Effects of Fluoxetine on Outcomes at 12 Months After Acute Stroke: Results From EFFECTS, a Randomized Controlled Trial.

Background and Purpose: The EFFECTS (Efficacy of Fluoxetine­a Randomised Controlled Trial in Stroke) recently reported that 20 mg fluoxetine once daily for 6 months after acute stroke did not improve functional outcome but reduced depression and increased fractures and hyponatremia at 6 months. The purpose of this predefined secondary analysis was to identify if any effects of fluoxetine were maintained or delayed over 12 months. Methods: EFFECTS was an investigator-led, randomized, placebo-controlled, double-blind, parallel group trial in Sweden that enrolled adult patients with stroke. Patients were randomized to 20 mg oral fluoxetine or matching placebo for 6 months and followed for another 6 months. The primary outcome was functional outcome (modified Rankin Scale), at 6 months. Predefined secondary outcomes for these analyses included the modified Rankin Scale, health status, quality of life, fatigue, mood, and depression at 12 months. Results: One thousand five hundred patients were recruited from 35 centers in Sweden between 2014 and 2019; 750 were allocated fluoxetine and 750 placebo. At 12 months, modified Rankin Scale data were available in 715 (95%) patients allocated fluoxetine and 712 (95%) placebo. The distribution of modified Rankin Scale categories was similar in the 2 groups (adjusted common odds ratio, 0.92 [95% CI, 0.76­1.10]). Patients allocated fluoxetine scored worse on memory with a median value of 89 (interquartile range, 75­100) versus 93 (interquartile range, 82­100); P=0.0021 and communication 93 (interquartile range, 82­100) versus 96 (interquartile range, 86­100); P=0.024 domains of the Stroke Impact Scale compared with placebo. There were no other differences in secondary outcomes. Conclusions: Fluoxetine after acute stroke had no effect on functional outcome at 12 months. Patients allocated fluoxetine scored worse on memory and communication on the Stroke Impact Scale compared with placebo, but this is likely to be due to chance. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02683213.

Effects of Hesel-coil deep transcranial magnetic stimulation for depression - a systematic review.

BACKGROUND: One third of the depressed patients are not improved by antidepressant drugs and psychological treatments, and there is a need for additional treatments. Repetitive transcranial magnetic stimulation (rTMS) is being developed towards an alternative in treatment-resistant depression. Deep transcranial stimulation (dTMS) with the Hesel-coil (H-coil) is a further development of rTMS aiming to enhance the effect by getting the magnetic pulses to penetrate deeper into the brain. AIMS: This report aims to assess the evidence-base for dTMS for depression. The report also includes an assessment of the ethical and economic aspects involved. METHODS: A systematic review of the effects of H-coil dTMS on depression was conducted and the scientific support was evaluated using GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: Only one controlled study was identified. In the sham-controlled randomized study, 212 participants with major depression that had not responded to antidepressant medication were enrolled. A two-point superiority in Hamilton Depression Rating Scale was observed in the dTMS arm vs the sham-arm at 4 weeks, but the difference was not statistically significant. No serious adverse events were reported apart from rare cases of epileptic seizures. CONCLUSIONS: The existing scientific support for H-coil dTMS therapy for depression is insufficient. The clinical implication is that the use of dTMS in depression should be restricted to the framework of clinical trials pending further studies. Fortunately, additional studies are underway and the evidence base should presumably improve over the next several years.

Does fluoxetine reduce apathetic and depressive symptoms after stroke? An analysis of the Efficacy oF Fluoxetine-a randomized Controlled Trial in Stroke trial data set.

OBJECTIVE: Apathy is a common and disabling symptom after stroke with no proven treatments. Selective serotonin reuptake inhibitors are widely used to treat depressive symptoms post-stroke but whether they reduce apathetic symptoms is unknown. We determined the effect of fluoxetine on post-stroke apathy in a post hoc analysis of the EFFECTS (Efficacy oF Fluoxetine-a randomized Controlled Trial in Stroke) trial. METHODS: EFFECTS enrolled patients ⩾18 years between 2 and 15 days after stroke onset. Participants were randomly assigned to receive oral fluoxetine 20 mg once daily or matching placebo for 6 months. The Montgomery-Åsberg Depression Rating Scale (MADRS) was administered at baseline and 6 months. Individual items on this scale were divided into those reflecting symptoms of apathy and depression. Symptoms were compared between fluoxetine and placebo groups. RESULTS: Of 1500 participants enrolled, complete MADRS data were available for 1369. The modified intention-to-treat population included 681 patients in the fluoxetine group and 688 in the placebo group. Confirmatory factor analysis revealed that apathetic, depressive, and anhedonic symptoms were dissociable. Apathy scores increased in both fluoxetine and placebo groups (both p ⩽ 0.00001). In contrast, fluoxetine was associated with a reduction in depressive scores (p = 0.002). CONCLUSION: Post-stroke apathetic and depressive symptoms respond differently to fluoxetine treatment. Our analysis suggests fluoxetine is ineffective in preventing post-stroke apathy.

Undetected depression in primary healthcare: occurrence, severity and co-morbidity in a two-stage procedure of opportunistic screening.

BACKGROUND: Depression often remains undetected in primary healthcare, and a two-stage screening procedure has been recommended for future research on the recognition, management and outcome of these patients. The aim of this study was to analyse the occurrence and the severity of depression, as well as gender, age and psychiatric co-morbidity in patients with previously undetected depression using a screening questionnaire followed by a diagnostic interview for detecting depression among patients visiting primary healthcare. METHODS: All patients visiting a primary healthcare centre during a period of 10 days were asked to fill in the self-rating version of the Montgomery-Åsberg Depression Rating Scale. Patients with a score of 12 or more were invited to participate in a structured diagnostic interview based on the Primary Care Evaluation of Mental Disorders. RESULTS: Out of 221 (=N) participants, 45 (20.4%) patients showed signs of depression (scores of 12 or more). Of these 45 patients, 31 consented to the structured interview, and of those, 28 (12.7%) fulfilled the criteria for depression, 17 (7.7%) had a major depression and 11 (5.0%) had a mixed depression-anxiety condition. CONCLUSIONS: The rate of undetected depression in primary healthcare was considerable. The majority of these patients had a major depression. Psychiatric co-morbidity among depressed patients was almost universal. The two-stage procedure of opportunistic screening with the Montgomery-Åsberg Depression Rating Scale and the Primary Care Evaluation of Mental Disorders seems to be a feasible method for detecting these patients in primary healthcare.

Correction to: Update on the EFFECTS study of fluoxetine for stroke recovery: a randomised controlled trial in Sweden.

Following publication of the original article [1], we were notified that one of the corresponding author's affiliations was omitted.

Update on the EFFECTS study of fluoxetine for stroke recovery: a randomised controlled trial in Sweden.

Studies have suggested that fluoxetine might improve neurological recovery after stroke, but the results remain inconclusive. The EFFECTS (Efficacy oF Fluoxetine - a randomisEd Controlled Trial in Stroke) reached its recruitment target of 1500 patients in June 2019. The purpose of this article is to present all amendments to the protocol and describe how we formed the EFFECTS trial collaboration in Sweden. METHODS: In this investigator-led, multicentre, parallel-group, randomised, placebo-controlled trial, we enrolled non-depressed stroke patients aged 18 years or older between 2 and 15 days after stroke onset. The patients had a clinical diagnosis of stroke (ischaemic or intracerebral haemorrhage) with persisting focal neurological deficits. Patients were randomised to fluoxetine 20 mg or matching placebo capsules once daily for 6 months. RESULTS: Seven amendments were made and included clarification of drug interaction between fluoxetine and metoprolol and the use of metoprolol for severe heart failure as an exclusion criterion, inclusion of data from central Swedish registries and the Swedish Stroke Register, changes in informed consent from patients, and clarification of design of some sub-studies. EFFECTS recruited 1500 patients at 35 centres in Sweden between 20 October 2014 and 28 June 2019. We plan to unblind the data in January 2020 and report the primary outcome in May 2020. CONCLUSION: EFFECTS will provide data on the safety and efficacy of 6 months of treatment with fluoxetine after stroke in a Swedish health system setting. The data from EFFECTS will also contribute to an individual patient data meta-analysis. TRIAL REGISTRATION: EudraCT 2011-006130-16. Registered on 8 August 2014. ISRCTN, ISRCTN13020412. Registered on 19 December 2014. ClinicalTrials.gov: NCT02683213. Retrospectively registered on 2 February 2016.

CSF 5-HIAA and DST non-suppression -independent biomarkers in suicide attempters?

BACKGROUND: Two major biomarkers of suicidal behaviour; low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and non-suppression in the dexamethasone suppression test (DST) have evidence for predictive power for suicide in mood disorders. Previous suicide attempt is the most robust clinical risk factor. PURPOSE OF STUDY: To study the interrelationship of suicide risk factors: low CSF 5-HIAA and the DST non-suppression in mood disorder patients with and without an index suicide attempt. METHODS: Fifty-eight hospitalised mood disorder patients (twenty-five with an index suicide attempt), who were not receiving any treatment with antidepressants, underwent lumbar puncture and DST. Plasma cortisol levels were determined from blood samples drawn the following day at 8:00 a.m., 4:00 p.m. and 11:00 p.m. and analysed in relation to CSF 5-HIAA. RESULTS: In the sample as a whole, the serum cortisol level at 4:00 p.m. showed a significant positive correlation to CSF 5-HIAA (r=0.3, p<0.02). In the patients with an index suicide attempt, the serum cortisol at 4.00 p.m. correlated positively with CSF 5-HIAA (r=0.65, p<0.0006), but not in the non-attempters (NS). CONCLUSION: The positive correlation means that low CSF 5-HIAA and DST non-suppression are relatively independent biomarkers of suicide risk in suicide attempters. The interrelation of the two systems seems to be different in suicide attempters compared to depressed inpatients without suicide attempt.

Individualized continuation electroconvulsive therapy and medication as a bridge to relapse prevention after an index course of electroconvulsive therapy in severe mood disorders: a naturalistic 3-year cohort study.

Electroconvulsive therapy (ECT) is recognized as an effective acute treatment for mood disorders but is associated with high risk of relapse. To minimize this risk, we introduced as a routine individually tapered continuation ECT with concomitant medication (C-ECT + Med) after an index series in January 2000. In August 2002, a chart review of all patients (n = 41) who had received C-ECT + Med for more than 4 months was carried out. Sixteen patients also participated in an extensive interview. Mean duration of administered C-ECT at follow-up was 1 year, but for most patients (63%), C-ECT had been terminated. For 49% of patients, adjustments between ECT sessions had been made due to early signs of relapse. Two weeks was the most common interval between sessions for patients with ongoing C-ECT. The frequency of lithium-treated patients had increased from 12% before index to 41% during C-ECT. However, the rated response to the drug varied. Need for hospital care 3 years before and after the initiation of C-ECT + Med was compared in a second evaluation of the cohort. The number of patients hospitalized, number of admissions, and total days in hospital were all significantly reduced. Hospital days were reduced by 76% (P < 0.001). Three patients with previously cumulative years in hospital are described as case vignettes after 6 years with no or minimal need for further hospitalization. This study supports previous findings that individually tapered C-ECT + Med can maintain initial response to ECT and serve as a bridge to long-term relapse prevention.

DST non-suppression predicts suicide after attempted suicide.

Most prospective studies of HPA axis have found that non-suppressors in the dexamethasone suppression test (DST) are more likely to commit suicide during the follow-up. Attempted suicide is a strong clinical predictor of suicide. The aim of this study was to assess the predictive value of DST for suicide in a group of depressed inpatients with and without an index suicide attempt. Historical cohort of 382 psychiatric inpatients with mood disorder admitted to the department of Psychiatry at the Karolinska University Hospital between 1980 and 2000 were submitted to the DST and followed up for causes of death. During the follow-up (mean 18 years), 36 suicides (9.4%) occurred, 20 of these were non-suppressors and 16 were suppressors. There was no statistically significant difference in suicide risk between the suppressors and non-suppressors for the sample as a whole. An index suicide attempt predicted suicide. In suicide attempters with mood disorder, the non-suppressor status was significantly associated with suicide indicating that HPA axis hyperactivity is a risk factor for suicide in this group. The dexamethasone suppression test may be a useful predictor within this population.

Double-blind comparison of sertraline and placebo in stroke patients with minor depression and less severe major depression.

BACKGROUND: Poststroke depression is a frequent condition and important to treat. The aim of this trial was to study the efficacy and tolerability of sertraline. METHOD: In 4 Swedish stroke centers, 123 patients (aged 70.7 +/- 9.9 years) were enrolled during the period September 1998 to January 2001 in a randomized, double-blind, placebo-controlled 26-week trial, at a mean of 128 +/- 97 days (range, 3-375 days) after stroke, if they fulfilled DSM-IV criteria of major depressive episode (N = 76) or minor depressive disorder (N = 47). The primary efficacy variable was a change in depression assessed by the Montgomery-Asberg Depression Rating Scale. The Emotional Distress Scale (EDS) was administered and the occurrence of emotionalism and quality of life (QoL) were assessed, as well as neurologic recovery. Efficacy analyses were intention-to-treat, short-term (week 6) and long-term (week 26). RESULTS: Of the 123 patients, 62 were treated with sertraline (50-100 mg/day) and 61 with placebo. Both groups improved substantially, with no differences between the treatments, either for major depressive episode or minor depressive disorder, or for short- or long-term antidepressant effect and neurologic outcome. EDS revealed a better outcome with sertraline at week 6 (p < .05). At week 26, the improvement in QoL was better in sertraline patients (p < .05) and there was a trend for emotionalism (p = .07). No serious side effects were seen. CONCLUSION: Poststroke depression as measured by a conventional depression rating scale improved over time irrespective of treatment. Positive effects specific to sertraline were identified in emotional distress, emotionalism, and QoL. The study indicates that poststroke emotional reactions comprise depression and other domains susceptible to pharmacologic therapy.

Bright white light therapy in depression: A critical review of the evidence.

BACKGROUND: Light therapy is an accepted treatment option, at least for seasonal affective disorder (SAD). Our aim was to critically evaluate treatment effects of bright white light (BWL) on the depressive symptoms in both SAD and non-seasonal depression. METHODS: The systematic review was performed according to the PRISMA guidelines. PubMed, Embase, and PsycINFO were searched (December 1974 through June 2014) for randomized controlled trials published in peer-reviewed journals. Study quality was assessed with a checklist developed by the Swedish Council on Technology Assessment in Health Care. Only studies with high or medium quality were used in the meta-analyses. RESULTS: Eight studies of SAD and two studies of non-seasonal depression met inclusion and quality criteria. Effects on SAD were estimated in two meta-analyses. In the first, week by week, BWL reached statistical significance only at two and three weeks of treatment (Standardized Mean Difference, SMD: -0.50 (-CI 0.94, -0.05); -0.31 (-0.59, -0.03) respectively). The second meta-analysis, of endpoint data only, showed a SMD of -0.54 (CI: -0.95, -0.13), which indicates an advantage for BWL. No meta-analysis was performed for non-seasonal depression due to heterogeneity between studies. LIMITATIONS: This analysis is restricted to short-term effects of BWL measured as mean changes in scores derived from SIGH-SAD, SIGH-SAD self-report, or HDRS rating scales. CONCLUSIONS: Most studies of BWL have considerable methodological problems, and the results of published meta-analyses are highly dependent on the study selection. Even though quality criteria are introduced in the selection procedures of studies, when the results are carefully scrutinized, the evidence is not unequivocal.

[Emotional reactions common sequelae of stroke]. / Emotionella reaktioner vanliga restsymtom efter stroke.

Emotional reactions are important sequelae of stroke. Mood disorders, such as depression, anxiety, post-traumatic stress syndrome and emotionalism, occur during the first post-stroke year, each of them in approximately 20-30% of patients. They often overlap, and prevalence estimates differ on account of differences in definitions; study populations; exclusion criteria and time of assessment. The risk seems to be greatest, at least for depression, in the first months after stroke. Some patients recover spontaneously but symptoms persist in up to one third. Pharmacological treatment can have a positive effect that also applies to rehabilitation, quality of life and cardiovascular mortality. However, study findings are not uniform and conclusive therapeutic and preventive intervention trials on mood disorders after stroke are urgently needed.

Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson's disease and major depression.

The biochemical basis of major depression (MD) in Parkinson's disease (PD) is largely unknown. To increase our understanding of MD in PD patients, the levels of monoamine metabolites (HVA, 5-HIAA and MHPG), BDNF, orexin-A, IL-6 and corticosterone were examined in cerebrospinal fluid. The analyses were performed in MD patients with (n = 11) and without (n = 12) PD at baseline and after 12 weeks' of treatment with the antidepressant citalopram, and in patients with solely PD (n = 14) at baseline and after 12 weeks. The major findings were that PD patients with MD had significantly lower baseline levels of MHPG, corticosterone and IL-6 when compared to patients with solely MD. In response to citalopram treatment, patients with solely MD exhibited an expected decrease in 5-HIAA and MHPG levels which was not found in PD patients with MD. Moreover, the levels of BDNF and IL-6 were lower in PD patients with MD compared with patients with solely MD after treatment with citalopram. Thus, the biochemical basis and the response to citalopram differ between PD patients with MD and patients with solely MD.

Health-related quality of life measured with EQ-5D in patients treated for depression in primary care.

OBJECTIVE: The objective of the present study was to assess the impact of depression on patients' health-related quality of life (HRQL) with the EQ-5D instrument over 6 months while on antidepressant treatment. METHODS: A total of 447 patients were recruited at 56 primary care centers to this naturalistic longitudinal observational study. Patients older than 18 years with depressive symptoms, and who initiated an antidepressant therapy because of depression were included in the study. Data on patients' sociodemographics, daily activity, and quality of life (EQ-5D) were collected using questionnaires completed during outpatient general practitioner visits for a follow-up period of 6 months. RESULTS: The mean EQ-5D utility score at baseline was 0.47 (0.44-0.49). Milder cases of depression reported a health utility of 0.60, whereas moderately and severely depressed patients reported utility values of 0.46 and 0.27, respectively (P < 0.01). At end of follow up the average utility was 0.69 (0.67-0.72), corresponding to an increase of 0.23 over 6 months (P < 0.01). Regression analyses showed that, all else equal, patients who were on sick leave were associated with 10% lower utility. CONCLUSIONS: Depression has a substantial impact on HRQL. Our results indicate that treatments for depression are associated with significant improvement in EQ-5D index score over a course of 6 months. Self-reported patient valuations are important outcomes for cost-utility analysis of new treatments for depression and the present study provides important evidence for future economic evaluations.

Post-stroke depression - effect on the life situation of the significant other.

The aim of this study was to describe the life situation among 'significant others' to patients with post-stroke depression, and to identify associations between the life situation of the significant others and patient characteristics. Seventy-one dyads consisting of patients with a diagnosed post-stroke depression and their significant others were included. The patients were assessed for depression with the Montgomery-Asberg Depression Rating Scale and diagnosed according to the DSM-IV. The assessments of significant others included their own life situation and proxy assessments of the patients' state of depression, anger, change of personality, and need of assistance. Significant others of male stroke patients reported a more negative impact on their life situation, than did significant others of female stroke patients (p = 0.04). There was a significant association between the patient's level of depression and physical function [activities of daily living (ADL)], with those with less impaired ADL having more major depression than those with more impaired ADL (p = 0.007). This study indicates that major post-stroke depression is more common among patients with limited functional deficits. This highlights the importance of assessment for depression also among seemingly recovered stroke patients in order to treat and support those in need. This study also stresses the importance of identifying different needs of the significant others in order to provide appropriate support in their caregiving role.

Electroconvulsive Therapy Effects on Cerebrospinal Fluid Monoamine Metabolites and Platelet Serotonin Uptake In Melancholia.

The effects of ECT on 5-hydroxyindoleacetic acid, homovanillic acid (HVA), and 4-hydroxy-3-methoxyphenylglycol in cerebrospinal fluid and on kinetic parameters of platelet serotonin uptake were studied in 12 patients with melancholia. There were no significant changes in the monoamine metabolites 3 weeks after initiation of ECT in 12 patients; however, there was a tendency for HVA to increase. The V(max) of serotonin uptake (measured in seven patients) remained unchanged after ECT, but there was a significant increase in K(m), indicating a decreased affinity for serotonin in the carrier.