The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke:a study protocol for three multicentre randomised controlled trials

BACKGROUND: Several small trials have suggested that fluoxetine improves neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials that aim to determine whether routine administration of fluoxetine (20 mg daily) for 6 months after acute stroke improves patients' functional outcome. METHODS/DESIGN: The three trial investigator teams have collaboratively developed a core protocol. Minor variations have been tailored to the national setting in the UK (FOCUS), Australia and New Zealand (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will subsequently provide the most precise estimate of the overall effect of fluoxetine after stroke and establish whether any effects differ between trials and subgroups of patients. The trials include patients ≥18 years old with a clinical diagnosis of stroke, persisting focal neurological deficits at randomisation between 2 and 15 days after stroke onset. Patients are randomised centrally via web-based randomisation systems using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for 6 months. Our primary outcome measure is the modified Rankin scale (mRS) at 6 months. Secondary outcomes include the Stroke Impact Scale, EuroQol (EQ5D-5 L), the vitality subscale of the Short-Form 36, diagnosis of depression, adherence to medication, adverse events and resource use. Outcomes are collected at 6 and 12 months. The methods of collecting these data are tailored to the national setting. If FOCUS, AFFINITY and EFFECTS combined enrol 6000 participants as planned, they would have 90 % power (alpha 5 %) to detect a common odds ratio of 1.16, equivalent to a 3.7 % absolute difference in percentage with mRS 0-2 (44.0 % to 47.7 %). This is based on an ordinal analysis of mRS adjusted for baseline variables included in the minimisation algorithm. DISCUSSION: If fluoxetine is safe and effective in promoting functional recovery, it could be rapidly, widely and affordably implemented in routine clinical practice and reduce the burden of disability due to stroke. TRIAL REGISTRATION: FOCUS: ISRCTN83290762 (23/05/2012), AFFINITY: ACTRN12611000774921 (22/07/2011). EFFECTS: ISRCTN13020412 (19/12/2014)

Citalopram - Plasma- und Liquorkonzentrationen - Zusammenhang mit neurobiologischen und klinischen Verlaufsparametern

The hypothesis of a relationship between drug concentrations in blood and in brain represents the basis for therapeutic drug monitoring of psychotropic drugs (TDM). However, available techniques do not allow to analyse separately the parent compound and its active metabolites in tissues of the central nervous (CNS) system, but cerebrospinal fluid (CSF) represents an accessible fluid, In order to evaluate the relationship between blood and CSF drug concentrations and its biological and clinical effect, plasma and CSF concentrations of the enantiomers of citalopram, its N-de-methylated (DCIT) and deaminated (CIT-PROP) metabolites were measured in plasma and CSF in 22 depressed patients after a 4-week treatment with 40 mg/day citalopram. CSF 5-HIAA and HVA were measured at baseline and after the 4-week citalopram medication period. Patients were assessed clinically, using the Hamilton depression rating scale (21-item HAM-D). Responders were defined by a >= 50% decrease of the HANI-D score (Delta HANI-D) after the 4-week treatment. CSF concentrations of S- and R-Citalopram were 10.6 +/- 4.3 ng/ml and 20.9 +/- 6 ng/ml, respectively and their CSF/plasma ratios were 52% 9% und 48% 6%, respectively. The Citalopram treatment resulted in a significant decrease (28%) of 5-HIAA and a significant increase (41%) of HVA in CSF. A HAM-D correlated significantly with CSF S-Citalopram (p < 0.05), CSF S-CIT-PROP (p=0.01) and 5-HIAA decrease (p=0.01). The demonstrated correlations between pharmacokinetic parameters and the clinical outcome as well as 5-HIAA changes indicate that monitoring of plasma S-Citalopram, CSF S-Citalopram- and CSF S-CIT-PROP may be of clinical relevanc