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 enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study.

The antidepressant activity of citalopram (R,S-CIT) is mainly due to its (S)-enantiomer (S-CIT). P-glycoprotein (P-gp), encoded by the ABCB1 gene, is a membrane transport protein which regulates the efflux of many drugs. Polymorphisms in the ABCB1 gene may have an impact on the expression and function of P-gp, thereby influencing the response to treatment with antidepressants, which are substrates of this protein. The influence of ABCB1 polymorphism on the disposition of R,S-CIT in plasma and cerebrospinal fluid (CSF) was examined under steady-state conditions in 15 patients with major depression treated with 40 mg/d R,S-CIT for 4 weeks. In contrast to the ABCB1 C3435T polymorphism, only the ABCB1 G2677T polymorphism significantly influences R,S-CIT plasma and CSF concentrations (46+/-11 ng/ml versus 69+/-20 ng/ml for TT versus GT/GG in plasma, p=0.027; 24+/-5 ng/ml versus 32+/-9 ng/ml for TT versus GT/GG in CSF, p=0.05). On the other hand, no significant influence of G2677T polymorphism was found on the plasma and CSF (S)/(R) ratio, suggesting a lack of stereoselectivity in the activity of this transporter. The 2677 GG/GT genotype was associated with a better treatment response (p=0.001) compared with 2677TT genotype. Furthermore, higher R,S-CIT plasma and CSF concentrations were observed in treatment responders. This study is the first to demonstrate that a P-gp polymorphism significantly influences plasma and CSF concentrations of R,S-CIT in depressive patients, therefore possibly influencing the activity of this antidepressant. These findings should be replicated in future studies with larger groups of patients. Because of the small number of subjects in the present study, future studies with larger groups of patients, also with different ethnicities

Sustained cognitive impairments after clinical recovery of severe depression

Neuropsychological impairment is prominent in patients with depression, but it is unclear whether deficits persist after clinical response. This study aimed to investigate neuropsychological functions in the course of the illness. Depressive patients were investigated in the acute state and after clinical response using an extensive neuropsychological test battery. After clinical response, there was only a partial improvement in learning and memory and there were no changes regarding working memory, executive functions, and attention. Transient impairments in visual learning and memory suggest a depression-related state effect. The continuing deficits in attention, working memory, and executive function might be considered a trait marker

Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram.

Neuropeptides appear to play a role in the pathophysiology of depression and electroconvulsive treatment and lithium affect these compounds in human cerebrospinal fluid (CSF) and rodent brain. Consequently, we investigated whether long-term treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram (Cit) would also affect neuropeptides in CSF of depressed patients. Changes in CSF monoamine metabolites were also explored. CSF concentrations of corticotropin-releasing hormone (CRH)-like immunoreactivity (-LI), neuropeptide Y (NPY)-LI, and Cit were determined in 21 patients with major depression. Lumbar puncture was performed in the morning at baseline and was repeated after at least 4 wk of Cit treatment (40 mg/d). The severity of depression was assessed by the Hamilton Rating Scale for Depression (HAMD). Cit treatment was associated with a significant increase in NPY-LI and decrease in CRH-LI. An evaluation of the relationship between changes in concentrations of NPY-LI, CRH-LI, and the clinical response showed significant correlations between these parameters. Significant NPY and CRH changes in CSF following treatment as well as correlations to changes in HAMD support the hypothesis that these two peptides play a role in affective disorders and are markers of therapeutic response