Víctor Pérez

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.

A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder

The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ⩾30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) – placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD.

SPECT mapping of cerebral activity changes induced by repetitive transcranial magnetic stimulation in depressed patients. A pilot study

Repetitive transcranial magnetic stimulation (rTMS) is being investigated as an alternative treatment for depression. However, little is known about the clinical role and the neurophysiological mechanisms of the action of rTMS in these patients. In this study, 99mTc-HMPAO single photon emission computed tomography (SPECT) was used to map the effects of left dorsolateral prefrontal rTMS on prefrontal activity in seven patients who met DSM-IV criteria for major depression resistant to pharmacological treatment. rTMS consisted of 30 trains of 2-s duration stimuli (20 Hz, 90% of motor threshold), separated by 30-s pauses. Each patient underwent three SPECTs: at baseline; during the first rTMS; and 1 week after 10 daily sessions of rTMS. Regional cerebral blood flow (rCBF) of each cerebral region was normalized to the rCBF value in the cerebellum and relative changes in normalized rCBF were addressed using a region-of-interest analysis. The Hamilton Depression Rating Scale (HDRS) was used for clinical evaluation before and after rTMS. A significant rCBF increase after the 10 sessions of rTMS was found in the left prefrontal region (MANOVA F=5.29, d.f.=2,10, P=0.027), but no significant rCBF changes were found during the first rTMS session. The remaining cerebral regions showed no significant rCBF changes at any time. Only two patients showed a clinical improvement after rTMS, with 50% reduction of the initial HDRS score. The study was repeated under placebo conditions (identical design but addressing coil discharges to the air) in these two patients, who failed to show any rCBF increase during sham-rTMS. No relationship was found between the percentage of left prefrontal rCBF change and the clinical findings. In conclusion, rTMS of the left prefrontal cortex induces a significant rCBF increase in this region, despite the limited clinical effect in our sample of depressed patients. Cerebral perfusion SPECT is a useful tool to map cerebral activity changes induced by rTMS.

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.

Pretreatment platelet 5-HT concentration predicts the short-term response to paroxetine in major depression

BACKGROUND A previous retrospective study revealed that a high pretreatment platelet serotonin (5-HT) concentration was associated with a low response to serotonergic antidepressants in drug-free major depressives. We have examined such a relationship in depressive patients treated with paroxetine. METHODS Seventy-four drug-free major depressives (DSM-IV) were admitted to the study. Clinical ratings were performed and blood was drawn prior to the initiation of treatment and after 4 weeks of paroxetine (20 mg/day). The concentrations of 5-HT, 5-hydroxyindoleacetic acid, and tryptophan were determined in plasma and blood. RESULTS Paroxetine treatment reduced platelet 5-HT to 17% of baseline after 4 weeks of treatment. Responder patients had a pretreatment platelet 5-HT concentration 22% lower than nonresponders (p < .035). Admission HAMD scores, plasma paroxetine concentration, or platelet 5-HT concentration at endpoint did not differ between responders and nonresponders. Yet, the response rate was 11% in patients with high pretreatment platelet 5-HT (> 900 ng/10(9) platelets) and 50% in those below that value (p < .004). CONCLUSIONS These findings support that depressed patients with a high pretreatment platelet 5-HT concentration have a poor therapeutic outcome after treatment with a standard paroxetine dose. These differences may be related to the existence of molecular differences in the 5-HT transporter.

Early vs. conventional switching of antidepressants in patients with MDD and moderate to severe pain: a double-blind randomized study.

BACKGROUND Concomitant painful physical symptoms in depressive patients frequently impair functioning and failure to treat these symptoms may adversely impact treatment outcomes of depression. Early vs. conventional switch of antidepressants were compared in patients with major depressive disorder (MDD) and moderate to severe pain. METHOD Pre-specified subgroup analysis of a 16-week, randomized, double-blind clinical study on MDD patients with >30 mm overall pain visual analog scale (VAS). Patients not achieving 30% reduction Hamilton Depression Rating Scale (HAM-D) after 4 weeks escitalopram (10 mg/day) were randomized to duloxetine 60-120 mg/day (early switch) or continued on escitalopram (conventional switch) with non-responders at week 8 switching to duloxetine. Endpoints were time to confirmed response and remission, VAS pain severity, and Sheehan disability scale (SDS). Switch strategies were compared using Kaplan-Meier, logistic regression, and repeated measures analyses. RESULTS No differences between early and conventional switching were found in time to confirmed response after randomization (3.9 vs. 4.1 weeks, p=0.511) or remission (6.0 vs. 8.0 weeks, p=0.238). Significantly lower VAS mean pain levels at for overall pain, headache, back pain, shoulder pain, interference with daily activities, and time being awake in pain were found for patients in the early switching group. Time to achieving normal functioning (SDS total score <6) was shorter in the early switching group (p=0.042). Safety results were comparable between switch strategies. CONCLUSIONS In MDD patients with moderate to severe painful physical symptoms not improving after 4 weeks of treatment with escitalopram, an earlier switch to duloxetine may lead to better pain and functional outcomes.

Propiedades psicométricas de la versión española de la escala Philadelphia Mindfulness Scale (PHLMS)

INTRODUCTION The Philadelphia Mindfulness Scale (PHLMS) is a brief questionnaire for assessing 2 key components of mindfulness: present moment awareness, and acceptance. This study was aimed at evaluating the psychometric properties of the Spanish version of PHLMS in a sample of participants with and without psychiatric conditions. MATERIAL AND METHODS The Spanish version of the PHLMS was administered to a sample of 395 volunteers (256 of them with a psychiatric condition, and 130 from a student sample). RESULTS Exploratory factor analysis found a two factor solution, which was also observed in the original version of the scale, with an explained variance of 44.02%. The scale showed good reliability (Cronbach α between 0.81 and 0.86), and an adequate convergent validity with other questionnaires of mindfulness and acceptance. The results also showed a similar discriminant validity to that in the original instrument validation between PHLMS and the clinical symptomatology reported. CONCLUSIONS The Spanish version of the PHLMS is a psychometrically sound measure for assessing two core components of mindfulness (i.e. awareness and acceptance) in clinical and research settings.

Corrigendum to “Optimal cutoff point of the Hamilton Rating Scale for Depression according to normal levels of social and occupational functioning” [Psychiatry Res. 186 (2011) 133-137]

a Clinical Research Department, Lilly, S.A., Avenida de la Industria, 30, Alcobendas E-28108, Madrid, Spain b Department of Psychiatry, Hospital de Sant Pau i de la Santa Creu. C/Sant Antoni Maria Claret, 167. E-08025, Barcelona, CIBERSAM, Spain c Department of Psychiatry, Hospital Universitari de Bellvitge. Feixa Llarga, sn. E-08907, Hospitalet de Llobregat, Barcelona, CIBERSAM, Spain d Universidad Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Spain