Ethical challenges in preclinical Alzheimer's disease observational studies and trials: Results of the Barcelona summit.

Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants.

Milnacipran and pindolol: a randomized trial of reduction of antidepressant latency.

BACKGROUND: New, better tolerated and faster treatments for depression are needed. Patients are understandably unhappy with having to wait 3 to 4 weeks for a response to an antidepressant, while experiencing side effects almost immediately. This frequently has an adverse effect on compliance and engagement with treatment. AIMS: The primary objective was to assess the activity of pindolol on the onset of antidepressive response of milnacipran. The secondary objective was to assess the number of responders among the patients who received milnacipran and pindolol versus patients who received milnacipran and placebo. The tertiary objective was to evaluate the safety of milnacipran and pindolol versus milnacipran and placebo. METHOD: Randomized, double-blind, placebo-controlled study over 42 days. SETTING: Inner city London community mental health teams. PARTICIPANTS: 80 patients were selected and gave written consent to treatment, 78 were randomized (39 in each group) and evaluated for safety (intention-to-treat, ITT, safety data set), 77 (ITT efficacy data set), and 64 (per protocol, PP, data set) were evaluated for efficacy. The mean age was 31.9 for the pindolol group and 32.3 for the placebo. INTERVENTION: All patients received milnacipran 50 mg twice a day plus either pindolol 2.5 mg (the 'pindolol group') or matching placebo (the 'placebo group') three times a day. OUTCOME MEASURES: The main efficacy variable was the Montgomery-Asberg depression rating scale (MADRS) score at days 0, 4, 7, 10, 14, 21, 28, 42 on PP data set in an observation carried (OC) approach. Secondary efficacy variables were clinical global impression (global improvement) and Hamilton depression rating scale (HDRS). RESULTS: Improvement in MADRS total score was greater in the pindolol group than in the placebo group from day 7 (p=0.03). Responder rates in the clinical global impression were 97.2% for the pindolol group and 60.6% for the placebo group. The treatment was well tolerated with the most common side effects being nausea (28.2%; 35.9%), vomiting (7.7%; 23.1%), hot flushes (15.4%; 5.1%) and sweating (12.8%; 12.8%). CONCLUSION: The milnacipran and pindolol combination is safe, well tolerated and efficacious in major depression, and represents a rational strategy for the possible acceleration or potentiation of antidepressant action.

Effect of pindolol and milnacipran versus milnacipran and placebo on plasma prolactin and adrenocorticotrophic hormone in depressed subjects.

OBJECTIVE: Evidence that pindolol accelerates the action of antidepressants has been contradictory, and it is not clear why. The present study analyses the relationship between plasma prolactin (PRL) and ACTH levels and changes in relation to a milnacipran and pindolol combination versus milnacipran plus placebo. METHOD: Eighty depressed patients agreed to take part in a double-blind randomized trial of milnacipran plus pindolol or placebo. Fifty-eight of them agreed to also take measures of ACTH and PRL levels. ACTH and PRL plasma levels were estimated on days 0 and 42 of the 6-week study. Age, gender and time of blood collection were recorded for each individual. The Montgomery-Asberg depression rating scale (MADRS) was used to measure the response to treatment. The patients were grouped into those with higher versus lower basal ACTH levels using the median of the sample (25 ng/l). RESULTS: There were statistical differences in MADRS scores between the treatment groups on day 42. There were correlations between PRL levels on days 0 and 42; age and PRL levels on day 0; time of the PRL sample and the PRL levels on day 0 and day 42; ACTH and PRL levels on day 42. Regression analysis of the 58 patients showed that on day 0, PRL levels were dependent on the ACTH plasma levels on day 0, the time of the collection of the blood sample and the age. On day 42, the PRL levels were dependent on the ACTH levels and the time of the blood collection but not on the age. Patients with lower baseline ACTH levels on day 0 displayed a better clinical outcome when taking the combination of milnacipran and pindolol as shown in the differences in MADRS on day 42. The same group of patients showed lower PRL levels on day 42. CONCLUSIONS: ACTH plasma levels at baseline or screening may help to predict the response to antidepressant treatment.