Lamotrigine augmentation in schizophrenia and schizoaffective patients with obsessive-compulsive symptoms.

Obsessive-compulsive symptoms (OCS) are clinically important phenomena in schizophrenia patients. Lamotrigine has a modulating effect on glutamatergic neurotransmission relevant to pathophysiology of both schizophrenia and OCD. Efficacy and tolerability of lamotrigine in schizophrenia and schizoaffective patients with comorbid OCS were evaluated. In an 8-week, open-label trial, lamotrigine (25 mg/day for 1 week, 50 mg for 2 weeks, 100 mg for 2 weeks, 200 mg for 3 weeks) was added to ongoing psychotropic drug regimens in schizophrenia (N = 5) and schizoaffective disorder (N = 6) patients with clinically significant OCS [Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score > 16]. The Y-BOCS score for nine completers decreased significantly from baseline to week 8 (22.9 +/- 6.1 vs 17.4 +/- 3.6; t = 2.33, df = 1, P = 0.033). Five patients, all with schizoaffective disorder, were responders (>or=35% decrease in Y-BOCS score). No significant changes were detected in schizophrenia symptom severity. Depressive symptoms, assessed with the Calgary Depression Rating Scale, improved significantly (6.4 +/- 1.5 vs 4.0 +/- 2.5; t = 3.19, df = 1, P = 0.013); this change positively correlated with OCS improvement (r = 0.69, P = 0.04). Lamotrigine was safe and well tolerated. Explicit evaluation of therapeutic efficacy of adjunctive lamotrigine in schizoaffective disorder patients with comorbid OCS merits further investigation.

Quetiapine versus clomipramine in the augmentation of selective serotonin reuptake inhibitors for the treatment of obsessive-compulsive disorder: a randomized, open-label trial.

After 12 weeks of selective serotonin reuptake inhibitor (SSRI) monotherapy with inadequate response, 10 patients received clomipramine and 11 received quetiapine as augmentation agents of the SSRI. The primary outcome measure was the difference between initial and final scores of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), rated in a blinded fashion, and the score of clinical global improvement (CGI-I). Statistical analyses were performed using nonparametric tests to evaluate treatment efficacy and the difference between treatment groups. Percentile plots were constructed with YBOCS scores from the clomipramine and quetiapine groups. Considering response a >or=35% reduction in the initial Y-BOCS score plus a rating of 'much improved' or 'very much improved' on CGI-I, four of eleven quetiapine patients and one out of ten clomipramine patients were classified as responders. The mean final Y-BOCS score was significantly lower than baseline in the quetiapine augmentation group (P = 0.023), but not in the clomipramine augmentation group (P = 0.503). The difference between groups showed a trend towards significance only at week 4, the mean Y-BOCS score being lower for those receiving quetiapine (P = 0.052). A difference between groups was also observed at week 4 according to percentile plots. These results corroborate previous findings of quetiapine augmentation efficacy in obsessive-compulsive disorder (OCD). Clomipramine augmentation did not produce a significant reduction in Y-BOCS scores. Higher target maximum dosages might have yielded different results.

Obsessive-compulsive disorder (OCD) with schizotypy vs. schizophrenia with OCD: diagnostic dilemmas and therapeutic implications.

Although schizophrenia and obsessive-compulsive disorder (OCD) are distinct diagnostic entities, there are substantial areas of overlap between the two disorders in clinical characteristics, affected brain areas and pharmacotherapy. Though OCD patients apparently do not have increased risk for developing schizophrenia, schizotypal personality disorder has consistently been found in OCD patients. Compelling evidence also points to an increased rate of OCD in schizophrenia patients. Accurate diagnosis of both disorders in their "pure" and overlapping forms is necessary in order to evaluate etiological mechanisms underlying schizophrenia and OCD, and to provide adequate treatment and prognosis. In this review, we address some aspects of the current status of research pertinent to the OCD-schizophrenia interface and suggest further steps towards the clinical and etiological identification of homogeneous subgroups on the putative OCD-schizophrenia axis.

The prevalence of clinically recognized obsessive-compulsive disorder in a large health maintenance organization.

OBJECTIVE: Little is known about the prevalence of obsessive-compulsive disorder (OCD) as recognized in clinical settings. The authors report data on the prevalence of clinically recognized OCD in a large, integrated, group practice health maintenance organization (HMO). METHOD: The authors examined the database of outpatient diagnoses for the 1.7 million people (age >or=6) in the San Francisco Bay Area and Sacramento who were continuously enrolled in Kaiser Permanente from May 1995 through April 1996. OCD diagnoses were confirmed by chart review. RESULTS: The 1-year prevalence of clinically recognized OCD was 84/100,000 (95% confidence interval: 80-89/100,000), or 0.084%. It varied among the 19 clinics within the HMO but was nowhere higher than 150/100,000. Prevalence was higher among women than among men but was higher among boys than among girls. Above age 65, OCD prevalence decreased markedly in both genders. Period prevalence rates increased by 60% as the length of the study period doubled from 1 to 2 years, more than would be expected for a chronic disease requiring regular care. About three-quarters of both children and adults with OCD had comorbid psychiatric diagnoses; major depression was common in both groups. CONCLUSIONS: Although previously reported prevalences of 1%-3% from community studies may have included many transient or misclassified cases of OCD not requiring treatment, the very low prevalence of clinically recognized OCD in this population suggests that many individuals suffering from OCD are not receiving the benefits of effective treatment.

Fluoxetine in pathologic skin-picking: open-label and double-blind results.

Various studies suggest that selective serotonin reuptake inhibitors (SSRIs) may be useful in treating pathologic skin-picking. The authors investigated the effectiveness of fluoxetine in treating this behavior. Fifteen subjects with clinically significant skin-picking were recruited by newspaper advertisement. They received 6 weeks of open-label treatment with fluoxetine. Responders were then randomized to 6 weeks of double-blind fluoxetine or placebo. Treatment effect was assessed with standardized rating scales. All 15 subjects completed open-label treatment, and 8 were responders. Of these eight, the four randomized to double-blind fluoxetine maintained clinically significant improvement. The four randomized to placebo returned to their baseline symptom level. Larger studies are needed to determine which individuals are likely to respond to fluoxetine and the relative effectiveness of fluoxetine, other SSRIs, and other forms of treatment.

Sertraline versus imipramine to prevent relapse in chronic depression.

BACKGROUND: Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study. METHODS: After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment. RESULTS: Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment. LIMITATIONS: The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates. CONCLUSIONS: Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.

Sumatriptan, 5-HT(1D) receptors and obsessive-compulsive disorder.

BACKGROUND: After considering the effects of 5-HT receptor agonists with different binding profiles on the symptoms of obsessive-compulsive disorder (OCD), Zohar and Kindler hypothesized that the 5-HT(1D) receptor was implicated in this disorder's pathophysiology. METHODS: We explored the 5-HT(1D) hypothesis in a 5-day, random, double-blind, placebo-controlled trial of oral sumatriptan 100 mg/day in medication-free adults with OCD. We hypothesized that sumatriptan, a 5-HT(1D) agonist, would diminish 5-HT release, thereby worsening OCD symptoms. We further hypothesized that by beginning to desensitize 5-HT(1D) receptors, sumatriptan pretreatment would promote a faster response or an increased likelihood of response to subsequent treatment with a selective serotonin reuptake inhibitor. RESULTS: The five sumatriptan subjects' OCD symptom worsening, as measured by the Yale-Brown scale ( upward arrow 17.6% (S.D. 14.6)), was significant when compared to the slight symptom decrease in the five placebo subjects ( downward arrow 5.2% (S.D. 4.9), P<0.015). The sumatriptan group did not exhibit a faster response or greater likelihood of response to a 90-day, open label trial of paroxetine. CONCLUSIONS: Longer term studies of the effects of 5-HT(1D) agonists on OCD symptoms are indicated. Zolmitriptan, a potent 5-HT(1D) receptor agonist with better penetration of the blood-brain barrier, may be a preferred challenge agent.

Effect of concurrent anxiety on response to sertraline and imipramine in patients with chronic depression.

Anxiety commonly complicates the clinical presentation of depression and has been associated with poorer long-term outcome, but little information is available on the clinical correlates, and comparative effect on treatment response, of subsyndromic or secondary anxiety. Patients diagnosed with chronic major or double depression were randomized to 12 weeks of double-blind treatment with either sertraline or imipramine in a 2:1 ratio. A high anxiety subgroup was operationally defined by a HAM-D anxiety/somatization factor score > or = 7. The effect of study treatment was measured utilizing the HAM-D, CGI, HAM-D anxiety/somatization factor, as well as a quality of life measure (Q-LES-Q) and a measure of psychosocial functioning (the MOS-SF-36). Two hundred nine patients were treated with imipramine and 426 patients were treated with sertraline. Thirty-six percent of the total met criteria for the high anxiety subgroup. According to Kaplan-Meier probability estimates, patients with significant concurrent anxiety symptoms were more likely to respond by 12 weeks (66.4%) than those without significant anxiety symptoms (54.2%). There was no significant difference in response rates for sertraline vs. imipramine. Both drugs were effective at treating high baseline levels of anxiety, with 60% of sertraline patients and 58% of imipramine patients having 50% or greater reduction from baseline in HAM-D anxiety/somatization factor scores, and only 4.6% and 9.9%, respectively, reporting treatment-emergent worsening in anxiety at study endpoint. Despite the chronicity of depressive illness, acute treatment with both sertraline and imipramine significantly improved psychosocial and quality of life measures. High baseline levels of anxiety did not reduce overall antidepressant response but did somewhat delay the onset of response to sertraline or imipramine in patients with chronic depression.

Pharmacotherapy of obsessive-compulsive disorder in a health maintenance organization.

The adequacy of pharmacotherapy for patients with obsessive-compulsive disorder (OCD) in a large, prepaid HMO was studied. An analysis was made of the computerized records for December 1, 1994, through April 30, 1998, for members of a Kaiser Permanente plan in northern California who were six years of age or older and had had continuous membership during an index year (May 1, 1995, to April 30, 1996) (1,728 million members). A total of 880 adults and 168 children and adolescents with chart-review-confirmed OCD and a pharmacy benefit were identified. The percentage of patients with an adequate drug trial, defined as > or = 56 days of continuous treatment with a serotonin-reuptake inhibitor or phenelzine at dosages at or above established minimal effective dosages, was determined. Forty-three percent of the adults and 28% of the children and adolescents who were newly diagnosed with OCD in the index year had an adequate trial of medication in the year after their first visit for OCD. By the second six months after the index year, only 75.2% of newly treated adults and 60.9% of newly treated children and adolescents continuing in the health plan filled at least one anti-OCD prescription. During the second follow-up year, these figures fell to 60.4% and 38.9%, respectively. Continuing-care patients filling a prescription in the index year were more likely than newly diagnosed patients to fill prescriptions in the two-year follow-up period, but their treatment still decreased substantially. Despite the typically chronic course of OCD, many patients with OCD who were enrolled in a large HMO appeared not to receive an adequate trial of pharmacotherapy or ongoing pharmacotherapy.

Quality of life in obsessive-compulsive disorder.

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.

Olanzapine augmentation for treatment-resistant obsessive-compulsive disorder.

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.

Lost human capital from early-onset chronic depression.

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.

Citalopram for treatment-resistant obsessive-compulsive disorder.

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.

Hoarding in obsessive-compulsive disorder: a report of 20 cases.

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.

Maintenance phase efficacy of sertraline for chronic depression: a randomized controlled trial.

CONTEXT: The chronic form of major depression is associated with a high rate of prevalence and disability, but no controlled research has examined the impact of long-term treatment on the course and burden of illness. OBJECTIVE: To determine if maintenance therapy with sertraline hydrochloride can effectively prevent recurrence of depression in the high-risk group of patients experiencing chronic major depression or major depression with antecedent dysthymic disorder ("double depression"). DESIGN: A 76-week randomized, double-blind, parallel-group study, conducted from September 1993 to November 1996. SETTING: Outpatient psychiatric clinics at 10 academic medical centers and 2 clinical research centers. INTERVENTION: Maintenance treatment with either sertraline hydrochloride (n = 77) in flexible doses up to 200 mg or placebo (n = 84). PATIENTS: A total of 161 outpatients with chronic major or double depression who responded to sertraline in a 12-week, double-blind, acute-phase treatment trial and continued to have a satisfactory therapeutic response during a subsequent 4-month continuation phase. MAIN OUTCOME MEASURE: Time to recurrence of major depression. RESULTS: Sertraline afforded significantly greater prophylaxis against recurrence than did placebo (5 [6%] of 77 in the sertraline group vs 19 [23%] of 84 in the placebo group; P = .002 for the log-rank test of time-to-recurrence distributions). Clinically significant depressive symptoms reemerged in 20 (26%) of 77 patients treated with sertraline vs 42 (50%) of 84 patients who received placebo (P = .001). With use of a Cox proportional hazards model, patients receiving placebo were 4.07 times more likely (95% CI, 1.51-10.95; P = .005) to experience a depression recurrence, after adjustment for study site, type of depression, and randomization strata. CONCLUSIONS: Maintenance therapy with sertraline is well tolerated and has significant efficacy in preventing recurrence or reemergence of depression in chronically depressed patients.

The treatment of chronic depression, part 1: study design and rationale for evaluating the comparative efficacy of sertraline and imipramine as acute, crossover, continuation, and maintenance phase therapies.

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 treatment of chronic depression, part 2: a double-blind, randomized trial of sertraline and imipramine.

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.

Intravenous clomipramine challenge in obsessive-compulsive disorder: predicting response to oral therapy at eight weeks.

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.