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      Antidepressants and the risk of hyponatremia: a Danish register-based population study

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          Abstract

          Objective

          To examine the association between classes of antidepressants and hyponatremia, and between specific antidepressants and hyponatremia.

          Design

          Retrospective register-based cohort study using nationwide registers from 1998 to 2012.

          Setting

          The North Denmark Region.

          Participants

          In total, 638 352 individuals were included.

          Primary and secondary outcome measures

          Plasma sodium was obtained from the LABKA database. The primary outcome was hyponatremia defined as plasma sodium (p-sodium) below 135 mmol/L and secondary outcome was severe hyponatremia defined as p-sodium below 130 mmol/L. The association between use of specific antidepressants and hyponatremia was analysed using multivariable Poisson regression models.

          Results

          An event of hyponatremia occurred in 72 509 individuals and 11.36% (n=6476) of these events happened during treatment with antidepressants. Incidence rate ratios and CIs for the association with hyponatremia in the first p-sodium measured after initiation of treatment were for citalopram 7.8 (CI 7.42 to 8.20); clomipramine 4.93 (CI 2.72 to 8.94); duloxetine 2.05 (CI 1.44 to 292); venlafaxine 2.90 (CI 2.43 to 3.46); mirtazapine 2.95 (CI 2.71 to 3.21); and mianserin 0.90 (CI 0.71 to 1.14).

          Conclusions

          All antidepressants except mianserin are associated with hyponatremia. The association is strongest with citalopram and lowest with duloxetine, venlafaxine and mirtazapine.

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          Most cited references34

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          Antidepressant use and risk of adverse outcomes in older people: population based cohort study

          Objectives To investigate the association between antidepressant treatment and risk of several potential adverse outcomes in older people with depression and to examine risks by class of antidepressant, duration of use, and dose. Design Cohort study of people aged 65 and over diagnosed as having depression. Setting 570 general practices in the United Kingdom supplying data to the QResearch primary care database. Participants 60 746 patients diagnosed as having a new episode of depression between the ages of 65 and 100 years from 1 January 1996 to 31 December 2007 and followed up until 31 December 2008. Main outcome measures Hazard ratios associated with antidepressant use for all cause mortality, attempted suicide/self harm, myocardial infarction, stroke/transient ischaemic attack, falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions, and hyponatraemia, adjusted for a range of potential confounding variables. Hazard ratios were calculated for antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use and for commonly prescribed individual drugs. Results 54 038 (89.0%) patients received at least one prescription for an antidepressant during follow-up. A total of 1 398 359 antidepressant prescriptions were issued: 764 659 (54.7%) for selective serotonin reuptake inhibitors, 442 192 (31.6%) for tricyclic antidepressants, 2203 (0.2%) for monoamine oxidase inhibitors, and 189 305 (13.5%) for the group of other antidepressants. The associations with the adverse outcomes differed significantly between the antidepressant classes for seven outcomes. Selective serotonin reuptake inhibitors were associated with the highest adjusted hazard ratios for falls (1.66, 95% confidence interval 1.58 to 1.73) and hyponatraemia (1.52, 1.33 to 1.75) compared with when antidepressants were not being used. The group of other antidepressants was associated with the highest adjusted hazard ratios for all cause mortality (1.66, 1.56 to 1.77), attempted suicide/self harm (5.16, 3.90 to 6.83), stroke/transient ischaemic attack (1.37, 1.22 to 1.55), fracture (1.64, 1.46 to 1.84), and epilepsy/seizures (2.24, 1.60 to 3.15), compared with when antidepressants were not being used. Tricyclic antidepressants did not have the highest hazard ratio for any of the outcomes. Significantly different associations also existed between the individual drugs for the same seven outcomes; trazodone (tricyclic antidepressant), mirtazapine, and venlafaxine (both in the group of other antidepressants) were associated with the highest rates for some of these outcomes. Absolute risks over 1 year for all cause mortality were 7.04% for patients while not taking antidepressants, 8.12% for those taking tricyclic antidepressants, 10.61% for selective serotonin reuptake inhibitors, and 11.43% for other antidepressants. Conclusions Selective serotonin reuptake inhibitors and drugs in the group of other antidepressants were associated with an increased risk of several adverse outcomes compared with tricyclic antidepressants. Among individual drugs, trazodone, mirtazapine, and venlafaxine were associated with the highest risks for some outcomes. As this is an observational study, it is susceptible to confounding by indication, channelling bias, and residual confounding, so differences in characteristics between patients prescribed different antidepressant drugs that could account for some of the associations between the drugs and the adverse outcomes may remain. Further research is needed to confirm these findings, but the risks and benefits of different antidepressants should be carefully evaluated when these drugs are prescribed to older people.
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            Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.

            The study objective was to determine the eventual consequences (falls, unsteadiness, and cognitive impairment) of mild chronic hyponatremia, which is generally considered as asymptomatic. In a case-control study, we focused on the incidence of falls among 122 patients (mean age 72+/-13 years) with asymptomatic chronic hyponatremia (mean serum sodium concentration [SNa] 126+/-5 mEq/L), who were admitted to the medical emergency department, compared with 244 matched controls. To explore the mechanisms of the excess of falls, we prospectively asked 16 comparable patients (mean age 63+/-15 years; SNa+/-2 mEq/L) to perform 8 attention tests and a gait test consisting of 3 steps "in tandem," in which we measured the "total traveled way" by the center of pressure or total traveled way. Thereafter, the patients were treated and tested again (50% of the patients were tested first with normal SNa to avoid learning biases). Epidemiology of falls: Twenty-six patients (21.3%) of 122 were admitted for falls, compared with only 5.3% of the control patients (adjusted odds ratio: 67; 95% confidence: 7.5-607; P <.001). The frequency of falls was the same regardless of the level of hyponatremia. Gait: The total traveled way by the center of pressure significantly increased in hyponatremia (1336+/-320 mm vs 1047+/-172 mm with normal SNa; P=.003). Attention tests: The mean response time was 673+/-182 milliseconds in hyponatremia and 615+/-184 milliseconds in patients with normal SNa (difference: 58 milliseconds, P <.001). The total error number in hyponatremia increased 1.2-fold (P=.001). These modifications were comparable to those observed after alcohol intake in 10 volunteers. Mild chronic hyponatremia induces a high incidence of falls possibly as the result of marked gait and attention impairments. Treating these patients might prevent a considerable number of hospitalizations.
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              Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin.

              We prospectively evaluated the frequency, cause, and outcome of hyponatremia (plasma sodium concentration, less than 130 meq/L), as well as the hormonal response to this condition, in hospitalized patients. Daily incidence and prevalence of hyponatremia averaged 0.97% and 2.48%, respectively. Two thirds of all hyponatremia was hospital acquired. Normovolemic states (so-called syndrome of inappropriate secretion of antidiuretic hormone) were the most commonly seen clinical setting of hyponatremia. The fatality rate for hyponatremic patients was 60-fold that for patients without documented hyponatremia. Nonosmotic secretion of vasopressin was present in 97% of hyponatremic patients in whom it was sought. In edematous and hypovolemic patients, plasma hormonal responses (increases in plasma renin activity and aldosterone and norepinephrine levels) were compatible with baroreceptor-mediated release of vasopressin. Hyponatremia is a common hospital-acquired electrolyte disturbance that is an indicator of poor prognosis. Nonosmotic secretion of arginine vasopressin is a major pathogenetic factor in this electrolyte disturbance.
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2016
                18 May 2016
                : 6
                : 5
                : e011200
                Affiliations
                [1 ]Department of Geriatric Medicine, Nykøbing Falster Hospital , Nykøbing Falster, Denmark
                [2 ]Department of Geriatric Medicine, Slagelse Hospital , Slagelse, Denmark
                [3 ]Clinical Pharmacology Unit, University Hospital Zealand , Roskilde, Denmark
                [4 ]Department of Biochemistry, University Hospital Zealand , Roskilde, Denmark
                [5 ]Department of Cardiology, Gentofte Hospital , Hellerup, Denmark
                [6 ]Institute of Health, Science and Technology, Aalborg University , Aalborg, Denmark
                Author notes
                [Correspondence to ] Dr Katja Leth-Møller; katja.biering.leth-moeller.01@ 123456regionh.dk
                Article
                bmjopen-2016-011200
                10.1136/bmjopen-2016-011200
                4874104
                27194321
                bacac3fe-3bc4-49d2-b125-5a3911d6e1e0
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 25 January 2016
                : 29 March 2016
                : 28 April 2016
                Categories
                Pharmacology and Therapeutics
                Research
                1506
                1723
                1712
                1698
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                Medicine
                hyponatremia
                Medicine
                hyponatremia

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