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  • 1. Ajob, Leith
    et al.
    Brännström, Ingrid
    Ott, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Werneke, Ursula
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Fellow of the Royal College of Psychiatrists (FRCPsych).
    ABC om Wernickes encefalopati2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, no ELZTArticle in journal (Refereed)
  • 2. Forssén, B.
    et al.
    Ott, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Werneke, Ursula
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lithium use among psychiatric patientsor: a risk factor for hypernatremia?2018In: Journal of Psychosomatic Research, ISSN 0022-3999, E-ISSN 1879-1360, Vol. 109, p. 103-103Article in journal (Other academic)
    Abstract [en]

    Aims: Hypernatremia is a serious condition that can potentially become life threatening. It is known, but not well-studied, that lithium can induce nephrogenic diabetes insipidus and thereby increase the risk for hypernatremia. In this study, we tested the hypothesis that lithium was a risk factor for hypernatremia in patients with severe affective disorders. Methods: A retrospective study of hypernatremia episodes in all patients aged 18 years or over in the county of Norrbotten who received treatment with lithium or any other mood stabilizing medication during 1997-2013. We identified all episodes of hypernatremia during this period and compared the patients using lithium with those who did not. Results: We identified a total of 204 hypernatremia episodes in 185 patients. For all the 204 episodes, infection (37%) was the dominating cause. Harmful use of substances including alcohol came second. Lithium was only identified as a cause for hypernatremia in 1 % of all the episodes. In patients aged 65 years or less, harmful use of substances including alcohol was the most common cause. Infection was the dominating cause in patients >65 years. There was no significant difference in hypernatremia episodes between lithium users and non-lithium users. Patients who had suffered episodes of hyponatremia or died of these were significantly older. Conclusion: Lithium does not increase the risk of hypernatremia in patients with severe affective disorder compared to patients who do not use lithium. However, in some patients using lithium, severe episodes of hypernatremia can still occur. Thus, clinicians need to remain vigilant. There is a need for more research concerning other risk factors that may contribute to hypernatremia in patients with severe affective disorder.

  • 3.
    Ott, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Forssén, Björn
    Werneke, Ursula
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Sunderby Research Unit, Umeå University, Umeå, Sweden.
    Lithium treatment, nephrogenic diabetes insipidus and the risk of hypernatraemia: a retrospective cohort study2019In: Therapeutic Advances in Psychopharmacology, ISSN 2045-1253, E-ISSN 2045-1261, Vol. 9Article in journal (Refereed)
    Abstract [en]

    Background: Hypernatraemia is a serious condition that can potentially become life threatening. It is known that lithium is associated with polyuria and nephrogenic diabetes insipidus, risk factors for hypernatraemia. In this study, we tested the hypothesis that lithium treatment was a risk factor for hypernatraemia.

    Methods: We performed a retrospective cohort study in the Swedish region of Norrbotten into the effects and potential adverse effects of lithium treatment and other mood stabilizers (LiSIE). For this particular study, we included all patients who had experienced at least one episode with a sodium concentration > 150 mmol/L between 1997 and 2013. Medical records were reviewed regarding past or current lithium exposure, diabetes insipidus and other potential risk factors for hypernatraemia.

    Results: Of 2463 patients included, 185 (7.5%) had experienced 204 episodes of hypernatraemia within the 17-year review period. In patients 65 years or older, infections dominated as the cause with 51%. In patients younger than 65 years, intoxications, particularly with alcohol, dominated as the cause with 35%. In the whole sample, dehydration accounted for 12% of episodes, 25% of which in the context of suspected or confirmed nephrogenic diabetes insipidus. Of all episodes, 25% resulted in death, with infection being the most common cause of death in 62% of cases.

    Conclusions: In our sample, infections and harmful use of substances including alcohol were the most common causes of hypernatraemia. Both current and past use of lithium also led to episodes of hypernatraemia, when associated with nephrogenic diabetes insipidus. Clinicians should remain vigilant, have a low threshold for checking sodium concentrations and consider even risk factors for hypernatraemia beyond lithium.

  • 4.
    Ott, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Mannchen, Julie K.
    Jamshidi, Fariba
    Werneke, Ursula
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Sunderby Research Unit.
    Management of severe arterial hypertension associated with serotonin syndrome: a case report analysis based on systematic review techniques2019In: Therapeutic Advances in Psychopharmacology, ISSN 2045-1253, E-ISSN 2045-1261, Vol. 9, p. 1-32Article, review/survey (Refereed)
    Abstract [en]

    Serotonin syndrome is thought to arise from serotonin excess. In many cases, symptoms are mild and self-limiting. But serotonin syndrome can become life threatening, when neuromuscular hyperexcitability spins out of control. Uncontainable neuromuscular hyperexcitability may lead to cardiovascular complications, linked to extreme changes in blood pressure. Currently, there is little guidance on how to control blood pressure in hyperserotonergic states. We report a case with treatment-resistant arterial hypertension, followed by a clinical review (using systematic review principles and techniques) of the available evidence from case reports published between 2004 and 2016 to identify measures to control arterial hypertension associated with serotonin syndrome. We conclude that classic antihypertensives may not be effective for the treatment of severe hypertension associated with serotonin syndrome. Benzodiazepines may lower blood pressure. Patients with severe hypertension not responding to benzodiazepines may benefit from cyproheptadine, propofol or both. In severe cases, higher cyproheptadine doses than currently recommended may be necessary.

  • 5. Ott, Michael
    et al.
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Salander Renberg, Ellinor
    Werneke, Ursula
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lithium intoxication: Incidence, clinical course and renal function - a population-based retrospective cohort study2016In: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 30, no 10, p. 1008-1019Article in journal (Refereed)
    Abstract [en]

    When prescribing lithium, the risk of toxicity remains a concern. In this study, we examined a cohort of patients exposed to lithium between 1997 and 2013. The aims of this study were to determine the frequency of lithium intoxication and to evaluate the clinical course and changes in renal function. Of 1340 patients, 96 had experienced at least one episode of lithium levels ⩾1.5 mmol/L, yielding an incidence of 0.01 per patient-year. Seventy-seven patients available for review had experienced 91 episodes, of whom 34% required intensive care and 13% were treated with haemodialysis. There were no fatalities. Acute kidney injury occurred, but renal function at baseline was not different to renal function after the episode. Renal impairment was often associated with co-morbidities and other factors. Both intermittent and continuous-venovenous haemodialysis were used, but the clearance of continuous-venovenous haemodialysis can be too low in cases where large amounts of lithium have been ingested. Saline and forced diuresis have been used and are safe. Lithium intoxication seems rare and can be safely managed in most cases. Physicians should not withhold lithium for fear of intoxication in patients who benefit from it. Yet, physicians should have a low threshold to screen for toxicity.

  • 6.
    Ott, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Salander Renberg, Ellinor
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Werneke, Ursula
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Sunderby Research Unit – Psychiatry.
    Prognosis and outcome of severe lithium poisoning: authors' reply2017In: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 31, no 9, p. 1275-1277Article in journal (Refereed)
  • 7.
    Ott, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Werneke, Ursula
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Sunderby Research Unit.
    A Mixed Presentation of Serotonin Syndrome Versus Neuroleptic Malignant Syndrome in a 12-Year-Old Boy2019In: Pediatric emergency care, ISSN 0749-5161, E-ISSN 1535-1815, Vol. 35, no 5, p. E98-E98Article in journal (Refereed)
  • 8. Wagner, C A
    et al.
    Ott, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Klingel, K
    Beck, S
    Melzig, J
    Friedrich, B
    Wild, K N
    Bröer, S
    Moschen, I
    Albers, A
    Waldegger, S
    Tümmler, B
    Egan, M E
    Geibel, J P
    Kandolf, R
    Lang, F
    Effects of the serine/threonine kinase SGK1 on the epithelial Na(+) channel (ENaC) and CFTR: implications for cystic fibrosis.2001In: Cellular Physiology and Biochemistry, ISSN 1015-8987, E-ISSN 1421-9778, Vol. 11, no 4Article in journal (Refereed)
    Abstract [en]

    Cystic fibrosis (CF) is characterized by impaired Cl(-) secretion and increased Na(+) reabsorption in several tissues including respiratory epithelium. Many CFTR mutations have been identified over the past years. However, only a poor correlation between the genotype and lung phenotype was found suggesting additional factors influencing the phenotype and course of the disease. The serine/threonine kinase SGK1 has recently been shown to stimulate the activity of the epithelial Na(+) channel ENaC. A variety of stimuli such as aldosterone, cell shrinkage, insulin or TGF-beta1 stimulate transcription and activate the SGK1 kinase. Here we further examined the effects of SGK1 on ENaC and CFTR which have mutual interactions and we analyzed sgk1 mRNA abundance in lung tissue from CF patients. Coexpression of CFTR and h-SGK1 in Xenopus oocytes increased ENaC currents as previously described. In addition CFTR mediated currents were also stimulated. h-SGK1 accelerated the expression of the amiloride sensitive Na(+)- current in Xenopus oocytes paralleled by increased ENaC-protein abundance in the oocyte membrane, an effect which was reversed by a h-SGK1(K127R) mutation lacking the ATP-binding site. The cation selectivity or Na(+) affinity were not affected. However, coexpression of h-SGK1 with ENaC altered the sensitivity of the Na(+)-channel to the inhibitors amiloride and triamterene. The inhibitory effect of CFTR expression on ENaC current was not affected by coexpression of h-SGK1 in Xenopus oocytes. Lung tissue from CF patients strongly expressed the serine/threonine kinase h-sgk1 which was not the case for non-CF lung tissue. Loss of CFTR function itself in a CF lung epithelial cell line did not increase SGK1 expression. In summary, enhanced expression of h-SGK1 in epithelial cells of CF-lung tissue may be a novel pathophysiological factor contributing to increased Na(+) channel activity and thus to increased Na(+) transport in CF.

  • 9.
    Werneke, Ursula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Sunderby Hospital, 97180 Luleå, Sweden.
    Jamshidi, Fariba
    Taylor, David M.
    Ott, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Conundrums in neurology: diagnosing serotonin syndrome - a meta-analysis of cases2016In: BMC Neurology, ISSN 1471-2377, E-ISSN 1471-2377, Vol. 16, article id 97Article in journal (Refereed)
    Abstract [en]

    Background: Serotonin syndrome is a toxic state, caused by serotonin (5HT) excess in the central nervous system. Serotonin syndrome's main feature is neuro-muscular hyperexcitability, which in many cases is mild but in some cases can become life-threatening. The diagnosis of serotonin syndrome remains challenging since it can only be made on clinical grounds. Three diagnostic criteria systems, Sternbach, Radomski and Hunter classifications, are available. Here we test the validity of four assumptions that have become widely accepted: (1) The Hunter classification performs clinically better than the Sternbach and Radomski criteria; (2) in contrast to neuroleptic malignant syndrome, the onset of serotonin syndrome is usually rapid; (3) hyperthermia is a hallmark of severe serotonin syndrome; and (4) serotonin syndrome can readily be distinguished from neuroleptic malignant syndrome on clinical grounds and on the basis of medication history.

    Methods: Systematic review and meta-analysis of all cases of serotonin syndrome and toxicity published between 2004 and 2014, using PubMed and Web of Science.

    Results: Two of the four assumptions (1 and 2) are based on only one published study each and have not been independently validated. There is little agreement between current criteria systems for the diagnosis of serotonin syndrome. Although frequently thought to be the gold standard for the diagnosis of the serotonin syndrome, the Hunter criteria did not perform better than the Sternbach and Radomski criteria. Not all cases seem to be of rapid onset and only relatively few cases may present with hyperthermia. The 0 differential diagnosis between serotonin syndrome and neuroleptic malignant syndrome is not always clear-cut.

    Conclusions: Our findings challenge four commonly made assumptions about serotonin syndrome. We propose our meta-analysis of cases (MAC) method as a new way to systematically pool and interpret anecdotal but important clinical information concerning uncommon or emergent phenomena that cannot be captured in any other way but through case reports.

  • 10.
    Werneke, Ursula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Sciences, Sunderby Research Unit.
    Ott, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Response to "The impact of modern treatment principles may have eliminated lithium-induced renal failure" Aiff et al. 20142014In: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 28, no 12, p. 1189-1190Article in journal (Refereed)
  • 11.
    Werneke, Ursula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Psychiatry, Sunderby Hospital, Lulea, Sweden.
    Ott, Michael
    Department of Nephrology Division of Internal Medicine Sunderby Hospital Luleå, Sweden.
    Salander Renberg, Ellinor
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Taylor, D.
    Pharmacy Department South London and Maudsley NHS Foundation Trust and the Institute of Pharmaceutical Sciences, King's College, London London, UK.
    Long-term lithium treatment and the risk of renal failure vs. risk of suicide: a decision analysis2012In: Journal of Psychosomatic Research, ISSN 0022-3999, E-ISSN 1879-1360, Vol. 72, no 6, p. 508-508Article in journal (Other academic)
  • 12.
    Werneke, Ursula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Ott, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Division of Internal Medicine, Department of Nephrology, Sunderby Hospital, Luleå, Sweden.
    Salander Renberg, Ellinor
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Taylor, D
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A decision analysis of long-term lithium treatment and the risk of renal failure2012In: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 126, no 3, p. 186-197Article in journal (Refereed)
    Abstract [en]

    Objective: To establish whether lithium or anticonvulsant should be used for maintenance treatment for bipolar affective disorder (BPAD) if the risks of suicide and relapse were traded off against the risk of end-stage renal disease (ESRD).

    Method: Decision analysis based on a systematic literature review with two main decisions: (1) use of lithium or at treatment initiation and (2) the potential discontinuation of lithium in patients with chronic kidney disease (CKD) after 20 years of lithium treatment. The final endpoint was 30 years of treatment with five outcomes to consider: death from suicide, alive with stable or unstable BPAD, alive with or without ESRD.

    Results: At the start of treatment, the model identified lithium as the treatment of choice. The risks of developing CKD or ESRD were not relevant at the starting point. Twenty years into treatment, lithium still remained treatment of choice. If CKD had occurred at this point, stopping lithium would only be an option if the likelihood of progression to ESRD exceeded 41.3% or if anticonvulsants always outperformed lithium regarding relapse prevention.

    Conclusion: At the current state of knowledge, lithium initiation and continuation even in the presence of long-term adverse renal effects should be recommended in most cases.

  • 13.
    Werneke, Ursula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Ott, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Salander Renberg, Ellinor
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Does severe affective disorder affect renal function?2015In: Journal of Psychosomatic Research, ISSN 0022-3999, E-ISSN 1879-1360, Vol. 78, no 6, p. 630-631Article in journal (Other academic)
    Abstract [en]

    Background: There is a relationship between affective and somatic morbidity. For instance, patients with bipolar affective disorder (BPAD) and schizophrenia have more diabetes mellitus and a higher cardiovascular mortality. Psychotropic medications seem to only partly account for such associations. The aim of the study was to compare renal function of patients with severe affective disorders with the general population. Method: We examined a representative sample of the population between 25 and 74 years (Northern Sweden Monica Study) and all individuals with comparable age in the Swedish county of Norrbotten with a diagnosis of BPAD, schizoaffective disorder or exposure to lithium between 1997 and 2013 as a proxy for severe affective disorder. All patients were included who consented to the review of their medical case notes and who had a serum creatinine level taken at least within one year of our analysis. We compared the most recent creatinine levels and the eGFR ascertained with the CKD-EPI formula. Results: 955 individuals with severe affective disorder (61% female, 39% male) had a serum creatinine measured in the year of study. 1549 persons (52% female, 48% male) were in the control group. Mean age differed significantly (p < 0.01) between control (mean 51.8 years, SD 13.5) and patients (mean 50.4 years, SD 13.3). 37.8% of the patients had never been exposed to lithium during the last 17 years, 14.3% less than one year, 15.2% 1–5 years and 32.7% more than 5 years. Mean eGFR for the control was 90.19 ml/min/1.73 m2 (SD 15.8) and 90.89 (SD 19.5) in the patient group (p = 0.33). Five people had renal function below 30 ml/min, two in the control group (eGFR 15–30) and three in the long-term lithium group (eGFR < 15). There was no statistically significant difference in renal function between patients and controls as measured. But patients were slightly younger than the controls (1.4 year difference in mean age). Only if the “natural” annual decline in GFR was assumed to be 1.5 ml/min or more, the renal function between both groups would be statistically different. Conclusion: Renal function in patients with severe affective disorders may be lower than in the general population. But, the difference is small and probably without clinical significance in most cases. This would speak against relevant other factors inherently linked to severe affective disorders apart from long-term lithium exposure. We will explore this further in forthcoming analyses.

  • 14.
    Öhlund, Louise
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Ott, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Oja, Sofia
    Bergqvist, Malin
    Lundqvist, Robert
    Sandlund, Mikael
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Renberg, Ellinor Salander
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Werneke, Ursula
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Sunderby Hospital – Psychiatry, 97180 Luleå, Sweden.
    Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study2018In: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 18, article id 37Article in journal (Refereed)
    Abstract [en]

    Background: Lithium remains first choice as maintenance treatment for bipolar affective disorder. Yet, about half of all individuals may stop their treatment at some point, despite lithium’s proven benefits concerning the prevention of severe affective episodes and suicide.

    Methods: Retrospective cohort study in the Swedish region of Norrbotten into the causes of lithium discontinuation. The study was set up to (1) test whether patients with bipolar affective disorder or schizoaffective disorder, treated with lithium maintenance therapy, were more likely to discontinue lithium because of adverse effects than lack of therapeutic effectiveness, (2) explore gender differences, (3) understand the role of diagnosis and (4) identify who, patient or doctor, took the initiative to stop lithium. Review of medical records for all episodes of lithium discontinuation that had occurred between 1997 and 2013 with the intent to stop lithium for good.

    Results: Of 873 patients treated with lithium, 54% discontinued lithium, corresponding to 561 episodes of lithium discontinuation. In 62% of episodes, lithium was discontinued due to adverse effects, in 44% due to psychiatric reasons, and in 12% due to physical reasons interfering with lithium treatment. The five single most common adverse effects leading to lithium discontinuation were diarrhoea (13%), tremor (11%), polyuria/polydipsia/diabetes insipidus (9%), creatinine increase (9%) and weight gain (7%). Women were as likely as men to take the initiative to stop lithium, but twice as likely to consult a doctor before taking action (p < 0.01). Patients with type 1 BPAD or SZD were more likely to discontinue lithium than patients with type 2 or unspecified BPAD (p < 0.01). Patients with type 1 BPAD or SZD were more likely to refuse medication (p < 0.01). Conversely, patients with type 2 or unspecified BPAD were three times as likely to discontinue lithium for lack or perceived lack of effectiveness (p < 0.001).

    Conclusions: Stopping lithium treatment is common and occurs mostly due to adverse effects. It is important to discuss potential adverse effects with patients before initiation and continuously during lithium treatment, to reduce the frequency of potentially unnecessary discontinuations.

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