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Emotional blunting is theorized to be an adverse effect of antidepressants, particularly serotonin reuptake inhibitors, but this has not been firmly established. Another possibility is that emotional blunting represents a residual depressive symptom.We analyzed data from adult outpatients with acute major depressive disorder who participated in three 8-week randomized controlled trials. Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383) and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the "inability to feel" item from the Montgomery-Åsberg Depression Rating Scale.Emotional responsiveness improved, on average, in all treatment groups. Only a minority of participants (≤6 %) experienced more emotional blunting post-treatment, compared to baseline, with no significant differences between treatment groups, although roughly 20-25 % continued to report an inability to feel normal emotions at the final assessment. In Trials 1 and 2, emotional blunting was associated with poorer outcomes in terms of depressive symptoms, suicidal ideation, and sexual function, but these correlations were nearly identical in the placebo group.The trials were short and cannot speak to the possibility of emotional blunting from long-term treatment. Emotional blunting was measured with a single item.The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response. In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect.

Selective serotonin reuptake inhibitors (SSRIs) have been associated with type 2 diabetes mellitus (T2DM) in youths, possibly via 5-HTUsing the UK Clinical Practice Research Datalink, we assembled a cohort of patients aged 5-24, newly prescribed a strong-affinity SSRI (citalopram, escitalopram, fluoxetine) or weak affinity (paroxetine, sertraline, fluvoxamine) between 1990 and 2019. We controlled for confounding using standardized mortality ratio weighting, estimated from calendar time-specific propensity scores. We used weighted Cox proportional hazards models to estimate hazard ratios (HRs) of incident T2DM with 95 % confidence intervals (CIs).The cohort included 347,368 new users of strong-affinity SSRIs and 131,359 of weak-affinity SSRIs. Strong-affinity SSRIs were not associated with an increased T2DM risk compared with weak-affinity SSRIs (incidence rate 2.8 vs 2.7 per 1000 person-years; HR 1.03, 95 % CI 0.85-1.25). T2DM risk did not vary with duration of use, age or sex. However, the HR was numerically higher in youths with normal or low weight (HR 1.30, 95 % CI 0.85-1.98) and with prior antipsychotic use (HR 1.62, 95 % CI 0.83-3.18).Median duration of SSRI use, in line with real-world SSRI prescribing, was relatively short.T2DM risk did not differ between strong- and weak-affinity SSRIs, providing reassurance for clinicians when choosing between SSRIs in youths.

BACKGROUND: Anxiety is a common comorbidity in patients with coronary heart disease (CHD) and is associated with worse prognosis. However, effective treatment for anxiety in CHD patients is uncertain. The UNWIND randomized clinical trial showed that 12-week treatment of escitalopram was better than exercise training or placebo in reducing anxiety in anxious CHD patients. The longer-term benefits of treatment for anxiety are not known. METHODS: Patients were randomized to 12 weeks of Escitalopram (up to 20 mg), Exercise (3 times/wk), or placebo pill. At the conclusion of treatment, participants were followed for 6-months to determine the persistence of benefit on the primary anxiety endpoint assessed by the Hospital Anxiety and Depression Scale-Anxiety scale (HADS-A) and to assess the effects of treatment on major adverse cardiac events over a follow-up period of up to 6 years. RESULTS: Of the 128 participants initially randomized, 120 (94%) were available for follow-up. Participants randomized to the Escitalopram condition exhibited lower HADS-A scores (3.9 [3.1, 4.7]) compared to those randomized to Exercise (5.5 [4.6, 6.3]) (P = .007) and Placebo (5.3 [4.1, 6.5]) (P = .053). Over a median follow-up of 3.2 years (IQR: 2.3, 4.5), there were 29 adverse events but no significant between-group differences. CONCLUSION: In the UNWIND trial, 12 weeks of escitalopram treatment was effective in reducing anxiety. These beneficial effects were sustained for 6 months posttreatment. Although moderate or vigorous physical activity has a number of health benefits, exercise was not an effective treatment for anxiety in patients with CHD.

Depression is a common illness with no definite treatment.The study involved 2 experimental periods; 45-day (P1) followed by 30-day (P2). 40 adult albino rats were randomly divided into 4 groups. Grp 1 received saline orally while Grp 2 reserpine inraperitoneally (ip) during P1 and P2. Grps 3 and 4 received reserpine during P1, followed by reserpine plus B. monnieri, and reserpine plus citalopram ip during P2, respectively. Forced swimming test (FST) was performed at beginning and end of P1 and P2. Animals were sacrificed by end of P2 and brain taken for histopathological examination and ELISA estimation of serotonin, dopamine, norepinephrine, BDNF, MCP-1, FAS, and Bcl-2.During P1, reserpine prolonged immobility time (IT) in FST in Grps 2, 3, and 4. IT was subsequently lowered in Grps 3 and 4 but remained elevated in Grp 2 by end of P2. Serotonin, dopamine and norepinephrine were lowered in Grps 2, 3, and 4, but in Grps 3 and 4, levels were comparable to Grp1. BDNF and Bc1-2 were reduced in Grps 2, 3, and 4, with higher levels in Grps 3 and 4 than Grp 2. MCP-1 and FAS were elevated in Grps 2, 3, and 4, but levels were lower in Grps 3 and 4 than in Grp 2. Histopathology showed congested cerebral cortex in Grp 2 and normal cortex in other groups.Only adult male rats were involved and effects of co-administration of B. monnieri and citalopram were not characterized.B. monnieri improves depression comparable to citalopram in reserpine-induced depression.

Wistar-Kyoto (WKY) rats as an endogenous depression model partially lack a response to classic selective serotonin reuptake inhibitors (SSRIs). Thus, this strain has the potential to be established as a model of treatment-resistant depression (TRD). However, the SSRI resistance in WKY rats is still not fully understood. In this study, WKY and control rats were subjected to a series of tests, namely, a forced swim test (FST), a sucrose preference test (SPT), and an open field test (OFT), and were scanned in a 7.0-T MRI scanner before and after three-week citalopram or saline administration. Behavioral results demonstrated that WKY rats had increased immobility in the FST and decreased sucrose preference in the SPT and central time spent in the OFT. However, citalopram did not improve immobility in the FST. The amplitude of low-frequency fluctuation (ALFF) analysis showed regional changes in the striatum and hippocampus of WKY rats. However, citalopram partially reversed the ALFF value in the dorsal part of the two regions. Functional connectivity (FC) analysis showed that FC strengths were decreased in WKY rats compared with controls. Nevertheless, citalopram partially increased FC strengths in WKY rats. Based on FC, global graph analysis demonstrated decreased network efficiency in WKY + saline group compared with control + saline group, but citalopram showed weak network efficiency improvement. In conclusion, resting-state fMRI results implied widely affected brain function at both regional and global levels in WKY rats. Citalopram had only partial effects on these functional changes, indicating a potential treatment resistance mechanism.

The effects of escitalopram vary markedly among MDD patients, and approximately one-third of patients fail to respond. A poor antidepressant response might be associated with excessively high C-reactive protein (CRP) levels, but the impact is not clear. We hypothesized that in adults with major depressive disorder, the peripheral biomarker, CRP, was associated with the response to escitalopram (SSRI).This was a prospective follow-up study. All 71 patients were treated with escitalopram for 12 weeks. Blood samples were collected at baseline and week 12. Remission was defined as a score of 7 or less on the HAMD-17 scale at week 12. Spearman correlations and multiple linear regressions were used to explore the relationship between continuous CRP levels and the HAMD-17 scores. Logistic regression was used to determine the predictors for remission. The restricted maximum likelihood (REML)-based mixed-effect model for repeated measures (MMRM) was used to examine the change of the HAMD-17 total scores between high and low CRP groups.Compared with the high CRP group (≥0.8 mg/l), the low baseline CRP group had a higher remission rate (22.73% vs. 48.89%, χ2 = 4.2, p = 0.0403). Logistic regression revealed that patients with lower CRPs were 3.920 times (95% CI: 1.142, 13.460) more likely to experience remission (p = 0.0300). The multiple linear regression model showed that the HAMD-17 total score reduction (baseline to week 12) was negatively correlated with the baseline CRP level (t = -2.00, p = 0.0494).We observed a predictive role of CRP for remission and symptomatic improvement after escitalopram treatment of MDD patients based on continuous or categorical CRP levels.

Background Complex Regional Pain Syndrome (CRPS) is a neuropathic pain condition with no universally recognised treatment. The study evaluates the efficacy of a therapeutic protocol consisting of oral citalopram and lidocaine injections in patients affected by CRPS. Methods Between January 2010 and December 2014, 150 consecutive patients with CRPS were enrolled in the study and randomly assigned into three groups: group one - lidocaine injection and oral citalopram, group two - lidocaine injection and oral placebo, group three - injective and oral placebo. The Impairment Sum Score (ISS) was used to assess the severity of CRPS before, as well as at regular intervals after treatment commenced. Statistical significance (p Results The combined treatment proved to be more effective (ISS 47.6 to 12.6) than local anesthetic alone (ISS 47.5 to 21.5) and to placebo (ISS 47.2 to 29.9). Conclusion This study indicates that CRPS may be managed with well-tolerated association of oral citalopram and lidocaine injections.

Background Some data suggests that citalopram has more risk of corrected QT interval (QTc) prolongation than other selective serotonin reuptake inhibitors. Consequently the U.S. Food and Drug Administration distributed a safety warning limiting the maximum dose for citalopram. There is also a suggestion that bupropion may decrease QTc in patients on drugs that increase QTc. The goals of this cross-sectional study were to examine (1) effects on QTc of citalopram compared to sertraline, bupropion, and tricyclic antidepressants; (2) dose dependent effects of citalopram; and (3) effects of bupropion on citalopram-mediated changes in QTc. Methods Records of subjects who received an EKG while taking one of the specified antidepressants were reviewed to collect demographic information, antidepressant history, and information about other confounders. Linear regression was used to examine the relationship between QTc and antidepressants. Results 487 subjects provided 798 EKG records. The sample was 95% male with an average age of 61 years. No differences were found in QTc between citalopram and other antidepressants. No dose relationship was detected between citalopram and QTc. Bupropion did not affect the relationship between citalopram and QTc (coefficient = -3.4; 95%CI = -14.2, 7.5; p = 0.54). Limitations Observational study designs are prone to biases from retrospective data collection. Some data subsets had small numbers of subjects. Conclusions No effect of citalopram on QTc was found at therapeutic doses. Neither was there evidence of a “QTc-sparing” effect of bupropion. The risk of adverse cardiovascular effects from citalopram at doses of 60 mg per day or less appears minimal.

Escitalopram is a selective serotonin reuptake inhibitor (SSRIs) antidepressant, drug that is currently used as first-line agents for the treatment of depression and it is also used in the treatment of other psychiatric disorders. The main goal of this study was to identify which brain areas are affected by escitalopram administration. This study was carried out on male Wistar rats that received escitalopram daily over 14 days and that were studied by 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG)-PET on the last day of treatment. Computed tomography (CT) images were acquired immediately before each PET scan and the main effects of drug administration were elucidated by Statistical Parametric Mapping. The results obtained indicated that repeated exposure to escitalopram increased metabolic activity in the retrosplenial and posterior cingulate cortices, while it decreased such activity in the ventral hippocampus, cerebellum, brainstem and midbrain regions, including the raphe nuclei and ventral tegmental area. Therefore, repeated exposure to escitalopram alters the activity of several brain areas closely related to the serotonergic system, and previously identified as key regions in the antidepressant effect induced by SSRIs. Furthermore, some of the changes found, such as the dampened metabolism in the ventral tegmental area, are similar to changes that have been described after treating with other fast-acting antidepressant approaches.

Daridorexant (ACT-541468) is a new dual orexin receptor antagonist being evaluated for the treatment of insomnia, which is a common comorbidity of depression and anxiety. Therefore, daridorexant is likely to be administered concomitantly with agents (e.g., citalopram) used to treat these disorders. In this single-centre, single-blind, randomized, placebo-controlled, sequential design Phase 1 study with the inclusion of two double-blind crossover parts, the pharmacokinetic (PK; blood sampling at regular intervals) and pharmacodynamic (PD; battery of objective and subjective PD tests performed at regular intervals) interactions between daridorexant (50 mg) and citalopram (20 mg, single dose and at steady state) as well as the safety/tolerability in healthy subjects were investigated. There were no relevant effects of citalopram (single dose/steady state) on daridorexant exposure and vice versa. PD variables measured after morning administration of daridorexant alone showed effects consistent with a sleep-promoting compound. Only co-administration of daridorexant with citalopram at steady state led to relevant changes in objective (unstable tracking) and subjective (visual analogue scale alertness and Karolinska Sleepiness Scale) PD endpoints compared to daridorexant alone. No serious or severe adverse events were reported, while no clinically relevant treatment-emergent effects on ECG parameters, clinical laboratory, or vital signs were observed. In conclusion, the co-administration of daridorexant and citalopram lead to only minor changes in PK parameters, while performance of PD assessments following co-administration were mainly driven by the expected central nervous system effects of daridorexant. Doses up to 50 mg daridorexant can be safely co-administered with citalopram.

Amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry is disrupted in pediatric anxiety disorders, yet how selective serotonin reuptake inhibitors (SSRIs) affect this circuitry is unknown. We examined the impact of the SSRI escitalopram on functional connectivity (FC) within this circuit, and whether early FC changes predicted treatment response in adolescents with generalized anxiety disorder (GAD).Resting-state functional magnetic resonance (MR) images were acquired before and after 2 weeks of treatment in 41 adolescents with GAD (12-17 years of age) who received double-blind escitalopram or placebo for 8 weeks. Change in amygdala-based whole-brain FC and anxiety severity were analyzed.Controlling for age, sex, and pretreatment anxiety, escitalopram increased amygdala-VLPFC connectivity compared to placebo (F = 17.79, p = .002 FWE-corrected). This early FC change predicted 76.7% of the variability in improvement trajectory in patients who received escitalopram (p .001) but not placebo (p = .169); the predictive power of early amygdala-VLPFC FC change significantly differed between placebo and escitalopram (p = .013). Furthermore, this FC change predicted improvement better than baseline FC or clinical/demographic characteristics. Exploratory analyses of amygdala subfields' FC revealed connectivity of left basolateral amygdala (BLA) -VLPFC (F = 19.64, p .001 FWE-corrected) and superficial amygdala-posterior cingulate cortex (F = 22.92, p = .001 FWE-corrected) were also increased by escitalopram, but only BLA-VLPFC FC predicted improvement in anxiety over 8 weeks of treatment.In adolescents with GAD, escitalopram increased amygdala-prefrontal connectivity within the first 2 weeks of treatment, and the magnitude of this change predicted subsequent clinical improvement. Early normalization of amygdala-VLPFC circuitry might represent a useful tool for identifying future treatment responders as well as a promising biomarker for drug development.Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety; https://www.clinicaltrials.gov/; NCT02818751.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring’s neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. A major gene altered by perinatal SSRI exposure is the G-protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3). Our present study shows that perinatal exposure to the SSRI citalopram increases mRNA expression of Bai3 and related molecules (including its C1ql ligands) in the early postnatal dentate gyrus of male and female offspring. Transient Bai3 mRNA knockdown in perinatal SSRI-exposed dentate gyrus lessened behavioral consequences of perinatal SSRI exposure, leading to increased active stress coping. To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls. Together these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms that drive adverse effects of perinatal SSRI exposure, and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia.

While serotonin reuptake inhibitors are sometimes used in clinical practice to treat acute bipolar depression, the neurophysiological substrates underlying their efficacy are little studied. In the context of a larger clinical efficacy trial, the present study explored neural mechanisms associated with citalopram versus placebo treatment for bipolar depression. FDG-PET imaging examined whole-brain metabolic changes before and after treatment. Clinical efficacy was similar for citalopram versus placebo. Neuroimaging results demonstrated greater glucose metabolism in the left orbitofrontal cortex (OFC) before treatment (combined citalopram and placebo subjects) relative to after treatment, but did not correlate with clinical recovery. Glucose metabolism in the left OFC was also a predictor of depression severity when baseline scans were regressed with baseline MADRS scores. Despite of our small sample size and possibly underpowered whole-brain analysis approach, these preliminary results suggest the OFC, a key region involved in reward circuity, may be a neural substrate for depressive symptom improvement in bipolar depression, regardless of whether due to active treatment or placebo.

Effective and targeted interventions for improving quality of life (QOL) in addition to achieving 'clinical remission' are imperatives for patients with major depressive disorder (MDD). This study aimed to examine potential predictors and moderators of QOL in depression. Data were obtained from the Algorithm Guided Treatment Strategies for Major Depressive Disorder (AGTs-MDD) study, a multisite, randomized controlled trial composed of 980 depressed patients. Mixed Model Repeated Measures (MMRM) analyses were conducted to identify baseline characteristics associated with QOL overall (predictors) and their interaction effects (moderators). Severe core depressive, anxiety and pain symptoms were found to be independently associated with poor QOL over the 12-week acute phase treatment. Severe depression, severe anxiety or pain symptoms, or severe suicidal ideation predicted a larger improvement of QOL during acute phase treatment, whereas males showed less improvement. None of the putative moderators were identified except for the educational level. Patients with lower educational level showed a larger improvement of QOL in the AGT started with escitalopram (AGT-E) group and AGT started with mirtazapine (AGT-M) group compared to the treatment as usual (TAU) group. These findings may help to instruct informed decision-making for heterogeneous patients with MDD in the view of full recovery.

Background A thorough QT study identified that escitalopram-induced QT prolongation was delayed. This study thus aimed to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model to characterize the relationship between escitalopram concentrations and the delayed effect on QT prolongation. Methods The data of completed subjects who had placebo (n=36) and a single dose of 20 mg escitalopram (n=33) from a previous thorough QT study were used. Population PK/PD analysis was performed by nonlinear mixed-effects modeling. A escitalopram concentration-drug effect model was developed with estimated individual PK and baseline QT parameters. To explain the relationship between escitalopram concentrations and QT prolongation delay, an effect compartment model was utilized. Results A two-compartment model with first-order absorption and lag time and first-order elimination adequately described the PK of escitalopram. The circadian rhythm of baseline QT interval was best explained by two harmonic cosine functions. A linear model properly characterized escitalopram-induced QT prolongation. The average estimated maximal QT prolongation was 5.4 ms (range: 1.9-7.6 ms). The equilibrium half-life of delayed QT prolongation was 1.9 h. The drug effect of QTc change compared with that at baseline remained relatively constant from 1.3 to 3.5 ms over 24 h, and the maximum QTc change occurred with a 3-h delay after the time to the maximum plasma concentration. Limitations We did not include genetic polymorphisms, such as CYP2C19, as potential covariates owing to limited information. Conclusions These results may provide useful information on when to monitor electrocardiogram in patients who require intensive care after drug administration.

Backgrounds Antidepressants are widely used to treat major depressive disorder. First-line treatments with antidepressants are only successful in one-third of patients; however, evidence from randomized controlled trials on second-line treatments is limited. Moreover, recently acceptability is suggested to be a good indicator of overall treatment success. Methods This is a multi-center two-arm, three-phased randomized controlled trial performed in Japan from December 2013 to March 2017 comparing the acceptability of escitalopram and duloxetine as a second-line drug. Patients, who failed to respond to antidepressants such as sertraline, paroxetine, fluvoxamine, milnacipran or mirtazapine for at least 3 weeks, were randomized to either escitalopram (Group A) or duloxetine (Group B) in Step 1 (8 weeks). In Step 2 (8 weeks), the drug was switched to the other if the first drug failed. The discontinuation rate at the end of Step 1 was the primary endpoint and non-inferiority of escitalopram vs duloxetine was tested. In addition, change in clinical measures from baseline were also assessed at the end of Step 1, 2 and up to 52 weeks. Results At the end of Step 1, Group A (n = 82) was significantly superior to Group B (n = 78) in discontinuation rate (4.9% to 19.2%, P = 0.007). The change in clinical indices from baseline were not different between the groups at either timepoint. Limitations As the major reason for discontinuation in Group B was the “withdrawal of consent” the concrete reason could not be verified. Conclusions As a second-line treatment drug, escitalopram was suggested to be non-inferior to duloxetine in acceptability. Trial registration UMIN CTR(UMIN000012367), registered on December 1st, 2013 and last updated on April 4th, 2017.

BACKGROUND: Magnetic resonance spectroscopy (MRS) methods have quantified changes in levels of neurotransmitters and other neurometabolites in patients with major depression across the lifespan. 7T field strengths and greater have not been a major focus of study in patients with late-life depression (LLD). METHODS: Nine LLD patients who met DSM-IV criteria for a current major depressive episode and nine non-depressed, healthy, age-matched controls underwent clinical and neuropsychological assessment and single-voxel 7T (1)H-MRS at baseline and after 10–12 weeks of antidepressant treatment (Citalopram; patients only). Spectra were acquired from two brain regions implicated in both depressive symptoms and neuropsychological deficits in LLD, the anterior (ACC) and posterior cingulate (PCC). Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr) using linear-combination modeling. RESULTS: Baseline Glu/tCr levels were not significantly different between groups. Decreased Glu/tCr levels levels after Citalopram treatment was observed in a subset of LLD patients, although the group difference was not statistically significant. Exploratory analyses showed that LLD patients had lower NAA levels in the PCC relative to controls. Higher levels of ml in the LLD patients relative to the controls and decreases after Citalopram treatment had large effect sizes but were not statistically significant. Further, decreases in PCC Glu/tCr and increases in ACC GSH/tCr were associated with improvement in depressive symptoms. LIMITATIONS: Sample size. CONCLUSIONS: These preliminary results suggest a role of neurochemicals and neurometabolites in the neurobiology of LLD and antidepressant treatment response.

Increasing evidence shows that the alternations under escitalopram treatment for Panic disorder (PD) patients are related to the cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). We aimed to explore the single nucleotide polymorphisms (SNPs) of genes BDNF and CREB1 in the treatment response to escitalopram on PD.There were 80 PD patients with DSM-5 diagnosis and 78 healthy controls. All PD patients have received escitalopram treatment for consecutive 8 weeks. The Chinese version of Panic Disorder Severity Scale (PDSS-CV) and the Hamilton Anxiety Scale (HAMA-14) were used to evaluate the severity of panic and anxious symptoms for PD patients at baseline, week-2, week-4, and week-8, respectively. Four SNPs (rs11904814, rs6740584, rs2253206, and rs2551941) in CREB1 gene and rs6265 in BDNF gene were genotyped using matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS). Quantitative and binary genetic associations between SNPs and escitalopram treatment response were performed.The comparisons of three genotypes in CREB1 SNPs rs11904814 and rs2551941 among the PDSS-CV responders showed significant differences at the end of week-2 (both p0.05). The results remained significant after Bonferroni corrections. For candidate genes in our present study, the gene CREB1 SNP rs11904814 (p=0.007) was significantly associated with changes of PDSS-CV scores under escitalopram treatment for 12 weeks in PD patients. And the result was still significant after adjusting age and gender.The findings provide preliminary evidence supporting the potential role of BDNF and CREB1 on a rapid response after escitalopram intervention in PD patients.

Major depressive disorder (MDD) accompanied by anxious distress is a chronic and disabling disorder. Its conventional drug therapies often have low patient compliance due to drug-related side effects. In Persian medicine, lavender-dodder syrup is one formula often recommended for such disorders.This study compares the effects of lavender-dodder syrup to the standard drug, citalopram, for treating MDD with anxious distress.This six-week, double-blind, randomized, clinical trial was carried out in a psychiatric outpatient clinic. During the six-week intervention period, patients in citalopram group received citalopram tablets 20 mg/d plus 5 mL placebo syrup every 12 h; patients in group B received placebo tablets once daily plus 5 mL of lavender-dodder herbal syrup every 12 h.Primary outcome measures, depression and anxiety, were evaluated using the Hamilton Depression/Anxiety Rating Scales, and were scored at the beginning of the study and at weeks three and six. Secondary outcome measures including response to treatment and remission rates were also compared between the two groups.Fifty-six participants with MDD and anxious distress were randomly assigned to two groups. Mean depression scores significantly decreased in citalopram and herbal groups at weeks three and six (time effect: P 0.001), although the observed changes were not significantly different between the groups (intervention effect: P = 0.61). Mean anxiety scores were not significantly different between the two groups at week three (P = 0.75). However, at the end of week six, the observed decrease was significantly higher in the herbal syrup group than the citalopram group (intervention effect: P = 0.007).The herbal syrup is an effective and tolerable supplement for treating MDD with anxious distress.IRCT2016102430459N1 on Iranian Registry of Clinical Trials.

Objectives The effects of sleep disturbance and its treatment on the prognosis of patients with acute coronary syndrome (ACS) are not well understood. This study investigated the impact of sleep disturbance on long-term all-cause mortality, according to depression comorbidity and treatment, in patients with ACS. Methods A cross-sectional baseline study and a nested 24-week double-blind escitalopram–placebo controlled trial were carried out from May 2007 to March 2013; 5–12-year follow-up for all-cause mortality was conducted. A total of 1152 patients with ACS were stratified by baseline depression comorbidity and treatment allocation into four groups: no depression (N = 706), depression on escitalopram (N = 149), depression on placebo (N = 151), and depression on medical care as usual (CAU; N = 146). Sleep disturbance was evaluated by the Leeds Sleep Evaluation Questionnaire. During the 5–12-year follow-up, Kaplan–Meyer event rates for all-cause mortality were calculated; hazard ratios (HRs) using Cox regression models were estimated after adjustment for a range of covariates. Results Worse sleep states at baseline increased long-term all-cause mortality in all patients (HRs 1.08–1.59). The associations between worse sleep states and long-term all-cause mortality were significant in patients without depression and in patients with depression who received CAU, but not in patients with depression who participated in the 24-week trial. Conclusions Routine evaluations of sleep disturbance in ACS and further treatment allocation may contribute to reducing long-term mortality associated with the disease. Trial registration ClinicalTrials.gov Identifier for the 24 week drug trial, NCT00419471 .

Adjunctive inflammatory modulation improved remission rates in treatment-resistant bipolar depression (TRBDD), but reliable biomarkers must be established to characterize the biosignature of TRBDD and the mechanisms underlying treatment response. In this molecular profiling study, we describe TRBDD and treatment response from the standpoint of interleukin-1 Beta (IL-1β) and KYN/TRP.47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10 mg-40 mg daily dose range) + celecoxib (CBX) (200 mg twice daily), or ESC (10 mg-40 mg daily dose range) + placebo (PBO) (twice daily). Plasma cytokine levels were measured in both treatment arms at baseline and week 8, and in a healthy control (HC) group of subjects (N = 43) once. A linear mixed model (LMM) was applied to evaluate whether clinical outcome is related to CBX and changes to biomarkers throughout treatment. A binary logistic regression model was formulated from this series to predict both the primary outcome of treatment response to CBX, and the secondary outcome of diagnosis of TRBDD using age, BMI, gender, and IL-1β at baseline.Patients receiving ESC + CBX had 4.278 greater odds of responding (p = 0.021) with NNT = 3, and 15.300 times more likely to remit (p 0.001) with NNT = 2, compared with ESC + PBO patients. Patient BMI (p = 0.003), baseline IL-1β (p = 0.004), and baseline KYN/TRP (p = 0.001) were most predictive of TRBDD diagnosis. By Week 8, responders showed a downtrend in IL-1β compared to non-responders in the ESC + CBX treatment arm. However, there was no statistical difference in the IL-1β or KYN/TRP change after treatment between placebo and ESC + CBX group responders/non-responders (p = 0.239, and p = 0.146, respectively). While baseline IL-1β was elevated in TRBDD compared to HC (p 0.001), there was no difference in IL-1β between treatment responders at Week 8 compared to HC (p = 0.067).Elevated IL-1β and low KYN/TRP at baseline are components of the TRBDD molecular signature. CBX but not baseline IL-1β or KYN/TRP predict treatment response. Change in IL-1β and KYN/TRP did not predict treatment response.

Background Depressed patients present increased plasma levels of lipopolysaccharide (LPS) and neuroinflammatory alterations. Here, we determined the neuroimmune effects of different classes of ADs by using the LPS inflammatory model of depression. Methods Male rats received amitriptyline (AMI) a tricyclic, S-citalopram (ESC) a selective serotonin reuptake inhibitor, tranylcypromine (TCP) a monoamine oxidase inhibitor, vortioxetine (VORT) a multimodal AD or saline for ten days. One-hour after the last AD administration, rats were exposed to LPS 0.83 mg/kg or saline and 24 h later were tested for depressive-like behavior. Plasma corticosterone, brain levels of nitrite, pro- and anti-inflammatory cytokines, phospho-cAMP Response Element-Binding Protein (CREB) and nuclear factor (NF)-kB p 65 were determined. Results LPS induced despair-like, impaired motivation/self-care behavior and caused anhedonia. All ADs prevented LPS-induced despair-like behavior, but only VORT rescued impaired self-care behavior. All ADs prevented LPS-induced increase in brain pro-inflammatory cytokines [interleukin (IL)-1β and IL-6] and T-helper 1 cytokines [tumor necrosis factor (TNF)-α and interferon-γ]. VORT increased striatal and hypothalamic IL-4 levels. All ADs prevented LPS-induced neuroendocrine alterations represented by increased levels of hypothalamic nitrite and plasma corticosterone response. VORT and ESC prevented LPS-induced increase in NF-kBp65 hippocampal expression, while ESC, TCP and VORT, but not IMI, prevented the alterations in phospho-CREB expression. Limitations LPS model helps to understand depression in a subset of depressed patients with immune activation. The levels of neurotransmitters were not determined. Conclusion This study provides new evidence for the immunomodulatory effects of ADs, and shows a possible superior anti-inflammatory profile of TCP and VORT.

Air pollution has recently been linked to central nervous system (CNS) diseases, possibly mediated by inflammation and oxidative stress. Hippocampal atrophy in individuals with first episode schizophrenia (FES) has also been associated with biomarkers of inflammation and oxidative stress, whereas hippocampal atrophy was not observed in matched healthy controls with similar biomarker levels of inflammation and oxidative stress. Fine particulate matter (PM2.5), one component of air pollution, is most strongly implicated in CNS disease. The present study examined the association between PM2.5 and hippocampal volume in individuals with FES who participated in a 52-week placebo-controlled clinical trial of citalopram added to clinician-determined antipsychotic treatment at four sites in the US and China. Left hippocampal volumetric integrity (LHVI; inversely related to atrophy) was measured at baseline and week 52 using an automated highly-reliable algorithm. Mean annual PM2.5 concentrations were obtained from records compiled by the World Health Organization. The relationships between baseline LHVI and PM2.5 and change in LHVI and PM2.5 were evaluated using regression analyses. 89 participants completed imaging at baseline and 46 participants completed imaging at week 52. Mean annual PM2.5 was significantly associated with both baseline LHVI and change in LHVI after controlling for age, sex, baseline LHVI, duration of untreated psychosis and baseline antipsychotic medication dose. Air pollution may contribute to the progression of hippocampal atrophy after a first episode of illness, but these findings should be considered preliminary since other unmeasured factors may have differed between cities and contributed to the observed effect.

Objective Despite the clinical importance of chronic and severe irritability, there is a paucity of controlled trials for its pharmacological treatment. Here, we examine the effects of adding citalopram (CTP) to methylphenidate (MPH) in the treatment of chronic severe irritability in youth using a double-blind randomized placebo-controlled design. Method After a lead-in phase of open treatment with stimulant, 53 youth meeting criteria for severe mood dysregulation (SMD) were randomly assigned to receive CTP or placebo (PBO) for 8 weeks. A total of 49 participants, 48 of them (98%) meeting disruptive mood dysregulation disorder (DMDD) criteria, were included in the intent-to-treat analysis. The primary outcome measure was the proportion of response based on improvements of irritability at the week 8 of the trial. Results At the end of the trial, a significantly higher proportion of response was seen in those participants randomly assigned to CTP+MPH compared to PBO+MPH (35% CTP+MPH versus 6% PBO+MPH; odds ratio = 11.70, 95% CI = 2.00−68.16, p = 0.006). However, there were no differences in functional impairment between groups at the end of the trial. No differences were found in any adverse effect between treatment groups, and no trial participant exhibited hypomanic or manic symptoms. Conclusion Adjunctive CTP might be efficacious in the treatment of chronic severe irritability in youth resistant to stimulant treatment alone. Clinical trial registration information A Controlled Trial of Serotonin Reuptake Inhibitors Added to Stimulant Medication in Youth With Severe Mood Dysregulation; https://clinicaltrials.gov ; NCT00794040 .

Background Recent evidence suggests that brain-derived neurotrophic factor (BDNF) levels and their early changes may predict antidepressant response in adults with major depressive disorder (MDD). However, in adolescents, BDNF levels in depression and their changes during antidepressant treatment are relatively unknown. We aimed to investigate whether pre-treatment BDNF levels and their early changes predict antidepressant response in depressed adolescents. Methods The study included 83 MDD adolescents and 52 healthy controls aged 12 to 17 years. All depressed adolescents were treated with escitalopram in an 8 week, open-label trial. Depression severity and serum BDNF level at baseline, and weeks 2 and 8 were measured with the Children's Depression Rating Scale-Revised (CDRS-R) and ELISA, respectively. Results Responders showed a significant decrease in BDNF levels at week 2 but non-responders and healthy controls had no changes in BDNF levels at week 2. The early decrease (baseline – week 2) of BDNF levels predicted SSRI response with moderate sensitivity and specificity. Logistic regression analysis revealed that early BDNF decrease predicted SSRI response at week 8 after controlling for other demographic and clinical variables. Limitations The follow-up duration of the study was limited in 8 weeks. It remains possible that serum BDNF levels would have changed with longer treatment. Conclusions This is the first longitudinal study to investigate the effect of antidepressants on BDNF levels in adolescents with MDD. Our findings suggest that a decrease of serum BDNF levels in early phase of SSRI treatment may be associated later SSRI response in adolescents with MDD.

Curtailment of sleep in modern society leads to a spectrum of neuropsychiatric disorders. However, the molecular mechanisms underlying the effects of sleep deprivation (SD) remain elusive and currently there is no effective therapy to alleviate these effects. Here, we aimed to examine SD-induced cellular and molecular alterations in mouse prefrontal cortex (PFC) and whether subchronic citalopram (CTM) treatment can negate these alterations. Three-month-old C57BL/6 J mice were divided into control (Ctrl), SD, CTM alone and CTM + SD groups. CTM and CTM + SD group mice were treated with CTM for five consecutive days at a dose of 10 mg/kg per day before the experimental procedure. SD and CTM + SD group mice were sleep-deprived for 24 h using an automated treadmill method. We found that 24 h SD causes a marked reduction in the levels of phosphorylated calcium/calmodulin kinase II (pCaMKII), phosphorylated cyclic AMP-responsive element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in mouse PFC. Patch clamp recording of pyramidal neurons from acute PFC slices revealed that SD decreases the amplitude of miniature excitatory postsynaptic currents (mEPSCs), suggesting a SD-induced postsynaptic alteration. Interestingly, subchronic CTM treatment prevents such SD-induced reductions in pCaMKII, pCREB and BDNF levels, and in mEPSC amplitude. These data suggest that CTM offers neuroprotection against SD-induced molecular and electrophysiological alterations.

Neurobiological underpinnings of treatment-resistant depression, a debilitating condition associated with significant functional impairment, have not been elucidated. Consequently, the aim of this study was to use animal models of response and resistance to antidepressant treatment, in an attempt to identify differences in associated transcriptional responses. Flinders Sensitive Line rats were subjected to maternal separation (MS) and chronically treated with Escitalopram or Nortriptyline. Antidepressants reduced immobility time in the forced swim test in non-MS rats, while lack of antidepressant behavioural response was observed in MS animals. We developed a novel bioinformatic algorithm that enabled identification of transcriptional signatures in hippocampus and pre-frontal cortex that discriminate vehicle- and antidepressant-treated subjects in both MS and non-MS rats. Functional annotation analysis showed that in antidepressant-responder rats the most enriched pathways included IQGAPs activation, toll-like receptor trafficking, energy metabolism, and regulation of endopeptidase activity. The analysis of interacting proteins implicated synaptic vesicles and neurotransmitter release, ubiquitin regulation, cytoskeleton organisation and carbohydrate metabolism. In contrast, in treatment-resistant MS rats, main expression changes were revealed in ribosomal proteins, inflammatory responses, transcriptional/epigenetic regulation, and small GTPases. Susceptibility signature shared Rtn1, Zdhhc5, Igsf6, and Sim1 genes with the latest depression GWAS meta-analysis, while antidepressant resistance signature shared Ctnnd1, Rbms3, Atp1a3, and Pla2r1 genes. In conclusion, this study demonstrated that distinct transcriptional signatures are associated with behavioural response or non-response to antidepressant treatment. The identification of genes involved in antidepressant response will increase the comprehension of the neurobiological underpinnings of treatment-resistant depression, thus contributing to identification of novel therapeutic targets.

Objective The goal of this study was to reduce treatment resistance and enhance antidepressant response in patients with treatment-resistant bipolar depression (TRBDD) by modulating inflammatory activation. Methods Forty-seven TRBDD patients completed a randomized, double-blind, placebo (PBO)-controlled two-arm study using celecoxib (CBX), a cyclooxygenase 2 (COX-2) inhibitor, in combination with escitalopram (ESC). The Hamilton Depression (17-Item) and the Hamilton Anxiety Rating Scales were used to quantify symptom severity. Self-rating instruments included BDI, BAI and QLES-Q questioner. An adverse events inventory was used, and the possibility of bleeding diathesis was monitored. Complete blood count (CBC), prothrombin time (PT), and activated partial thromboplastin time (APTT) were determined. Comparison of mood scores between the CBX and PBO groups were conducted using a mixed ANOVA and an Independent Sample Student t-test. Results The CBX adjunctive treatment produced significantly more responders and remitters than the PBO arm. Compared to the PBO group (n = 20), the CBX group (n = 27) experienced lower depression severity through the entire course of the study, showing significant decrease in depression and anxiety scores as early as week 1. Except for initial mild nausea, no adverse events were reported and study medications were well tolerated. Conclusions Modulation of the inflammatory response through targeted inhibition of the enzyme COX-2 by means of CBX reduces TRBDD and augments and accelerates treatment response in an efficacious and safe manner. Future studies should replicate these findings and additionally investigate whether prolonged administration of CBX is required to maintain remission by adding a discontinuation phase to the study design. Trial Registration Clinicaltrials.gov ID: NCT01479829.

Hair analysis can provide information regarding previous drug intake and use patterns, as the drugs consumed are incorporated into the hair. Therefore, reference values for drugs in hair are valuable in forensic investigations, especially when evaluating drug intake and assessing drug tolerance. The aim of the study was to determine concentrations of citalopram, escitalopram, and their primary metabolites in hair segments from deceased individuals with mental illness. Concentrations in up to six months prior to death were evaluated and compared with the estimated daily doses. Hair samples collected from 47 deceased individuals, were segmented in one to six 1 cm segments, and extracted overnight in medium. The concentrations in hair were quantified via ultra-high-performance liquid chromatography–tandem mass spectrometry. Following this quantification, the extracts were reanalyzed qualitatively using a chiral method to distinguish between citalopram and escitalopram intake. We found hair concentrations (10–90 percentile (perc.)) of citalopram from 0.12 to 67 ng/mg with a median of 8.2 ng/mg (N = 40 individuals, n = 182 segments) and of escitalopram from 0.027 to 7.0 ng/mg with a median of 3.9 ng/mg (N = 4, n = 23). The metabolite-to-drug ratios in hair (10–90 perc.) of citalopram were 0.091–0.57 with a median of 0.30 (N = 39) and of escitalopram were 0.053–0.63 with a median of 0.41 (N = 3). No correlations were found between concentrations in the hair and the estimated daily dose. However, our results indicate higher concentrations in dark hair compared to light hair, given the estimated doses, and thus an influence of hair color on the results. A significant positive correlation was found between the concentration of citalopram in the proximal segment and the blood concentrations. The median R/S-ratio of citalopram in hair was 1.5 and was similar to previously reported ratios in blood. In the present study, we report concentrations of citalopram and escitalopram in postmortem hair and their relation to an estimated daily dose and thus contribute valuable information in forensic investigations.

Increases in power and frequency of hippocampal theta activity have been related to efficient place learning and memory acquisition in hippocampal-dependent tests. The complex medial septum-diagonal band of Broca (MS/DBB) is the pacemaker of hippocampal theta activity, influenced by the ascending synchronizing system, and modulated by serotonergic raphe medial afferents, acting on cholinergic and GABAergic septal neurons. The suppression of hippocampal theta expression and the modulation of hippocampal learning and memory are attributed to serotonin. To simultaneously test these hypotheses, a daily local serotonin increase was induced by citalopram (CIT) infusion (100 µM, 0.88 µl, 0.2 µl/m) 15 min before training in the Morris water maze. The theta activity was recorded in the MS/DBB, dentate gyrus (DG) and CA1 of one group infused with artificial cerebrospinal liquid (ACL) and the other with CIT on Days 1-6 of training. After a probe trial (Day 7) and one resting day, the treatments were reversed (Days 8-11). The CIT MS/DBB infusion in the first 6 training days reduced the efficiency of spatial learning in association with reduced power in the DG, reduced MS/DBB-DG coherence, increased DG-CA1 coherence, and a lack of a negative correlation between MS/DBB power and swam distances. No effect of the CIT occurred once the information was acquired under ACL training. These results support a role of serotonin, in acting on the MS/DBB in the fine tuning of hippocampal learning and memory efficiency through the modulation of learning-related theta activity power and septohipocampal synchronization.

Children with irritability and outbursts pose a serous therapeutic problem. Many of them have attention-deficit/hyperactivity disorder (ADHD) with emotion dysregulation, which is sometimes captured in the diagnosis of disruptive mood dysregulation disorder (DMDD). Some follow-up data find a connection between DMDD and depression and anxiety in adults. This prompted Towbin and colleagues1 to launch a trial where children (ages 7-17) with DMDD were treated first with methylphenidate (MPH) and then randomized to citalopram (CTP) or placebo over 8 weeks. The response to CTP was complicated by lack of specific measures of both irritable mood and severity of outbursts. Future studies should include standardized and normed parent and teacher measures of both externalizing and internalizing behavior as well as irritability specific measures rating how the child feels. Studies also need better measures of the actual outbursts-not just their frequency but how agitated or aggressive the child gets during an outburst (ie, what the child does) and how long the outbursts last. Measuring DMDD on inpatient units is especially complicated because of the therapeutic nature of the setting. Further work is needed with much larger samples to identify who improves with the treatment, exactly which domains of psychopathology improve and by how much. Finally, It is also critical to conduct longer-term trials to determine the stability of the response beyond 8 weeks.

Tricyclic antidepressants, citalopram, venlafaxine and monoamine oxidase inhibitors are the most toxic antidepressants in overdose. Features include hypotension and arrhythmias that are best managed by aggressive correction of metabolic acidosis with sodium bicarbonate. Antipsychotic drugs differ in their chemical structure and specificity at dopamine receptors. Overdose produces a range of adverse effects including sedation and acute extrapyramidal reactions. Cardiovascular effects including hypotension, prolongation of the QT interval and, potentially, arrhythmias including torsade de pointes are also seen.

Background Escalating doses of selective serotonin reuptake inhibitors are often used to treat patients with a suboptimal response to the standard dose. This study assessed the efficacy and safety of dose escalation of escitalopram, up to 30 mg, in non-remitters with major depressive disorder (MDD) after treatment with the standard dose. Method We recruited 98 patients with MDD (aged 18–65 years). After 4 weeks of open-label treatment with 10–20 mg of escitalopram per day, non-remitters [Montgomery–Asberg Depression Rating Scale (MADRS) score > 10] were randomized 1:1 for double-blind treatment with either escitalopram (30 mg per day) or escitalopram (20 mg per day) plus placebo for 6 weeks. The primary efficacy outcome was a change in the total MADRS score. Results After 4 weeks of open-label treatment, 12 patients achieved remission, and 36 dropped out, leaving 50 non-remitters, of whom 44 (88%) completed the double-blind study. The primary outcome measure, the least-squares mean (standard error) change in the total MADRS score at week 6 was significantly different (p = 0.046) between the groups [−8.0 (1.2) in the placebo dose-escalation and −11.8 (1.2) in the escitalopram dose-escalation]. The dose escalation of escitalopram was well tolerated. However, the response and remission rates and quality of life showed no significant differences. Limitations Small sample size and short follow-up period Conclusion This study suggests that dose escalation of escitalopram up to 30 mg per day may be beneficial for the treatment of depressive symptoms in non-remitters after standard (10–20 mg/day) treatment.

Background MDD patients with abnormal EEG patterns seem more likely to be non-responsive to the antidepressants escitalopram and venlafaxine, but not sertraline, than patients without EEG abnormalities. This finding suggests that patients with both MDD and abnormal EEGs may differentially respond to antidepressant treatment. In the current study, we investigated whether depressed patients with an abnormal EEG show a normalization of the EEG related to antidepressant treatment and response and whether such effect is drug specific, and whether having had early life stress (ELS) increases the chance of abnormal activity. Methods Baseline and week 8 EEGs and depression symptoms were extracted from a large multicenter study (iSPOT-D, n = 1008) where depressed patients were randomized to escitalopram, sertraline, or venlafaxine-XR treatment. We calculated Odds Ratios of EEG normalization and depression response in patients with an abnormal EEG at baseline, comparing sertraline versus other antidepressants. Results Fifty seven patients with abnormal EEGs were included. EEGs did not normalize significantly more with sertraline compared to other antidepressants (OR = 1.9, p = .280). However, patients with a normalized EEG taking sertraline were 5.2 times more likely to respond than subjects taking other antidepressants (p = .019). ELS was not significantly related to abnormal activity. Limitations Neurophysiological recordings were limited in time (two times 2-minute EEGs) and statistical power (n = 57 abnormal EEGs). Conclusions Response rates in patients with normalized EEG taking sertraline were significantly larger than in subjects treated with escitalopram/venlafaxine. This adds to personalized medicine and suggests a possible drug repurposing for sertraline.

For the first time the MAE/UHPLC-TOFMS method was developed and used in order to determine the antidepressant drugs within the human bone marrow aspirate in real forensic cases. The following drugs, belonging to the group of selective serotonin (or serotonin-norepinephrine) reuptake inhibitors, were tested in this study: venlafaxine, citalopram, fluoxetine, sertraline and paroxetine. The sample preparation proposed in the present article included several steps: homogenization in ultrasound bath, liquid-liquid extraction, fat removal and evaporation under nitrogen. The extraction involved microwave-assisted extraction, performed for 15 min at 55 °C, with hexane-isoamyl alcohol (99:1, v/v) mixture, as an extraction solvent. Time and temperature of extraction were optimized using the simplex method. The fat removal step was introduced because of the fatty nature of the bone marrow that resulted in insufficiently purified samples, impossible to analyze using HPLC. It was achieved by adding a mixture of ethanol, water and formic acid to samples consisting of hexane and isoamyl alcohol, so that the analytes could diffuse to polar phase and fat could stay in non-polar phase. The method was validated and parameters such as: LOD, LOQ, linearity, matrix effect, recovery were determined. The validation parameters obtained allowed to recognize the method as quantitative. Due to lack of the data on therapeutic and toxic levels of considered drugs in bone marrow, data regarding serum has been used for reference. Under this assumption, the developed method allows for quantification of all mentioned drugs at therapeutic levels. Moreover this method has been used in real cases. Finally four analytes: venlafaxine (104 ng/mL), fluoxetine (84 ng/mL), paroxetine (about 3.6 μg/mL) and citalopram (68 ng/mL) were found in three case samples.

Background Extensive research into psychoneuroimmunology has led to substantial advances in our understanding of the reciprocal interactions between the central nervous system and the immune system in neuropsychiatric disorders. To date, inflammation has been implicated in the pathogenesis of depression and anxiety. The immunomodulating effects of antidepressants on depression have been reported, however, there is no evidence of the similar effects of antidepressants on anxiety. The aim of the study was to investigate the effects of selective serotonin reuptake inhibitors (SSRIs) on peripheral inflammatory cytokines in patients with first episode generalized anxiety disorder (GAD). Methods A prospective cohort design was employed: 42 patients with first episode GAD were treated with either escitalopram or sertraline for 12 weeks. Anxiety was measured by the Generalized Anxiety Disorder Scale and the State Trait Anxiety Inventory, serum pro-inflammatory cytokine levels were measured by the enzyme-linked immunosorbent assay (ELISA), and CRP determined by an immunoturbidimetric method before and after SSRIs treatment Results Baseline levels of anxiety and pro-inflammatory cytokines including IL-1α, IL-6, IL-8, IL-12, IFN-γ, and CRP were significantly reduced after treatment of SSRIs (p

Agitation is a common neuropsychiatric symptom (NPS) in the early and middle stages of Alzheimer's disease (AD) dementia, which is difficult to treat and causes much distress. The U.S. Food and Drug Administration (U.S. FDA) issued black box warnings against the use of antipsychotics in dementia in 2005 and 2008 due to the increased risk of morbidity and mortality, resulting in the reduction in antipsychotic use for treating dementia-related NPS and spurring the quest for safer and more effective pharmacological options. The data favoring the use of citalopram for treating agitation in AD dementia is particularly compelling, and this may be a class effect for all selective serotonin reuptake inhibitors. However, concerns about the cardiac side-effects of citalopram have limited its widespread use for this indication. In this article, available efficacy and safety data for the use of citalopram and escitalopram in treating agitation in AD dementia is reviewed, using a composite case to illustrate key points. Practical recommendations are made to facilitate the use of these medications in routine clinical practice, risk mitigation strategies are discussed and salient issues for future clinical research are emphasized.

Background This study evaluated the non-inferiority of bupropion extended-release (XL) compared to escitalopram for acute-phase treatment of Chinese patients with major depressive disorder (MDD). Methods This randomized (1:1), double-blind, active-control study conducted between February 2015 and October 2016 included patients with MDD (DSM-IV) (N = 538). The treatment phase had three dose levels (level 1 [Week 1], level 2 [Week 2–4], and level 3 [Week 5–8]), which included either bupropion XL 150 mg, 300 mg, 300 mg or escitalopram 10 mg, 10 mg, 10–20 mg (once-daily), respectively. Primary outcome was mean change from baseline in Hamilton Depression Rating Scale-17 (HAMD-17) total score at Week 8. Results Overall, 534 patients (bupropion XL, n = 266; escitalopram, n = 268) received at least one dose of study medication. The least square mean (standard error) change from baseline in HAMD-17 total score at Week 8 was −14.5 (0.41) in bupropion XL group and −15.4 (0.39) in escitalopram group (mean difference: 0.8 [−0.27, 1.94]). The response rate was 69.6% versus 72.9%, remission rate was 39.7% versus 47.2%, sustained response rate was 51.6% versus 56.3%, and sustained remission rate was 25.5% versus 28.6%, respectively, for bupropion XL versus escitalopram group. Adverse events were reported by 313 patients (bupropion XL, n = 157; escitalopram, n = 156); the most common on-treatment adverse event in both groups was nausea (10.5% versus 18.7%, respectively). Limitations A non-inferiority short-term (8 weeks) study without a placebo arm. Conclusion Results from this study demonstrated that the efficacy of bupropion XL was non-inferior to that of escitalopram in Chinese patients with MDD.

Background Patient expectancy of therapeutic improvement is a primary mediator of placebo effects in antidepressant clinical trials, but its mechanisms are poorly understood. This study employed a novel antidepressant trial design, with integrated functional magnetic resonance imaging (fMRI), to manipulate patient outcome expectancy and examine its neural mediators. Method Twenty-three depressed outpatients, in a randomized controlled trial were assigned to either Open (high outcome expectancy) or Placebo-controlled (low outcome expectancy) treatment with citalopram for eight weeks. fMRI scans were acquired before and after the expectancy manipulation (before medication treatment), while participants performed a masked emotional face task. Focusing on an amygdala region-of-interest (ROI), we tested a model where reduction in amygdala activation mediated outcome expectancy effects on the slope of change in depressive symptoms. Results Following the manipulation, significant differences between conditions were found in neural activation changes in the amygdala, as well as in superior temporal gyrus, insula, and thalamus. Findings support the proposed mediation model according to which activation in the left amygdala ROI decreased significantly in the Open as opposed to the Placebo-controlled group following randomization (p = 0.009) for sad vs. neutral face contrast. The reduced left amygdala activation, in turn, was a significant predictor of decreased depressive symptoms during the trial (p = 0.007), and the mediation model was significant. Conclusions Results from this study, the first designed to identify the neural mechanisms of expectancy augmentation in an antidepressant randomized control trial, suggest that therapeutic modulation of amygdala activity may be an important pathway by which patient outcome expectancy influences depressive symptoms. Clinicaltrials.gov identifier NCT01919216; Trial name: Placebo Effects in the Treatment of Depression: Cognitive and Neural Mechanisms, URL: https://clinicaltrials.gov/ct2/show/NCT01919216

Summary 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 Lakarutbildning och Forskning), Bertil Hallsten's Foundation, and Soderberg's Foundation.

Background Transcranial direct current stimulation (tDCS) is a promising intervention for major depression. However, its clinical effects are heterogeneous. We investigated, in a subsample of the randomized, clinical trial Escitalopram versus Electrical Direct Current Therapy for Depression Study (ELECT-TDCS), whether the volumes of left and right prefrontal cortex (PFC) and anterior cingulate cortex (ACC) were associated with prefrontal tDCS response. Methods Baseline structural T1 weighted MRI data were analyzed from 52 patients (15 males). Patients were randomized to the following conditions: escitalopram 20 mg/day, bifrontal tDCS (2 mA, 30min, 22 sessions), or placebo. Antidepressant outcomes were assessed over a treatment period of 10 weeks. Voxel-based gray matter volumes of PFC and ACC were determined using state-of-the-art parcellation approaches. Results According to our a priori hypothesis, in the left dorsal PFC, larger gray matter volumes were associated with depression improvement in the tDCS group (n = 15) compared to sham (n = 21) (Cohen's d = 0.3, 95% confidence interval [0.01; 0.6], p = 0.04). Neither right PFC nor ACC volumes were associated with depression improvement. Exploratory analyses of distinct PFC subregions were performed, but no area was associated with tDCS response after correction for multiple comparisons. Conclusion Left PFC baseline gray matter volume was associated with tDCS antidepressant effects. This brain region and its subdivisions should be investigated further as a potential neurobiological predictor for prefrontal tDCS treatment in depression and might be correlated with tDCS antidepressant mechanisms of action.

Autism spectrum disorder (ASD) is diagnosed by two core symptoms: impaired social communication and the presence of repetitive, stereotyped behaviors and/or restricted interests. Alterations in serotonergic signaling are involved in the genesis of ASD. Selective serotonin reuptake inhibitors (SSRIs) have been reported to reduce repetitive behaviors and rescue social deficits in ASD mouse models and patients. In the present study, we examined the potential of citalopram (a representative selective serotonin reuptake inhibitor) on sociability and repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse model of ASD. We found that the deficits of sociability in the BTBR mice were reversed by a 20 mg/kg dose of citalopram treatment without any adverse effects on locomotor activity or anxiety level. In addition, both high (20 mg/kg) and low (10 mg/kg) doses decreased the repetitive behavior of marble burying but did not affect self-grooming behavior. Furthermore, both doses were shown to have antidepressant-like activity in both the B6 and the BTBR mice in the tail suspension test. Taken together, these findings further demonstrate that citalopram can alleviate behavioral abnormalities in the BTBR autism model and lend support to the hypothesis that SSRIs may be potential therapeutic drugs for the treatment of behavioral dysfunctions in ASD.

Pharmacological imaging of the effects of selective serotonin reuptake inhibitors (SSRI) may aid the clarification of their mechanism of action and influence treatment of highly prevalent neuropsychiatric conditions if the detected effects could be related to patient outcomes. In a randomized double-blind design, 38 healthy participants received a constant infusion of 8 mg citalopram or saline during either their first or second of two PET/MR scans. Resting-state functional MRI (fMRI) was acquired simultaneously with PET data on the binding of serotonin transporters (5-HTT) using [11C]DASB. Three different approaches for modeling of pharmacological fMRI response were tested separately. These relied on the use of regressors corresponding to (1) the drug infusion paradigm, (2) time courses of citalopram plasma concentrations and (3) changes in 5-HTT binding measured in each individual, respectively. Furthermore, the replication of results of a widely used model-free analysis method was attempted which assesses the deviation of signal in discrete time bins of fMRI data acquired after start of drug infusion. Following drug challenge, average 5-HTT occupancy was 69±7% and peak citalopram plasma levels were 111.8 ± 21.1 ng/ml. None of the applied methods could detect significant differences in the pharmacological response between SSRI and placebo scans. The failed replication of SSRI effects reported in the literature despite a threefold larger sample size highlights the importance of appropriate correction for family-wise error in order to avoid spurious results in pharmacological imaging. This calls for the development of analysis methods which take regional specialization and the dynamics of brain activity into account.

Major depression is associated with endothelial dysfunction and arterial stiffening, which may mediate development of hypertension and increased cardiovascular risk. The effect of response to antidepressant treatment on these vascular parameters has not been elucidated.We aimed to assess the net effect of antidepressant therapy on endothelial function and arterial stiffness in patients with psychotic depression.Thirty-seven patients with major psychotic depression, according to DSM-IV-TR, were treated with titrated citalopram 20-60 mg and risperidone 0.5-1 mg and were followed for 6 months. Twelve additional patients who denied treatment, or were non-compliant, were also followed for the same time period. Vascular function was assessed by flow-mediated dilatation (FMD), carotid-femoral pulse wave velocity (PWV) and augmentation index (AI), at baseline and at the end of follow-up.Aortic and peripheral blood pressure (BP), PWV, FMD and AI (p 0.05 for all) were significantly improved in the group that received treatment. Overall, only responders to treatment (n = 24) presented significant improvements in all hemodynamic and vascular parameters (p 0.05 for all), irrespectively of traditional cardiovascular risk factors (TRFs), vasoactive medication and BP lowering. In a secondary analysis, patients with psychotic depression presented worse endothelial function as compared to controls matched for TRFs.Non-randomized study.Patients who respond to therapy for major psychotic depression present sustained improvement in vascular function. Given that depressed patients are considered to be at high cardiovascular risk and are often non-compliant with treatment, further research to assess cardiovascular benefits of vigilant monitoring of antidepressant therapy is warranted.

The contribution of serotonin and noradrenaline to the modulation of pruriceptive processing was evaluated by administrating antidepressants or noradrenaline reuptake inhibitors. The pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of scratching behavior by chloroquine, a representative pruritogen, indicating the involvement of serotonin and/or noradrenaline in the modulation of pruriceptive processing. By contrast, the single administration of noradrenaline reuptake inhibitor such as atomoxetine and nisoxetine or serotonin reuptake inhibitor such as fluvoxamine and escitalopram had little effect on chloroquine-induced scratching, whereas the induction of scratching behavior by chloroquine was significantly ameliorated by co-administration of serotonin reuptake inhibitors and noradrenaline reuptake inhibitors. These results indicate that the simultaneous increases of serotonin and noradrenaline elicit the attenuating effect on pruriceptive processing induced by acute itch, and may also play a crucial role in the descending itch inhibitory system.

Background Although the US Food and Drug Administration (FDA) recommended upper limits for citalopram dosing in older adults due to risk of corrected-QT (QTc) prolongation, which was adopted, and extended to escitalopram by Health Canada, the scientific basis is unclear. The objective of this study was to assess the relationship between citalopram/escitalopram dosages and QTc interval in a real-world geriatric setting. Methods We reviewed electronic health records at a university-affiliated geriatric health care center, over a 7-year period, to identify patients prescribed citalopram and escitalopram, who had an ECG within 90 days of initiation or dosage change. Linear regression analyses were conducted to assess the relationship between antidepressant dosage and QTc interval. Results 137 patients were identified (citalopram=97, escitalopram=40). No association was found between citalopram, escitalopram and QTc, in unadjusted or adjusted analyses. Among covariates, older age was significantly associated with QTc prolongation in the escitalopram group. Limitations Limitations to the current study include its retrospective design and the small sample size. Conclusions These data do not support the FDA or Health Canada's recommended maximum dosages of citalopram or escitalopram in the elderly. Therefore, for patients already on higher doses of these medications, the risk of QTc prolongation may not always outweigh the risk of dose lowering, such as relapse. Until larger prospective studies become available, the decision to comply or not with these federal agencies’ recommendations should be weighed on an individual basis, taking into consideration all potential risk factors.

Background It is clinically important to know who are likely to respond more or less to antidepressants. However, meaningful effect modifiers (variables associated with differential response depending on the treatment) are yet to be identified. Methods We conducted individual participant data (IPD) meta-analysis and meta-regression to explore effect modifiers in placebo-controlled antidepressant trials conducted so far in Japan. Results We obtained access to IPD from seven placebo-controlled trials comparing bupropion, duloxetine, escitalopram, mirtazapine, paroxetine or venlafaxine with placebo in the acute phase treatment of major depression (total n = 2803). The higher the guilt subscale score of the baseline Hamilton Rating Scale for Depression (HRSD), the greater the difference in reduction in depression severity between the antidepressants and placebo at week 6, while the older the current age or the age at onset, the smaller the difference. At week 8, the guilt subscale score of HRSD and presence of suicidal ideation at baseline predicted greater, and the anhedonia subscale and insomnia subscale scores of HRSD and early response at week 2 predicted smaller, difference in reduction. Limitations Different studies measured different sets of baseline variables and we were able to analyze only a limited set of candidate variables for effect modification. Conclusion Age, age at onset, several HRSD subscales including guilt, anhedonia and insomnia, presence of suicidal ideation at baseline and early response are potential effect modifiers for response to antidepressants in the acute phase antidepressant treatment of major depression. Future trials need to measure these and additional variables in concerted efforts to enable matching of treatments with individual characteristics in depression.

A large number of studies have attempted to use neuroimaging tools to aid in treatment prediction models for major depressive disorder (MDD). Most such studies have reported on only one dimension of function and prediction at a time. In this study, we used three different tasks across domains of function (emotion processing, reward anticipation, and cognitive control, plus resting state connectivity completed prior to start of medication to predict treatment response in 13–36 adults with MDD. For each experiment, adults with MDD were prescribed only label duloxetine (all experiments), whereas another subset were prescribed escitalopram. We used a KeyNet (both Task derived masks and Key intrinsic Network derived masks) approach to targeting brain systems in a specific match to tasks. The most robust predictors were (Dichter et al., 2010) positive response to anger and (Gong et al., 2011) negative response to fear within relevant anger and fear TaskNets and Salience and Emotion KeyNet (Langenecker et al., 2018) cognitive control (correct rejections) within Inhibition TaskNet (negative) and Cognitive Control KeyNet (positive). Resting state analyses were most robust for Cognitive control Network (positive) and Salience and Emotion Network (negative). Results differed by whether an -fwhm or -acf (more conservative) adjustment for multiple comparisons was used. Together, these results implicate the importance of future studies with larger sample sizes, multidimensional predictive models, and the importance of using empirically derived masks for search areas.

Parenterally administered selective serotonin reuptake inhibitors, such as citalopram, increase intestinal mucosal absorptive surface by day 7 of treatment. We hypothesized that enteral citalopram would also induce intestinal mucosal growth, thus allowing for therapy with an oral agent.Following a habituation period, C57BL/6 mice received peanut butter pellets containing 10, 50, or 100 mg/kg/d citalopram for 7 d (n = 5); or 25 mg/kg/d citalopram for 14 (n = 3) or 21 (n = 5) d; or plain peanut butter pellets for 7 (n = 2), 14 (n = 2), or 21 d (n = 3). Two-centimeter ileal segments were harvested and prepared for microscopic assessment of villus height (VH), crypt depth, villus width (VW), and crypt width. Mucosal surface area (MSA) was calculated and data were compared using Student's t-test.Enteral administration of citalopram had virtually no effect on VH, VW, or crypt depth after 7 d; crypt width decreased significantly (P value range 0.0002 to0.0001), likely contributing to the increases in MSA (P value range 0.0578 to 0.0006). After 14 d of treatment, citalopram significantly increased VH (P 0.0001), VW (P = 0.0058), and ileal MSA per mmEnteral citalopram given for 14 d results in increased VH and ileal MSA, which remains increased by day 21. Selective serotonin reuptake inhibitors show potential as oral therapy for serious intestinal disorders such as short bowel syndrome.

Background There has been number of studies suggesting experiences of adversity in early life interrelated subsequent brain development, however, neurobiological mechanisms confer risk for onset of psychiatric illness remains unclear. Methods In order to elucidate the pathogenic mechanisms underlying early life adversity-induced refractory depression in more detail, we administered corticosterone (CORT) to adolescent rats with or without prenatal ethanol exposure followed by an antidepressant or antipsychotic and examined alterations in depressive and social function behaviors and brain-derived neurotrophic factor (BDNF) levels in serum, the hippocampus, anterior cingulate cortex, and nucleus accumbens. Results The combined stress exposure of prenatal ethanol and adolescent CORT prolonged immobility times in the forced swim test (FST), and increased investigation times and numbers in the social interaction test (SIT). A treatment with escitalopram reversed depression-like behavior accompanied by reductions in BDNF levels in serum and the nucleus accumbens, while a treatment with blonanserin ameliorated abnormal social interaction behavior with reductions in serum BDNF levels. Limitations Further studies are needed to clarify the clinical evinces responding to these results, and many questions remain regarding the mechanisms by which refractory depression and antidepressant/antipsychotic treatments cause changes in serum and brain regional BDNF levels. Conclusion These results strongly implicate changes in BDNF levels in serum and the nucleus accumbens in the pathophysiology and treatment of early life combined stress-induced depression and highlight the therapeutic potential of escitalopram and new generation antipsychotic blonanserin for treatment-resistant refractory depression.