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Rationale: We have previously shown that in rats, capsaicin (Cap) has antidepressant-like properties when assessed using the forced swimming test (FST) and that a sub-threshold dose of amitriptyline potentiates the effects of Cap. However, synergistic antidepressant-like effects of the joint administration of Cap and the selective serotonin reuptake inhibitor citalopram (Cit) have not been reported., Objectives: To assess whether combined administration of Cap and Cit has synergistic effects in the FST and to determine whether this combination prevents the side effects of Cit., Methods: Cap, Cit, and the co-administration of both substances were evaluated in a modified version of the FST (30-cm water depth) conducted in rats, as well as in the open field test (OFT), elevated plus maze (EPM), and Morris water maze (MWM)., Results: In line with previous studies, independent administration of Cap and Cit displayed antidepressant-like properties in the FST, while the combined injection had synergistic effects. In the OFT, neither treatment caused significant increments in locomotion. In the EPM, the time spent in the closed arms was lower in groups administered either only Cap or a combination of Cap and Cit than in groups treated with Cit alone. In the MWM, both Cap and the joint treatment (Cap and Cit) improved the working memory of rats in comparison with animals treated only with Cit., Conclusion: Combined administration of Cap and Cit produces a synergistic antidepressant-like effect in the FST and reduces the detrimental effects of Cit on anxiety and working memory.

Objective: The objective of this work was to describe treatment-emergent sexual dysfunction (TESD) and tolerability following a switch from selective serotonin reuptake inhibitor (SSRI: citalopram, paroxetine, or sertraline) monotherapy to vortioxetine or escitalopram monotherapy in adults with well-treated major depressive disorder (MDD) and SSRI-induced sexual dysfunction., Methods: Data were analyzed from the primary study, an 8-week, randomized, double-blind, head-to-head study in which participants with well-treated depressive symptoms but experiencing TESD with SSRIs were directly switched to flexible doses (10/20 mg) of vortioxetine or escitalopram. Sexual functioning was assessed by the Changes in Sexual Functioning Questionnaire-14 (CSFQ-14), efficacy by the Montgomery-Åsberg Depression Rating Scale scores (MADRS) and Clinicians Global Impression of Severity/Improvement (CGI-S/CGI-I), and tolerability by adverse events. Efficacy and tolerability were assessed by pre-switch SSRI therapy where possible, and by participant characteristics., Results: Greater improvements in TESD were seen in the vortioxetine compared with escitalopram groups based on: participant demographics (≤45 years, women; P = 0.045), prior SSRI treatment (P = 0.044), number of prior major depressive episodes (MDEs) (1-3; P = 0.001), and duration of prior SSRI therapy (>1 year; P = 0.001). Prior SSRI treatment did not appear to influence the incidence or severity of TEAEs, except for nausea. Regardless of prior SSRI, both treatments maintained antidepressant efficacy after 8 weeks., Conclusion: Results suggest that vortioxetine is a safe and effective switch therapy for treating SSRI-induced sexual dysfunction in adults with well-treated MDD. Also, improvement in sexual dysfunction with vortioxetine or escitalopram may be influenced by prior SSRI usage, sex, age, and history of MDEs.

Background: Depression is characterized by significant and low mood. Classical antidepressants are still not adequate in treating depression because of undesirable side effects. Folic acid, a member of the vitamin B complex, in considered to be strongly associated with the function and development of the central nervous system. Thus, in this study, we established a model of depression through chronic unpredictable mild stress (CUMS) in rats and assessed the antidepressant effects and mechanisms of folic acid., Methods: Sprague-Dawley rats were randomly divided into four groups: control, chronic unpredictable mild stress (CUMS), CUMS treated with folic acid, and CUMS treated with citalopram. Rats were assessed in terms of weight change, open-field test and sucrose preference. Homocysteine, monoamine neurotransmitters, interleukin-6, brain-derived neurotrophic factor (BDNF), β-endorphin levels in the serum and brains of rats were analysed., Results: Folic acid exhibited antidepressant-like effects in open-field and sucrose preference tests. Folic acid treatment effectively increased the levels of monoamine neurotransmitters, BDNF and β-endorphin, interleukin-6 and homocysteine levels were also significantly suppressed by folic acid administration., Conclusions: These findings serve as preclinical evidence that folic acid plays an antidepressant-like role in several pathways involving monoamine neurotransmitters. Thus, folic acid may be used as a potential antidepressant.

Background: Reports claiming that antidepressants are effective only in patients with severe depression have affected treatment guidelines but these reports usually use a disputed measure of improvement, a decrease in the sum-score of the 17-item Hamilton Depression Rating Scale (HDRS-17), and are based on group-level rather than patient-level data., Method: In this item-based, patient-level, post-hoc analysis, we pooled data from all completed, acute-phase, placebo-controlled, industry-sponsored, HDRS-based trials of the SSRIs citalopram, paroxetine, or sertraline in adult major depression. Patient-level data were pooled and subjected to item-based post-hoc analyses to assess the effect of baseline severity of depression on the response to treatment as assessed with HDRS-17 sum score, the depressed mood item of the HDRS, a six-item HDRS subscale (HDRS-6), and the remaining 11 HDRS items not included in this subscale (non-HDRS-6). Patients were defined as having non-severe depression if they had a baseline HDRS-17 sum score of 18 points or less and as having severe depression if they had a score of 27 points or more., Findings: Our study population consisted of 8262 patients from 28 placebo-controlled SSRI trials. Participants were treated with either citalopram (n=744), paroxetine (n=2981), sertraline (n=1202), fluoxetine (active-control group; n=754), or placebo (n=2581). 654 patients were defined as having non-severe depression and 1377 as having severe depression. Patients with non-severe and severe depression did not differ with respect to SSRI-induced decrease in depressed mood and other HDRS symptoms belonging to the HDRS-6 subscale. However, after exclusion of patients with rare extreme baseline values, a positive association was seen between severity and efficacy when using HDRS-17 sum score as the effect parameter. This result was largely due to a more pronounced response to treatment with respect to non-HDRS-6 items in patients with severe depression than in those with non-severe depression. This outcome could be explained by non-HDRS-6 items, more so than HDRS-6 items, being more severe and prevalent at baseline in severe than in non-severe cases; hence, less room was left for improvement in these areas in patients with non-severe depression., Interpretation: The use of an outcome measure that includes symptoms that rate low at baseline in patients with non-severe depression might result in the interpretation that SSRIs are ineffective in these patients. With respect to alleviation of HDRS-6 items, SSRIs appear to be as effective in patients with non-severe depression as in those with severe depression., Funding: Swedish Medical Research Council, AFA Insurance, Swedish Brain Foundation, Sahlgrenska University Hospital (Avtal om Läkarutbildning och Forskning), Bertil Hållsten's Foundation, and Söderberg's Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Vascular depression can respond poorly to antidepressants. This study aimed to explore the efficacy and safety of tandospirone plus escitalopram for treating vascular depression with anxiety. This pilot randomized controlled trial included consecutive inpatients/outpatients with vascular depression/anxiety at the Department of Neurology, Fujian Medical University Union Hospital, China (January 2014 to December 2016). Among 157 patients screened, 100 were randomly divided into the tandospirone + escitalopram (combination therapy) and escitalopram (monotherapy) groups equally, and then followed for 8 weeks. Efficacy was evaluated using the Hamilton Depression (HAMD), Hamilton Anxiety (HAMA), Clinical Global Impression (CGI) and Mini-Mental State examination (MMSE) scales. Adverse events (AEs) were assessed with the Treatment Emergent Symptom Scale (TESS). HAMD and HAMA scores decreased progressively, showing reductions versus baseline at 1, 2, 4 and 8 weeks in both groups (P < 0.001). HAMD and HAMA scores were lower in the tandospirone + escitalopram group than those in the escitalopram group at 1 and 2 weeks (P < 0.001), but not at 4 and 8 weeks. Improvements in CGI scores (severity, improvement and efficacy indexes) were greater in the tandospirone + escitalopram group than that in the escitalopram group at 1 and 2 weeks (P < 0.01), but not at 4 and 8 weeks. The tandospirone + escitalopram group had higher MMSE scores than that in the escitalopram group at 4 and 8 weeks (P < 0.01). All AEs were mild, and the rates were comparable between groups. Augmentation of escitalopram with tandospirone accelerates the onset of anti-depressive and anxiolytic effects and improves cognitive function in patients with vascular depression and anxiety., (Copyright © 2019. Published by Elsevier Ltd.)

Objectives: This study aimed to investigate whether social support deficit has moderating effects on depressive and cardiac outcomes in an antidepressant trial for depressed patients with acute coronary syndrome as a secondary analysis using Escitalopram for DEPression in acute coronary syndrome study (ClinicalTrial.gov registry number: NCT00419471)., Methods: In total, 217 acute coronary syndrome patients with Diagnostic and Statistical Manual of Mental Disorders, 4th edition depressive disorders were randomized into two groups that received escitalopram (N = 108) or placebo (N = 109) for 24 weeks. Social support deficit was evaluated by validated scales at study entry. Depressive outcomes were measured using the Hamilton Depression Rating Scale, the Montgomery Asberg Depression Rating Scale, and the Beck Depression Inventory. Cardiac outcomes included echocardiography (left ventricular ejection fraction and wall motion scores), electrocardiography (heart rate, PR interval, QRS duration, and QTc duration), and laboratory test results (troponin I and creatine kinase-MB)., Results: A higher social support deficit at baseline was significantly associated with less improvement in Hamilton Depression Rating Scale, Montgomery Asberg Depression Rating Scale, Beck Depression Inventory scores, and serum troponin I levels after adjustment for corresponding baseline scores, covariates associated with social support deficit at baseline, and treatment status. The strength of these associations was more prominent in the placebo group compared to the escitalopram group., Conclusions: Evaluation of social support deficit in depressed acute coronary syndrome is important, and particularly during the acute phase, depressed acute coronary syndrome patients with social support deficit should be treated more carefully to improve treatment outcomes, given that social support deficit was predictive of poorer depressive and cardiac outcomes during the 24-week treatment period. Acute coronary syndrome patients with social support deficit should be treated more carefully to improve treatment outcomes.

Objective: To explore the effect of ginkgo biloba extract (EGb) as an adjunctive treatment of elderly patients with depression and the effect on the expression of serum S100B., Methods: 136 elderly patients with depression were divided into EGb +  citalopram (Cit) group and Cit group equally. Efficacy was evaluated by Hamilton Depression Rating Scale (HAMD). Wisconsin Card Classification Test (WCST) was used to evaluate cognitive function. Serum S100B expression was measured with ELISA. The relationship of S100B with HAMD, Hamilton Anxiety Scale (HAMA) score, and WCST results was evaluated subsequently., Results: The time of onset of efficacy was significantly shorter in EGb + Cit group. There were significant differences in HAMD and HAMA scores after treatment than before treatment between groups (all P < .05). After treatment, total number of WCST test, the number of continuous errors and non-persistent errors in both groups were less than those before treatment. The correct number and classifications number were increased than before treatment. In EGb + Cit group, correct numbers and classifications were increased, and the number of persistent errors was decreased. After treatment, S100B level was decreased, and S100B levels change in EGb + Cit group was greater than in Cit group. Serum S100B level was positively correlated with HAMD and HAMA scores before treatment and positively correlated with persistent errors number in WCST., Conclusion: EGb, as an adjunctive treatment, can effectively improve depressive symptoms and reduce expression of serum S100B, which is a marker of brain injury, suggesting that EGb restores neurologic function during the treatment of depression in elderly patients and S100B participates in the therapeutic mechanism. EGb combined with depressive drugs plays synergistic role, and the time of onset of efficacy is faster than single antidepressants.

Chronic stress, a causal factor for depression, can also cause cognitive impairments and tau pathology. However, whether and how the selective serotonin reuptake inhibitor antidepressant escitalopram ameliorates these effects are still unclear. In the present study, rats were subjected to chronic mild unpredictable stress for 8 weeks. Following the initial 4 weeks, the stressed animals were separated into susceptible (depressive) and unsusceptible (resistant) groups based on behavioral tests. Then, escitalopram (10 mg/kg i.p.) was administered for 28 days. Pathophysiological changes were assessed by performing behavioral and biochemical analyses. The results showed that both depressive and resistant rats displayed spatial memory deficits and an accumulation of tau in the hippocampus. Increased levels of corticosterone and insulin and a decreased level of glucocorticoid receptor were found in both depressive and resistant rats. We also found that activity-dependent phosphorylated insulin receptor substrate and glycogen synthase kinase-3β (Ser9 site) were significantly decreased in both depressive and resistant rats. However, other important kinases, such as cyclin-dependent kinase 5 and mitogen-activated protein kinase kinase-1/2, did not change in our study. Furthermore, we found that the mRNA expression of tau was increased in depressive and resistant rats. No significant change in LC3B expression was found. Interestingly, almost all the pathological changes in depressive and resistant rats previously mentioned could be reversed by escitalopram. Our results suggested that escitalopram ameliorates cognitive impairments and selectively attenuates phosphorylated tau accumulation in stressed rats through the regulation of hypothalamic-pituitary-adrenal axis activity and the insulin receptor substrate/glycogen synthase kinase-3β signaling pathway., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Recent preclinical and clinical data suggest that low dose of caffeine enhances the effects of common antidepressants. Here we investigated the effects of chronic administration of caffeine (5mg/kg, twice daily for 14days) and its withdrawal on day 15th on the activity of per se ineffective doses of fluoxetine (5mg/kg) and escitalopram (2mg/kg) given on day 15th. We found decreased immobility time in the forced swim and tail suspension tests in mice in which caffeine was administered simultaneously with antidepressants on day 15th following a 14-day caffeine treatment and no alterations in the spontaneous locomotor activity. A decrease in the level of escitalopram and an increase in the level of caffeine in serum were observed after concomitant administration of these compounds, while the joint administration of caffeine and fluoxetine was not associated with changes in their levels in serum or brain. Caffeine withdrawal caused a decrease in Adora1 mRNA level in the cerebral cortex (Cx). Administration of escitalopram or fluoxetine followed by caffeine withdrawal caused an increase in this gene expression, whereas administration of escitalopram, but not fluoxetine, on day 15th together with caffeine caused a decrease in Adora1 mRNA level in the Cx. Furthermore, antidepressant-like activity observed after joint administration of the tested drugs with caffeine was associated with decreased Slc6a15 mRNA level in the Cx. The results show that withdrawal of caffeine after its chronic intake may change activity of antidepressants with concomitant alterations within monoamine, adenosine and glutamate systems., (Copyright © 2017 Elsevier Inc. All rights reserved.)

There is little research on the effects of adolescent administration of antidepressants on behavioural function and inflammation in early-life stressed adult mice. Using maternal separation (MS), a paradigm of early adversity, we investigated the effects of adolescent (PND 33-54) escitalopram (ES; 10mg/kg) exposure on depression- and anxiety-like behaviours and the levels of inflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, and IL-10) in the ventral hippocampus (HPV), prefrontal cortex (PFC), and serum in adult (PND 61) male offspring mice. The results showed that MS has no effect on locomotor activity, but increased depression-like behaviours in the saccharin preference test and increased anxiety-like behaviours in the social preference and elevated plus maze tests. MS increased the levels of IL-1β in the HPV, PFC, and serum, while decreasing the level of IL-10 in the HPV. Furthermore, adolescent ES treatment inhibited these depression- and anxiety-like behaviours, decreased the levels of IL-1β, and increased the level of IL-10 in the HPV. The results also showed that there are no effects of chronic escitalopram administration on normal behaviour in control mice. Taken together, the current data provide experimental evidence that MS increases depression and anxiety levels in adult male offspring. Additionally, the findings support the idea that early pharmacological intervention with ES may be an effective treatment for reducing the behavioral abnormalities induced by early adversity and regulating the underlying inflammatory mechanisms involved., (Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.)

Anhedonia, the loss of interest or pleasure in previously enjoyable activities, is a core symptom of major depressive disorder, suggesting that the brain reward system may be dysfunctional in this condition. Neurochemical changes in the mesolimbic dopamine (DA) system are not fully understood in animal models of depression. We investigated reward (30% sucrose intake)-induced DA release in the nucleus accumbens (NAc) and the effect of chronic treatment with the antidepressant escitalopram (5mg/kg, intraperitoneally twice daily for 3 weeks) in two animal models of depression. Exposure to chronic mild stress (CMS) during adulthood completely suppressed reward-induced intra-NAc DA release; however, this effect was reversed by chronic treatment with escitalopram. Our findings suggest that reward-induced intra-NAc DA release may be an indicator of depression severity and therapeutic efficacy. Exposure to neonatal maternal separation (MS) and CMS in adulthood completely suppressed reward-induced intra-NAc DA release. Chronic treatment with escitalopram did not restore reward-induced DA release in these animals, suggesting that this paradigm may serve as an animal model for treatment-resistant depression. Further study of the mesolimbic dopaminergic system in these animal models of depression may clarify the neural mechanisms underlying depression and treatment resistance., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rationale Limited research is available on electrophysiological abnormalities such as epileptiform EEG or EEG slowing in depression and its association with antidepressant treatment response. Objectives We investigated the association between EEG abnormalities and antidepressant treatment response in the international Study to Predict Optimized Treatment in Depression (iSPOT-D). Methods Of 1008 participants with major depressive disorder randomized to escitalopram, sertraline, or venlafaxine-XR, 622 completed 8 weeks of treatment per protocol. The study also recruited 336 healthy controls. Treatment response was established after 8 weeks using the 17-item Hamilton Rating Scale for Depression (HRSD 17 ). The resting-state EEG was assessed at baseline with eyes closed. EEG abnormalities including epileptiform activity, EEG slowing, and alpha peak frequency (APF) were scored for all subjects, blind to treatment outcome. Results Patients and controls did not differ in the occurrence of EEG abnormalities. Furthermore, in the per protocol sample the occurrence of epileptiform EEG and EEG slowing (as a combined marker) were associated with a reduced likelihood of responding to escitalopram (P = .019; odds ratio [OR] = 3.56) and venlafaxine-XR (P = .043; OR = 2.76), but not sertraline (OR = 0.73). The response rates for this "any EEG abnormality" groups versus the "no-abnormality" group were 33% and 64% for escitalopram and 41% and 66% for venlafaxine-XR, respectively. A slow APF was associated with treatment response only in the sertraline group (P = .21; d = .027). Conclusions EEG abnormalities are associated with nonresponse to escitalopram and venlafaxine-XR, but not sertraline, whereas a slow APF is associated to response for sertraline only., (© EEG and Clinical Neuroscience Society (ECNS) 2015.)

Background: Mood and emotional disturbances are common in patients with stroke, and adversely affect the clinical outcome. We aimed to evaluate the efficacy of early administration of escitalopram to reduce moderate or severe depressive symptoms and improve emotional and neurological dysfunction in patients with stroke., Methods: This was a placebo controlled, double-blind trial done at 17 centres in South Korea. Patients who had had an acute stroke within the past 21 days were randomly assigned in a 1:1 ratio to receive oral escitalopram (10 mg/day) or placebo for 3 months. Randomisation was done with permuted blocks stratified by centre, via a web-based system. The primary endpoint was the frequency of moderate or severe depressive symptoms (Montgomery-Åsberg Depression Rating Scale [MADRS] ≥16). Endpoints were assessed at 3 months after randomisation in the full analysis set (patients who took study medication and underwent assessment of primary endpoint after randomisation), in all patients who were enrolled and randomly assigned (intention to treat), and in all patients who completed the trial (per-protocol analysis). This trial is registered with ClinicalTrials.gov, number NCT01278498., Findings: Between Jan 27, 2011, and June 30, 2014, 478 patients were assigned to placebo (n=237) or escitalopram (n=241); 405 were included in the full analysis set (195 in the placebo group, 210 in the escitalopram group). The primary outcome did not differ by study group in the full analysis set (25 [13%] patients in the placebo group vs 27 [13%] in the escitalopram group; odds ratio [OR] 1·00, 95% CI 0·56-1·80; p>0·99) or in the intention-to-treat analysis (34 [14%] vs 35 [15%]; OR 1·01, 95% CI 0·61-1·69, p=0·96). The study medication was generally well tolerated; the most common adverse events were constipation (14 [6%] patients who received placebo vs 14 [6%] who received escitalopram), muscle pain (16 [7%] vs ten [4%]), and insomnia (12 [5%] vs 12 [5%]). Diarrhoea was more common in the escitalopram group (nine [4%] patients) than in the placebo group (two [1%] patients)., Interpretation: Escitalopram did not significantly reduce moderate or severe depressive symptoms in patients with acute stroke., Funding: Dong-A Pharmaceutical and Ministry for Health, Welfare, and Family Affairs, South Korea., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The prevalence or recurrence of depression is seriously increased in women during the transition to and after menopause. The chronic hypo-estrogenic state of menopause may reduce the response to antidepressants; however the influence of estrogen therapy on their efficacy is still controversial. This study aimed at investigating the effects of combining escitalopram with 17β-estradiol on depression and cognitive impairment induced by ovariectomy, an experimental model of human menopause. Young adult female Wistar rats were subjected to either sham operation or ovariectomy. Ovariectomized animals were treated chronically with escitalopram (10mg/kg/day, i.p) alone or with four doses of 17β-estradiol (40μg/kg, s.c) given prior to the behavioral tests. Co-administration of 17β-estradiol improved escitalopram-induced antidepressant effect in forced swimming test verified as more prominent decrease in the immobility time without opposing its memory enhancing effect in Morris water maze. 17β-estradiol augmented the modulatory effects of escitalopram on the hippocampal levels of brain-derived neurotrophic factor and serotonin reuptake transporter as well as tumor necrosis factor-alpha without altering its effects on the gene expressions of serotonin receptor 1A, estrogen receptors alpha and beta, or acetylcholinestearase content. This combined therapy afforded synergistic protective effects on the brain histopathological architecture, particularly, the hippocampus. The antidepressant effect of 17β-estradiol was abolished by pretreatment with estrogen receptor antagonist, tamoxifen (10mg/kg, p.o). In conclusion, 17β-estradiol-induced antidepressant effect was confined to intracellular estrogen receptors activation. Moreover, 17β-estradiol enhanced escitalopram's efficiency in ameliorating menopausal-like depression, via exerting synergistic neuroprotective and serotonin reuptake transporter modulatory effects, without impeding escitalopram-mediated cognitive improvement., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We investigated roles of plasma homocysteine and MTHFR gene in relation to risks and treatment responses of depression in ACS. A sample of 969 patients with recent ACS were recruited and 711 followed 1 year later. In addition, of 378 baseline participants with depressive disorder, 255 were randomized to a 24-week double blind trial of escitalopram (N = 127) or placebo (N = 128). A higher homocysteine concentration was independently associated with prevalent depressive disorder at baseline irrespective of MTHFR genotype; and with both incident and persistent depressive disorder at follow-up only in the presence of TT genotype. MTHFR genotype was not itself associated with depressive disorder after ACS. No associations were found with 24-week antidepressant treatment responses. Plasma homocysteine could be a biomarker for depressive disorder particularly in the acute phase of ACS. Focused interventions for those with higher homocysteine level and MTHFR TT genotype might reduce the risk of later depressive disorder.

Serotonin reuptake inhibitors (SSRIs) have immediate effects on synaptic levels of serotonin but their therapeutic effects are often delayed. This delay has been suggested to reflect time required for new learning and therefore that SSRIs might be having effects on the learning process. We examined the effects of elevating serotonin levels, through short-term SSRI administration (escitalopram), on learning about perceptions of instrumental control. A randomised double blind procedure was used to allocate healthy people, categorised as mildly depressed (high BDI⩾10: n=76) or not depressed (low BDI⩽5: n=78) to either a drug (escitalopram, 10mg/7days) or placebo control group. Following treatment, participants were trained with a simple task that involved learning the effectiveness of an instrumental action (key press) and the background context at eliciting an outcome (auditory cue) where there was no programmed contingency. The effects of the drug were (i) to moderate response rates and (ii) to enhance sensitivity to the background or context rate of occurrence of the outcome. These findings suggest that serotonin modulates learning about the long-term rate of outcomes, which supports perception of instrumental control, and that this may provide a clue to the mechanism for supporting the development of the therapeutic effects of the drug., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Deconstruction of a ghostwritten report of a randomized, double-blind, placebo-controlled efficacy and safety trial of citalopram in depressed children and adolescents conducted in the United States., Methods: Approximately 750 documents from the Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-(NMG) were deconstructed., Results: The published article contained efficacy and safety data inconsistent with the protocol criteria. Procedural deviations went unreported imparting statistical significance to the primary outcome, and an implausible effect size was claimed; positive post hoc measures were introduced and negative secondary outcomes were not reported; and adverse events were misleadingly analysed. Manuscript drafts were prepared by company employees and outside ghostwriters with academic researchers solicited as 'authors'., Conclusion: Deconstruction of court documents revealed that protocol-specified outcome measures showed no statistically significant difference between citalopram and placebo. However, the published article concluded that citalopram was safe and significantly more efficacious than placebo for children and adolescents, with possible adverse effects on patient safety.

Major depression is known to be associated with cardiovascular abnormalities, and oxidative stress has been suggested to play a role. We tested the hypothesis that antidepressant treatment reduces oxidative stress and endothelial dysfunctions in the chronic mild stress (CMS) model of depression in rats. Rats with >30% reduction in sucrose intake after 4 wk of CMS were defined in the study as CMS-susceptible and compared with unstressed controls. Sixteen CMS-susceptible and eight unstressed rats were treated during weeks 5 to 8 of the CMS protocol with escitalopram. Escitalopram-treated rats with >20% recovery in the sucrose consumption during the last 2 wk of treatment were defined as escitalopram responders. Rats that did not reach these criteria were defined as escitalopram nonresponders. In the open field test, escitalopram responders demonstrated anxiolytic effect of treatment. In mesenteric small arteries, escitalopram affected neither NO nor cyclooxygenase-1 (COX-1)-mediated vasodilation. Escitalopram potentiated endothelium-dependent hyperpolarization-like response, which was suppressed in the vehicle-treated CMS-susceptible rats and reduced COX-2-dependent relaxation, which was elevated in the vehicle-treated CMS-susceptible rats. Escitalopram did not affect blood pressure and heart rate, which were elevated in the vehicle-treated CMS-susceptible rats. Oxidative stress markers were changed in association with CMS in liver, heart, and brain. Escitalopram normalized oxidative stress markers in the majority of tissues. This study demonstrates that the antidepressant effect of escitalopram is associated with partial improvement of endothelial function in small arteries affecting COX-2 and endothelium-dependent hyperpolarization-like pathways., (Copyright © 2015 the American Physiological Society.)

Objective: Observational studies show that when a depressed mother's symptoms remit, her children's psychiatric symptoms decrease. Using randomized treatment assignment, the authors sought to determine the differential effects of a depressed mother's treatment on her child., Method: The study was a randomized double-blind 12-week trial of escitalopram, bupropion, or the combination of the two in depressed mothers (N=76), with independent assessment of their children (N=135; ages 7-17 years)., Results: There were no significant treatment differences in mothers' depressive symptoms or remission. Children's depressive symptoms and functioning improved significantly among those whose mothers were in the escitalopram group (compared with those whose mothers were in the bupropion and combination treatment groups). Only in the escitalopram group was significant improvement of mother's depression associated with improvement in the child's symptoms. Exploratory analyses suggested that this may be due to changes in parental functioning: Mothers in the escitalopram group reported significantly greater improvement, compared with the other groups, in their ability to listen and talk to their children, who as a group reported that their mothers were more caring over the 12 weeks. Maternal baseline negative affectivity appeared to moderate the effect of maternal treatment on children, although the effect was not statistically significant. Children of mothers with low negative affectivity improved in all treatment groups. Children of mothers with high negative affectivity improved significantly only for those whose mothers were in the escitalopram group., Conclusions: The effects of the depressed mother's improvement on her children may depend on her type of treatment. Depressed mothers with high anxious distress and irritability may require medications that reduce these symptoms in order to show the effect of her remission on her children.

Background: A small literature suggests that pharmacotherapy may be useful in the prophylaxis of posttraumatic stress disorder in patients presenting with major trauma. There is relatively little data, however, on the use of selective serotonin reuptake inhibitors (SSRIs) in this context., Methods: 24 week, double-blind placebo controlled study. 31 participants presenting immediately after trauma, and meeting diagnostic criteria for full or partial acute stress disorder were randomized to treatment with 10-20 mg of escitalopram or placebo daily for 24 weeks. 2 participants were excluded from the analysis due to early drop out, leaving 29 participants (escitalopram = 12, placebo = 17) for inclusion in an intent- to- treat analysis. Participants were followed up until 56 weeks, and assessed with the Clinician Administered PTSD Scale (CAPS). A mixed model repeated measures analysis of variance (RMANOVA) was undertaken to determine the efficacy of the intervention on the CAPS score., Results: There was a significant reduction in CAPS score over the course of treatment (F(7, 142) = 41. 58, p < 0.001) in both the escitalopram and placebo groups, with a greater reduction in CAPS score in the placebo group F(7, 142) = 2.12, p = 0.045. There were improvements on all secondary measures, including the Clinical Global Impressions scale, and scales assessing depression, anxiety and disability. Only functional disability outcomes (F(7, 141) = 2.13, p = .04), were significantly different between treatment and placebo groups. In the sample as a whole, improvement in scores were maintained at the 52 week follow-up. Side effects were comparable between the groups., Conclusions: These data are consistent with other recent work indicating that the SSRIs may not be efficacious in the prevention of PTSD. Nevertheless, the small sample size and baseline differences between groups limit the explanatory power of the study. Although a consideration of the possibility of medication prophylaxis in PTSD remains important, both from conceptual and clinical perspectives, caution is needed with regards to the use of SSRIs until their efficacy can be proven., Trial Registration: Clinical Trials NCT00300313.

Background: We analyzed the public STAR*D database to better characterize the baseline clinical characteristics and functional outcomes of patients with major depressive disorder (MDD) who experienced partial response in order to better understand the burden associated with this outcome., Method: Patients (n=2,876) received treatment with citalopram. The last available Quick Inventory of Depressive Symptoms (QIDS-SR) from the 12-week treatment period was used to assign subjects to one of three groups: remitters QIDS-SR≤5; non-responders QIDS-SR >5 and <25% reduction from baseline; and partial responders QIDS-SR >5 and ≥25% reduction from baseline. Baseline sociodemographic and clinical characteristics were compared across groups, as well as functional outcomes at Level 1 exit. RESULTS. Of the 2,876 patients, 943 patients (33%) were classified as remitters, 1069 (37%) as partial responders, and 854 (30%) as non-responders. The groups differed on a number of pre-treatment course of illness variables and comorbidities. In addition, remitters, partial responders, and non-responders all separated on posttreatment quality of life and functional outcomes at Level 1 exit., Conclusion: Partial responders demonstrated significant functional impairment at Level 1 exit, differing significantly from the patients who remitted on quality of life, mental and physical functioning, and social and work-related impairment. Adjusted outcomes showed similar differences. Differences in baseline rates of suicidality, comorbidity, and atypical presentations of depression were also observed between outcome groups. Given the substantial clinical and economic burden associated with functional impairment in depression, the need to fully treat partially responding patients to achieve depression remission and restoration of functioning is highlighted by this work.

Interleukin (IL)-2, a T-cell cytokine used to treat malignant melanoma, can induce profound depression. To determine whether pretreatment with the antidepressant escitalopram could reduce IL-2-induced neuroendocrine, immune, and neurobehavioral changes, 20 patients with Stage IV melanoma were randomized to either placebo or the serotonin reuptake inhibitor, escitalopram (ESC) 10-20 mg/day, 2 weeks before, and during IL-2 treatment (720 000 units/kg Q8 h × 5 days (1 cycle) every 3 weeks × 4 cycles). Generalized estimation equations were used to examine HPA axis activity (plasma ACTH and cortisol), immune activation (plasma IL-6), and depressive symptoms (Hamilton Depression Rating Scale (HDRS) score). Tolerance of IL-2 treatment (concomitant medications required) and adherence (number of IL-2 doses received) were also assessed. Both the groups (ESC (n=9), placebo (n=11)) exhibited significant IL-2-induced increases in plasma cortisol, IL-6, and depressive symptoms (p<0.05), as well as a temporal trend for increases in plasma ACTH (p=0.054); the effects of age and treatment were not significant. Higher plasma ACTH concentrations were associated with higher depressive symptoms during cycles 1-3 of IL-2 therapy (p<0.01). Although ESC had no significant effects on ACTH, cortisol, IL-6, tolerance of, or adherence to IL-2, ESC treatment was associated with lower depressive symptoms, ie, a maximal difference of ∼3 points on the HDRS, which, though not statistically significant (in part, due to small sample size), represents a clinically significant difference according to the National Institute for Health and Clinical Excellence guidelines. A larger sample size will establish whether antidepressant pretreatment can prevent IL-2-induced neurobehavioral changes.

Rationale: A rigorously investigated model of stress and antidepressant administration during pregnancy is needed to evaluate possible effects on the mother., Objective: The objective of this study was to develop a model of clinically relevant prenatal exposure to an antidepressant and stress during pregnancy to evaluate the effects on maternal care behavior., Results: Female rats implanted with 28-day osmotic minipumps delivering the SSRI escitalopram throughout pregnancy had serum escitalopram concentrations in a clinically observed range (17-65 ng/ml). A separate cohort of pregnant females exposed to a chronic unpredictable mild stress paradigm on gestational days 10-20 showed elevated baseline (305 ng/ml), and acute stress-induced (463 ng/ml), plasma corticosterone concentrations compared to unstressed controls (109 ng/ml). A final cohort of pregnant dams were exposed to saline (control), escitalopram, stress, or stress and escitalopram to determine the effects on maternal care. Maternal behavior was continuously monitored over the first 10 days after parturition. A reduction of 35 % in maternal contact and 11 % in nursing behavior was observed due to stress during the light cycle. Licking and grooming behavior was unaffected by stress or drug exposure in either the light or dark cycle., Conclusions: These data indicate that: (1) clinically relevant antidepressant treatment during human pregnancy can be modeled in rats using escitalopram; (2) chronic mild stress can be delivered in a manner that does not compromise fetal viability; and (3) neither of these prenatal treatments substantially altered maternal care post parturition.

Evidence suggests that the serotonin 2A receptor (5-HT2AR) modulates the therapeutic activity of selective serotonin reuptake inhibitors (SSRIs). Indeed, among the genetic factors known to influence the individual response to antidepressants, the HTR2A gene has been associated with SSRIs response in depressed patients. However, in these pharmacogenetic studies, the consequences of HTR2A gene polymorphisms on 5-HT2AR expression or function are lacking and the precise role of this receptor is still matter of debate. This study examined the effect of 5-HT2AR agonism or antagonism with DOI and MDL100907, respectively, on the serotonergic system and the antidepressant-like activity of the SSRI escitalopram in mouse. The 5-HT2AR agonist DOI decreased the firing rate of 5-HT neurons in the dorsal raphe (DR) nucleus of 5-HT2AR(+/+) anesthetized mice. This inhibitory response persisted in 5-HT2CR(-/-) but was completely blunted in 5-HT2AR(-/-) mutants. Moreover, the suppressant effect of DOI on DR 5-HT neuronal activity in 5-HT2AR(+/+) mice was attenuated by the loss of noradrenergic neurons induced by the neurotoxin DSP4. Conversely, in 5-HT2AR(+/+) mice, the pharmacological inactivation of the 5-HT2AR by the selective antagonist MDL100907 reversed escitalopram-induced decrease in DR 5-HT neuronal activity. Remarkably, in microdialysis experiments, a single injection of escitalopram increased cortical extracellular 5-HT, but not NE, levels in awake 5-HT2AR(+/+) mice. Although the addition of MDL100907 did not potentiate 5-HT neurotransmission, it allowed escitalopram to increase cortical NE outflow and consequently to elicit an antidepressant-like effect in the forced swimming test. These results suggest that the blockade of the 5-HT2AR may strengthen the antidepressant-like effect of escitalopram by facilitating the enhancement of the brain NE transmission. They provide support for the use of atypical antipsychotics with SSRIs as a relevant antidepressant augmentation strategy.

The fact that selective serotonin reuptake inhibitors (SSRIs) have antidepressant effects in some patients supports the notion that serotonin plays a role in the mode of action of antidepressant drugs. However, neither the way in which serotonin may alleviate depressed mood  nor the reason why several weeks needs to elapse before the full antidepressant effect of treatment is expressed  is known. Here, we propose a neuropsychological theory of SSRI antidepressant action based on the ability of SSRIs to produce positive biases in the processing of emotional information. Both behavioural and neuroimaging studies show that SSRI administration produces positive biases in attention, appraisal and memory from the earliest stages of treatment, well before the time that clinical improvement in mood becomes apparent. We suggest that the delay in the clinical effect of SSRIs can be explained by the time needed for this positive bias in implicit emotional processing to become apparent at a subjective, conscious level. This process is likely to involve the re-learning of emotional associations in a new, more positive emotional environment. This suggests intriguing links between the effect of SSRIs to promote synaptic plasticity and neurogenesis, and their ability to remediate negative emotional biases in depressed patients.

Background: "Evergreening" refers to the numerous strategies whereby owners of pharmaceutical products use patent laws and minor drug modifications to extend their monopoly privileges on the drug. We aimed to evaluate the impact of evergreening through the case study of the antidepressant citalopram and its chiral switch form escitalopram by evaluating treatment efficacy and acceptability for patients, as well as health insurance costs for society., Methods: To assess efficacy and acceptability, we performed meta-analyses for efficacy and acceptability. We compared direct evidence (meta-analysis of results of head-to-head trials) and indirect evidence (adjusted indirect comparison of results of placebo-controlled trials). To assess health insurance costs, we analyzed individual reimbursement data from a representative sample of the French National Health Insurance Inter-regime Information System (SNIIR-AM) from 2003 to 2010, which allowed for projecting these results to the whole SNIIR-AM population (53 million people)., Results: In the meta-analysis of seven head-to-head trials (2,174 patients), efficacy was significantly better for escitalopram than citalopram (combined odds ratio (OR) 1.60 (95% confidence interval 1.05 to 2.46)). However, for the adjusted indirect comparison of 10 citalopram and 12 escitalopram placebo-controlled trials, 2,984 and 3,777 patients respectively, efficacy was similar for the two drug forms (combined indirect OR 1.03 (0.82 to 1.30)). Because of the discrepancy, we could not combine direct and indirect data (test of inconsistency, P = 0.07). A similar discrepancy was found for treatment acceptability. The overall reimbursement cost burden for the citalopram, escitalopram and its generic forms was 120.6 million Euros in 2010, with 96.8 million Euros for escitalopram., Conclusions: The clinical benefit of escitalopram versus citalopram remains uncertain. In our case of evergreening, escitalopram represented a substantially high proportion of the overall reimbursement cost burden as compared with citalopram and the generic forms.

Background: Insufficient response to treatment and declining quality of life illustrate the continuing need to find new treatment modalities for allergic rhinitis (AR). The purpose of this study was to assess how escitalopram affects symptoms and quality of life among AR patients., Methods: This study included 120 patients with AR, who were divided into four treatment groups of 30 patients each. Patients were assessed before treatment and at the end of the 3rd month based on nasal symptom scores, otorhinolaryngological examination, the Rhinoconjunctivitis Quality of Life Questionnaire, and the Beck Depression and Anxiety Inventory. All patients received standardized treatments. Group A patients with positive Beck Depression and Anxiety Inventory scores received escitalopram, and group B patients with positive Beck Depression and Anxiety Inventory scores received placebo. Group C patients with negative Beck Depression and Anxiety Inventory scores received escitalopram, and group D patients with negative Beck Depression and Anxiety Inventory scores received placebo., Results: Anxiety scores pre- and posttreatment revealed a statistically significant reduction in groups A, C, and D. All four groups exhibited reduced posttreatment scores for sleep, nonnasal and noneye symptoms, eye symptoms, and emotions. A statistically significant difference appeared between groups A and B in terms of general complaints and nasal symptom scores., Conclusion: The positive effects of escitalopram on posttreatment quality of life in the Beck-positive patient group were a predictable outcome. Otolaryngologists should pay more attention to the moods of their patients with AR while they evaluate treatment during clinical follow-up visits.

The BH3-interacting domain death agonist (Bid) is a pro-apoptotic member of the B-cell lymphoma-2 (Bcl-2) protein family. Previous studies have shown that stress reduces levels of Bcl-2 in brain regions implicated in the pathophysiology of mood disorders, whereas antidepressants and mood stabilizers increase Bcl-2 levels. The Bcl-2 protein family has an essential role in cellular resilience as well as synaptic and neuronal plasticity and may influence mood and affective behaviors. This study inhibited Bid in mice using two pharmacological antagonists (BI-11A7 and BI-2A7); the selective serotonin reuptake inhibitor citalopram was used as a positive control. These agents were studied in several well-known rodent models of depression-the forced swim test (FST), the tail suspension test (TST), and the learned helplessness (LH) paradigm-as well as in the female urine sniffing test (FUST), a measure of sex-related reward-seeking behavior. Citalopram and BI-11A7 both significantly reduced immobility time in the FST and TST and attenuated escape latencies in mice that underwent the LH paradigm. In the FUST, both agents significantly improved duration of female urine sniffing in mice that had developed helplessness. LH induction increased the activation of apoptosis-inducing factor (AIF), a caspase-independent cell death constituent activated by Bid, and mitochondrial AIF expression was attenuated by chronic BI-11A7 infusion. Taken together, the results suggest that functional perturbation of apoptotic proteins such as Bid and, alternatively, enhancement of Bcl-2 function, is a putative strategy for developing novel therapeutics for mood disorders.

Many new guidelines and studies of interest to the geriatric population have emerged in the areas of falls and fracture prevention, cardiovascular care, depression, and Alzheimer disease. Some of these guidelines and studies translate to immediate changes that should be made to clinical practice; others are new areas of controversy.

Alcoholism is characterized by a high frequency of comorbid depression, and both diseases have a mutual negative impact. The frequent comorbidity of alcoholism and depression (as well as disorders related to anxiety) serves as the basis for use of antidepressants for individuals suffering from alcohol dependence. Among the drugs of choice in the treatment of alcohol dependence complicated by depression and anxiety disorders, is escitalopram.

Pain is common among opioid-dependent patients, yet pharmacologic strategies are limited. The aim of this study was to explore whether escitalopram, a selective serotonin reuptake inhibitor, was associated with reductions in pain. The study used longitudinal data from a randomized, controlled trial that evaluated the effects of escitalopram on treatment retention in patients with depressive symptoms who were initiating buprenorphine/naloxone for treatment of opioid dependence. Participants were randomized to receive escitalopram 10 mg or placebo daily. Changes in pain severity, pain interference, and depression were assessed at 1-, 2-, and 3-month visits with the visual analog scale, Brief Pain Inventory, and the Beck Depression Inventory II, respectively. Fixed-effects estimators for panel regression models were used to assess the effects of intervention on changes in outcomes over time. Additional models were estimated to explore whether the intervention effect was mediated by within-person changes in depression. In this sample of 147 adults, we found that participants randomized to escitalopram had significantly larger reductions on both pain severity (b=-14.34, t=-2.66, P<.01) and pain interference (b=-1.20, t=-2.23, P<.05) between baseline and follow-up. After adjusting for within-subject changes in depression, the estimated effects of escitalopram on pain severity and pain interference were virtually identical to the unadjusted effects. This study of opioid-dependent patients with depressive symptoms found that treatment with escitalopram was associated with clinically meaningful reductions in pain severity and pain interference during the first 3 months of therapy., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Rationale: The neural basis of depression-associated cognitive impairment remains poorly understood, and the effect of antidepressants on learning and synaptic plasticity in animal models of depression is unknown. In our previous study, learning was impaired in the neonatal clomipramine model of endogenous depression. However, it is not known whether the cognitive impairment in this model responds to antidepressant treatment, and the electrophysiological and neurochemical bases remain to be determined., Objectives: To address this, we assessed the effects of escitalopram treatment on spatial learning and memory in the partially baited radial arm maze (RAM) task and long-term potentiation (LTP) in the Schaffer collateral-CA1 synapses in neonatal clomipramine-exposed rats. Also, alterations in the levels of biogenic amines and acetylcholinesterase (AChE) activity were estimated., Results: Fourteen days of escitalopram treatment restored the mobility and preference to sucrose water in the forced swim and sucrose consumption tests, respectively. The learning impairment in the RAM was reversed by escitalopram treatment. Interestingly, CA1-LTP was decreased in the neonatal clomipramine-exposed rats, which was restored by escitalopram treatment. Monoamine levels and AChE activity were decreased in several brain regions, which were restored by chronic escitalopram treatment., Conclusions: Thus, we demonstrate that hippocampal LTP is decreased in this animal model of depression, possibly explaining the learning deficits. Further, the reversal of learning and electrophysiological impairments by escitalopram reveals the important therapeutic effects of escitalopram that could benefit patients suffering from depression.

Objectives: Given the challenges in the clinical management of geriatric depression, research over the past decade has focused on developing early neurobiological markers of antidepressant treatment response. This study tested the hypothesis that lower baseline glucose metabolism and greater acute cerebral metabolic responses to a single, intravenous (IV) dose of the selective serotonin reuptake inhibitor (SSRI) citalopram would be associated with greater improvement of depressive symptoms after 12 weeks of citalopram treatment in geriatric depression., Methods: sixteen geriatric depressed patients underwent two scans to measure cerebral glucose metabolism after administration of either a saline placebo or citalopram infusion (40 mg, IV). Then, the patients were treated with the oral citalopram medication for 12 weeks., Results: greater improvement of depressive symptoms was associated with lower baseline metabolism in anterior cingulate, superior, middle, and inferior frontal gyri (bilaterally), inferior parietal lobule (bilaterally), precuneus (right), insula (left), parahippocampal gyrus (right), caudate (bilaterally), and putamen (left) regions. Greater improvement of depressive symptoms was associated with greater reductions in metabolism after acute citalopram administration in similar brain regions, including additional posterior cortical regions., Conclusions: lower baseline cerebral metabolism and greater decreases with acute citalopram administration are associated with better antidepressant response to chronic citalopram treatment. These data are consistent with previous studies of total sleep deprivation and suggest that dynamic, early adaptive changes or normalization of cerebral metabolism may represent early neurobiological markers of chronic SSRI treatment response in geriatric depression., (2011 American Association for Geriatric Psychiatry.)

It is generally accepted that cognitive processes, such as learning and memory, are affected in depression. The present study used a rat model of depression, chronic unpredictable mild stress (CUMS), to determine whether hippocampal volume and neurochemical changes were involved in learning and memory alterations. A further aim was to determine whether these effects could be ameliorated by escitalopram treatment, as assessed with the non-invasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Our results demonstrated that CUMS had a dramatic influence on spatial cognitive performance in the Morris water maze task, and CUMS reduced the concentration of neuronal marker N-acetylaspartate (NAA) in the hippocampus. These effects could be significantly reversed by repeated administration of escitalopram. However, neither chronic stress nor escitalopram treatment influenced hippocampal volume. Of note, the learning and memory alterations of the rats were associated with right hippocampal NAA concentration. Our results indicate that in depression, NAA may be a more sensitive measure of cognitive function than hippocampal volume.

These experiments were made to study the mechanisms underlying the antidepressant-like effects of the beta(3) adrenoceptor agonist amibegron (SR58611A). To this purpose, the expression levels of the hippocampal cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), B-cell lymphoma-2 (Bcl-2) and Bax proteins were assessed, by using western blot analysis, in rats tested in the forced swim test (FST). Under basal conditions (no previous exposure to stressors), different groups of male Wistar rats received acutely or repeatedly (once/day for 7days) intraperitoneal (i.p.) injections of amibegron (1, 5 and 10mg/kg), the tricyclic antidepressant (TCA) clomipramine (50mg/kg), the selective serotonin reuptake inhibitor (SSRI) citalopram (15mg/kg) or their vehicles. The influence of stress-related conditions was studied in rats subjected to acute (4h) or repeated (4h/day for 7days) restraint stress, applied prior to the FST procedure. Compared to the control groups, both stressor procedures increased the immobility time in the FST and reduced hippocampal BDNF and Bcl-2/Bax ratio proteins expression, which were counteracted by amibegron (5 and 10mg/kg) treatment. Opposite effects were found in the CREB expression, since it was lower after acute and higher after repeated stress procedure, respectively. Again, these effects were reversed by amibegron treatment. Different results were obtained in animals treated with clomipramine or citalopram. Hence, it is likely that the observed behavioral effects of amibegron could be due, at least in part, to its action on hippocampal expression of neurotrophic and/or anti-apoptotic factors, supporting the hypothesis that beta(3) adrenoceptors may be a therapeutic target for the treatment of stress-related disorders., (Copyright 2010 Elsevier B.V. and ECNP. All rights reserved.)

Objective: To examine the effects of citalopram augmentation of antipsychotics on suicidal ideation in middle-aged and older people with schizophrenia and subthreshold depressive symptoms., Method: In this placebo-controlled trial conducted from September 1, 2001, to August 31, 2007, 198 outpatients > or = 40 years old with DSM-IV-diagnosed schizophrenia or schizoaffective disorder and subthreshold depressive symptoms were randomly assigned to flexible-dose citalopram (n = 104) or placebo (n = 94) augmentation of their antipsychotic for 12 weeks. Depression was measured with the Hamilton Depression Rating Scale (HDRS) and Calgary Depression Rating Scale (CDRS). Primary suicidal ideation measures were the Clinical Global Impressions-Severity of Suicide scale (CGI-SS) and the InterSePT Scale for Suicidal Thinking (ISST); secondary outcomes were the Scale for Suicidal Ideation (SSI), Beck Hopelessness Scale (BHS), HDRS item 3, and CDRS item 8., Results: Compared to placebo, at the final visit, citalopram was associated with lower BHS scores (4.21 vs 4.98; P < .05) and lower likelihood of having suicidal ideation on the ISST (17.7% vs 38.7%; P < .005) and HDRS item 3 (14.4% vs 22.6%; P < .05). Among the 114 participants with no baseline suicidal ideation, there were no significant differences between citalopram and placebo regarding "emergent" ideation on either primary outcome. Among the 55 participants with baseline suicidal ideation, fewer treated with citalopram had endpoint ideation on the ISST (28.6% vs 66.7%; P < .05). Significantly more depression responders than nonresponders went from having baseline suicidal ideation to no suicidal ideation on both the ISST (75.0% vs 31.4%; P < .05) and CGI-SS (84.6% vs 31.3%; P < .05)., Conclusions: Treatment-emergent suicidal ideation was no more common with citalopram than placebo. In participants with baseline suicidal ideation, citalopram reduced suicidal ideation, especially in those whose depressive symptoms responded to treatment., ((c) Copyright 2010 Physicians Postgraduate Press, Inc.)

The purpose of this study was to analyze the antidepressant-like actions of estradiol valerate (1 or 2 mg/rat, single injection) or citalopram (5 or 10 mg/kg, chronically administered for 21 days) given independently or combined at low doses, to middle-aged ovariectomized female rats, as a model of human menopause. Animals were exposed to chronic mild stress, a model of depression that mimics anhedonia as revealed by diminished sucrose solution intake. Stressed rats decreased their sucrose preference 1 week after chronic stress and treatment with vehicle did not reverse this reduction. A single injection of estradiol valerate (2 mg/rat) produced an antidepressant-like action, evidenced as an increase in sucrose preference specific to stressed rats. Chronic citalopram (10 mg/kg) produced an antidepressant-like effect after 1 week. A single low-dose of estradiol valerate (1 mg/rat) did not potentiate or shorten the latency of action of chronic citalopram (5 mg/kg). These results reveal the antidepressant-like action of estrogens in middle-aged rats exposed to chronic stress. These data may be of importance for clinical depression in menopausal women.

We investigated the hypothesis that hippocampal neurogenesis related to Notch1 signaling could be a valid index for a combined citalopram and WAY100635 pharmacotherapy for the treatment of depression arising after stroke. Adult rats were exposed to a chronic mild stress paradigm after ischemic surgery. Behavioral tests included the open-field test and a sucrose consumption test. Proliferating cells in the hippocampus ipsilateral to ischemia and their fate were monitored by bromodeoxyuridine labeling and confocal laser scanning microscopy for up to 28 days (day 28) after ischemia. Expression of the Notch1 signaling cascade, including its ligand and downstream target genes, was also examined. WAY100635 shortened the onset of citalopram action to less than the day 21 required with citalopram alone and also proved more effective. The activity of the Notch1 signaling pathway in the hippocampus fluctuated in its function in proliferation (day 21) and differentiation (day 28) of newly formed cells in animals receiving the combination treatment. This indicated that augmentation of citalopram by cotreatment with a selective 5-hydroxytryptamine 1A antagonist would be an efficacious strategy for poststroke depression. The observed effects are most likely because of enhanced poststroke neurogenesis mediated by the Notch1 signaling cascade.

Background & Aims: Data on the benefit of selective serotonin reuptake inhibitors (SSRIs) in irritable bowel syndrome (IBS) are conflicting. The longitudinal relationship between clinical symptoms and sensitivity to barostat-mediated rectal distension in IBS remains unclear. We assessed the benefit of citalopram and explored the relationships between symptoms, quality of life (QOL), and rectal sensitivity to barostat distension in non-depressed IBS patients., Methods: Patients from primary, secondary, and tertiary care settings were randomly assigned to receive citalopram (20 mg/day for 4 weeks, then 40 mg/day for 4 weeks) or placebo in a study with double-masking and concealed allocation. Symptoms were assessed weekly, and IBS-QOL and rectal sensation by barostat were assessed at the beginning and end of the study., Results: Patients receiving citalopram did not achieve a higher rate of adequate relief of IBS symptoms than patients receiving placebo (12/27 [44%] vs 15/27 [56%]; P = .59), regardless of IBS subtype. The odds ratio for weekly response with citalopram vs placebo was 0.80 (95% confidence interval, 0.61-1.04). Improvements in specific symptom and IBS-QOL scores were not superior for citalopram. Changes in IBS-QOL score and pressure eliciting pain showed a modest correlation (r = 0.33; 95% confidence interval, 0.03-0.57), but changes in symptoms and IBS-QOL scores or rectal sensitivity were not correlated substantially., Conclusions: Citalopram was not superior to placebo in treating non-depressed IBS patients. Changes in symptoms were not substantially correlated with changes in rectal sensation assessed by barostat. Any benefit of citalopram in non-depressed IBS patients is likely to be modest at best., (Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Preclinical data support the view that brain-derived neurotrophic factor (BDNF) and serotonergic systems regulate circuits involved in affective disorders. The present study examined neurochemical and behavioural consequences of an acute intrahippocampal injection of BDNF combined with an antidepressant by using in-vivo intracerebral microdialysis in the ventral hippocampus (vHi) in conscious mice and behavioural paradigms predictive of antidepressant and anxiolytic-like effects [the mouse forced swim test (FST), the open-field (OF) paradigm and the elevated plus maze (EPM)]. Neurochemical data revealed that BDNF (100 ng) potentiated the effects of the systemic administration of a serotonin selective reuptake inhibitor (SSRI; paroxetine 4 mg/kg i.p.) and that of a locally applied citalopram perfusion on dialysate 5-HT levels in the vHi. These neurochemical changes correlated with behavioural data since, in the FST, antidepressant-like activity of paroxetine as measured on swimming behaviour was potentiated by BDNF. These data suggest an interesting synergy between BDNF and SSRI on antidepressant-like activity. Furthermore, in both the OF and EPM paradigms BDNF induced an anxiogenic-like activity, whereas paroxetine prevented this effect. Finally, the neurochemical and behavioural effects of BDNF on the serotonergic system might occur at both pre- and post-synaptic levels since by using in-situ hybridization, we showed that TrkB-R mRNA was expressed in the hippocampus and the dorsal raphe nucleus in adult mice. Taken together the neurochemical and behavioural effects of BDNF suggest that these behavioural changes were mediated by increases in 5-HT neurotransmission in vHi. Thus a BDNF+SSRI combination may offer new alternatives to treat mood disorders.

Findings from the National Institute of Mental Health's Sequenced Treatment Alternatives to Relieve Depression trial indicate that approximately 50% of patients with major depressive disorder do not experience a treatment response after adequate first-line treatment with a selective serotonin reuptake inhibitor (SSRI). This study was designed to test the hypothesis that, after treatment failure with an SSRI, switching to venlafaxine extended release (ER) would offer advantages over switching to another SSRI, citalopram. The objectives of this trial were to compare the efficacy and safety of venlafaxine ER and citalopram in the treatment of moderate-to-severe depression in patients who did not experience a treatment response to an SSRI other than citalopram and to investigate the effects of severity of depression by categorizing treatment groups according to baseline severity. This was a 12-week, double-blind, randomized, parallel-group, multicenter study. Participants were adult outpatients who, following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram and had not responded, met the diagnostic criteria for depression as described in the Diagnostic and statistical manual of mental disorders, fourth edition, and had a score > or =20 on the 21-item Hamilton Rating Scale for Depression (HAM-D21). After a 7-day screening period, patients were randomly assigned to receive venlafaxine ER 75 mg/day or citalopram 20 mg/day for the first 2 weeks. Doses could be increased every 2 weeks through week 6. Treatment lasted 12 weeks and was followed by a 1-week tapering period. Maximum dosages were venlafaxine ER 300 mg/day or citalopram 60 mg/day. The primary end point was the final on-therapy total HAM-D21 score. To investigate the treatment effects of the severity of depression on efficacy, a subgroup analysis was performed for baseline HAM-D21 total score < or =31 and >31. The analyses for HAM-D21, Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions - Severity (CGI-S), and Clinical Global Impressions - Improvement scores were based on intent-to-treat (ITT) population, for both the primary analysis and subgroup analysis according to baseline HAM-D21 total scores < or =31 or >31. Safety assessments included the recording of adverse events (AEs). A total of 406 patients (200 venlafaxine ER, 206 citalopram) were randomly assigned and 396 patients were included in the ITT population (194 venlafaxine ER, 202 citalopram). Treatment groups were similar in terms of demographics and baseline psychiatric assessments. Two hundred and eighty-four patients (137 venlafaxine ER, 147 citalopram) were present in the ITT population with a baseline HAM-D21 total score < or =31 and 112 patients (57 venlafaxine ER, 55 citalopram) in the >31 group. In the primary analysis, there was no statistical difference between groups. The group with a baseline HAM-D21 total score of 20-31 did not differ significantly in any efficacy parameters. In the group with a baseline HAM-D21 total score >31, the venlafaxine ER group differed significantly from the citalopram group on the primary end point HAM-D21 total score (P=0.0121). The secondary end point CGI-S score was statistically significant (P=0.0359), although the MADRS total score (P=0.0930) was not. AEs were reported by 57.8 and 63.4% of venlafaxine ER and citalopram patients, respectively. Overall discontinuation rates were 24.5% for venlafaxine ER and 20.9% for citalopram. Discontinuation rates owing to an AE as a primary or secondary reason were 5.5% for venlafaxine ER and 5.3% for citalopram. Overall, venlafaxine ER and citalopram showed similar efficacy in patients who had an inadequate response to an SSRI. In the subset of more severely depressed patients, venlafaxine ER was significantly more effective on a number of efficacy measures. Patients who remain severely depressed following treatment with an SSRI may gain more benefit from the dual-action drug venlafaxine, rather than switching to another SSRI.

Depression is the most common psychiatric complication in Parkinson's disease (PD). The pathophysiological events leading to PD-associated depression, however, remain largely unknown. The present study tested the differential implication of dopaminergic systems in depressive-like behavior in rats and its response to l-Dopa and the selective serotonin reuptake inhibitor citalopram. The learned helplessness model was used as a behavioral paradigm. Rats were lesioned in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) and assigned to subgroups with respect to the stereologically verified extent of the nigral and/or VTA degeneration. Both lesions increased depressive-like behavior in rats, which was reduced by both citalopram and l-Dopa treatment. We conclude that dopaminergic lesions of either the SNc or the VTA contribute to the manifestation of depressive-like behavior in rats. The effects of citalopram administration on depressive behavior induced by lesions of dopaminergic brain regions furthermore suggest an involvement of serotonergic pathways in dopaminergic cell loss-induced depression.

Background: Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical central nervous system changes, reminiscent of symptoms of human depression. Moreover, depression-like behavior after OBX can be reversed with antidepressant drugs. However, the lasting effects of these antidepressant drugs on behavior after cessation of treatment have never been studied., Methods: Male rats received OBX or sham surgery. After recovery, animals received 14 consecutive daily doses of imipramine (20 mg/kg), escitalopram (5 and 10 mg/kg), or vehicle. Animals were tested in an open field after acute, sub-chronic, and chronic injections, as well as 1, 2, 6, and 10 weeks after cessation of treatment., Results: The OBX-induced hyperactivity was normalized after sub-chronic administration of imipramine and escitalopram. Two weeks after treatment, activity of OBX animals was comparable to sham-treated animals, but after 6 weeks, OBX animals treated with both doses of escitalopram had returned to pre-treatment hyperactivity levels. The OBX animals treated with the high imipramine dose (20 mg/kg) retained activity levels comparable to sham-treated animals until 10 weeks after cessation of treatment., Conclusions: Chronic but not acute administration of imipramine and escitalopram normalizes OBX-induced hyperactivity. This effect continues for up to 10 weeks after cessation of treatment in a dose dependant manner.