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Escitalopram is the (S)-enantiomer of citalopram that has a potential QT prolonging effect. In this study, 12 healthy elderly individuals received a single oral dose of escitalopram (20 mg), and their pharmacokinetics and QT effect data were compared with data from 33 younger adults obtained in a previous study. Serial blood samples for pharmacokinetic analysis were collected and ECG was performed up to 48 h postdose. The elderly and younger adults showed similar pharmacokinetic profiles. The geometric mean ratios (90% confidence interval) of the elderly compared with the younger adults were 1.02 (0.89-1.17) and 1.01 (0.86-1.17) for the maximum plasma concentration and area under the concentration-time curve, respectively. The mean baseline-adjusted QT (dQT) time profiles were similar and the mean values of maximum dQT were not significantly different between the elderly and the younger adults. The linear mixed-effect model indicated a weak but positive relationship between the escitalopram concentration and dQT, with an estimated coefficient of concentration of 0.43-0.54. In conclusion, the pharmacokinetics and QT effect of a single dose of escitalopram observed in the elderly without comorbidities and younger adults were generally similar.

Previously, we found an anxiolytic effect of ziprasidone augmentation to escitalopram (compared with placebo augmentation) in patients with depression in an 8-week, randomized, double-blind, parallel-group, placebo-controlled trial. Here, we carried out a post-hoc analysis, comparing changes in the Hamilton Depression and Anxiety Rating Scales between patients with anxious depression versus nonanxious depression, using a moderator analysis. Hamilton Depression Rating Scales total change scores from baseline and endpoint were not significantly different (interaction term P=0.91) in patients with anxious depression on ziprasidone augmentation (n=19; -9.1±4.9) or placebo (n=19; -6.1±8.9) versus patients without anxious depression on ziprasidone (n=52; -5.5±6.7) or placebo (n=49; -2.3±4.5). There was a trend toward statistical significance (interaction term P=0.1) in favor of patients without anxious depression for a difference in Hamilton Anxiety Rating Scale total change scores from baseline to endpoint [patients with anxious depression on ziprasidone augmentation (n=19; -2.7±5.3) or placebo (n=19; -3.3±5.8) versus patients without anxious depression on ziprasidone (n=51; -3.9±6.6) or placebo (n=44; -0.9±4.7)]. Ziprasidone augmentation was equally efficacious in treating depression in patients with versus without anxious depression. However, the observed anxiolytic effect for patients with higher anxiety was not clinically significant., Competing Interests: Conflicts and Disclosures: George I. Papakostas: Consultant: Abbott Laboratories, AstraZeneca PLC, Avanir Pharmaceuticals, Brainsway Ltd, Bristol-Myers Squibb Company, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer Inc., Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company LTD, Theracos, Inc., and Wyeth, Inc.; Grant/Research Support: AstraZeneca PLC, Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, PAMLAB LLC, Pfizer Inc., Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Pharmaceuticals, and Theracos, Inc.; Honoraria (for consulting or educational activities): Abbott Laboratories, Astra Zeneca PLC, Avanir Pharmaceuticals, Bristol-Myers Squibb Company, Brainsway Ltd, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, H. Lundbeck A/S, Novartis Pharma AG, Otsuka Pharmaceuticals, Pamlab LLC, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company LTD, Theracos, Inc., Titan Pharmaceuticals, and Wyeth Inc.; Speaker or Advisory Boards: BristolMyersSquibb Co and Pfizer, Inc. (Previous). This study was supported by the National Institute for Mental Health (NIMH R01MH081235), Pfizer Inc. (providing free blinded ziprasidone/placebo pills), and Forest Laboratories, Inc. (providing free escitalopram). Richard C. Shelton: Consultant: Cerecor, Inc., Clintara, LLC, Janssen Pharmaceutica, MSI Methylation Sciences, Inc., Naurex, Inc., Nestle’ Health-Pamlab, Inc., Pfizer, Inc., Ridge Diagnostics. Grant/research support: Alkermes, Inc., Assurex Health, Avanir Pharmaceuticals, Forest Pharmaceuticals (Allergan), Genomind, Janssen Pharmaceutica, Johnson & Johnson, Naurex Inc., Novartis Inc., Otsuka Pharmaceuticals, Nestle’ Health-Pamlab, Inc., Takeda Pharmaceuticals. Dawn F. Ionescu: Received research funding from a Young Investigator Award through the Brain and Behavior Research Foundation, KL2/CMeRIT Award from the Harvard Catalyst, K23 award from the National Institute for Mental Health (1K23MH107776-01), and from the Executive Committee on Research at Massachusetts General Hospital.

Drugs that increase monoamine neurotransmission are effective in both anxiety and depression. The therapeutic effects of monoamine-based antidepressant drugs may involve indirect effects on neurotransmission through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR). Thus, chronic antidepressant treatment increases AMPAR-mediated neurotransmission and AMPAR-positive allosteric modulators have shown antidepressant-like efficacy in rodents. Here, the effect of enhanced AMPAR neurotransmission on the antidepressant-like and anxiolytic-like actions of the selective serotonin reuptake inhibitor citalopram (0-10 mg/kg) was investigated in mice using the AMPAR-positive allosteric modulator LY451646 (0-3 mg/kg). Antidepressant-like effects were assessed using the forced-swim test (FST), whereas anxiolytic-like effects were tested using the elevated zero maze (EZM) and the marble burying test. LY451646 (3 mg/kg) increased swim distance in the FST and a subactive dose of LY451646 (1 mg/kg) enhanced the effect of citalopram in the FST. In the EZM, LY451646 (3 mg/kg) did not show anxiogenic effects alone, but blocked the anxiolytic-like action of citalopram in the EZM, as reflected by an increase in the latency to enter the open areas and a decrease in the number of entries and time spent in the open areas in citalopram-treated mice. In the marble burying test, LY451646 (3 mg/kg) showed no effect alone, but significantly attenuated the anxiolytic-like effect of citalopram (1.25-2.5 mg/kg) by increasing the number of marbles buried in citalopram-treated mice. These results suggest that AMPAR neurotransmission plays opposite roles in anxiety and depression as AMPAR potentiation facilitated the antidepressant-like effects of citalopram while attenuating its anxiolytic-like effect. These findings have ramifications in the search for AMPAR-based novel anxiolytic and antidepressant treatments.

The serotonin system plays an important role in the pathogenesis of major depressive disorder (MDD) and genetic variations in serotonin-related genes affect the efficacy of antidepressants. The aim of this study was to investigate the relationship between genotypic variation in six candidate serotonergic genes (ADCY9, HTR1B, GNB3, HTR2A, TPH2, SLC6A4) and depressive and anxiety symptom severity trajectories as well as remission following escitalopram treatment. A total of 166 Chinese patients with MDD were treated with escitalopram (open-label) for 8 weeks. TPH2 rs4570625 GG carriers were more likely to achieve depressive and anxiety symptom remission compared with T-allele carriers. At the trend level (P(corrected)=0.05), depressive symptom severity trajectories were moderated by TPH2 rs4570625. Patients with the GT or the GG genotype showed more favorable depressive symptom severity trajectories compared with TT genotype carriers. Polymorphisms in ADCY9, HTR1B, and HTR2A were nominally associated with symptom remission, but did not withstand correction for multiple comparisons. The HTTLPR polymorphism was not included in our final analysis because of a high percentage of missing data. These results suggested that genotypic variation in TPH2 may moderate the therapeutic response to esciatlopram among Chinese patients with MDD.

The treatment goal of major depressive disorder (MDD) is achieving and maintaining remission. One of the major obstacles in attaining remission is poor adherence to the medication regimen. Community pharmacists (CPs) are accessible to primary care patients and are in a unique position to help improve adherence. The aim was to compare the effectiveness of pharmacist intervention with standard care for patients with MDD. This was an exploratory controlled trial conducted in 17 general pharmacies with clinical pharmacists in Israel. Participants were patients with MDD prescribed escitalopram by their general practitioner. CP medication review was initiated at enrollment, with face-to-face pharmacist adherence support at treatment initiation and every month throughout the study. Treatment as usual (TAU) was derived from computerized medical charts for the same pharmacies during the same time period. Comparison with published 'historical' controls was also carried out. No blinding was possible. Continuous antidepressant treatment at 6 months as reflected in computerized pharmacy records was the primary outcome. Within a 1-year period, 173 patients were enrolled. There were 49 men (28%) and 124 women (72%) in the CP group, mean age 53.9 ± 18.9 years. There were 4079 men (32%) and 8667 women (68%) in the TAU group, mean age 50.4 ± 17.8 years. Ninety-six patients (55%) completed 6 months of antidepressant treatment. At 1 month, the adherence rate was 71% in the CP arm and at 6 months, the rates were 55% versus published norms of 42% (P=0.004). At 1 month, the adherence rate was 57% (N=7256) in the TAU arm and at 6 months, the rate was 15.2% (N=1934) (compared with CP rates: P<0.0001). There were no differences between sites in adherence rates. CPs participating in this study reported higher levels of confidence in supporting MDD patients at the end of the study. This is the first trial of pharmacist adherence support in Israel, and shows benefits for patients in the community with MDD.

Patients with schizophrenia often have anxiety and depression, and thus are treated with multiple psychotherapeutic medications. This practice of polypharmacy increases the possibility for drug-drug interactions. However, the pharmacological and behavioral mechanisms underlying drug-drug interactions in schizophrenia remain poorly understood. In the present study, we adopted a preclinical approach and examined a less known behavioral mechanism, drug-drug conditioning (DDC) between haloperidol (a typical antipsychotic) or olanzapine (atypical antipsychotic) and citalopram (a selective serotonin reuptake inhibitor). A rat two-way conditioned avoidance response paradigm was used to measure antipsychotic activity and determine how DDC may alter the antipsychotic efficacy in this model. Following acquisition of the avoidance response, rats were then randomly assigned to receive vehicle, citalopram (10.0 mg/kg, intraperitoneally), haloperidol (0.05 mg/kg, subcutaneously), olanzapine (1.0 mg/kg, subcutaneously), combined haloperidol with citalopram, or combined olanzapine with citalopram treatment for seven avoidance test sessions. In comparison with antipsychotic treatment alone, combined treatment with citalopram potentiated the antiavoidance effect of olanzapine or haloperidol (to a lesser extent) during the seven drug-test sessions. In addition, repeated pairing of citalopram with haloperidol or olanzapine caused citalopram to show a newly acquired avoidance-disruptive effect. This effect was context specific because citalopram paired with haloperidol or olanzapine outside the avoidance testing context (i.e. home cages) did not show such an effect. These findings indicate that concurrent antidepressant and antipsychotic treatments may engender a DDC process that follows the general Pavlovian associative conditioning principles. They also indicate that adjunctive citalopram treatment may enhance the antipsychotic efficacy of haloperidol and olanzapine in the treatment of schizophrenia.

This study explored the efficacy and tolerability of very high doses (maximum dose of >40 mg/day), high doses (maximum dose of 25-40 mg/day), and standard doses (maximum dose of ≤20 mg/day) of escitalopram (ESC) as an anti-obsessive-compulsive disorder treatment in a naturalistic clinical setting. We reviewed the medical records of all patients with obsessive-compulsive disorder (n=246) who had taken ESC between May 2006 and September 2009, and assigned Clinical Global Impression (CGI) scores, retrospectively. Of the total sample, 24.4, 38.2, and 37.4% patients received very high, high, and standard doses of ESC, and the mean daily maximum doses of ESC were 57.3±12.0 mg, 33.9±5.4 mg, and 13.4±5.8 mg, respectively. The CGI-Severity scores in each group decreased significantly after treatment with ESC, as evidenced by response rates (i.e. CGI-Improvement scores of 1 or 2) of 46.3, 43.2, and 26.2%, respectively. Although some adverse events increased in a dose-dependent manner, most could be managed with an ESC dose adjustment. These results imply that doses less than or equal to 40 mg/day ESC are sufficient for symptomatic improvement with good tolerability for most patients. Very high doses of ESC, on the other hand, can be considered for patients with inadequate therapeutic responses to the administration of 40 mg/day ESC.

The objective of this study was to evaluate the efficacy and tolerability of escitalopram versus serotonin and noradrenaline reuptake inhibitors (SNRIs) as second step treatment (defined operationally as poor response or intolerability to an antidepressant) for major depressive disorder (MDD). Results from all eligible head-to-head clinical trials of MDD (which excluded patients who earlier failed two or more antidepressants) sponsored by Lundbeck or Forest comparing escitalopram and SNRIs (venlafaxine and duloxetine) were pooled. A second step treatment subgroup was identified, defined as patients treated earlier with any antidepressant in the 6-month period before baseline. Data from three clinical trials were included in the analysis; 132 patients were identified in the second step treatment subgroup (66 in each of the escitalopram and SNRI groups). The primary efficacy analysis showed that the patients subsequently treated with escitalopram had significantly lower Montgomery Asberg Depression Rating Scale total scores after 8 weeks compared with those subsequently treated with SNRIs (difference = -6.4, P<0.0001). Escitalopram treatment was also associated with higher clinical response (73 vs. 44%, P=0.0004) and remission rates (62 vs. 41%, P=0.0083) compared with subsequent treatment with SNRIs. Escitalopram showed a better tolerability profile with lower all-cause withdrawals from study (9 vs. 23%, P<0.04) and lower withdrawals because of adverse events (2 vs. 17%, P<0.003). In conclusion, escitalopram is associated with a better efficacy and tolerability profile than SNRIs (duloxetine and venlafaxine) when used as a second step treatment in patients with MDD. These results should be confirmed in prospective randomized clinical trials.

Antidepressants that enhance both serotonergic and noradrenergic neurotransmission may be more effective than selective serotonin reuptake inhibitors (SSRIs) for acute-phase therapy of major depressive disorder. Mirtazapine in particular has been suggested to have a faster onset of action than reuptake inhibitors. The aim of this study is to compare the remission rates and time to remission in patients with major depression taking either mirtazapine or an SSRI in an all-inclusive set of studies. Data were obtained from all eligible randomized controlled studies contrasting mirtazapine and SSRIs. Meta-analyses of remission rates and time to remission, together with a supportive analysis of mean change from baseline Hamilton Depression Rating Scales-17 were performed, using individual patient data from 15 randomized controlled trials of mirtazapine (N = 1484) versus various SSRIs (N = 1487) across 6 weeks of double-blind therapy. Analyses were repeated for the eight studies that lasted at least 8 weeks. Remission rates for patients treated with mirtazapine were significantly higher when compared with those treated with an SSRI after 1 (3.4 vs. 1.6%, P = 0.0017), 2 (13.0 vs. 7.8%, P<0.0001), 4 (33.1 vs. 25.1%, P<0.0001), and 6 weeks (43.4 vs. 37.5%, P = 0.0006) of treatment. Mirtazapine-treated patients had a 74% higher likelihood of achieving remission during the first 2 weeks of therapy compared with patients treated with SSRIs. In conclusion, the findings indicate that mirtazapine may be a more rapidly effective antidepressant than SSRIs.

Numerous studies have assessed the acute efficacy of antidepressants, including selective serotonin reuptake inhibitors, in treating dysthymic disorder; however, escitalopram, the S-enantiomer of citalopram, has not been studied. Thirty-six outpatients with Structured Clinical Interview for DSM-III-R-diagnosed dysthymic disorder, aged 23-65 years (mean±SD=44.7±11 years), were randomly assigned to double-blind escitalopram (maximum dose 20 mg/day) versus placebo for 12 weeks. Inclusion criteria included age 18-65 years and Hamilton Depression Rating Scale (HDRS) score≥12. We hypothesized that escitalopram would be superior to placebo in the HDRS-24 item total score at week 12. We also hypothesized the superiority of escitalopram over placebo for secondary measures, including the percentage of participants classified as responders and remitters, as well as social functioning (Social Adjustment Scale), clinical global impression-improvement, Global Assessment of Functioning Scale. Participants' baseline HDRS-24 averaged 23.4±5.9. Final HDRS-24 scores at last observation carried forward did not differ significantly between escitalopram-treated (mean±SD=10.88±5.83) and placebo-treated individuals (mean±SD=16.4±6.34) (F=2.82, degrees of freedom=1,32, P=0.10). Significant differences favoring active medication were found on the Social Adjustment Scale and the Clinical Global Impression Severity and Global Assessment of Functioning Scale, but not in the percentages of responders or remitters. A larger study sample or higher escitalopram dose may show more significant placebo-medication differences.

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.

Serotonin-selective reuptake inhibitors (SSRIs) have been shown to enhance the locomotor stimulatory, discriminative-stimulus, and convulsive effects of cocaine in rodents. A pharmacokinetic mechanism for the interaction is supported by increases in the brain levels of cocaine by fluoxetine treatment. Furthermore, the locomotor-stimulant effects of cocaine in rodents are enhanced by fluoxetine and fluvoxamine, SSRIs known to inhibit cocaine-metabolizing cytochrome P450 enzymes, whereas citalopram, an SSRI that does not inhibit P450 enzymes, does not enhance cocaine's locomotor-stimulant effects. Citalopram, however, attenuated the discriminative-stimulus effects of cocaine in squirrel monkeys trained to discriminate cocaine from saline, though it enhanced the discriminative-stimulus effects of a low dose of cocaine in rats trained to discriminate high and low doses of the drug. This study investigated the effects of citalopram on cocaine's discriminative-stimulus effects in rats trained more simply to discriminate cocaine from saline. Citalopram alone produced predominantly saline-appropriate responding, but when administered before cocaine, citalopram dose-dependently shifted the cocaine dose-response curve leftward. The present findings suggest that enhancement of cocaine's discriminative-stimulus effects may occur through a mechanism different from that underlying enhancement of cocaine's locomotor effects or that another action of citalopram selectively blocks locomotor enhancement.

This study sought to investigate the efficacy of escitalopram at different dosages for the treatment of obsessive-compulsive disorder (OCD). Thirty individuals were enrolled in a 16-week, open-label trial of escitalopram and randomly assigned to the 20 or 30 mg study arm. Study measures assessing OCD symptoms, anxiety, depression, and quality of life were administered at baseline and weeks 2, 4, 8, 12, and 16. For the 23 study completers, pretreatment and posttreatment analyses revealed significant improvements (P<0.05) on clinician-rated and self-rated measures of OCD symptoms, quality of life, anxiety, and depression. Approximately half of the sample (n = 12) satisfied full medication response criteria and less than one-quarter (n = 5) were partial medication responders. Intention-to-treat analyses showed similar improvements (P<0.05) on all study measures. At study completion, a superior responder rate and more improvement on the Yale-Brown Obsessive Compulsive Scale (P<0.05) was reported for those in the 30 versus 20 mg study arm. The difference between the two groups, however, disappeared when initial differences in baseline depression and anxiety scores were used as analysis covariates. These results suggest that the 30 mg (vs. 20 mg) dose of escitalopram may provide a superior reduction in OCD symptoms for those sufferers with comorbid depression and/or anxiety.

Approximately 30-45% of patients with major depressive episode (MDE) do not fully respond to standard recommended treatments and further strategies of intervention, including pharmacological augmentation, have been proposed for these patients. This study was aimed to evaluate the efficacy of short-term, low-dose (10 mg/day) intravenous (i.v.) citalopram augmentation versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors (SSRIs). Thirty-six patients with a Diagnostic and Statistical Manual for Mental Disorders, 4th edition, text revision criteria MDE and partial or no response to oral SSRIs were selected and randomly assigned to citalopram (n=18) or to placebo (n=18) i.v. augmentation. The augmentation regimen lasted 5 consecutive days during which the patients were maintained on their current treatment with oral SSRIs. Analyses of variance with repeated measures on Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale total scores, administered daily with blind-raters conditions, were done. With regard to the Hamilton Depression Rating Scale total scores, a significant time effect (F=42.02, P<0.0001) and timextreatment effect (F=21.17, P<0.0001) were found in favor of citalopram. Similar results were obtained from the analysis on Montgomery-Asberg Depression Rating Scale total scores: time effect (F=50.07, P<0.0001), timextreatment effect (F=19.91, P<0.0001), and treatment effect (F=4.07, P=0.05). Even though referred to a small sample, the present findings seem to suggest that short-term, low-dose, i.v. citalopram augmentation may be effective in depressed patients with partial or no response to oral SSRIs. Further controlled studies performed with double-blind conditions are warranted to confirm the present results.

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.

The aim of this study was to evaluate the efficacy and tolerability of high-dose escitalopram in patients suffering from obsessive-compulsive disorder (OCD). In an open-label, 16-week prospective study, patients with OCD received escitalopram at a dose of 20 mg/day for 3 weeks, after a 1-week titration at 10 mg/day. Patients who did not achieve a > or =25% reduction from baseline in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score during these 4 weeks were continued on higher doses of escitalopram (maximum 50 mg/day) for 12 weeks. The primary efficacy measure of OCD symptoms was change from baseline in the Y-BOCS score. Overall, 67 patients (33 women, 34 men) with a mean Y-BOCS score of 29.6 entered the study. After 4 weeks of standard-dose escitalopram treatment, one patient discontinued owing to pregnancy, and two patients achieved a reduction in Y-BOCS > or =25%. Consequently, 64 patients were eligible to receive high-dose escitalopram (mean dose, 33.8 mg/day at endpoint). At endpoint, high-dose escitalopram had significantly improved the OCD symptoms (Y-BOCS score) and all the other efficacy measures (P<0.001), compared with baseline. Escitalopram was also well tolerated, with no discontinuations during the 12-week high-dose phase. The only reported adverse drug reactions were dry mouth (n=8, 12.1%) and decreased sexual desire (n=21, 31.8%). Preliminary investigation shows that high-dose escitalopram is an efficacious and well tolerated treatment for patients suffering from severe OCD. Randomized, blinded studies are needed to reinforce these findings.

The present study has addressed the question of what is more important for the occurrence of adaptive changes observed in the organism treated with antidepressant drugs: a daily dosing of the drug or the period of time necessary for the plastic events to develop. Here, we report on the effects of desipramine given to rats acutely (and tested following 2 drug-free weeks) as when the drug was administered repeatedly, on behavior in the forced swim test (i.e. significant shortening of immobility time by ca. 60%) and on the binding of [3H]CGP12177 to beta-adrenergic receptors in the rat brain cortex (significant decrease of the binding by ca. 15%). Additionally, using the procedure of the repeated forced swim test (six times over 21 days), we show that the shortening of immobility time induced by a single dose of imipramine persisted throughout the whole experimental period and was similar to that seen in a group of animals treated repeatedly with the drug. Also, the effects of citalopram on immobility and climbing were similar after acute treatment and delayed testing to those seen after repeated drug exposure. The results obtained in the present study may question some conclusions that are usually drawn from the behavioral and, especially, biochemical studies concerning the need for repeated treatment with antidepressant drugs to induce various adaptive changes in the brain, which are thought to be responsible for the therapeutic efficacy of these drugs.

This multinational, randomized, double-blind, flexible-dose study evaluated the short- and long-term antidepressant tolerability and efficacy of escitalopram and paroxetine. Tolerability was assessed by monitoring adverse events throughout the study, and discontinuation events during brief treatment interruption and tapered withdrawal. Discontinuation-emergent effects were evaluated in two separate double-blind periods. First, to mimic the consequences of non-compliance, patients were randomized to one of two treatment interruption periods (placebo-substitution for 3-5 days). Second, patients were randomized to a 1-2-week tapered withdrawal period randomly scheduled between weeks 28 and 31. The pre-specified primary efficacy endpoint was the mean change from baseline in total Montgomery-Asberg Depression Rating Scale (MADRS) score at week 8, using the principle of last observation carried forward. A total of 323 patients entered 8 weeks of double-blind treatment and received at least one flexible dose of escitalopram (10-20 mg/day) or paroxetine (20-40 mg/day). Patients who demonstrated evidence of a significant clinical improvement (Clinical Global Impression-Improvement of 1 or 2) at week 8 entered a 19-week, double-blind maintenance period during which they were treated with the same dose they received at week 8, followed by a 1-2-week tapered withdrawal period. A total of 89 patients (28%) withdrew during the study; significantly (P<0.01) more patients withdrew from the paroxetine group (34%) than from the escitalopram group (21%), and significantly (P<0.05) more paroxetine patients withdrew due to lack of efficacy. The mean MADRS total score improved for both treatment groups from baseline to week 8, with no statistical difference between groups. In severely depressed patients (baseline MADRS total score >or=30), escitalopram was superior (P<0.05) to paroxetine at week 27 (end of maintenance treatment). There was a high prevalence of sexual dysfunction at baseline: the mean Arizona Sexual Experience Scale (ASEX) score was approximately 20 points in both treatment groups. Mean total ASEX scores increased slightly above baseline values during the acute period and declined slightly below baseline values towards the end of the maintenance period. During taper and cessation of treatment, patients in the paroxetine group demonstrated significantly more discontinuation symptoms relative to escitalopram based on the Discontinuation Emergent Signs and Symptoms scores.

Escitalopram is the S-enantiomer of citalopram. In this study, we compared the efficacy of equivalent dosages of escitalopram and citalopram in the treatment of moderate to severe major depressive disorder (MDD), based on data from two, pooled, randomized, double-blind, placebo-controlled studies of escitalopram in which citalopram was the active reference. The primary efficacy parameter was the mean change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score. Significant differences in favour of escitalopram were observed for the MADRS [P<0.05, observed cases (OC)/last observation carried forward (LOCF)] and Clinical Global Improvement-Severity of Illness scores (CGI-S; P<0.05, OC/LOCF). Escitalopram separated from placebo at week 1 on the primary efficacy parameter, whereas citalopram first separated from placebo at week 6. An analysis of time to response showed that escitalopram-treated patients responded significantly faster to treatment than citalopram-treated patients (P<0.01). More patients responded to and achieved remission with escitalopram than to citalopram (P<0.05, OC). The HAMD scale was only used in the fixed-dose study, where escitalopram-treated patients had a significant reduction in HAMD-17 total score at week 8 compared to citalopram-treated patients (P<0.05, OC/LOCF). In the pooled subpopulation of severely ill patients (MADRS> or = 30), escitalopram-treated patients showed greater improvement than citalopram-treated patients (P<0.05, LOCF/OC). Escitalopram showed consistently superior efficacy compared to citalopram in the treatment of moderate to severe MDD on all efficacy parameters, and was similarly well tolerated.

This study aimed to provide preliminary data on the tolerability and effectiveness of citalopram for patients with dysthymic disorder. Twenty-one adult subjects meeting DSM-IV criteria for dysthymic disorder were enrolled in this 12-week open-label study, of whom 15 had pure dysthymia (e.g. no major depression in the past 2 years). Citalopram was initiated at 20 mg/day, and increased to a maximum of 60 mg/day. Response was defined as 50% or greater drop in score on the Hamilton Depression Rating Scale (HDRS) and a Clinical Global Impressions-I score of 1 ('very much improved') or 2 ('much improved'). Of these 15 pure dysthymic disorder subjects, all completed the trial, and 11 (73.3%) were treatment responders. All paired sample t-tests were highly significant, demonstrating significant average improvement on all measures of symptomatology and functioning. Scores on the 24-item HDRS decreased from 22.3+/-4.3 at baseline to 9.1+/-7.8 at week 12 [t(14)=6.1, P<0.001]. In addition, improvement was noted in self-reported measures of temperament and social functioning. The average final dose of citalopram was 39 mg/day. Side-effects were reported by nine of 15 subjects (60%), most frequently gastrointestinal symptoms (n=5), dry mouth (n=5) and sexual side-effects (n=3). These findings suggest the effectiveness and tolerability of citalopram in treating dysthymic disorder. Double-blind prospective studies are needed comparing citalopram both to placebo and to other medications, assessing both initial and sustained response to treatment.

Escitalopram was compared to placebo in moderately to severely depressed patients in primary care with citalopram as the active reference. Patients were randomized to receive flexible doses of 10-20 mg/day escitalopram (n=155), 20-40 mg/day citalopram (n=160), or placebo (n=154) over an 8-week double-blind period. The primary efficacy parameter was the change from baseline to last assessment in the Montgomery-Asberg Depression Rating Scale total score. Escitalopram produced a statistically significant therapeutic difference of 2.9 points (P=0.002) compared to placebo, and escitalopram was consistently and statistically significantly more efficacious than placebo from week 1 onwards. Analysis of Clinical Global Impression-Severity and Clinical Global Impression-Improvement confirmed the primary efficacy results. By week 8, significantly more patients had responded to treatment with escitalopram than with citalopram (P=0.021) or placebo (P=0.009). Escitalopram was as well tolerated as citalopram and had a similar adverse event profile. Both escitalopram- and citalopram-treated patients had placebo-level adverse event withdrawal rates (3% and 4%, respectively). This study demonstrates the consistent antidepressant efficacy and excellent tolerability of escitalopram 10-20 mg/day in primary care patients with major depressive disorder.

Escitalopram, a selective serotonin reuptake inhibitor (SSRI), was compared to placebo in a study of patients with major depressive disorder (DSM-IV) who had baseline Montgomery-Asberg Depression Rating Scale (MADRS) total scores >or=22 and

Serotonin reuptake inhibitors appear to be uniquely effective treatments for obsessive-compulsive disorder (OCD). This double-blind, placebo-controlled study was the first trial to assess the efficacy of the most selective of the serotonin reuptake inhibitors, citalopram, in OCD. A total of 401 patients were randomized to receive citalopram 20, 40 or 60 mg/day or placebo for 12 weeks. All three doses of citalopram were significantly more effective than placebo measured on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) change score (P < 0.01). The highest response rate, defined as 25% improvement in Y-BOCS entry score, was observed in the 60 mg group (65%). This compared with 52% and 57.4% in the 40 mg and 20 mg groups. Response rate on placebo was 36.6% (P < 0.05 for all three doses of citalopram compared to placebo). There was no significant difference between the individual doses of citalopram. An advantage was seen for citalopram on the Sheehan Disability Scale compared with placebo (P < 0.05 on all three citalopram groups versus placebo for both the work situation and the family life and home responsibilities and P < 0.05 on citalopram 60 mg and 20 mg versus placebo for the social life and home activities). Citalopram was well tolerated; only 4 to 6 patients in each dose group discontinued the study prematurely due to adverse events.

In this preliminary, 12-week open-label study, eight adolescents with moderate to severe post-traumatic stress disorder (PTSD) were treated with citalopram (the most selective of the selective serotonin reuptake inhibitors) in a fixed daily dose of 20 mg, and rated at 2-week intervals. The Clinician-Administered PTSD Scale (Child and Adolescent Version) was the primary measure used to assess treatment outcome. Core PTSD symptoms (re-experiencing, avoidance, and hyperarousal symptoms) showed statistically significant improvement at week 12 on the Clinician-Administered PTSD Scale (Child and Adolescent Version) (CAPS-CA), with a 38% reduction in total CAPS scores between baseline and endpoint. Citalopram failed to effect improvement on self-reported depressive symptoms. All seven adolescent completers were rated as much improved or very much improved on Clinical Global Impression Improvement scores. Citalopram was well-tolerated overall with reported adverse experiences being relatively benign. However, larger, controlled trials are needed to consolidate these preliminary results.

The behavioural consequences of repeated social defeat, coupled with the stress of continuously living opposite a dominant animal, were assessed in male NMRI mice. The method adopted here differed from the previously published techniques in that the physical element of the social defeat procedure was reduced to a minimum. The subordinate animals consistently weighed less than control animals, and displayed a reduced number of visits to the partition compared to the dominant animals, which has previously been used as a marker of social behaviour. The subordinate animals did not show any differences in the amount of ethanol solution consumed compared to controls, and did not display an increase in immobility time measured in the forced swimming test. The subordinate animals did, however, display anxiogenic-like behaviour as indicated by an increased aversion of the light section of the black/white test box, which was partially reversed by chronic treatment (3weeks; 20mg/kg/day) with the antidepressant, citalopram. Decreased exploration by the subordinate animals in the black/white test box was also observed, which was reversed by chronic citalopram treatment. It is suggested that, whilst the model requires further validation, it may be a useful approach for the study of antidepressant compounds.

Antidepressants are frequently used in the treatment of depressive symptoms associated with schizophrenia. In patients taking clozapine, choice of antidepressant is complicated by additive pharmacodynamic effects and by pharmacokinetic interactions. We predicted that citalopram would not elevate plasma clozapine levels when the two drugs were co-administered because it does not inhibit the relevant enzyme systems. In this preliminary study of five patients given citalopram and clozapine there was no overall change in mean clozapine levels. Based on this limited evidence, citalopram might be the antidepressant of choice in patients taking clozapine.

Establishing the optimum therapeutic dose of a putative antidepressant is important to avoid unnecessarily high doses, which may be associated with increased frequency of severity of unwanted side effects, or too low a dose which may not achieve the best therapeutic effect. Flexible dose regimes that are often used in clinical trial programmes may lead to the use of too high a dose because of the attribution of response in depression to the higher dose used later in the study rather than being identified as a delayed response to a lower dose used earlier. Fixed dose studies provide a more reliable view of the dose response relationship and, where differences between doses are small, metanalysis of large databases may provide a useful tool for the establishing of the minimum therapeutic dose. Metanalysis of the placebo controlled results with citalopram demonstrated that the dose-response curves based on log odds ratios showed a very flat curve across the 20-60 mg range and that 20 mg appeared therefore to be the minimum effective dose. There was evidence that in some subgroups of depressed patients a better response may be seen with a higher dose. For example in patients with severe depression citalopram was effective compared with placebo in doses of both 20 mg and 40 mg. However there was a more pronounced therapeutic effect with the higher dose. Similar results have been reported with other selective serotonin reuptake inhibitors.

The aim of the present study was to determine whether, in patients with depression who had responded favourably to the selective serotonin reuptake inhibitor citalopram, there was a therapeutic benefit in continuation treatment. Three hundred and ninety-one depressive patients were included in an open short-term citalopram treatment period. Only patients who responded to treatment at 8 weeks (total score of 12 or less on the MADRS scale) were randomized to the 24 week double-blind phase. Seventy-four patients were treated with placebo and 152 with citalopram at the same constant dose to which the patient had responded in the first phase. Relapse was defined as a total score of 25 or more on the MADRS scale. Twenty-one patients (13.8%) continuing to receive citalopram relapsed compared with 18 patients (24.3%) receiving placebo. The log rank test for survival data used to test the quality of relapse hazards between the placebo group and the citalopram group showed that patients treated with citalopram had a significantly lower relapse rate (p = 0.04). The results of this study are in general agreement with those of other studies on antidepressants, and support the hypothesis that full dose continuation is more effective than placebo in preventing relapse of depression.

Optimal dosing schedules for an antidepressant drug can only be established during clinical studies in depressed patients. The benefits of antidepressant therapy are usually progressive, and thus patients must be maintained on a particular treatment for at least 3-4 weeks to assess the efficacy of different doses. Meta-analysis, a widely accepted statistical technique which allows the combination of the results of multiple studies, was used to assess the efficacy of several doses of citalopram over nine placebo-controlled clinical trials. Statistically significant differences between citalopram and placebo were found at both the 20 and 40 mg dose levels. The minimal effective dose of citalopram was shown to be 20 mg. However, analysis of patient subgroups revealed a tendency for those patients suffering from severe or recurrent depression to achieve better results with a higher dosage (40 mg), while patients experiencing their first period of depression or with less severe depression responded well to the minimally effective dose of 20 mg.

Two dose levels of citalopram, 10-30 mg and 20-60 mg, were compared with imipramine, 50-150 mg, in depressed patients treated in general practice. This was a multicentre study carried out in Denmark, Sweden, Norway, and Finland. The duration of treatment was 6 weeks with an optional continuation phase of a further 16 weeks. The patients were assessed by means of the Hamilton Rating Scale for Depression (HAMD), Clinical Global Impressions (CGI), and a visual analogue self-rating scale for depression. Observed and spontaneously reported adverse events were recorded. A total of 472 patients were entered into the study and 400 patients completed the 6 week trial period. A total of 297 patients completed the optional 22 week double-blind period. A clear reduction of the HAMD total scores was seen in all three treatment groups with no significant differences between groups. A reduction of the HAMD anxiety factor and sleep factor scores was also seen with no significant differences between treatments. The imipramine-treated patients showed a higher frequency of adverse events, especially the anticholinergic type, than citalopram-treated patients. Most patients entered into the continuation phase remained well.

A total of 147 patients who had responded in a placebo-controlled study to 6 weeks treatment of an episode of DSM-III-R major depression with either 20 mg or 40 mg citalopram were randomized double-blind to continue on the same dose of citalopram or to receive placebo during a 24-week study of the efficacy of citalopram in the prevention of relapse. The citalopram 20 and 40 mg groups showed a significant advantage compared with placebo both in relapses (p < 0.05) and in the survival analysis of time to relapse (p = 0.01 and p = 0.02, respectively). Both 20 and 40 mg citalopram appeared similarly safe and well tolerated with little difference in side effects from placebo. The results demonstrate that citalopram, at a dose of both 20 and 40 mg is effective and well tolerated in continuation treatment to consolidate response. The relapse rate in patients who had responded to placebo during the 6-week acute treatment study, who were continued double-blind with placebo but not included in the efficacy analysis, was similar to the rate in the formal placebo control group, suggesting that patients who respond to placebo in a short treatment course may nonetheless require long-term active treatment to prevent relapse.