Biomedical subjects
Publications and source records attributed to L M Koran.
Available data suggest that OCD has a substantial adverse effect on the HRQL of sufferers and their families. Although no consensus exists as to how to conceptualize or measure HRQL, studies using various concepts and measures will create a greater appreciation of the suffering and impairment entailed in this illness and a greater understanding of the costs, benefits, and limitations of treatment.
OBJECTIVE: Chronic depression starts at an early age for many individuals and could affect their accumulation of "human capital" (i.e., education, higher amounts of which can broaden occupational choice and increase earnings potential). The authors examined the impact, by gender, of early- (before age 22) versus late-onset major depressive disorder on educational attainment. They also determined whether the efficacy and sustainability of antidepressant treatments and psychosocial outcomes vary by age at onset and quantified the impact of early- versus late-onset, as well as never-occurring, major depressive disorder on expected lifetime earnings. METHOD: The authors used logistic and multivariate regression methods to analyze data from a three-phase, multicenter, double-blind, randomized trial that compared sertraline and imipramine treatment of 531 patients with chronic depression aged 30 years and older. These data were integrated with U.S. Census Bureau data on 1995 earnings by age, educational attainment, and gender. RESULTS: Early-onset major depressive disorder adversely affected the educational attainment of women but not of men. No significant difference in treatment responsiveness by age at onset was observed after 12 weeks of acute treatment or, for subjects rated as having responded, after 76 weeks of maintenance treatment. A randomly selected 21-year-old woman with early-onset major depressive disorder in 1995 could expect future annual earnings that were 12%-18% lower than those of a randomly selected 21-year-old woman whose onset of major depressive disorder occurred after age 21 or not at all. CONCLUSIONS: Early-onset major depressive disorder causes substantial human capital loss, particularly for women. Detection and effective treatment of early-onset major depressive disorder may have substantial economic benefits.
BACKGROUND: Adding the atypical neuroleptic risperidone to a serotonin reuptake inhibitor (SRI) has benefited patients with treatment-refractory obsessive-compulsive disorder (OCD). Since olanzapine and risperidone have similar serotonergic and dopaminergic receptor binding profiles, we tested the hypothesis that olanzapine augmentation would be beneficial in treatment-unresponsive OCD. METHOD: For this 8-week trial, we recruited 10 adult OCD patients (DSM-IV criteria) unresponsive to fluoxetine (> or =60 mg/day) for > or =10 weeks, which was continued throughout the trial. Other psychotropic medications were discontinued. Subjects had OCD for > or =1 year, a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of > or =18, and no organic, psychotic, or other primary Axis I disorder. Two weeks after olanzapine, 2.5 mg/day, was added, and in the absence of responder status (Y-BOCS score decrease > or =25%) and limiting side effects, we increased the dose to 5 mg/day, and after 2 more weeks, to 10 mg/day for 4 weeks. RESULTS: The subjects had failed a mean of 3.3 SRI trials (range, 1-5) and had a mean +/- SD baseline Y-BOCS score of 29.0 +/- 4.9. Nine patients completed the trial. The subjects' mean +/- SD endpoint Y-BOCS score was 24.4 +/- 8.0 (a 16% decrease). The 3 responders' Y-BOCS scores dropped 68%, 30%, and 29%, but only 1 patient was rated "much improved." He maintained this improvement during a 6-month follow-up period taking olanzapine, 5 mg/day. Improvement in OCD was independent of improvement in mood symptoms. Six patients (60%) experienced significant weight gain. CONCLUSION: Olanzapine augmentation may benefit treatment-unresponsive OCD. Double-blind, placebo-controlled trials are warranted along with trials comparing risperidone and olanzapine augmentation.
We investigated the comparative efficacy of citalopram vs. citalopram administered with clomipramine, in treatment-resistant obsessive-compulsive disorder (OCD). Sixteen adult outpatients participated in a 90-day, randomized, open-label trial. Eligible patients were aged 18 to 45 years, had moderate to severe DSM-III-R OCD of >/= one year's duration, a baseline Yale-Brown scale (Y-BOCS) score of >/= 25 and no other active axis I diagnosis, and had failed adequate clomipramine and fluoxetine trials. The citalopram-plus-clomipramine group (n = 9) experienced a significantly larger percent decrease in mean Y-BOCS score by day 90 than the citalopram alone group (n = 7). Only one citalopram patient decreased her score by >/= 35%, and two by >/= 25%. All nine citalopram-plus-clomipramine patients experienced decreases of 35%. Side effects were mild to moderate in both groups. We also treated with citalopram six OCD patients who had not tolerated fluoxetine alone and clomipramine alone; three achieved Y-BOCS score decreases of >/= 35% at 90 days. Since citalopram does not significantly affect clomipramine metabolism, the improvement in the combined drug group is unlikely to have resulted from increased plasma clomipramine levels. Double-blind controlled trials are needed of citalopram in OCD, and of combining citalopram with clomipramine in treatment-resistant OCD.
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BACKGROUND: We describe the demographic characteristics, hoarding phenomenology, comorbid disorders, family histories, and treatment response of 20 adult obsessive-compulsive disorder (OCD) patients exhibiting hoarding behavior. METHOD: We utilized the Structured Clinical Interview for DSM-III-R, the Yale-Brown Obsessive Compulsive Scale, and a semistructured interview to gather data. RESULTS: We studied 9 women and 11 men. Their hoarding began from age 5 years to age 46 years (mean +/- SD age at onset = 20 +/- 11 years); hoarding was evident before the onset of other OCD symptoms in 9 patients. The most commonly hoarded items were newspapers and magazines, junk mail, old clothes, notes or lists, and old receipts. Hoarded material occupied from one room plus most or all closets to more than one room plus all closets, the garage, and yard. Seven patients rented additional storage space for hoarded items. Eighty-four percent of patients reported a family history of hoarding, and 80% grew up in a household where someone else hoarded. The most frequent primary motives for hoarding were fears of discarding something useful and discarding something that would be needed in the future. Lifetime prevalence of major depression and of impulse-control disorders, especially compulsive shopping, were high; only 3 patients met DSM-IV criteria for obsessive-compulsive personality disorder. Response of hoarding to selective serotonin reuptake inhibitors was less robust than is expected for obsessive-compulsive disorder. CONCLUSION: Whether hoarding behaviors mark a subset of obsessive-compulsive disorder patients with a different pathophysiology or functional anatomy deserves investigation.
BACKGROUND: Challenge with intravenous clomipramine (CMI) is serotonin selective and has been reported to transiently exacerbate symptoms in obsessive-compulsive disorder (OCD) patients, and to predict subsequent response to oral CMI therapy. METHODS: We administered CMI (12.5 mg, i.v.) to medication free OCD patients (N = 29) and normal controls (N = 22) to characterize neurohormonal response. A subset of OCD patients (26/29), was then treated with either pulse load i.v. or oral CMI followed by 8 weeks of oral CMI therapy. RESULTS: In response to CMI challenge, OCD patients exhibit blunted cortisol and exaggerated growth hormone response relative to normal controls. OCD patients differ from controls in "sadness" ratings, with control exhibiting increased dysphoria in response to CMI. Growth hormone response to CMI challenge predicts treatment response (> or = 25% decreases YBOCS from baseline) to oral CMI at 8 weeks. CONCLUSIONS: Growth hormone abnormalities associated with OCD in response to CMI challenge differentiates nonresponders after 8 weeks of oral CMI treatment from responders.
OBJECTIVE: We compared gradually increased to pulse loaded doses of open-label, intravenous clomipramine (CMI) in patients with obsessive-compulsive disorder (OCD). METHOD: We treated adult outpatients with DSM-III-R OCD, who had no prior exposure to effective treatments. Pulse loading patients received 150 mg on day 1; 150 mg or 200 mg on day 2. Gradual dosing patients received 25 mg per day increased to 200 mg per day over 2 weeks and then continued for a mean of 43 days (n=40). After i.v. dosing, all patients received oral CMI; the total treatment period was 6 months. RESULTS: Pulse loading completers (n=7) had a rapid, dramatic response (mean Y-BOCS score decrease of 32% five days after pulse-loading). At this point (day 7), completers in the gradual intravenous group (n=20) exhibited no mean change in Y-BOCS score. The pulse loading group reached both a 25% or greater and a 50% or greater decrease in Y-BOCS score statistically and clinically significantly faster than the gradual group. CONCLUSIONS: Pulse-loaded intravenous CMI for the treatment of OCD deserves further study.
BACKGROUND: Chronic depression appears to be a common, frequently disabling illness that is often inadequately treated. Unlike episodic depressions with shorter illness duration, neither acute nor long-term treatment approaches for chronic depression have been well studied. METHOD: 635 outpatients at 12 sites who met DSM-III-R criteria for chronic major depression or double depression were randomly assigned to 12 weeks of double-blind treatment with either sertraline (in daily doses of 50-200 mg) or imipramine (in daily doses of 50-300 mg). Efficacy and safety were assessed either weekly or every 2 weeks during the 12 weeks of acute treatment. RESULTS: Despite high rates of chronicity (mean duration of major depression = 8.9+/-9.1 years; mean duration of dysthymia = 23+/-13 years) and high rates of comorbidity, 52% of patients achieved a satisfactory therapeutic response to sertraline or imipramine (by a conservative, intent-to-treat analysis). Approximately 21% of the patients who had achieved a therapeutic response at week 12 had not done so at week 8, confirming the longer time to response in depressions with high chronicity. Patients treated with sertraline reported significantly fewer adverse events and were significantly less likely to discontinue treatment due to side effects than imipramine-treated patients (6.3% vs. 12.0%). CONCLUSION: These results indicate that patients suffering from depression with high chronicity can achieve a good therapeutic response to acute treatment with either sertraline or imipramine, although sertraline is better tolerated.
BACKGROUND: The literature on predictors of response to treatment of nonchronic major depression has identified shorter duration of illness, acute onset, and less severity of illness as positive predictors. Unfortunately, there are almost no data on predictors of response to treatment for chronic depression. This study examined predictors of response to pharmacotherapy (sertraline or imipramine) in the treatment of outpatients who had DSM-III-R-defined chronic major or double depression. METHOD: The acute phase of the Chronic Major Depression and Double Depression Study is a double-blind, randomized, parallel-group 12-week comparison of sertraline and imipramine. Analyses are based on 623 patients who comprised the intent-to-treat sample, of whom 299 were nonresponders and 324 were responders, defined by a priori criteria as either remission or satisfactory therapeutic response. A stepwise logistic multiple regression analysis was performed on candidate clinical, psychosocial, and demographic variables previously identified as statistically significant in an attempt to develop a predictive model of positive antidepressant response. RESULTS: The sociodemographic variables that were predictive of positive response included living with spouse or partner or being at least a high school graduate. With regard to symptomatology and clinical history, responders had significantly lower baseline depression severity scores. In general, comorbid anxiety, substance abuse, and personality disorders did not influence rates of response. However, the presence of depressive personality traits was associated with a higher nonresponse rate. Among psychosocial variables, longer duration of personal relationships as well as higher baseline quality of life were associated with positive response. A stepwise logistic multiple regression identified 5 variables-living with spouse or partner, higher educational level, passive-aggressive personality, lower introverted-tense personality traits, and higher quality of life--that significantly and independently contributed to the predictive model. This model correctly classified 67% of patients. CONCLUSION: A higher baseline quality of life, living with spouse or partner, and having more education were the strongest predictors of response to acute pharmacotherapy among chronically depressed patients. Clinical variables and comorbidity were not identified as independent predictors, although personality traits did appear to influence treatment response. Overall, the predictive value of these baseline measures was modest, and therefore of limited clinical utility.
BACKGROUND: Chronic depressions are common, disabling, and undertreated, and prior chronicity predicts future chronicity. However, few studies directly inform the acute or maintenance phase treatments of chronic depressions and even less is known about the effects of treatment on psychosocial functioning. METHOD: We describe the design and rationale for 2 parallel double-blind, randomized, multicenter acute and maintenance phase treatment trials. One focused on DSM-III-R major depression currently in a chronic (> or = 2 years) major depressive episode, the other on DSM-III-R major depression with concurrent DSM-III-R dysthymia ("double depression"). RESULTS: Considering the critical knowledge deficits, we designed a 12-week acute phase safety and efficacy trial of sertraline versus imipramine, followed by a 16-week continuation treatment phase for subjects with a satisfactory therapeutic response. Patients receiving sertraline who successfully completed the continuation phase entered a 76-week maintenance trial to compare sertraline with placebo; those taking imipramine continued without a placebo substitution. As part of the acute trial, subjects completing but failing to respond to the initial 12-week acute phase medication were crossed over (double-blind) to the alternative medication for a 12-week acute phase trial. We obtained naturalistic follow-up data (up to 18 months) for subjects exiting the protocol at any time. CONCLUSION: Multiphase protocols for chronic depression can test efficacy by randomized contrasts as well as shed light on key clinical issues such as the degree of response or attrition expected at particular times in a trial or the preferred medication sequence in a potential multistep treatment program.
The present study investigated the tolerability, safety profile, and anti-obsessional efficacy of sertraline, a selective serotonin reuptake inhibitor, during long-term treatment of patients with obsessive-compulsive disorder (OCD). Fifty-nine OCD patients who had completed a 1 year double-blind, fixed dose study comparing sertraline and placebo subsequently entered a 1-year open extension. Among the 51 patients who had been treated with sertraline during the double-blind phase, the mean total duration of sertraline treatment was 690 days. Only treatment responders who completed the 52-week double-blind treatment phase were permitted to enter the open extension. The higher rate (p < 0.02) of sertraline patients (51 out of 241) than of placebo patients (eight out of 84), who responded to treatment and entered the open-label phase is therefore consistent with the greater mean improvement observed in the sertraline group during double-blind treatment. Placebo responders differed from sertraline responders in that they were less impaired at baseline of the double-blind study [Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) of 18.5 versus 23.4] and they exhibited less improvement during double-blind treatment (-6.1 versus -11.4). In the open-label phase all patients received sertraline at a starting dose of 50 mg once a day, titrated in 50 mg increments to a maximum dose of 200 mg according to clinical response. At end-point the mean Y-BOCS score for all patients decreased by a further 3.6 points. Patients previously treated with placebo showed greater improvement after being switched to sertraline than those who received continued sertraline treatment. Patients who completed the study and received 2 full years of sertraline treatment (n = 38) exhibited a mean improvement of 15.6 points using the Y-BOCS. Sertraline was well tolerated during both the double-blind phase and the open extension, and the incidence of adverse experiences was generally reduced during the second year of treatment. Three patients discontinued open treatment because of adverse experiences. Long-term sertraline treatment did not appear to be associated with the emergence, increased incidence, or increased severity of adverse experiences or clinically significant abnormalities in laboratory tests, vital signs, or the electrocardiogram. The study supports the long-term safety and tolerability of sertraline over a 2-year treatment course and the sustained efficacy of sertraline in patients with OCD.
OBJECTIVE: The authors conducted a randomized, double-blind, placebo-controlled trial of intravenous versus oral pulse loading of clomipramine in patients with obsessive-compulsive disorder to test two hypotheses: 1) intravenous pulse loading will cause greater immediate improvement than oral pulse loading and 2) patients who respond to pulse loading will continue to improve during 8 weeks of oral clomipramine treatment. METHOD: Fifteen patients with DSM-III-R obsessive-compulsive disorder of at least 1 year's duration and baseline Yale-Brown Obsessive Compulsive Scale scores of 17 or higher were enrolled in the study. Yale-Brown scale ratings were made 4.5 days after double-blind oral or intravenous pulse loading of clomipramine, and patients were then given 150 mg/day of oral clomipramine with increases of 25 mg every 4 days to 250 mg/day as tolerated or, in two cases, other selective serotonin reuptake inhibitors (SSRIs). RESULTS: The first hypothesis was confirmed: 4.5 days after the second pulse-loaded dose, six of seven patients given intravenous clomipramine but only one of eight given oral medication responded to the drug. After 8 weeks of oral clomipramine, the results partially supported the second hypothesis: four of six patients who had responded to intravenous clomipramine continued their improvement, but those who had responded to pulse loading did not improve statistically significantly more than those who had not. CONCLUSIONS: Intravenous pulse loading of clomipramine may be a valuable new treatment for obsessive-compulsive disorder, particularly for patients who have failed oral treatment trials.
BACKGROUND: Recent reports suggest that pregnancy and the puerperium may precipitate or exacerbate obsessive-compulsive disorder (OCD). The influence of this illness on other reproductive events, such as the premenstruum, is unknown. We examined retrospectively the relationships of pregnancy, the puerperium, and premenstruum to the course of OCD in 57 women. METHOD: Women outpatients with OCD meeting DSM-III-R criteria completed a standardized telephone interview administered by a psychiatric resident. They were asked retrospectively about the clinical course of their illness premenstrually and during and after pregnancy. RESULTS: Of 72 women eligible for the study, 79% (N = 57) completed the interview. Premenstrual worsening of OCD was described by 24 (42%) of the 57 women, and 12 (21%) described premenstrual dysphoria. Of the 57 women, 38 (67%) had been pregnant at least once; 31 (54%) had delivered at least one child. Pregnancy was associated with the onset of OCD in only 5 (13%) of the 38 women. Of the 29 women with preexisting OCD who became pregnant, 20 (69%) described no change in symptoms during pregnancy, 5 (17%) described worsening, and 4 (14%) described improvement. Postpartum exacerbation of OCD symptoms was reported by 7 (29%) of the 24 women with preexisting OCD who completed full-term pregnancies. Nine (37%) of the 24 women with both preexisting OCD and completed pregnancies also reported postpartum depression. CONCLUSION: The premenstrual and postpartum exacerbation of OCD symptoms in some women suggests that the course of this disorder may, in some cases, be influenced by changes in gonadal hormones. Our finding that women with OCD may be at increased risk for postpartum depression underscores the importance of careful postpartum evaluation of women with OCD to prevent maternal and infant morbidity.
The efficacy and tolerability of fluvoxamine (100-300 mg/day) and clomipramine (100-250 mg/day) were compared in a randomized, double-blind, parallel-group study of 79 patients with obsessive-compulsive disorder (OCD) without coexisting major depression. After a 2-week placebo lead-in period, patients were randomized to fluvoxamine (37 patients) or clomipramine (42 patients) for 10 weeks. Efficacy was evaluated with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the National Institute of Mental Health Obsessive-Compulsive scale, and Patient and Clinical Global Improvement scales. Hamilton Rating Scale for Depression scores and somatic symptoms were also assessed. Seventy-eight percent of fluvoxamine patients and 64% of clomipramine patients completed the study. At the end of treatment, 56% of fluvoxamine patients were classified as responders (> or = 25% decrease in Y-BOCS score), compared with 54% of clomipramine patients. Both groups showed steady improvement throughout the study; no statistically significant differences were observed between the groups for any efficacy variable at any time. A similar percentage of patients in both groups withdrew because of adverse events. No serious adverse events related to drug occurred with either drug. Insomnia, nervousness, and dyspepsia were more statistically frequent with fluvoxamine; dry mouth and postural hypotension were more frequent with clomipramine. In this study, fluvoxamine and clomipramine were equally effective in reducing OCD symptoms over a 10-week treatment period but displayed different side effect profiles.
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OBJECTIVE: Because physical illness may influence quality of life, we assessed its impact on functional status and treatment outcome in older depressed patients who participated in a clinical trial, which showed a significantly higher remission rate for fluoxetine over placebo (31.6% vs 18.6%, P < .001). DESIGN: Six-week, randomized, double-blind, placebo-controlled trial of fluoxetine, 20 mg daily. SETTING: Multiple clinical sites, both university and private. PARTICIPANTS: Outpatients (N = 671) were > or = 60 years (mean +/- SD = 67.7 +/- 5.7), met DSM-III-R criteria for unipolar major depression and had baseline scores > or = 16 on the Hamilton Depression Rating Scale. MEASUREMENTS: The 36-item short-form health survey (SF-36) was used to measure baseline and posttreatment functional health and well-being. Physical illness was rated by number of current chronic or historical illnesses. Change from baseline to endpoint in the Hamilton Depression Rating Scale total score was used to measure depression outcome. MAIN RESULTS: Most patients reported physical illness: 83% had one or more chronic illness, and 89% had one or more historical illness. Greater numbers of baseline chronic illness indicated worse physical functioning, general health perceptions, and vitality and greater bodily pain and role limitation from physical problems. Historical physical illness was associated with worse physical functioning, vitality, general health perceptions, social functioning, and mental health. Although the number of chronic illnesses did not influence treatment response, historical physical illness was associated with greater fluoxetine response and lower placebo response. CONCLUSIONS: These findings suggest that both current and previous physical illness are associated with lower quality of life in geriatric depression and that depressed older patients with chronic physical illness respond to antidepressants as well as those without such illness. Recovery from previous physical illness should be explored as a potential predictor of antidepressant treatment outcome.
OBJECTIVE: In obsessive-compulsive disorder, the relationship between blood levels of serotonin reuptake inhibitors and clinical outcome is unclear. In a multicenter trial, the authors examined the relationship between steady state plasma levels of fluoxetine and norfluoxetine (determined after 7 weeks of treatment), and their sum, and clinical outcome. METHOD: Ratings of symptom severity of obsessive-compulsive disorder (Yale-Brown Obsessive Compulsive Scale scores) were obtained at baseline and after 13 weeks for 200 adult outpatients with moderately severe obsessive-compulsive disorder treated with fluoxetine doses of 20 mg/day (N = 68), 40 mg/day (N = 64), and 60 mg/day (N = 68). RESULTS: Mean plasma levels of fluoxetine and norfluoxetine were statistically significantly higher with higher dose. Statistical analyses revealed no significant relationship for plasma level of either molecule or their sum in predicting endpoint percent change in obsessive-compulsive scores. Plasma levels of patients with a marked response (decrease of 50% or more in obsessive-compulsive score) did not differ significantly from those of nonresponders (less than a 25% decrease in obsessive-compulsive score). No hint was seen of a therapeutic window or of a relationship limited to one gender or within the lowest dose group (20 mg/day). However, since S-norfluoxetine is a much more potent serotonin reuptake inhibitor than R-norfluoxetine, the absence of chiral (stereospecific) assays in this study limits the results. CONCLUSIONS: Steady state plasma levels of fluoxetine and norfluoxetine are not related to clinical outcome in patients with obsessive-compulsive disorder. Individual patients can be told only that the optimum dose of fluoxetine for them will be the dose that produces the largest therapeutic effect with the smallest side effect burden. Future studies should examine the predictive utility of measures of serotonergic neuronal function and, if plasma levels of norfluoxetine are examined, the use of chiral assays.