Cathryn M. Clary

The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder

RationaleA common polymorphism (5HTTLPR) within the promoter region of the serotonin transporter gene (LSC6A4) has been shown to influence response time as well as overall response to selective serotonin reuptake inhibitors (SSRIs) in subjects with major depressive disorder. We hypothesized that a similar effect in response time to sertraline would be observed and that no effect on response time would be seen in a placebo arm.ObjectivesWe tested the hypothesis that subjects homozygous for the long allele at the 5HTTLPR polymorphism would respond more rapidly to sertraline than subjects carrying one or two copies of the short allele.MethodsHAM-D and CGI-I responses to sertraline and placebo were measured weekly in the context of an 8-week, placebo-controlled study in elderly depressed subjects. Genotyping of the 5HTTLPR polymorphism was performed to test for correlations with response at each week in the sertraline and placebo groups (n=206).ResultsSubjects homozygous for the long allele of 5HTTLPR showed a significant increase in response at week 1 and week 2, as assessed by the CGI-I scale compared with subjects carrying one or two copies of the short allele (P=0.01 at both weeks). No significant difference was observed in the placebo group.ConclusionsThese results suggest that genetic variation in the serotonin transporter gene effects the response time to sertraline and provides complementing evidence to previous reports that this polymorphism affects response time to other SSRIs.

Placebo-controlled trial of venlafaxine for the treatment of major depression.

Results are presented of the first double-blind, placebo-controlled trial of a novel antidepressant venlafaxine, which preclinically has demonstrated serotonin, norepinephrine, and dopamine reuptake inhibiting effects. Sixty outpatients meeting DSM-III-R criteria for major depression were randomized to receive 6 weeks of treatment with one of three fixed doses of venlafaxine—25 mg three times a day, 75 mg three times a day, or 125 mg three times a day—or placebo. Significant improvement was observed in depression scores at all doses, with the high dose resulting in earlier improvement, by week 2. For the combined venlafaxine treatment groups, 68% achieved a moderate or marked improvement on the Clinical Global Impression scale, compared with only 31% for the placebo group. Venlafaxine was well tolerated, and nervousness, sweating, and nausea were the only adverse effects observed more frequently with drug compared with placebo.

Efficacy, Safety, and Tolerability of Sertraline in Patients with Late-Life Depression and Comorbid Medical Illness

Objectives: To report on the efficacy, safety, and tolerability of sertraline in the treatment of elderly depres‐sed patients with and without comorbid medical illness.

Comparative efficacy and safety of sertraline versus nortriptyline in major depression in patients 70 and older.

BACKGROUND Few randomized, double-blind studies that examine antidepressant treatment in patients 70 years and older are available. To provide additional data on the safety and efficacy of antidepressants in this rapidly growing population segment, a subgroup analysis of a larger sertraline vs. nortriptyline elderly depression treatment study was performed. METHODS Outpatients (N = 76) who met DSM-III-R criteria for major depression with a minimum Hamilton Depression Rating Scale (HAM-D) severity score of 18 were randomized to 12 weeks of flexible dose treatment with sertraline (50-150 mg) or nortriptyline (25-100 mg). RESULTS Both treatments significantly improved depression as measured by the HAM-D and Clinical Global Impression scales. At Weeks 10, 12, and endpoint, sertraline demonstrated a significantly greater reduction in depression severity compared to nortriptyline as measured by improvement on the 24-item HAM-D (mean adjusted change score of 14.8 vs. 7.6, respectively, at Week 12; p = .001). Sixty-five percent of sertraline-treated patients were responders by Week 12 (50% or greater reduction from baseline in 24-item HAM-D score) compared to 26% of nortriptyline-treated patients (p < .05). Sertraline treatment had a significantly more positive effect, when compared to nortriptyline, across almost all associated measures of cognitive function, energy, anxiety, and quality of life and was better tolerated than nortriptyline, with a lower attrition rate/side effect burden. CONCLUSION The efficacy advantage of sertraline appeared to be even greater in this subgroup of older patients drawn from a larger treatment study of depression that included elderly individuals over the age of 60.

Affective and anxiety comorbidity in post-traumatic stress disorder treatment trials of sertraline.

Comorbidity of mood and anxiety disorders is common in patients suffering from post-traumatic stress disorder (PTSD). The current study evaluated the efficacy and tolerability of sertraline in a subgroup of PTSD patients suffering from anxiety or depression comorbidity. Two multicenter, 12-week, double-blind, flexible-dose US studies of adult outpatients from the general population with a DSM-III-R diagnosis of PTSD evaluated the safety and efficacy of sertraline (50 to 200 mg/d) compared to placebo in the treatment of PTSD. The total severity score of the Clinician-Administered PTSD Scale (CAPS-2) and the Davidson Trauma Scale (DTS) were used to examine the effect of comorbidity on treatment outcome. Among the combined 395 subjects enrolled in the two trials, 32.9% had a comorbid depressive diagnosis (no anxiety diagnosis), 6.3% had a comorbid anxiety disorder diagnosis (no depression), 11.4% had both a depression and anxiety disorder diagnosis, and 49.4% had no comorbidity. The correlation, at baseline, between Hamilton Depression Rating Scale (HAM-D) total score and the three CAPS-2 clusters was 0.37 for the re-experiencing/intrusion cluster, 0.52 for the avoidance/numbing cluster, and 0.45 for the hyperarousal cluster. Patients suffering from PTSD complicated by a current diagnosis of both depression and an anxiety disorder showed the highest baseline CAPS-2 cluster score severity. Patients treated with sertraline improved significantly (P <.05) compared to placebo on both the CAPS-2 and DTS whether or not they had a comorbid depressive or anxiety disorder. Sertraline was well tolerated. The presence of comorbidity was associated with a modest and mostly nonspecific increase in the side effect burden of approximately 10% to 20% on both study treatments. Patients suffering from dual depression and anxiety disorder comorbidity benefited from somewhat higher doses (147 mg v 125 mg; P =.08). Similarly, the presence of dual comorbidity resulted in a modest but nonsignificant increase in the mean time to response from 4.5 weeks to 5.5 weeks. We conclude that sertraline (50 to 200 mg/d) is effective and well tolerated in the treatment of PTSD for patients suffering from a current, comorbid depressive or anxiety disorders.

Clinical and treatment response characteristics of late-life associated with vascular disease: A pooled analysis of two multicenter trials with sertraline

Abstract 1. The safety and efficacy of sertraline in the treatment of moderate-to-severe major depression in elderly outpatients, aged 60 years and older, with comorbid vascular disease was evaluated. 2. An analysis of the pooled results for the sertraline treatment group drawn from two prospective, randomized, double-blind studies (sertraline vs. fluoxetine, and sertraline vs. nortriptyline) was done. Patients were retrospectively categorized into one of 3 clinical groups: 1) patients with a current diagnosis of hypertension but no other past or present cardiovascular illness (HTN), 2) patients reporting a current or past history of cardiovascular illness, but excluding hypertension (VASC), and 3) patients with no hypertension, and no other comorbid vascular illness (No VASC). Patients received 12- 3. weeks od double-blind treatment sertraline in flexible daily doses in the range of 50 – 150 mg (in the nortriptyline comparator trial) or 50 – 100 mg (in the fluoxetine comparator trial). 4. Sertraline treatment yielded comparable levels of response in all 3 groups (response criterion: CGI-much or very much improved) at treatment endpoint on both a completer analysis (HTN, 86%; VASC, 89%; NoVASC, 77%) and significantly higher response rates on a 12-week endpoint analysis (HTN, 74%, VASC, 69%; NoVASC, 58%; p 5. Sertraline was found to be safe, well-tolerated, and effective as an antidepressant in elderly patients suffering from hypertension and other forms of vascular comorbidity.

Early improvement predicts endpoint remission status in sertraline and placebo treatments of panic disorder

The early identification of likely remitters and non-remitters to pharmacotherapy for panic disorder may have important implications for clinical treatment decisions. To address this question, combined data from two fixed-dose and two flexible dose placebo-controlled studies of sertraline treatment of panic disorder were examined. Patients (N=544) diagnosed with panic disorder, with or without agoraphobia, were treated with 50 mg of sertraline, 100 mg of sertraline, flexible dosages of sertraline, or placebo. Measures of early improvement included panic attack frequency (full + limited symptom attacks), anticipatory anxiety, the Hamilton Anxiety Rating Scale (HAM-A), and the Clinical Global Impression Improvement (CGI-I) Scale. Improvement as reflected in CGI-I ratings and change from baseline in the HAM-A at weeks 1, 2, and 3 significantly (P<0.0001) predicted endpoint clinical remission (defined at endpoint as no full panic attacks and a CGI-Severity rating of 1 or 2). Improvements in panic attack frequency and anticipatory anxiety were not consistent predictors in multivariate predictive models. Receiver-Operator Curve analyses revealed good specificity (0.83) for change in CGI-I at week 2, and good sensitivity (0.82) for change in HAM-A at week 3. Predictive success for HAM-A and CGI-I was not significantly different for fixed vs. flexible dose sertraline treatment, nor for sertraline vs. placebo treatment. The use of ROC analyses for examination of early response as a predictor of final remission holds promise for aiding clinicians in decision making regarding the need for alternative or supplemental treatment approaches during the course of pharmacotherapy for panic disorder.

The efficacy of sertraline in panic disorder: combined results from two fixed-dose studies.

&NA; Data from two fixed‐dose studies of sertraline in panic disorder were pooled in order to provide sufficient power for the analysis of treatment response in clinically relevant subgroups. Male and non‐fertile female patients meeting DSM‐III‐R criteria for moderate‐to‐severe panic disorder with or without agoraphobia completed a 1‐2 week placebo run‐in period, and then were randomized to 12 weeks of double‐blind treatment with either placebo, or one of three fixed daily doses of sertraline (50 mg, 100 mg, or 200 mg). Eighty‐two patients were treated with placebo and 240 patients were treated with one of three doses of sertraline. All three sertraline doses produced significant efficacy compared to placebo, with no consistent evidence of a dose‐response effect. For the subset of patients with subsyndromic depression at baseline [baseline Hamilton Depression Rating scale (HAM‐D > 12 and ≤ 21], sertraline yielded a significantly higher panic‐free rate than did placebo (P = 0.021), again, by a conservative endpoint (Last Observation Carried Forward method, LOCF) analysis. Sertraline was well‐tolerated at all dose levels, with no significant between‐dose differences in patients discontinuing due to adverse events. The presence of mild‐to‐moderate subsyndromic levels of depression did not reduce the anti‐panic efficacy of sertraline. Int Clin Psychopharmacol 15:335‐342

Symptoms of Late-Life Depression: Frequency and Change During Treatment

OBJECTIVE The authors determined the symptoms frequently present in older patients with major depression that showed the greatest change during treatment and that best correlated with an independent measure of improvement (the Clinical Global Impression scale [CGI]). METHODS Subjects included 728 patients over the age of 60 years with major depression who were selected for entry into a clinical trial. Authors determined the frequency of symptoms on the 17-item Hamilton Rating Scale for Depression (Ham-D) and the effect size of symptom change during treatment. RESULTS Nine symptoms were identified that were frequent, showed the greatest change during treatment, and best correlated with CGI. The items included depressed mood; loss of interest in work and activities; psychic anxiety; somatic symptoms, general (decreased energy); somatic anxiety; guilt; middle insomnia; late insomnia; and suicidal ideation. These nine items accounted for 92% of the variance in the 17-item Ham-D score, correlated with the CGI at a level similar to the 17-item Ham-D, and were at least as sensitive as the 17-item Ham-D for detecting drug-placebo differences. A comparison with five other similar approaches in non-geriatric samples suggested that the symptoms identified were relatively similar in both age-groups. CONCLUSIONS Symptoms frequent in patients with late-life depression are similar to those in mixed-aged samples. Nine of the Ham-D items appear most useful for assessment of change during treatment.

Efficacy of sertraline in posttraumatic stress disorder secondary to interpersonal trauma or childhood abuse

BACKGROUND: In posttraumatic stress disorder (PTSD), the nature of the trauma and the age of occurrence may have substantial effects on psychobiological sequelae and treatment response. Interpersonal trauma (physical/sexual assault) and childhood abuse are both prevalent and associated with later PTSD. This analysis was conducted to specifically assess the efficacy of sertraline in the treatment of PTSD secondary to interpersonal trauma or childhood abuse. METHODS: 395 adult patients with PTSD were randomized to 12-weeks double-blind treatment with flexible dose sertraline (50-200 mg/d) or placebo. Patients with different index traumas were compared in terms of baseline demographic and clinical characteristics, as well as treatment response. Primary efficacy variables included part 2 of the Clinician Administered PTSD Scale (CAPS-2). RESULTS: Interpersonal trauma and childhood abuse were both more common in females than males, and were associated with early age at time of index trauma and longer duration of PTSD, but not with PTSD symptom severity. Sertraline was significantly more effective than placebo on most primary efficacy variables, irrespective of whether patients had experienced interpersonal trauma or childhood abuse. CONCLUSIONS: These data demonstrate that sertraline is valuable for the treatment of PTSD, irrespective of whether the precipitating trauma involves interpersonal trauma in general, or childhood abuse in particular. Language: en