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Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise.

ABSTRACT: BACKGROUND AND PURPOSE: Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5-hydroxytryptaminergic (serotonergic) dysregulation. EXPERIMENTAL APPROACH: We performed tests of depression-related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with running-wheels. Functional assessments of 5-HT(1A) and 5-HT(2A) receptors were performed by measuring behavioural and physiological responses following administration of specific agonists, in combination with analysis of hippocampal gene expression. Finally we assessed the effect of exercise on hippocampal cell proliferation. KEY RESULTS: Female HD mice recorded increased immobility time in the forced-swimming test, reduced saccharin preference and a hyperthermic response to stress compared with wild-type animals. These alterations were improved by chronic sertraline treatment. Wheel-running also resulted in similar improvements with the exception of saccharin preference but failed to correct the hippocampal cell proliferation deficits displayed by HD mice. The benefits of sertraline treatment and exercise involved altered 5-HT(1A) autoreceptor function, as demonstrated by modulation of the exaggerated 8-OH-DPAT-induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to restore the reduced 5-HT(1A) and 5-HT(2) heteroceptor function observed in HD animals. CONCLUSIONS AND IMPLICATIONS: We report for the first time a crucial role for 5-HT(1A) autoreceptor function in mediating the sex-specific depressive-like phenotype of female R6/1 HD mice. Our data further support a differential effect of chronic sertraline treatment and exercise on hippocampal cell proliferation despite common behavioural benefits.

SUBMITTER: Renoir T

PROVIDER: S-EPMC3372723 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise.

Renoir Thibault T Pang Terence Y C TY Zajac Michelle S MS Chan Grace G Du Xin X Leang Leah L Chevarin Caroline C Lanfumey Laurence L Hannan Anthony J AJ

British journal of pharmacology 20120301 5

<h4>Background and purpose</h4>Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5-hydroxytryptaminergic (serotonergic) dysregulation.<h4>Experimental approach</h4>We performed tests of depression-related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with running-wheels. Functional assessments of 5-HT(1A) and 5-HT(2A) rec ...[more]

PMID: 21718306

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Project description:ImportanceMajor depressive disorder (MDD) is prevalent among patients with chronic kidney disease (CKD) and is associated with morbidity and mortality. The efficacy and adverse events of selective serotonin reuptake inhibitors in these patients are unknown.ObjectiveTo determine whether treatment with sertraline improves depressive symptoms in patients with CKD and MDD.Design, setting, and participantsThe Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) was a randomized, double-blind, placebo-controlled trial involving 201 patients with stage 3, 4, or 5 non-dialysis-dependent CKD, who were enrolled at 3 US medical centers. The Mini Neuropsychiatric Interview was used to establish MDD. The first participant was randomized in March 2010 and the last clinic visit occurred in November 2016.InterventionsAfter a 1-week placebo run-in, participants were randomized to sertraline (n = 102) for 12 weeks at an initial dose of 50 mg/d (escalated to a maximum dose of 200 mg/d based on tolerability and response) or matching placebo (n = 99).Main outcomes and measuresThe primary outcome was improvement in depressive symptom severity from baseline to 12 weeks determined by the 16-item Quick Inventory of Depression Symptomatology-Clinician Rated (QIDS-C16) (score range, 0-27; minimal clinically important difference, 2 points). Secondary outcomes included improvement in quality of life (Kidney Disease Quality of Life Survey-Short Form; score range, 0-100; higher scores indicate more favorable quality of life) and adverse events.ResultsThere were 201 patients (mean [SD] age, 58.2 [13.2] years; 27% female) randomized. The primary analysis included 193 patients who had at least 1 outcome assessment after randomization. The mean (SD) baseline QIDS-C16 score was 14.0 (2.4) in the sertraline group (n = 97) and 14.1 (2.4) in the placebo group (n = 96). The median participation time was 12.0 weeks and the median achieved dose was 150 mg/d, which was not significantly different between the groups. The QIDS-C16 score changed by -4.1 in the sertraline group and by -4.2 in the placebo group (between-group difference, 0.1 [95% CI, -1.1 to 1.3]; P = .82). There was no significant between-group difference in change in patient-reported overall health on the Kidney Disease Quality of Life Survey (median score, 0 in the sertraline group vs 0 in the placebo group; between-group difference, 0 [95% CI, -10.0 to 0]; P = .61). Nausea or vomiting occurred more frequently in the sertraline vs placebo group (22.7% vs 10.4%, respectively; between-group difference, 12.3% [95% CI, 1.9% to 22.6%], P = .03), as well as diarrhea (13.4% vs 3.1%; between-group difference, 10.3% [95% CI, 2.7% to 17.9%], P = .02).Conclusions and relevanceAmong patients with non-dialysis-dependent CKD and MDD, treatment with sertraline compared with placebo for 12 weeks did not significantly improve depressive symptoms. These findings do not support the use of sertraline to treat MDD in patients with non-dialysis-dependent CKD.Trial registrationclinicaltrials.gov Identifier: NCT00946998.

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Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise.

Publications

Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise.

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