Inmaculada Gilaberte

Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment

BACKGROUND Major depression affects more than 5% of the population and is a serious health and economic problem. Antidepressants have a slow onset of action and are effective in less than two-thirds of patients. The biochemical effects of selective serotonin reuptake inhibitors may be limited by the negative feedback from serotonin autoreceptors. Pindolol is an antagonist of both serotonin autoreceptors and beta-adrenoceptors. We studied the effect of the addition of pindolol to fluoxetine antidepressant treatment. METHODS Of 132 eligible patients with major depression, 111 were randomly assigned to treatment with fluoxetine (20 mg daily) and either placebo or pindolol (7.5 mg daily). Patients were assessed twice a week for the first 3 weeks of active treatment and then once a week until the end of the study (42 days). Hamilton and Montgomery-Asberg depression-rating scales were used to assess depression severity. FINDINGS The proportion of patients who responded to treatment with fluoxetine and pindolol was greater than that with fluoxetine and placebo (41/55 [75%] vs 33/56 [59%], [90% CI 1.1-30.1], p = 0.04). The proportion of patients who achieved a sustained response was also greater in the fluoxetine and pindolol group than in the fluoxetine and placebo group (38/55 [69%] vs 27/56 [48%] [5.9-35.9], p = 0.03). The number of days to reach a sustained response was lower in the fluoxetine and pindolol group than in the fluoxetine and placebo group (median 19 vs 29 days, p = 0.01), however, there was no difference in the time-to-onset of clinical improvement when stringent conditions were used (15 vs 18 days, p = 0.20). INTERPRETATION The addition of pindolol to fluoxetine antidepressant treatment increases the effectiveness of fluoxetine therapy. Further work is needed to resolve whether the time to clinical improvement benefits from this combination and whether the increase in efficacy occurs with other antidepressants.

Recovery from schizophrenia: Results from a 1-year follow-up observational study of patients in symptomatic remission

OBJECTIVES This report presents the results of an observational empirical clinical investigation about the prevalence and correlates of a proposed definition of recovery from schizophrenia in outpatients in Spain. METHODS Of 1010 outpatients with schizophrenia (DSM-IV-TR), a subgroup of 452 patients in symptomatic remission (SR) was followed for 1 year. SR was defined according to Andreasens severity criteria based on the Scales for the Assessment of Positive (SAPS) and Negative (SANS) Symptoms. A Global Assessment of Functioning scale score of >80 was considered to be indicative of adequate functioning (AF). Correlates of recovery were identified by logistic regression. RESULTS At baseline, 103 (22.8%; N=452) patients fulfilled the recovery definition (SR + AF). After 1 year, 338 patients (89.9%; N=376) maintained SR. Among these, the proportion of patients in recovery increased to 27.1% (102 out of 376). Better premorbid adjustment (PA) and improved social cognition correlated with recovery at baseline. After 1 year, PA, duration of untreated psychosis (DUP), type of pharmacotherapy, attitudes toward medication, and variation of depressive symptoms and social cognition determined the likelihood of recovery. CONCLUSIONS The proportion of patients in recovery increased among those fulfilling SR criteria. After 1 year, in addition to known factors like shorter DUP and better PA, social cognitive abilities and depressive symptoms were found to correlate with recovery.

Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naïve children and adolescents with attention deficit/hyperactivity disorder.

Abstract Objective: To test the hypothesis that first-line treatment with atomoxetine provides superior efficacy than placebo for up to 12 weeks in improving the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). Research design and methods: This double-blind, randomized, placebo-controlled, parallel clinical trial included 151 treatment-naïve children (n = 113) and adolescents (n = 38) with newly diagnosed (≤3 months) ADHD. Atomoxetine dose was uptitrated from 0.5 to 1.2 mg/kg/day after two weeks. Outcome assessments included the ADHD Rating Scale-IV-Parent-reported Investigator-rated (ADHDRS-IV-Parent:Inv), the Clinical Global Impression of Severity of ADHD (CGI-ADHD-S), and the incidence of adverse events. Mixed-model repeated measures analysis was used to compare scale score changes between groups. Clinical trial registration: Trial registered at www.clinicaltrials.gov (study internal code: B4Z-XM-LYDM, identifier: NCT00191945). Results: Most patients were male (79.2%), of caucasian origin (96.0%) and severely ill (72.5%). Their mean age was 10.3 years. Atomoxetine-treated patients showed greater reductions from baseline to week 12 of total ADHDRS-IV-Parent:Inv score than placebo-treated patients (least square mean difference: −7.9 [95% CI: −11.0 to −4.8], corresponding to a large effect size of 0.8). Between-group mean differences increased progressively with treatment exposure from week 6 to 12 (−2.7 [−4.9 to −0.6] for total and −1.6 [−2.9 to −0.3] for inattention scores). At the end of the study, 50% of atomoxetine-treated patients (14% with placebo) showed a reduction ≥40% in total ADHDRS-IV-Parent:Inv score, and only 29% (46% with placebo) were severely ill (by CGI-ADHD-S). Treatment-related adverse events were significantly more frequent with atomoxetine (65.0%) than with placebo (37.3%), the most frequent being decreased appetite and somnolence. Only one case of decreased appetite was rated as severe. No patient discontinued treatment because of adverse events. Conclusions: A continued improvement of symptoms is expectable until 12 weeks in treatment-naïve ADHD patients treated with atomoxetine as first-line medication. Chief limitations are the small, national sample size and the absence of data beyond the 12-week time-point.

Generalized anxiety disorder, with or without co-morbid major depressive disorder, in primary care: Prevalence of painful somatic symptoms, functioning and health status

BACKGROUND Painful physical symptoms (PPS) have received little attention in patients with generalized anxiety disorder (GAD). The objective of the present study was to assess the prevalence of PPS in patients with GAD vs patients with GAD and co-morbid major depressive disorder (MDD) and a control group (patients neither with GAD nor MDD). METHODS This is a cross-sectional, multi-center, epidemiological study, in primary care. Patients were screened for GAD (HADS-A), followed by a diagnosis confirmation (MINI). Patients were considered to have PPS when VAS overall pain score >30. Functioning and health status was assessed (SDS, EUROQoL-5D). Relationships between the presence of PPS and functioning and health status was analyzed (ANCOVA models). Results were adjusted for confounding factors. RESULTS Of 7152 patients, 1546 (22%) screened positive for GAD, 981 (14%) had confirmed GAD diagnosis, of whom 559 (8%) had GAD with co-morbid MDD and 422 (6%) had GAD alone. Of the 5292 (74%) patients screened negative for GAD, 336 (5%) were confirmed as controls. PPS in patients with GAD were twice as prevalent as in the control group: 59.0% vs. 28.3%; p<0.001. The presence of co-morbid MDD was associated with a significantly higher prevalence of PPS: 78.0% vs. 59.0%; p<0.001. PPS were significantly associated with functioning and health status impairment (p<0.001) both in GAD alone and in GAD and co-morbid MDD compared with controls. LIMITATIONS Results do not prove causal relationships. CONCLUSIONS Our results support the clinical relevance of PPS in patients suffering from GAD; therefore they need to be considered when evaluating the patient.

Remission in schizophrenia: Results from a 1-year follow-up observational study

OBJECTIVES This study used the Remission in Schizophrenia Working Group operational-severity criteria to, a) provide descriptive data on prevalence and stability of symptomatic remission, b) attempt a criterion (concurrent) validation of this measure of remission, and c) explore correlates of remission stability. METHODS From an unselected sample of 1010 stable outpatients with schizophrenia (DSM-IV-TR), a subgroup of 452 (44.8%) in symptomatic remission was followed for 1 year. Of these, 376 were re-evaluated in a research diagnostic assessment. In addition to relevant sociodemographic and clinical data, measures included symptoms, depression, functioning, social cognition, attitudes towards medication, and quality of life. Estimates of point prevalence are provided. Correlates of remission were identified by logistic regression. RESULTS Symptomatic remission at baseline correlated with better premorbid adjustment, better social cognition, good treatment compliance, younger age, the absence of comorbid substance abuse, current or past participation in psychotherapy, and a lack of past participation in rehabilitation. After 1 year, 338 out of the 376 (89.9%) patients re-evaluated were found again in remission. In this assessment, better premorbid adjustment, good treatment compliance, and improvement of depressive symptoms and social cognition during follow-up again correlated with remission. CONCLUSIONS The results of this study suggest that symptomatic remission (as defined above) has considerable criterion validity and is a realistic goal in the treatment of schizophrenia. Attaining and sustaining remission may warrant better clinical and functional outcomes for patients.

Fluoxetine in the prevention of depressive recurrences: a double-blind study.

Optimal outcomes from depression treatment are long-term recovery and, in the case of recurrent depression, prevention of new episodes. However, few data are available concerning the long-term efficacy of antidepressants in prophylactic treatment to prevent recurrences of depression. The efficacy and safety of fluoxetine 20 mg/day was evaluated in reducing the number of depressive episodes and in extending the time free of symptoms in patients with recurrent unipolar major depression. Patients with recurrent unipolar major depression according to DSM-III-R criteria and who responded to 32 weeks of open-label fluoxetine were randomly assigned to receive fluoxetine 20 mg/day (N = 70) or placebo (N = 70) for 48 weeks of double-blind maintenance treatment. Outcome measures were the percentage of recurrences and time to recurrence. Safety assessments included treatment-emergent adverse events, reasons for discontinuation, vital signs, and laboratory measures. Fluoxetine was associated with a statistically significantly smaller percentage of patients who had a recurrence compared with placebo (20% vs. 40%; χ 2 analysis, p = 0.010). The symptom-free period was significantly longer for patients treated with fluoxetine versus placebo (295 vs. 192 days; Kaplan-Meier estimates, log-rank test, p = 0.002). Treatments were well tolerated during maintenance treatment. The only statistically significant difference in adverse events between treatment groups was anxiety, which was more frequent in the placebo group (fluoxetine, 12.9% vs. placebo, 30%; χ 2 analysis, p = 0.013). Two placebo-treated patients and no fluoxetine-treated patients were withdrawn because of adverse events. In conclusion, fluoxetine at 20 mg/ day was effective and well tolerated for the prophylactic treatment of recurrent unipolar major depression.

Social and occupational functioning impairment in patients in partial versus complete remission of a major depressive disorder episode. A six-month prospective epidemiological study

PURPOSE To evaluate social and occupational functioning in patients in partial remission (PR) compared with patients in complete remission (CR) of a major depressive disorder (MDD) episode. SUBJECTS AND METHODS This is a six-month prospective study. PR was defined as a score more than 7 and less or equal to 15 in the Hamilton Depression Rating Scale, and CR as less or equal to 7. All patients had been on acute antidepressant treatment during the previous three months and no longer met criteria for MDD. Functioning was assessed by the Social and Occupational Functioning Assessment Scale (SOFAS). RESULTS Mean (S.D.) patient age was 50.5 (14.5) years (N=292) and 77% were female. At baseline, partial remitters showed greater impairment in social and occupational functioning than complete remitters (62.8 [12.6] versus 80.4 [10.5], respectively; P<.0001). After six months, only 47% PR versus 77% CR reached normal functioning, and SOFAS ratings for PR were below normal range (76.2 [12.3] PR versus 84.6 [9.4] CR; P<.0001). PR reported three times more days absent from work due to sickness than CR (63 days versus 20 days; P<.001). CONCLUSION We conclude that PR of an MDD episode is associated with significant functional impairment that persists even after nine months of antidepressant treatment. Our results underline the importance of treating the patient until achieving full remission.

Optimal cutoff point of the Hamilton Rating Scale for Depression according to normal levels of social and occupational functioning

The main goal in the treatment of major depressive disorder (MDD) is to achieve remission, defined as the resolution of symptoms and the return to normal levels of functionality. However, the clinical assessment of remission is usually merely based on scores of symptomatic rating scales. One of the most widely used scales to measure remission is the HAM-D(17), in which remission is defined as a score ≤ 7. Nevertheless, several studies have shown that this cutoff could be too high when also functioning is considered. This is a post-hoc analysis of a 6-month prospective study, performed over a sample of 292 Spanish patients with MDD, in order to find the optimal cutoff in the HAM-D(17) scale, considering normal levels of functionality, evaluated by the SOFAS; by means of plotting Receiver Operating Characteristics (ROC) curves. Our results show that a score of ≤ 5 maximized both sensitivity and specificity for identifying normal levels of functionality with respect to other scores, and thus agree with previous works, which suggest that a cutoff ≤ 7 might be too high to consider remission in patients with MDD, when normal levels of functioning are taken into account.

Duloxetine in the treatment of major depressive disorder: an open-label study

BackgroundMajor depressive disorder (MDD) is a chronic and highly disabling condition. Existing pharmacotherapies produce full remission in only 30% to 40% of treated patients. Antidepressants exhibiting dual reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE) may achieve higher rates of remission compared with those acting upon a single neurotransmitter. In this study, the safety and efficacy of duloxetine, a potent dual reuptake inhibitor of 5-HT and NE, were examined.MethodsPatients (N = 533) meeting DSM-IV criteria for MDD received open-label duloxetine (60 mg once a day [QD]) for 12 weeks during the initial phase of a relapse prevention trial. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD17) total score ≥18 and a Clinical Global Impression of Severity (CGI-S) score ≥4 at baseline. Efficacy measures included the HAMD17 total score, HAMD17 subscales, the CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQ-SS). Quality of life was assessed using the Sheehan Disability Scale (SDS) and the Quality of Life in Depression Scale (QLDS). Safety was evaluated by recording spontaneously-reported treatment-emergent adverse events, changes in vital signs and laboratory analytes, and the Patient Global Impression of Sexual Function (PGI-SF) scale.ResultsThe rate of discontinuation due to adverse events was 11.3%. Treatment-emergent adverse events reported by ≥10% duloxetine-treated patients were nausea, headache, dry mouth, somnolence, insomnia, and dizziness. Following 12 weeks of open-label duloxetine therapy, significant improvements were observed in all assessed efficacy and quality of life measures. In assessments of depression severity (HAMD17, CGI-S) the magnitude of symptom improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment.ConclusionIn this open-label phase of a relapse prevention study, duloxetine (60 mg QD) was shown to be safe and effective in the treatment of MDD.Trial registrationNCT00036309.

Residual symptoms and functioning in depression, does the type of residual symptom matter? A post-hoc analysis

BackgroundThe degrees to which residual symptoms in major depressive disorder (MDD) adversely affect patient functioning is not known. This post-hoc analysis explored the association between different residual symptoms and patient functioning.MethodsPatients with MDD who responded (≥50% on the 17-item Hamilton Rating Scale for Depression; HAMD-17) after 3 months of treatment (624/930) were included. Residual core mood-symptoms (HAMD-17 core symptom subscale ≥1), residual insomnia-symptoms (HAMD-17 sleep subscale ≥1), residual anxiety-symptoms (HAMD-17-anxiety subscale ≥1), residual somatic-symptoms (HAMD-17 Item 13 ≥1), pain (Visual Analogue Scale ≥30), and functioning were assessed after 3 months treatment. A stepwise logistic regression model with normal functioning (Social and Occupational Functioning Assessment Scale ≥80) as the dependent variable was used.ResultsAfter 3 months, 59.5% of patients (371/624) achieved normal functioning and 66.0% (412/624) were in remission. Residual symptom prevalence was: core mood symptoms 72%; insomnia 63%; anxiety 78%; and somatic symptoms 41%. Pain reported in 18%. Factors associated with normal functioning were absence of core mood symptoms (odds ratio [OR] 8.7; 95% confidence interval [CI], 4.6–16.7), absence of insomnia symptoms (OR 1.8; 95% CI, 1.2–2.7), episode length (4–24 weeks vs. ≥24 weeks [OR 2.0; 95% CI, 1.1–3.6]) and better baseline functioning (OR 1.0; 95% CI, 1.0–1.1). A significant interaction between residual anxiety symptoms and pain was found (p = 0.0080).ConclusionsDifferent residual symptoms are associated to different degrees with patient functioning. To achieve normal functioning, specific residual symptoms domains might be targeted for treatment.