Paroxetine Controlled-release Research Articles

REFERENCE-SCALED AVERAGE BIOEQUIVALENCE STUDY OF PAROXETINE UNDER FED CONDITIONS: VALIDATION OF SAMPLE SIZE ESTIMATION BY BOOTSTRAPPING TECHNIQUE

Objective: New technique was adopted and validated to estimate pivotal sample size from the pilot study data and to establish bioequivalence (BE) of highly variable drugs (HVD), paroxetine, a novel controlled release (CR) matrix tablets utilized ghatti Gum as a rate controlling membrane, in human subject under fed conditions by reference scale design.
 Methods: Bootstrapping technique was adopted to calculate the pivotal sample size from pilot study data for HVD paroxetine. The reliability and validation of the method were tested in a semi replicate three sequence (RRT, RTR, and TRR where T stand for test drug and R stand for reference drug) cross-over BE study in 24 healthy subjects under fed conditions.
 Results: The ratio of the pharmacokinetic (PK) metric obtained from the bootstrapping technique after log transformation was 1.04 for Cmax, 1.23 for AUCT, and 1.21 for AUCI with corresponding power of the study which was greater than 80% from pilot study data simulation. The ratio of the PK metric obtained from the reference scaling design in the present study was 1.00 for Cmax, 1.21 for AUCT, and 1.17 for AUCI. The upper limit of the Cmax, AUCT, and AUCI at 95% confidence limit was −0.143, −0.136, and −0.17, respectively.
 Conclusion: The test paroxetine CR formulation was bioequivalent with reference drug under fed conditions. The technique used for estimation of the sample size in the pivotal study was found reliable, and bootstrapping technique plays an important role in calculating sample size where intrasubject variability was immaterial.

Effects of anxiety on suicidal ideation: exploratory analysis of a paroxetine versus bupropion randomized trial.

It is unclear whether anxiety increases or decreases suicidal risk. This may contribute to the lack of guidance on which antidepressant medications are best for suicidal depressed patients who present with high anxiety. This study explored whether anxiety predicts suicidal ideation in depressed individuals treated with paroxetine or bupropion. An 8-week double-blind trial comparing controlled-release paroxetine (N=36) versus extended-release bupropion (N=38) for effect on suicidal ideation and behavior in depressed patients with suicidal ideation, past attempt, or both found an advantage for paroxetine, but anxiety effects were not investigated. This secondary analysis explored the relationship, measured at baseline and weekly, of anxiety with suicidal ideation. Anxiety severity measured weekly correlated with suicidal ideation severity irrespective of treatment (P=0.012). Patients with high baseline anxiety showed a trend toward faster reduction of suicidal ideation with paroxetine compared with bupropion treatment (standard P=0.047; bootstrap P=0.077). The latter finding, if confirmed in larger samples, could enhance choice of antidepressant medication for suicidal, depressed patients presenting with high levels of anxiety.

Comparative effectiveness of switching paroxetine formulation for treatment of major depressive disorder: an open-label multicenter study.

AimTo assess the effectiveness and safety of switching the antidepressant formulation from immediate-release (IR) to controlled-release (CR) paroxetine in patients with major depressive disorder (MDD).Patients and methodsA total of 113 outpatients with MDD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, and treated with a stable dose of IR paroxetine for at least 6 months were enrolled. Patients were then switched to CR paroxetine for 8 weeks. Effectiveness was evaluated by scores on the Himorogi Self-Rating Depression/Anxiety Scales (HSDS/HSAS) and the Clinical Global Impression – Severity (CGI-S). Safety was evaluated based on the reported adverse drug reactions (ADRs). Medication satisfaction and preference were assessed based on questionnaire responses using Likert-type scales.ResultsThe overall patient HSDS/HSAS scores significantly improved after switching from IR to CR paroxetine (P<0.001). Furthermore, CR paroxetine was superior to IR paroxetine (P<0.001) according to the results of the CGI-S evaluation. ADRs were experienced by 14 (12.4%) patients, including dry mouth, nausea/vomiting, somnolence/drowsiness, and wakefulness/arousal during sleep. Satisfaction and preference for paroxetine improved after switching to the CR formulation (P<0.001; chi-square test).ConclusionThese results suggest that switching the treatment from IR to CR paroxetine could improve depressive symptoms and decrease ADRs. However, these results may have been caused by the psychological effect of drug switching. Hence, future studies with blinded evaluation methods are required to confirm and expand our findings.

Safety and effectiveness of controlled-release paroxetine in routine clinical practice: results of a postmarketing surveillance study of patients with depression.

ObjectiveSelective serotonin reuptake inhibitors are commonly used in the pharmacotherapy of depression. However, adverse events can lead to their early discontinuation. This study evaluated the safety and effectiveness of paroxetine controlled-release (CR) tablets in Japanese patients with depression/depressive state (hereafter referred to as depression) in routine clinical practice in Japan.Patients and methodsThis was an open-label, noninterventional, prospective, postmarketing surveillance study. A total of 3,213 patients aged 12–92 years with depression were prescribed paroxetine CR for 8 weeks at the physician’s discretion. Safety was evaluated on the basis of the reporting of adverse drug reactions. Effectiveness was evaluated on the basis of the physician’s assessment using the Clinical Global Impression-Global Improvement (CGI-GI) and the Clinical Global Impression-Severity of Illness (CGI-SI) scales, as well as on the basis of the patients’ self-reported satisfaction. The primary effectiveness outcome was the improvement rate based on the physician’s assessment using the CGI-GI.ResultsThe incidence of adverse drug reactions was 11.2% (359/3,213; 95% confidence interval [CI]: 10.1%–12.3%). The common adverse drug reactions that accounted for 1.0% or more of the incidence were nausea (3.5%) and somnolence (2.7%). The proportion of patients who continued paroxetine CR at week 8 was 80.2% (2,577/3,213; 95% CI: 78.8%–81.6%). The improvement rate at week 8 (last observation carried forward) was 72.8% (2,132/2,927; 95% CI: 71.2%–74.4%). The proportion of patients with CGI-SI scores of moderately or severely ill decreased from 63.6% at baseline to 17.9% at week 8. The proportion of patients who were satisfied with paroxetine CR treatment was 69.8% (2,040/2,921; 95% CI: 68.1%–71.5%).ConclusionThe results of this study suggest that paroxetine CR is a well-tolerated and efficacious treatment for depression in routine clinical practice.

P.2.b.033 A randomized study of escitalopram and paroxetine controlled-release in the treatment of Japanese patients with major depressive disorder

The extent to which affective reactivity and associated neural underpinnings are altered by depression remains equivocal. This study assessed striatal activation in fifty-one unmedicated female participants meeting DSM-IV criteria for Major Depressive Disorder (MDD) and 61 age-matched healthy females (HC) aged 17–63 years. Participants completed an affective reactivity functional magnetic resonance imaging task. Data were preprocessed using SPM8, and region-of-interest analyses were completed using MarsBaR to extract caudate, putamen, and nucleus accumbens (NAcc) activation. General linear repeated measure ANOVAs were used to assess group differences and correlational analyses were used to measure the association between activation, depression severity, and anhedonia. Main effects of hemisphere, valence, and group status were observed, with MDD participants demonstrating decreased striatal activation compared with HC. Across groups and valence types, the left hemisphere demonstrated greater activation than the right hemisphere in the putamen and nucleus accumbens, whereas the right hemisphere demonstrated greater activation than the left in the caudate. Additionally, unpleasant stimuli elicited greater activation than pleasant and neutral stimuli in the caudate and putamen, and unpleasant stimuli elicited greater activation than neutral stimuli in the NAcc. There were no significant associations between activation, depression severity, and anhedonia. Overall, depression was characterized by reduced affective reactivity in the striatum, regardless of stimuli valence, supporting the emotion context insensitivity model of depression.

Paroxetine controlled‐release formulation in the treatment of major depressive disorder: A randomized, double‐blind, placebo‐controlled study in Japan and Korea

The main purpose of this study was to evaluate the efficacy of paroxetine controlled-release (CR) formulation compared to placebo. A secondary objective was to test the hypothesis that the CR decreases selective-serotonin-reuptake-inhibitors-induced nausea as its formulation allows more distal gastrointestinal absorption than the paroxetine immediate-release (IR) formulation. We conducted this study in Japanese and Korean patients with major depressive disorder (MDD) in order to demonstrate the efficacy and safety of paroxetine CR compared with placebo. The primary efficacy end-point was the adjusted mean change from baseline in the 17-item Hamilton Rating Scale for Depression total score at Week 8. A total of 416 patients with MDD were randomly assigned to the CR, IR and placebo groups. The mean change from baseline in the 17-item Hamilton Rating Scale for Depression was -12.8 in the CR group, -12.5 in the IR group, and -10.4 in the placebo group, which showed a statistically significant difference compared to placebo in CR (P < 0.001) and IR (P = 0.015). The incidence of adverse events was 65% in CR, 69% in IR and 55% in placebo. The adverse events were mostly mild or moderate in severity. In the early treatment period, when initiated from 12.5 mg, the incidence of nausea in the CR group was 6%, which was comparable with that of placebo (5%). Paroxetine CR is efficacious in the acute treatment of MDD and may have the potential benefit of decreasing the incidence of nausea in the early treatment period.

A Double-Blind Placebo-Controlled Trial of Lamotrigine as an Antidepressant Augmentation Agent in Treatment-Refractory Unipolar Depression

Previous reports have suggested that lamotrigine is effective as an antidepressant augmentation agent in patients with treatment-resistant unipolar depression. This study is the largest double-blind placebo-controlled study conducted to date of lamotrigine in this role. In this multicenter trial, conducted at 19 sites, patients aged 18-65 years with a DSM-IV/ICD-10 diagnosis of unipolar, nonpsychotic major depressive disorder (confirmed by the Mini-International Neuropsychiatric Interview) who had failed at least 1 adequate trial of an antidepressant (N = 183) were first treated for 8 weeks with open-label paroxetine or paroxetine controlled-release in dosages up to 50 mg/d or 62.5 mg/d, respectively. Individuals with a 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 15 (n = 96) were then randomized on a double-blind basis to receive either placebo or lamotrigine in dosages titrated upward to a maximum of 400 mg/d for 10 weeks. Sixty-five patients completed the study. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS), and the main secondary outcome measures were the HDRS-17 and Clinical Global Impressions-Severity of Illness (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) ratings. Data were collected from 2003 to 2006. Results of the primary efficacy analysis of the randomized patients using the MADRS, HDRS-17, CGI-S, and CGI-I did not demonstrate a statistically significant difference between lamotrigine and placebo groups, although some secondary analyses were suggestive of efficacy, particularly in those patients who completed the study (completer analysis) and in more severely ill patients (HDRS-17 ≥ 25). This add-on study of patients with treatment-resistant depression failed to detect a statistically significant difference between lamotrigine and placebo given for 10 weeks. However, post hoc analyses suggest that future studies of lamotrigine's efficacy might focus on specific subgroups with depression. clinicaltrials.gov Identifier: NCT00901407.

Increased neural response to trauma scripts in posttraumatic stress disorder following paroxetine treatment: A pilot study

Neuroimaging studies of individuals with posttraumatic stress disorder (PTSD) have revealed altered patterns of activity in medial prefrontal brain regions, including the anterior cingulate cortex (ACC), an area implicated in affect regulation. Selective serotonin reuptake inhibitors (SSRIs) have been shown to effectively treat PTSD symptoms, but there remains a lack of functional neuroimaging research examining the effects of psychopharmacological treatment on brain function in PTSD. The purpose of this pilot study was to assess the effects of the SSRI paroxetine on neural responses to traumatic memories in a small sample of patients with PTSD, as measured with PET imaging; we hypothesized that paroxetine treatment would be associated with increased regional cerebral blood flow (rCBF) in the medial prefrontal cortex. Thirteen participants with PTSD were given controlled-release paroxetine (paroxetine CR) or placebo in a randomized, double-blind fashion for 12 weeks. Participants underwent brain imaging using positron emission tomography (PET) before and at the end of treatment in conjunction with exposure to neutral scripts and personalized trauma scripts. Participants treated with paroxetine CR and placebo both exhibited significantly increased rCBF in the ACC during trauma versus neutral script presentations; however, we noted an increase in function in the orbitofrontal cortex (OFC) in paroxetine-treated (but not placebo-treated) participants. Participants in both groups showed decreases in overall PTSD symptomatology following treatment; paroxetine-treated participants showed a slightly greater percentage decrease in symptoms. These preliminary findings indicate that increased ACC function represents a nonspecific response to treatment, whereas increased OFC function is specifically associated with paroxetine treatment in PTSD. These pilot data reveal putative mechanisms for SSRI treatment in PTSD and substantiate the need for large-scale placebo-controlled studies investigating these effects.

History of depressive and/or anxiety disorders as a predictor of treatment response: A post hoc analysis of a 12-week, randomized, double-blind, placebo-controlled trial of paroxetine controlled release in patients with fibromyalgia

Background Despite of a high comorbidity of depressive and/or anxiety disorders with fibromyalgia, information on the clinical implications of this comorbidity is limited but antidepressants are commonly prescribed to treat fibromyalgia in clinical practice. We investigated whether a history of depressive and/or anxiety disorders was associated with response to paroxetine controlled release (CR) in the treatment of fibromyalgia. Methods One hundred sixteen (116) fibromyalgia subjects were randomized to receive paroxetine CR or placebo for 12 weeks. The primary outcome was treatment response defined as ≥ 25% reduction in the Fibromyalgia Impact Questionnaire (FIQ) score. In multivariate logistic regression, we determined if a history of depression and/or anxiety disorders was an independent predictor of response to paroxetine CR. Results In logistic regression, the history of depression and/or anxiety did not predict treatment response as measured by ≥ 25% reduction in Fibromyalgia Impact Questionnaire (FIQ) score (OR = 0.66, 95% CI = .29–1.49, Wald = 0.97, p = 0.32), while the drug status (paroxetine CR) was significantly associated with treatment response (OR = 2.57, CI = 1.2–5.61, Wald = 5.5, p = 0.02). Conclusion A significant proportion of patients with fibromyalgia had a history of anxiety and or depressive disorders. However response to treatment of fibromyalgia symptoms with paroxetine CR was not associated with a history of depressive and/or anxiety disorders. Our findings need to be confirmed in more adequately-powered and well-designed subsequent studies.

Comparison of Immediate-Release and Controlled-Release Paroxetine Ingestions Reported to Texas Poison Control Centers between 2002 and 2008

Background: Controlled-release (CR) paroxetine was created to improve the tolerability of immediate-release (IR) paroxetine while maintaining therapeutic benefits. There is limited information comparing the toxicity of the 2 paroxetine formulations. Objective: To compare the toxicity and management of paroxetine IR and paroxetine CR ingestions reported to poison control centers. Methods: Cases of ingestion of paroxetine that were reported to Texas poison control centers between 2002 and 2008, in which the final medical outcome and dose were known, were retrospectively reviewed. The rates for selected variables were determined for paroxetine IR and paroxetine CR and comparisons between the 2 were made by calculating the ratio of the drug's CR rate to the IR rate and 95% confidence interval. Compliance with simplified algorithms of triage management guidelines was determined for both formulations. Results: Included in the analysis were 405 cases of paroxetine IR ingestion and 169 cases of paroxetine CR ingestion for which a reported dose and final medical outcome were known. There were no statistically significant differences between the paroxetine CR and paroxetine IR formulations with respect to serious medical outcomes (ratio 0.69, 95% CI 0.34 to 1.31), self-harm or malicious intent (ratio 0.82, 95% CI 0.60 to 1.12), or referral to a healthcare facility (ratio 1.18, 95% CI 0.76 to 1.83). The rate of compliance with the triage algorithm for cases not already en route to or at a healthcare facility when the poison control center was contacted was 87% for paroxetine IR and 89% for paroxetine CR. Conclusions: The toxicity and management of paroxetine IR and paroxetine CR ingestions reported to Texas poison control centers were similar after adjusting for differences in dosage.

History of early abuse as a predictor of treatment response in patients with fibromyalgia: A post-hoc analysis of a 12-week, randomized, double-blind, placebo-controlled trial of paroxetine controlled release

Objectives. We conducted a post-hoc analysis to determine whether a history of physical or sexual abuse was associated with response to treatment in a double-blind, randomized, placebo-controlled trial of paroxetine controlled release (CR) in fibromyalgia. Methods. A randomized, double-blind, placebo-controlled trial of paroxetine controlled release (CR) (dose 12.5–62.5 mg/day) was conducted in patients with fibromyalgia for 12 weeks. A total of 112 subjects provided complete information on childhood history of abuse that was recorded using the Sexual and Physical Abuse Questionnaire and randomized to treatments. Outcome evaluations in the abuse subgroup were identical to those in the entire sample. Health Status was determined using the 36-Item Short Form Health Survey (SF-36), the Sheehan Disability Scale (SDS), and the Perceived Stress Scale (PSS). Fibromylagia symptom severity was determined using the Fibromyalgia Impact Questionnaire (FIQ) and the Visual Analogue Scale for Pain (VAS). The primary outcome was treatment response defined as ≥25% reduction in the FIQ-total score. Secondary outcomes include changes in scores on the Clinical Global Impression-Severity and Improvement (CGI-S and CGI-I respectively) and SF-36. Results. The rate of childhood physical and/or sexual abuse was 52.7% (n=59). The baseline characteristics (health status, perceived stress, symptom severity) were not associated with abuse history. In logistic regression, the history of abuse did not predict treatment response as measured by ≥25% reduction in FIQ-total score (OR = 1.16, 95% CI = 1.18–1.60, P = 0.35), while the drug status (paroxetine CR) was significantly associated with treatment response (OR = 2.51, 95% CI = 1.12–5.64, P = 0.02). Abuse history did not predict CGI-I (P = 0.32) or CGI-S (P = 0.74) improvements during treatment. After 12 weeks of treatment, subjects with sexual abuse history showed significantly lower mean change in health status (SF-36) than those without sexual abuse history (P = 0.04). Conclusions. Although, a significant proportion of patients with fibromyalgia reported a history of abuse, it does not appear to have any significant clinical correlates at baseline. History of abuse did not predict response to treatment in patients with fibromyalgia participating in a controlled trial of paroxetine controlled release. Prospective, well-designed studies are needed to confirm whether selective serotonin uptake inhibitors are effective in patients with fibromyalgia irrespective of their abuse history.

A Double-Blind, Randomized, Placebo-Controlled Trial of Paroxetine Controlled-Release in Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disease that causes significant impairment in quality of life and accounts for $8 billion per year to the healthcare system and loss of productivity in the workplace. The authors examined the efficacy and safety of paroxetine controlled-release (paroxetine-CR) in patients with IBS. Seventy-two patients with IBS participated in a 12-week, double-blind, randomized, placebo-controlled study of paroxetine-CR (12.5 mg-50 mg/day). Efficacy was measured by Composite Pain Scores (primary outcome) and the Clinical Global Impression-Improvement (CGI-I) and Severity (CGI-S) ratings. In intent-to-treat analyses, there were no significant differences between paroxetine-CR (N=36) and placebo (N=36) on reduction in Composite Pain Scores, although the proportion of responders on CGI-I was significantly higher in the paroxetine-CR group. The treatment was well tolerated. The study did not demonstrate a statistically significant benefit for paroxetine-CR over placebo on the primary outcome measure, although there was improvement in secondary outcome measures. Overall, paroxetine-CR seems to have potential benefit in IBS. Studies with adequate samples may clarify the role of paroxetine-CR in IBS.

Childhood abuse and treatment response in patients with irritable bowel syndrome: apost-hocanalysis of a 12-week, randomized, double-blind, placebo-controlled trial of paroxetine controlled release

Although irritable bowel syndrome (IBS) is frequently comorbid with childhood trauma, information on the clinical implications of this comorbidity is limited. We investigated whether a history of abuse was associated with response to treatment in a double blind, randomized, placebo controlled trial of paroxetine controlled release (CR) in IBS. Seventy-two IBS subjects were randomized to receive paroxetine CR (dose 12.5-50 mg/day) or placebo for 12 weeks. Subject selection was independent of abuse history. Sixty-one subjects completed the Sexual and Physical Abuse Questionnaire about their childhood abuse history. IBS symptoms were recorded using the Interactive Voice Response System (IVRS). Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Perceived Stress Scale (PSS) and Clinical Global Impression (CGI) were also measured. The primary outcome was treatment response defined as > or =25% reduction in composite pain scores (CPS) on the IVRS from randomization to end of treatment. The rate of abuse history was 50.8% (n = 31/61). Baseline demographic clinical characteristics (CPS, BDI, BAI, PSS, CGI scores) were not associated with abuse history. After 12 weeks of treatment, subjects with abuse history showed significantly higher CPS (t = 2.422, P = 0.018) than subjects without a history and less mean change of CPS (t = 3.506, P = 0.001). In a logistic regression analysis, history of abuse did not predict treatment response as measured by > or =25% reduction in CPS (OR = 0.481, CI = 0.164-1.406, P = 0.181), while the drug status (paroxetine CR) was significantly associated with treatment response as defined by a CGI improvement score of 1-2 (OR = 12.121, CI = 2.923-50.271, P = 0.001). Abuse history did not predict CGI-I (Fisher's exact, P = 0.500) improvements during the trial. History of abuse did not appear to have any significant clinical correlates at baseline and did not predict treatment response. Further studies are needed to confirm whether SSRIs are effective in IBS patients irrespective of their abuse history.

Paroxetine: safety and tolerability issues

Paroxetine is a selective serotonin re-uptake inhibitor (SSRI) available in immediate release and controlled release (CR) formulations. Paroxetine is the most potent inhibitor of serotonin re-uptake among the now available SSRIs. Paroxetine has been approved for the treatment of major depressive disorder (MDD), obsessive–compulsive disorder, panic disorder (PD), generalised anxiety disorder, post traumatic stress disorder (PTSD), and social anxiety disorder (SAD) in adults, whereas paroxetine CR is approved for the treatment of MDD, SAD, PD and premenstrual dysphoric disorder in adults. The overall efficacy of paroxetine seems to be comparable to other SSRIs in the treatment of approved indications, although paroxetine treatment induces more sedation, constipation, sexual dysfunction, discontinuation syndrome and weight gain than other SSRIs. Recent data suggest that paroxetine treatment leads to increased rates of congenital malformations, although this evidence is not conclusive. Paroxetine and paroxetine CR are not indicated for use in the paediatric population and are categorised as Pregnancy Class D. In conclusion, whether the tolerability profile of paroxetine differs substantially from other new antidepressants (including other SSRIs) needs to be determined in adequately powered well-designed randomised controlled comparative clinical trials.

History of Depressive and Anxiety Disorders and Paroxetine Response in Patients With Irritable Bowel Syndrome

Although irritable bowel syndrome (IBS) is highly comorbid with depressive and anxiety disorders, information on the clinical implications of this comorbidity is limited. We investigated whether a history of depressive and/or anxiety disorders was associated with response to treatment in a double-blind, randomized, placebo-controlled trial of paroxetine controlled release (CR) in IBS. Seventy-two IBS subjects (diagnosed using Rome II criteria) were recruited from August 2003 to November 2005 and randomly assigned to receive flexibly dosed paroxetine CR (dose, 12.5-50 mg/day) or placebo for 12 weeks. The Mini-International Neuropsychiatric Interview (MINI-Plus version) was used to ascertain current (exclusionary) or past diagnoses of depressive and anxiety disorders. Subjective depression, anxiety, and stress were assessed at entry and throughout the trial using the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Perceived Stress Scale (PSS). Severity of IBS symptoms was determined by the Composite Pain Score (CPS), administered via Interactive Voice Response System, and the Clinical Global Impressions scale (CGI). The primary outcome was treatment response defined as ≥ 25% reduction in CPS from randomization to end of treatment. A post hoc analysis (multivariate logistic regression) was done to evaluate whether a history of depressive and/or anxiety disorder was associated with response to medication. Baseline demographic and clinical characteristics (CPS, BDI, BAI, PSS, CGI scores) were similar between groups (history of depressive/anxiety disorder vs. no history). In multivariate logistic regression analysis, treatment response was not predicted by history of depressive and/or anxiety disorder (OR = 0.58, CI = 0.29 to 1.68, p = .32) or drug status (paroxetine CR vs. placebo) (OR = 1.26, CI = 0.68 to 3.21, p = .19). Drug status was significantly associated with the secondary outcome variable of treatment response as defined by a CGI improvement score of 1 to 2 (OR = 12.14, CI = 2.9 to 48.4, p < .001). Paroxetine CR was safe and well tolerated during the study. History of depressive and/or anxiety disorder was not associated with response of IBS symptoms to paroxetine CR. Conclusions are limited due to insufficient statistical power. Further research is needed to clarify the role of selective serotonin reuptake inhibitors in the treatment of IBS and to elucidate the treatment ramifications of comorbid psychiatric disorders. clinicaltrials.gov Identifier: NCT00610909.

Low Doses of Controlled-Release Paroxetine in the Treatment of Late-Life Depression

To evaluate the efficacy and tolerability of low daily doses of controlled-release (CR) paroxetine in patients with late-life depression. This was a 10-week, multicenter, placebo-controlled, double-blind, fixed-dose trial randomly assigning patients >or= 60 years old to daily doses of paroxetine CR 12.5 mg (N = 168), paroxetine CR 25 mg (N = 177), or placebo (N = 180). Patients had major depressive disorder (DSM-IV criteria) and 17-item Hamilton Rating Scale for Depression (HAM-D) total scores of >or= 18. The primary efficacy variable was the change from baseline to study endpoint in total HAM-D scores. The study was conducted from June 2003 to October 2004. The drug/placebo difference in HAM-D change from baseline at study endpoint was -1.8 (95% CI = -3.41 to -0.19, p = .029) for paroxetine CR 12.5 mg, and -3.3 (95% CI = -4.84 to -1.68, p < .001) for paroxetine CR 25 mg. A significantly larger percentage of patients achieved remission (HAM-D total score <or= 7 at endpoint) with paroxetine CR 25 mg (41%), but not with 12.5 mg (31%), as compared with placebo (28%) (p = .008). Both doses of paroxetine CR also achieved statistical significance compared to placebo for the Clinical Global Impressions-Severity of Illness scale (p < .01) and the patient-rated measures of depression severity (p < .05) and quality of life (p <or= .001). Both active treatments were generally well tolerated, with adverse event withdrawal rates of 6%, 8%, and 7% for paroxetine CR 12.5 mg, paroxetine CR 25 mg, and placebo, respectively. These data demonstrate that paroxetine CR 12.5 mg and 25 mg daily are efficacious and well tolerated in the treatment of major depressive disorder in patients >or= 60 years of age, although effect sizes are relatively smaller with the 12.5 mg/day dose.

The pharmacokinetics of standard antidepressants with aripiprazole as adjunctive therapy: studies in healthy subjects and in patients with major depressive disorder

Possible effects of the atypical antipsychotic aripiprazole on the pharmacokinetics of standard antidepressant therapies (ADTs) were assessed in two open-label, non-randomised studies in healthy subjects (Studies 1 and 2) and two placebo-controlled studies in patients with major depressive disorder (MDD) (Studies 3 and 4). Healthy subjects received venlafaxine 75 mg/day (Study 1; N = 38) or escitalopram 10 mg/ day (Study 2; N = 25) with the addition of aripiprazole 10-20 mg/day (10 mg/day fixed dose in Study 2) for 14 days. Patients with MDD (N = 498; Studies 3 and 4) received escitalopram (10-20 mg/day), fluoxetine (20-40 mg/day), paroxetine controlled-release (37.5-50 mg/day), sertraline (100-150 mg/day) or venlafaxine extended-release (150-225 mg/day) for 8 weeks plus placebo. Incomplete responders were randomised (1:1) to placebo or adjunctive aripiprazole 2-20 mg/day. Blood samples were collected for pharmacokinetic analysis of ADTs. Plasma concentration-time data from Studies 3 and 4 were combined for statistical analysis. In healthy subjects, point estimates [90% CI] for the ratios of geometric means of C( max) (venlafaxine 1.148 [1.083-1.217]; escitalopram 1.04 [0.99-1.09]) and AUC(TAU) (venlafaxine 1.183 [1.130-1.238]; escitalopram 1.07 [1.04-1.11]) indicated no meaningful increase in ADT exposure in the presence of aripiprazole. In patients, point estimates for mean plasma concentration ratios indicated no substantial effect of aripiprazole on any ADT escitalopram 0.970 [0.911-1.033], fluoxetine 1.177 [1.049-1.321], paroxetine 0.730 [0.598-0.892], sertraline 0.958 [0.887-1.035] or venlafaxine 0.966 [0.887-1.051]. Aripiprazole had no meaningful effects on the pharmacokinetics of standard ADTs in either healthy subjects or patients with MDD.

Role of patient experience in antidepressant adherence: A retrospective data analysis

Background: In a previous study, we found that past medication use was associated with medication adherence in patients prescribed atypical antipsychotics. Objective: The present study aimed to determine whether past medication experience was associated with adherence in patients prescribed selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Methods: Deidentified computerized pharmacy records of patients from 1157 pharmacies throughout the United States were used to select patients who were dispensed extended-release venlafaxine, controlled-release paroxetine, sertraline, fluoxetine, escitalopram, and/or citalopram between October 1, 2003, and March 31, 2004. Patients who were dispensed an antidepressant during this enrollment period were stratified into 2 groups. One group consisted of patients to whom an antidepressant medication had not been dispensed in the 180-day period prior to the index date. The other group was composed of individuals who had been dispensed an antidepressant during that period. Discontinuation was defined as being ≥30 days late for a scheduled refill. Adherence was measured using Kaplan-Meier analysis during a 360-day follow-up period. Results: Of 211,565 patients analyzed, 38.5% had not received an antidepressant previously; 74.0% of the total sample were women. The mean age was 50.5 years. The median times to medication discontinuation were 67 days in patients not previously dispensed an antidepressant and 184 days in those who were. Discontinuation in the first 30 days was observed in 38.8% of patients not previously dispensed an antidepressant and in 18.8% of those who were. Conclusions: Prior antidepressant receipt rather than the use of a particular medication was associatedwith antidepressant adherence in this analysis. Patients without prior antidepressant receipt faced twice the risk for discontinuation during the first 30 days of treatment.

Management Strategies for Premenstrual Syndrome/Premenstrual Dysphoric Disorder

To evaluate the current nonpharmacologic and pharmacologic treatment options for symptoms of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). Literature was obtained through searches of MEDLINE Ovid (1950-March week 3, 2008) and EMBASE Drugs and Pharmacology (all years), as well as a bibliographic review of articles identified by the searches. Key terms included premenstrual syndrome, premenstrual dysphoric disorder, PMS, PMDD, and treatment. All pertinent clinical trials, retrospective studies, and case reports in human subjects published in the English language were identified and evaluated for the safety and efficacy of pharmacologic and nonpharmacologic treatments of PMS/PMDD. Data from these studies and information from review articles were included in this review. Selective serotonin-reuptake inhibitors (SSRIs) have been proven safe and effective for the treatment of PMDD and are recommended as first-line agents when pharmacotherapy is warranted. Currently fluoxetine, controlled-release paroxetine, and sertraline are the only Food and Drug Administration-approved agents for this indication. Suppression of ovulation using hormonal therapies is an alternative approach to treating PMDD when SSRIs or second-line psychotropic agents are ineffective; however, adverse effects limit their use. Anxiolytics, spironolactone, and nonsteroidal antiinflammatory drugs can be used as supportive care to relieve symptoms. Despite lack of specific evidence, lifestyle modifications and exercise are first-line recommendations for all women with PMS/PMDD and may be all that is needed to treat mild-to-moderate symptoms. Herbal and vitamin supplementation and complementary and alternative medicine have been evaluated for use in PMS/PMDD and have produced unclear or conflicting results. More controlled clinical trials are needed to determine their safety and efficacy and potential for drug interactions. Healthcare providers need to be aware of the symptoms of PMS and PMDD and the treatment options available. Treatment selection should be based on individual patient symptoms, concomitant medical history, and need for contraception.

The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder

Nonresponse to one or more antidepressants is common and an important public health problem. This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to standard antidepressant therapy (ADT) in patients with major depressive disorder who showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospective ADT. The study comprised a 7-28-day screening, an 8-week prospective treatment, and a 6-week randomization phase. During prospective treatment, patients experiencing a major depressive episode (17-item Hamilton Rating Scale for Depression total score > or = 18) received single-blind adjunctive placebo plus clinicians' choice of ADT (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release). Subjects with inadequate response were randomized to adjunctive placebo (n = 190) or adjunctive aripiprazole (n = 191) (starting dose 5 mg/d, dose adjustments 2-20 mg/d, mean end-point dose of 11.0 mg/d). The primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale total score from end of prospective treatment phase to end of randomized treatment phase (last observation carried forward). Mean change in Montgomery-Asberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than placebo (-8.5 vs -5.7; P = 0.001). Remission rates were significantly greater with adjunctive aripiprazole than placebo (25.4% vs 15.2%; P = 0.016) as were response rates (32.4% vs 17.4%; P < 0.001). Adverse events occurring in 10% of patients or more with adjunctive placebo or aripiprazole were akathisia (4.2% vs 25.9%), headache (10.5% vs 9.0%), and fatigue (3.7% vs 10.1%). Incidence of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs adjunctive aripiprazole [3.7%]). Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to standard ADT.