mechanisms may involve the regulation of brain monoamine neurotransmitter homeostasis, based on the detected content of NE, 5-HT, and MAO in mouse brain tissue. [ABSTRACT FROM AUTHOR]

Background: Resistance to antidepressant drug treatment remains a major health problem. Animal models of depression are efficient in detecting effective treatments but have done little to increase the reach of antidepressant drugs. This may be because most animal models of depression target the reversal of stress-induced behavioural change, whereas treatment-resistant depression is typically associated with risk factors that predispose to the precipitation of depressive episodes by relatively low levels of stress. Therefore, the search for treatments for resistant depression may require models that incorporate predisposing factors leading to heightened stress responsiveness. Method: Using a diathesis-stress framework, we review developmental, genetic and genomic models against four criteria: (i) increased sensitivity to stress precipitation of a depressive behavioural phenotype, (ii) resistance to chronic treatment with conventional antidepressants, (iii) a good response to novel modes of antidepressant treatment (e.g. ketamine; deep brain stimulation) that are reported to be effective in treatment-resistant depression and (iv) a parallel to a known clinical risk factor. Results: We identify 18 models that may have some potential. All require further validation. Currently, the most promising are the Wistar-Kyoto (WKY) and congenital learned helplessness (cLH) rat strains, the high anxiety behaviour (HAB) mouse strain and the CB1 receptor knockout and OCT2 null mutant mouse strains. Conclusion: Further development is needed to validate models of antidepressant resistance that are fit for purpose. The criteria used in this review may provide a helpful framework to guide research in this area. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the relationship between overactive bladder (OAB) and use of antidepressants in women. Methods: This is a prospective trial, and in total, 205 consecutive female (113 patient taking antidepressants for various disorders and 92 healthy controls) outpatients from our outpatients were enrolled in this study. The patients were also divided into those with OAB symptoms, OAB-Validated 8 (OAB-V8 score of ≥8), and without OAB symptoms <8. The prevalence of OAB in the antidepressant users and healthy controls was compared. In addition, the prevalence of OAB was compared according to antidepressant type. Results: The mean age of the participants was 36 ± 13 years. The demographic data of the two groups (OAB-V8 ≥ 8 and OAB-V8 < 8) were similar. The Beck Depression Inventory, OAB-V8, and Incontinence Questionnaire--Short Form scores of the antidepressant users were significantly higher than those of the control group ( p < 0.001, p < 0.001, and p = 0.001, respectively). The prevalence of OAB was significantly higher in antidepressant users (64 %) than in the control group (33 %) ( p = 0.003). The highest prevalence of OAB was detected in patients taking fluoxetine (63.6 %), and the lowest was observed in those taking sertraline (42.3 %) ( p = 0.038). Conclusion: There were more OAB symptoms in antidepressant users than in control group. Each SSRI and SNRI has a unique pharmacological profile, and this could explain the opposing reports in the literature. We recommend that patients taking antidepressants be carefully monitored for OAB symptoms. [ABSTRACT FROM AUTHOR]

Purpose: The population-based National Health Insurance database was used to investigate the trends, correlates, and disease patterns for elderly people in Taiwan who use antidepressants.Methods: The National Health Research Institute provided a database of 1000,000 random subjects for study. We created a sample of subjects who were older than 65 years from 1997 to 2005. Trends, prevalence, and associated factors of antidepressant use were detected. We also examined the proportion of antidepressant use for psychiatric and medical disorders.Results: The one-year prevalence of antidepressant use in elderly persons increased from 5.8 % in 1997 to 9.8 % in 2005. The one-year prevalence rates of tricyclic antidepressant (TCA), selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), serotonin modulator, and other antidepressant use in 2005 were 5.3, 2.6, 0.4, 2.9, and 0.6 %, respectively. Overall antidepressant use was higher for those in the 75- to 84-year-old age group, females, and those with higher Charlson Comorbidity Index scores. Among subjects using TCAs, 77.6 % users did not have a psychiatric diagnosis. Psychiatric disorders were commonly found in most SSRI and SNRI users (85.1 and 90.1 %, respectively). Subjects using SSRIs and SNRIs had higher proportions of psychiatric disorders such as neurotic depression, major depression, senile and presenile organic psychotic conditions, and anxiety.Conclusion: The prevalence of antidepressant use among elderly persons increased greatly from 1997 to 2005. SSRIs, SNRIs, and other antidepressants were used mostly by subjects with psychiatric disorders, whereas TCAs were used mostly by subjects with nonpsychiatric disorders. [ABSTRACT FROM AUTHOR]

Rationale: Successive negative contrast (SNC) describes a change in the behaviour of an animal following a downshift in the quantitative or qualitative value of an expected reward. This behavioural response has been hypothesised to be linked to affective state, with negative states associated with larger and/or prolonged shifts in behaviour. Objective: This study has investigated whether different psychopharmacological treatments have dissociable actions on the SNC effect in rats and related these findings to their actions on different neurotransmitter systems and affective state. Methods: Animals were trained to perform a nose-poke response to obtain a high-value food reward (four pellets). SNC was quantified during devalue sessions in which the reward was reduced to one pellet. Using a within-subject study design, the effects of acute treatment with anxiolytic, anxiogenic, antidepressant and dopaminergic drugs were investigated during both baseline (four pellets) or devalue sessions (one pellet). Results: The indirect dopamine agonist, amphetamine, attenuated the SNC effect whilst the D1/D2 antagonist, alpha-flupenthixol, potentiated it. The antidepressant citalopram, anxiolytic buspirone and anxiogenic FG7142 had no specific effects on SNC, although FG7142 induced general impairments at higher doses. The α-adrenoceptor antagonist, yohimbine, increased premature responding but had no specific effect on SNC. Results for the anxiolytic diazepam were mixed with one group showing an attenuation of the SNC effect whilst the other showed no effect. Conclusions: These data suggest that the SNC effect is mediated, at least in part, by dopamine signalling. The SNC effect may also be attenuated by benzodiazepine anxiolytics. [ABSTRACT FROM AUTHOR]

The solid phase extraction (SPE) is described for preconcentration of the antidepressant drugs amitriptyline and nortriptyline prior to their determination by HPLC with UV detection. It is based on the use of water-dispersible core-shell nanoparticles (NPs) of the FeO@ZrO@N-cetylpyridinium type. The positively charged surfactant N-cetylpyridinium forms mixed aggregates with the drugs on the surface of the core-shell and thereby improves the adsorption of amitriptyline and nortriptyline through hydrophobic and/or ionic interactions. Their extraction depends on the type and amount of surfactant, sample pH, extraction time, desorption conditions, sample volume and amount of NPs that were optimized by application of experimental design. The enrichment factors are 220 and 250, respectively, for amitriptyline and nortriptyline, and the detection limits are 0.04 and 0.08 ng·mL‾. This protocol enables accurate and precise quantification of the two drugs in complex and low content samples. It was applied to the determination of the two drugs in plasma samples with relative recoveries in the range from 89 to 105 % and RSDs less than 4 %. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Rationale: Cytochrome P450 enzymes are important in the metabolism of antidepressants. The highly polymorphic nature of these enzymes has been linked to variability in antidepressant metabolism rates, leading to hope regarding the use of P450 genotyping to guide treatment. However, evidence that P450 genotypic differences underlie the variation in treatment outcomes is inconclusive. Objectives: We explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large ( n = 868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline. Methods: Patients were genotyped for the enzymes CYP2C19 and CYP2D6, and serum concentrations of both antidepressant and primary metabolite were measured after 8 weeks of treatment. Side effects were assessed weekly. We investigated associations between P450 genotypes, serum concentrations of antidepressants and side effects, as well as the relationship between P450 genotype and study discontinuation. Results: P450 genotype did not predict total side effect burden (nortriptyline: n = 251, p = 0.5638, β = −0.133, standard error (SE) = 0.229; escitalopram: n = 340, p = 0.9627, β = −0.004, SE = 0.085), study discontinuation (nortriptyline n = 284, hazard ratio (HR) = 1.300, p = 0.174; escitalopram n = 376, HR = 0.870, p = 0.118) or specific side effects. Serum concentrations of antidepressant were only related to a minority of the specific side effects measured: dry mouth, dizziness and diarrhoea. Conclusions: In this sample where antidepressant dosage is titrated using clinical judgement, P450 genotypes do not explain differences between patients in side effects with antidepressants. Serum drug concentrations appear to only explain variability in the occurrence of a minority of specific side effects. [ABSTRACT FROM AUTHOR]

Recent advances in the developmental epidemiology, neurobiology, and treatment of pediatric anxiety disorders have increased our understanding of these conditions and herald improved outcomes for affected children and adolescents. This article reviews the current epidemiology, longitudinal trajectory, and neurobiology of anxiety disorders in youth. Additionally, we summarize the current evidence for both psychotherapeutic and psychopharmacologic treatments of fear-based anxiety disorders (e.g., generalized, social, and separation anxiety disorders) in children and adolescents. Current data suggest that these disorders begin in childhood and adolescence, exhibit homotypic continuity, and increase the risk of secondary anxiety and mood disorders. Psychopharmacologic trials involving selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SSNRIs) are effective in pediatric patients with anxiety disorders and have generally demonstrated moderate effect sizes. Additionally, current data support cognitive behavioral therapy (CBT) for the treatment of these conditions in youth and suggest that the combination of psychotherapy + an SSRI may be associated with greater improvement than would be expected with either treatment as monotherapy. [ABSTRACT FROM AUTHOR]

The pharmacogenetics of antidepressants has been not only a challenging but also frustrating research field since its birth in the 1990s. Indeed, great expectations followed the first evidence of familiar aggregation of antidepressant response. Despite the progress from candidate gene studies to genome-wide association studies (GWAS), results fell out the expectations and they were often inconsistent. Anyway, the cumulative evidence supports the involvement of some genes and molecular pathways in antidepressant efficacy. The best single genes are SLC6A4, HTR2A, BDNF, GNB3, FKBP5, ABCB1, and cytochrome P450 genes ( CYP2D6 and CYP2C19). Molecular pathways involved in inflammation and neuroplasticity show the greatest support. The first studies evaluating benefits of genotype-guided antidepressant treatments provided encouraging results and confirmed the relevance of SLC6A4, HTR2A, ABCB1, and cytochrome P450 genes. Further progress in genotyping and data analysis would allow to move forward and complete the understanding of antidepressant pharmacogenetics and its translation into clinical applications. [ABSTRACT FROM AUTHOR]

Some components of generalized anxiety disorder, such as physical symptoms, are thought to reflect autonomic nervous system arousal. This study primarily assessed the relationships between psychophysiological and clinical measures using venlafaxine extended release or applied relaxation, and secondarily, the impact of combination treatment in patients not remitting after 8 weeks. Fifty-eight patients were randomly assigned to 8 weeks of treatment with either venlafaxine or applied relaxation (Phase I). Non-remitted patients received combination treatment for an additional 8 weeks (Phase II). Assessments included the Hamilton Anxiety Scale (HAM-A), Beck Depression Inventory, Penn State Worry Questionnaire and the Stroop Color-Word Task coupled with electrophysiological measures (skin conductance and frontalis electromyography (EMG)). In Phase 1, a time effect was found for the clinical and skin conductance measures. Thirteen patients from each group were in remission. In Phase 2, seven additional patients remitted. Baseline psychophysiological measures were not associated with baseline clinical variables or with clinical outcomes. Independently of treatment allocation, a reduction in frontal EMG values at week 4 was significantly associated with a decrease in HAM-A scores at week 8. At week 4, responders from the applied relaxation group had lower electrophysiological activity than the venlafaxine group. Baseline psychophysiological measures were not linked with clinical measures at study inclusion or with treatment response. Frontal EMG response at week 4 is a possible predictor of treatment response. Treatment combination enhances treatment response after initial failure. [ABSTRACT FROM AUTHOR]

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is among the most consistent neuroendocrine abnormalities in major depressive disorder (MDD). The peptide adrenocorticotropin hormone (ACTH) mediates HPA axis function during stress and is encoded by the proopiomelanocortin (POMC) gene polycistronically. After screening 39 POMC polymorphisms, we evaluated the association of polymorphisms with susceptibility to MDD in 145 MDD patients and 193 normal subjects; in patients, we also evaluated the response to treatment with antidepressants. Additionally, we investigated the role of gene-environment interaction between POMC haplotypes and stressful life events (SLE) in the treatment response. Although genotypes and haplotypes were not significantly associated with the risk of MDD, non-remitters were more likely to carry haplotype 1 ( ht1) and to have no ht2 than were remitters (corrected P = 0.010-0.035). Although observations were limited in patients without SLE, a significant haplotype-SLE interaction was observed ( P = 0.020). Additionally, at 1, 2, and 8 weeks of treatment, the 21-item Hamilton Depression Rating scores of MDD subjects with POMC ht2 were significantly ( P = 0.003-0.044) lower than those of patients with ht1 in subjects those did not experience SLE. MDD subjects possessing POMC ht2 achieved remission significantly ( P = 0.013; survival analysis) faster than patients with ht1. This study suggests that POMC haplotypes, via an interaction with SLE, are associated with antidepressant treatment outcomes in MDD patients. Regarding SLE, haplotypes of the POMC gene could be useful markers for predicting the response to antidepressant treatment in MDD patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with a significant comorbidity with depressive disorders. Prevalence rates for major depressive disorder (MDD) range from 36 % to 54 % and the rate is around 22 % for adjustment disorders. Selective serotonin reuptake inhibitors (SSRIs) are considered well-tolerated first-line treatment. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are generally reserved for second-line use after SSRIs, because of sedating or anticholinergic side effects. SNRIs, with the exception of duloxetine, and combinations of newer antidepressants have failed to treat depression due to their side effects profile and frequent interaction with other drugs. Among SSRIs, sertraline is usually the first option, starting at 25 mg/day and increasing to 50 mg/day; and waiting a few weeks to assess drug effects before increasing the dose. The maximum is generally 200 mg/day in a single dose. Paroxetine is the second choice, starting at 10 mg/day for the first 5 days, and then at 20 mg/day thereafter. The maximum dose is about 50 mg/day in a single dose. Fluvoxamine is used at 100-200 mg/day, starting with 25 mg/day, and increasing 25 mg/day every 5 days until 200 mg/day is reached. We should take into account increasing blood level amounts of MS treatments (corticosteroids and cyclophosphamide) with fluvoxamine. With duloxetine, doses will be at 60-120 mg/day. The initial dose for depression is 40 mg/day in two doses; it can increase to 60 mg/day in one to two doses if necessary. The maximum dose is generally 120 mg/day. Duloxetine may increase liver problems through interaction with these MS treatments: teriflunomide, interferon beta-1a, and interferon beta-1b. Considering psychotherapy, only cognitive behavior therapy and mindfulness-based interventions have shown efficacy in improving depression disorders in MS. A comprehensive treatment for depression should include pharmacotherapy and psychotherapy. [ABSTRACT FROM AUTHOR]

To better understand the relationship of repeated exposure to adversity during early development as a risk factor for refractory depression, we exposed pregnant female rats to ethanol and the resulting pups to corticosterone during adolescence. A stressful forced swim test was then used to induce depression-like behavior. The adolescent rat brains were examined for the possible therapeutic benefit of a combination of sertraline, an antidepressant, and neural stem cells (NSCs) complexed with atelocollagen in relation to the level of GABAergic interneuron and synaptic protein density in different brain regions. The combined exposures of prenatal and adolescent stress resulted in a reduction in parvalbumin (PV)-positive phenotype of GABAergic interneurons and reduced postsynaptic density protein 95 (PSD-95) levels in the anterior cingulate cortex, amygdala, and hippocampus. Treatments with sertraline and NSCs reversed the reductions in PV-positive cells and PSD-95 levels. Furthermore, the combined treatment of sertraline and NSCs resulted in reduced depressive-like behaviors. These experiments underscore a potentially important role for synaptic remodeling and GABAergic interneuron genesis in the treatment of refractory depression and highlight the therapeutic potential of stem cell and pharmacological combination treatments for refractory depression. [ABSTRACT FROM AUTHOR]

Seventeen 7-alkyl-7 H-tetrazolo[1,5- g]purine derivatives were synthesized, and their anticonvulsant and antidepressant activities were evaluated in a mouse model. The anticonvulsant effect and neurotoxicity of the compounds were evaluated with a maximal electroshock test and a rotated test in mice, respectively. Most of the compounds had anticonvulsant activity; among the compounds studied, 7-(3-chlorobenzyl)-7 H-tetrazolo[1,5- g]purine ( 3h) was found to be the most potent compound with a median effective dose (ED) value of 28.9 mg/kg and a protective index value of 15.8, possessing better anticonvulsant activity and higher safety than the marketed drug carbamazepine. To explain the possible mechanism of anticonvulsant activity, compound 3h was tested in pentylenetetrazole-induced seizures tests, and the results suggest that compound 3h exerts anticonvulsant activity through a GABA-mediated mechanism. Forced swimming test showed that at a dose of 40 mg/kg, five compounds have significant antidepressant activity, the most active compound was 7-(2-chlorobenzyl)-7 H-tetrazolo[1,5- g]purine ( 3g), which decreased immobility time by 56 %. [ABSTRACT FROM AUTHOR]

Rationale: Gender may influence antidepressant (AD) treatment outcome. In order to address this preclinically, the potential effects of ovarian hormones on AD treatment in ovariectomized female rats were investigated. Objectives: In the first study, the effect of acute administration of estrogen and progesterone on the antidepressant-like effects of desipramine (DMI), a selective norepinephrine reuptake inhibitor (SNRI), was investigated in the forced swimming test (FST). In the second study, the effect of chronic administration of these hormones on the effects of chronically administered DMI was investigated. Results: In the acute study, the hormones blocked the effects of DMI in the FST as demonstrated by the absence of either a reduction in immobility or an increase in climbing behavior in animals treated with DMI in combination with the hormones. Concentration-response experiments on hippocampal synaptosomes revealed no changes in the Km or Bmax for uptake of H-NE in hormone-treated rats. In the chronic study, the antidepressant-like effects of DMI in the FST were not blocked by chronic administration of hormones. Interestingly, the hormones affected the serum concentrations of DMI. These levels were significantly higher in animals receiving 10 or 15 mg/kg/day in hormone-treated rats as compared to those with placebo. Conclusions: Acute administration of hormones blocked the effects of DMI (given three times over 24 h) in the FST. However, chronic administration of these hormones failed to block the effects of chronically administered DMI (at a dose that produces clinically relevant serum concentrations). [ABSTRACT FROM AUTHOR]

Cdk5 is a member of cyclin-dependent kinase (Cdk), a proline-directed serine/threonine kinase, and plays a key role in normal neural development and function. Evidence of previous study showed that chronic inhibition of Cdk5 in hippocampal dentate gyrus (DG) blocked the development of depressive-like symptoms, suggesting that Cdk5 plays a role in development of depression. Forced swim test, novelty-suppressed feeding test, and learned helplessness were used to evaluate the cellular and molecular mechanisms underlying the behavioral regulation of Cdk5 inhibitors in rats. Two Cdk5 inhibitors butyrolactone and roscovitine were used to investigate the possible antidepressant-like actions of Cdk5 blockade and the potential mechanisms. Systemic administration of butyrolactone (200 mg/kg, IP) or roscovitine (100 mg/kg, IP) produced effective antidepressant-like actions. Moreover, infusion (5 mM) of GSK3β activator LY294002 into DG abolished the antidepressant-like actions of butyrolactone and roscovitine, suggesting that inhibition of GSK3β might be involved in the antidepressant effect of Cdk5 inhibitors. Moreover, pretreatment of LY294002 (5 mM) blocked the antidepressant-like effect of butyrolactone and roscovitine in learned helplessness. Additionally, inescapable footshock induced a significant increase of GSK3β activity, while butyrolactone and roscovitine decreased GSK3β activity. In contrast, pretreatment of LY294002 prevented the inhibitory effects of butyrolactone and roscovitine on GSK3β activation. Finally, a specific GSK3β inhibitor, SB216763 (1 ng, DG), demonstrated an effective antidepressant-like action. These findings demonstrate that systemic administration of Cdk5 inhibitors produced antidepressant-like actions and that inhibition of GSK3β is involved in behavioral response of Cdk5 inhibitors. [ABSTRACT FROM AUTHOR]

Antidepressant-induced sexual dysfunction (ADISD) is a common problem and is associated with a significant risk of nonadherence. Serotonergic antidepressants are associated with a substantial risk of ADISD. Bupropion, transdermal selegiline, nefazodone, and moclobemide are associated with a lower risk of ADISD, and early data suggests that this may also be true for vilazodone. Only 10 % of patients show spontaneous improvement in ADISD on waiting and watching. This strategy should be reserved for patients earlier in the course of the adverse effect. When possible, switching to an antidepressant with a lower incidence of ADISD is a recommended strategy. When continuation of the offending antidepressant is essential, addition of an antidote may be tried. While early data were not encouraging, two large randomized, controlled trials have provided strong evidence supporting the use of bupropion as an antidote for ADISD. Phosphodiesterase-5 inhibitors like sildenafil and tadalafil have been shown to be efficacious in a substantial proportion of patients. Attention to ADISD is very important given that it is an important cause of nonadherence to antidepressants. [ABSTRACT FROM AUTHOR]

The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery. [ABSTRACT FROM AUTHOR]

Rationale and objective: Hypericum perforatum (St John's wort) is used to treat depression, but the effectiveness has not been established. Recent guidelines described the analysis of clinical trials with missing data, inspiring the reanalysis of this trial using proper missing data methods. The objective was to determine whether hypericum was superior to placebo in treating major depression. Methods: A placebo-controlled, randomized clinical trial was conducted for 8 weeks to determine the effectiveness of hypericum or sertraline in reducing depression, measured using the Hamilton depression scale. We performed sensitivity analyses under different assumptions about the missing data process. Results: Three hundred forty participants were randomized, with 28 % lost to follow-up. The missing data mechanism was not missing completely at random. Under missing at random assumptions, some sensitivity analyses found no difference between either treatment arm and placebo, while some sensitivity analyses found a significant difference from baseline to week 8 between sertraline and placebo (−1.28, 95 % credible interval [−2.48; −0.08]), but not between hypericum and placebo (0.56, [−0.64;1.76]). The results were similar when the missing data process was assumed to be missing not at random. Conclusions: There is no difference between hypericum and placebo, regardless of the assumption about the missing data process. There is a significant difference between sertraline and placebo with some statistical methods used. It is important to conduct an analysis that takes account of missing data using valid statistically principled methods. The assumptions about the missing data process could influence the results. [ABSTRACT FROM AUTHOR]

Effects of the antidepressant fluoxetine in therapeutic concentration on stimulation-dependent synaptic vesicle recycling were examined in cultured rat hippocampal neurons using fluorescence microscopy. Short-term administration of fluoxetine neither inhibited exocytosis nor endocytosis of RRP vesicular membranes. On the contrary, acute application of the drug markedly increased the size of the recycling pool of hippocampal synapses. This increase in recycling pool size was corroborated using the styryl dye FM 1-43, antibody staining with αSyt1-CypHer™5E and overexpression of synapto-pHluorin, and was accompanied by an increase in the frequency of miniature postsynaptic currents. Analysis of axonal transport and fluorescence recovery after photobleaching excluded vesicles originating from the synapse-spanning superpool as a source, indicating that these new release-competent vesicles derived from the resting pool. Super resolution microscopy and ultrastructural analysis by electron microscopy revealed that short-term incubation with fluoxetine had no influence on the number of active synapses and synaptic morphology compared to controls. These observations support the idea that therapeutic concentrations of fluoxetine enhance the recycling vesicle pool size and thus the recovery of neurotransmission from exhausting stimuli. The change in the recycling pool size is consistent with the plasticity hypothesis of the pathogenesis of major depressive disorder as stabilization of the vesicle recycling might be responsible for neural outgrowth and plasticity. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder is often comorbid with behavioral disturbances such as irritability, aggression and hyperactivity. Throughout the mid 2000s, several large-scale controlled clinical trials were published leading to the approval of two medications (aripiprazole and risperidone) for treatment of irritability in this condition. This review serves as an update regarding new research findings regarding psychopharmacology for children and adolescents with ASD. In summary, the past five years have yielded no further approved medications with ASD as a primary indication. Important new research results include 1) long-term safety and efficacy data (52 week) regarding treatment with aripiprazole for irritability, 2) consensus regarding potential harm from SSRIs for treatment of repetitive behaviors in children/ adolescents with ASD, 3) a randomized controlled trial showing modest benefits from atomoxetine on hyperactivity, 4) many novel agents currently under investigation. [ABSTRACT FROM AUTHOR]

Antidepressants have been shown to affect levels of brain-derived neurotrophic factor (BDNF) and VGF (non-acronymic) whose transcriptions are dependent on cAMP response element binding protein (CREB) in long term treatment. The aim of this study was to verify the subacute antidepressant effects of crocin, an active constituent of saffron (Crocus sativus L.), and its effects on CREB, BDNF, and VGF proteins, transcript levels and amount of active, phosphorylated CREB (P-CREB) protein in rat hippocampus.Methods Crocin (12.5, 25, and 50 mg/kg), imipramine (10 mg/kg; positive control) and saline (1 mL/kg; neutral control) were administered intraperitoneally (IP) to male Wistar rats for 21 days. The antidepressant effects were studied using the forced swimming test (FST) on day 21 after injection. Protein expression and transcript levels of genes in the rat hippocampus were evaluated using western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. Results Crocin significantly reduced the immobility time in the FST. Western blot analysis showed that 25 and 50 mg/kg of crocin increased the levels of CREB and BDNF significantly and dose dependently. All doses of crocin increased the VGF levels in a dose-dependent manner. Levels of p-CREB increased significantly by 50 mg/kg dose of crocin. Only 12.5 mg/kg crocin could significantly increase the transcript levels of BDNF. No changes in CREB and VGF transcript levels were observed in all groups. Conclusions These results suggest that crocin has antidepressant-like action by increasing CREB, BDNF and VGF levels in hippocampus. [ABSTRACT FROM AUTHOR]

Coastal areas are subject to growing pressures and impacts because of the increase in human activities. Lipophilic organic contaminants, such as polycyclic aromatic hydrocarbons (PAHs) or polychlorinated biphenyls (PCBs), have been monitored for decades within monitoring programs. However, until now, little information on the detection of so-called 'emerging contaminants' such as hydrophilic organic compounds in the marine environment and no data on its metabolites or transformation products in marine organisms is available. In this report, a sensitive analytical methodology for identification and confirmation of venlafaxine (VEN) residues and five of its main metabolites in the marine mussels Mytilus galloprovincialis was validated. The sample preparation procedure was based on the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) approach. An analytical method was developed to quantify these compounds at trace levels by liquid chromatography coupled to high-resolution mass spectrometry. The method was then applied to marine mussels collected from the Mediterranean Sea in southeastern France. Residues of the antidepressant VEN were occasionally detected at ng/g dw level. In addition, the approach allowed us to identify several transformation products in the analyzed samples. N-desmethylvenlafaxine (NDV) was the most frequently detected metabolite followed by N,O-di-desmethylvenlafaxine (NODDV). [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Purpose: Psychotherapy is recommended as first-line treatment in patients presenting with mild-to-moderate depression. Although this disorder is mostly managed in primary care, little is known about General Practitioners' (GPs) practice of prescribing psychotherapy. The objectives were to explore GPs' opinion on psychotherapy for depression, and the personal and professional characteristics associated with reported strategies for prescribing psychological therapy and/or an antidepressant in mild-to-moderate depression. Methods: A cross-sectional survey was carried out among participants in a panel of randomly selected GPs (2,114/2,496 participated: 84.7 %). GPs were interviewed using a standardized questionnaire covering their professional and personal characteristics, their practices and opinions in the area of depression management. A multi-model averaging approach was used to explore the characteristics associated with practice of prescribing psychological therapy in mild-to-moderate depression. Results: Most GPs had a favourable opinion regarding the efficacy of psychotherapy in depression. Slightly more than one out of four reported prescribing psychological therapy alone often/very often in mild-to-moderate depression. These GPs were more likely to be female (OR = 1.56, 95 % CI 1.24; 1.97), to have a personal history of psychotherapy (OR = 1.76, 95 % CI 1.31; 2.38), no history of depression in someone close (OR = 0.80, 95 % CI 0.65; 0.99), and to consider that antidepressants are over-prescribed (OR = 2.02, 95 % CI 1.63; 2.49). No association was found with professional characteristics. Conclusions: GPs' personal experience has a greater impact on psychological therapy prescription than professional characteristics. This finding suggests that educational efforts are required for providing GPs decision-making skills regarding psychological therapy prescription, based upon evidence-based medicine rather than subjective factors. [ABSTRACT FROM AUTHOR]

Rationale: Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water ('flower pot') method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melanin-concentrating hormone (MCH) expressing neurons in the hypothalamus. MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS. Objectives: We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons. Methods: Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats. During the 3-h-long 'rebound sleep', electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry. Results: During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease. All these effects of REMS deprivation were significantly attenuated by escitalopram treatment. Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound. Conclusions: These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel. Escitalopram caused a shift from REMS to slow wave sleep during the rebound. Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders. [ABSTRACT FROM AUTHOR]

Aegle marmelos is well documented for antihyperglycemic effect and PPAR-γ activation has been suggested to be the molecular mechanism of its action. Also, the plant has been used in Ayurveda as a brain tonic and has been postulated to have antidepressant activities. The present study was designed to investigate the anticonvulsant effects of A. marmelos leaf extract (AME) in pentylenetetrazole and maximal electroshock induced convulsions; involvement of PPAR-γ, nitric oxide pathway and effect of chronic AME treatment on post-ictal depression. AME was administered at doses of 50, 100 and 200 mg kg in PTZ and MES model. Severity of convulsions was noted in both the models. Pretreatment with bisphenol A diglycidyl ether (BADGE) was used to study the involvement of PPAR-γ and l-arginine and N-nitro- l-arginine methyl ester hydrochloride ( l-NAME) to study the involvement of nitric oxide (NO). Chronic treatment with AME interspersed with sub maximal doses of PTZ (50 mg kg) on every fifth day up to 15 days was given to study post-ictal depression using forced swimming and actophotometer. AME showed significant increase in the onset time and decrease in the duration of convulsions in PTZ and MES models dose dependently. In MES a dose of 100 mg kg had effect comparable to phenytoin. Pretreatment with BADGE and l-arginine reversed the protective effect while l-NAME did not alter the protective effect, thereby indicating possible involvement of PPAR-γ and inhibition of NO. Chronic AME treatment ameliorated the post-seizure depression significantly as evidenced by increase in the locomotor activity and decrease in the immobility time. [ABSTRACT FROM AUTHOR]

Rationale: Behavioural antidepressant-like effects of ketamine have been reported in the forced swimming test (FST). The mechanisms mediating such effects are unknown. Objectives: As serotonin (5-HT) is an important transmitter mediating antidepressant responsiveness in the FST, the influence of 5-HT depletion on the antidepressant-like effect of ketamine was assessed. Methods: The effect of ketamine (25 mg/kg, i.p., 1 or 24 h prior to test) was assessed in the FST in naive rats or animals subjected to 5-HT depletion, repeated stress or following a combination of 5-HT depletion and stress. Endogenous 5-HT was depleted using the tryptophan hydroxylase inhibitor para-chlorophenylalanine (3 × 150 mg/kg, i.p.). Stress was induced by physical restraint (2 h/day for 10 days). Results: In naive rats, ketamine administered 24 or 1 h prior to test produced a characteristic antidepressant-like reduction in immobility time in the FST. Depletion of 5-HT blocked this reduction in immobility when ketamine was administered 24 h prior FST, indicative of 5-HT dependency. The increase in immobility provoked by repeated restraint stress (2 h/day for 10 days) was blocked by ketamine when administered 24 h prior to FST, but this effect dissipated when animals were subjected to 5-HT depletion. Conclusions: These observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5-HT transmission which underlies the antidepressant response. [ABSTRACT FROM AUTHOR]

Rationale: Affective states are known to influence behaviour in humans resulting in cognitive affective biases, which may play an important role in the development and treatment of mood disorders. Similar biases have recently been shown in animals, including the rat, providing an opportunity to investigate these processes in non-human species. Objective: This study sought to investigate the psychopharmacology of cognitive affective bias in rats using systemic treatments with anxiolytic (diazepam) and antidepressant drugs (reboxetine or fluoxetine). Methods: Lister hooded rats were trained to discriminate two distinct tones and respond on the appropriate lever to either obtain reward (food) or avoid punishment (mild foot shock). Cognitive affective bias, following acute or chronic drug treatment, was investigated using test sessions where both reference tones and intermediate ambiguous tones were included. Results: Rats exhibited a negative judgement bias under vehicle conditions which was not significantly attenuated by any of the acute drug treatments, diazepam (0.3, 1.0 mg/kg), reboxetine (0.3-3.0 mg/kg) or fluoxetine 0.1-1.0 mg/kg). Acute reboxetine induced a significant and dose-dependent decrease in the anticipation of reward. Chronic treatment with fluoxetine tended to reduce the negative bias observed in the rats after 1 week of treatment although no significant main effect of treatment was observed. Conclusions: The results from these initial psychopharmacological studies show that drug treatments can differentially affect motivation to respond to cues associated with reward versus punishment. Our data also suggest that cognitive affective bias, quantified using this method, may be sensitive to chronic but not acute antidepressant treatment. [ABSTRACT FROM AUTHOR]

The effective treatment of depression in people with bipolar disorder remains a clinical challenge. The role of antidepressant medication in treating bipolar depression has been controversial. While early studies and meta-analyses supported a role for antidepressant medication, more recent, high quality randomized controlled trials in bipolar depression have generally not demonstrated efficacy for antidepressant medications. Although the risk of affective switch and long-term de-stabilization remains a concern when using antidepressant medications in bipolar disorder, the magnitude of this risk has been difficult to ascertain with confidence. Maintenance use of antidepressant medication has generally not demonstrated a favorable risk-benefit ratio. Future studies should explore the patient characteristics and response patterns that predict a more favorable response profile to antidepressants amongst patients with bipolar disorder so that the medications can be rationally used in those who are most likely to benefit. [ABSTRACT FROM AUTHOR]

Major depression represents one of the most disabling illnesses worldwide and current treatments are only partially effective. All antidepressant agents modulate the monoamine system, which likely accounts for the similar efficacy profile of available treatments. Herein we summarize the current state of depression therapeutics and assess the antidepressant development pipeline. Antidepressant response rates in controlled trials are estimated at ~54 % and real-world effectiveness data suggests a somewhat lower rate. Response rates are lower still in patients who have not responded to previous treatment attempts and meaningful advancements will likely come only from identification of mechanistically novel agents. Monoaminergic agents largely dominate the antidepressant development pipeline, however the glutamate neurotransmitter system represents a bright spot on the antidepressant horizon. We review in detail findings regarding the antidepressant effects of the glutamate N-methyl-d-aspartate receptor antagonist ketamine in order to highlight the promise of novel agents as future treatments for major depression. [ABSTRACT FROM AUTHOR]

The rising burden of unipolar depression along with its often related sleep disturbances, as well as increasing rates of sleep restriction in modern society, make the search for an extended understanding of the aetiology and pathophysiology of depression necessary. Accumulating evidence suggests an important role for the immune system in mediating disrupted neurobiological and chronobiological processes in depression. This review aims to provide an overview of the neuroimmunomodulatory processes involved with depression and antidepressant treatments with a special focus on chronobiology, chronotherapeutics and the emerging field of immune-circadian bi-directional crosstalk. Increasing evidence suggests that chronobiological disruption can mediate immune changes in depression, and likewise, immune processes can mediate chronobiological disruption. This may suggest a bi-directional relationship in immune-circadian crosstalk. Furthermore, given the immunomodulatory effects of antidepressants and chronotherapeutics, as well as their associated beneficial effects on circadian disturbance, we-and others-suggest that these therapeutic agents may exert their chronobiotic effects partially via the neuroimmune system. Further research is required to better elucidate the mechanisms of immune involvement in the chronobiology of depression. [ABSTRACT FROM AUTHOR]

In recent years, the growing numbers of patients seeking care for a wide range of psychiatric illnesses in the primary care setting has resulted in an increase in the number of psychotropic medications prescribed. Along with the increased utilization of psychotropic medications, considerable variability is noted in the prescribing patterns of primary care providers and psychiatrists. Because psychiatric patients also suffer from a number of additional medical comorbidities, the increased utilization of psychotropic medications presents an elevated risk of clinically significant drug interactions in these patients. While life-threatening drug interactions are rare, clinically significant drug interactions impacting drug response or appearance of serious adverse drug reactions have been documented and can impact long-term outcomes. Additionally, the impact of genetic variability on the psychotropic drug's pharmacodynamics and/or pharmacokinetics may further complicate drug therapy. Increased awareness of clinically relevant psychotropic drug interactions can aid clinicians to achieve optimal therapeutic outcomes in patients in the primary care setting. [ABSTRACT FROM AUTHOR]

Background: RX-10100 (Serdaxin®), a nonantibiotic small molecule beta-lactam compound, has shown potent antidepressant and anxiolytic activities in preclinical models. RX-10100 does not bind to the serotonin transporter or other receptors associated with monoamine activity. In microdialysis studies with rats, RX-10100 increased the release of dopamine and serotonin metabolites. A clinical proof-of-concept study was conducted to determine the clinical effectiveness of RX-10100 in treating depression. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel group study of people with depression ( n = 77; HAM-D-17 baseline score ≥ 20). Eligible subjects were randomly assigned to receive RX-10100 (5, 10, or 15 mg twice daily) or placebo for 8 weeks. Change from baseline in the MADRS total score was the primary endpoint. Results: Mean changes in MADRS scores were −46.0%, −37.9%, and −41.4%, for 5, 10, and 15 mg RX-10100, respectively, as compared with 43.1% for placebo. In subjects with severe depression (baseline MADRS ≥ 29; n = 28) scores improved 55.6% with 5 mg RX-10100 but only 34% with placebo ( p = 0.041). In an analysis of responders (i.e., subjects with 50% change from baseline score), 64.3% of subjects treated with 5 mg RX-10100 responded. All doses of RX-10100 were well-tolerated. Conclusion: In this proof-of-concept study, RX-10100 treatment (5 mg twice daily) improved MADRS scores in subjects with severe depression. RX-10100 does not appear to have many of the typical side effects of other antidepressants. These results indicate a need for larger studies further evaluating RX-10100 at 5 mg and lower doses. [ABSTRACT FROM AUTHOR]

Objective: Current pharmacological treatments for depression have a significant treatment-onset-response delay, an insufficient efficacy for many patients and fail to reverse cognitive dysfunction. Erythropoietin (EPO) has neuroprotective and neurotrophic actions and improves cognitive function in animal models of acute and chronic neurodegenerative conditions and in patients with cognitive decline. Methods: We systematically reviewed the published findings from animal and human studies exploring the potential of EPO to treat depression-related cognitive dysfunction and depression. Results: We identified five animal studies (two in male rats, two in male mice and one in male rats and mice) and seven human proof-of-concept studies (five in healthy volunteers and two in depressed patients) that investigated the above. All of the reviewed animal studies but one and all human studies demonstrated beneficial effects of EPO on hippocampus-dependent memory and antidepressant-like effects. These effects appear to be mediated through direct neurobiological actions of EPO rather than upregulation of red cell mass. Conclusions: The reviewed studies demonstrate beneficial effects of EPO on hippocampus-dependent memory function and on depression-relevant behavior, thus highlighting EPO as a candidate agent for future management of cognitive dysfunction and mood symptoms in depression. Larger-scale clinical trials of EPO as a treatment for mood and neurocognitive symptoms in patients with mood disorder are therefore warranted. [ABSTRACT FROM AUTHOR]

Rationale: Early life adversity, such as early abuse or parental loss, is thought to increase risk for developing psychiatric disorders in adulthood including mood and anxiety disorders. Human retrospective studies also suggest that early life adversity predicts poor response to antidepressants in adulthood. Objectives: We used the infant maternal separation (IMS) paradigm to examine the effects of early adversity on adult emotional behavior, the antidepressant response, and cognitive performance in BALB/cJ mice. Methods: Mice were subjected to either standard facility rearing (SFR) or 3 h of daily separation from the dam from postnatal days 2-15. During adulthood, SFR and IMS mice received chronic treatment (∼3 weeks) with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (18 mg/kg/day), and were assessed for anxiety- and depression-related behavior in the light/dark test and forced swim tests (FST), respectively. We then evaluated the effects of IMS on cognition in the fear conditioning, novel object recognition, and T-maze spatial learning and reversal learning tasks. Results: Chronic fluoxetine treatment produced robust antidepressant effects in both SFR and IMS mice in the FST. IMS did not affect the antidepressant response, or emotional behavior in the light/dark test or FST. However, IMS reduced fear conditioning to the tone and context, disrupted novel object recognition in females, and impaired both spatial and reversal learning in males. Conclusions: Our findings suggest that IMS induces deficits in adult emotional, episodic, and spatial memory and reversal learning, but does not alter adult emotional behavior or the response to chronic SSRI treatment in mice. [ABSTRACT FROM AUTHOR]

novel method based on three-phase hollow fiber microextraction technique (HF-LPME) coupled with electrospray ionization-ion mobility spectrometry (ESI-IMS) was developed for the simultaneous determination of two antidepressant drugs (trimipramine and desipramine) in urine and plasma samples. The effects of various parameters such as type of organic solvent, composition of donor and acceptor phase, stirring rate, salt addition, extraction time, and temperature were investigated. Under the optimized conditions, the relative standard deviation was in the range of 5-6%, and the method quantitation limit (MQL) of utilizing HF-LPME/ESI-IMS was 5 μg/L for both drugs. The relative recoveries obtained by the proposed method from urine and plasma samples were in the range 94% to 97% for trimipramine and 92% to 96% for desipramine. Finally, the feasibility of the proposed method was successfully confirmed by extraction and determination of trace amounts of trimipramine and desipramine in biological samples without any significant matrix effect. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT7) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT7 receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT7 receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT7 receptor antagonists may represent a new class of antidepressants with faster therapeutic action. [ABSTRACT FROM AUTHOR]