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Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder

  • Paula V. Nunes (a1), Orestes V. Forlenza (a1) and Wagner F. Gattaz (a1)
Summary

Bipolar disorder is associated with increased risk for dementia. We compared the prevalence of Alzheimer's disease between 66 elderly euthymic patients with bipolar disorder who were on chronic lithium therapy and 48 similar patients without recent lithium therapy. The prevalence of dementia in the whole sample was 19% v. 7% in an age-comparable population. Alzheimer's disease was diagnosed in 3 patients (5%) on lithium and in 16 patients (33%) who were not on lithium (P < 0.001). Our case-control data suggest that lithium treatment reduced the prevalence of Alzheimer's disease in patients with bipolar disorder to levels in the general elderly population. This is in accordance with reports that lithium inhibits crucial processes in the pathogenesis of Alzheimer's disease.

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Copyright
Corresponding author
Professor Wagner F. Gattaz, Department & Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil. Email: gattaz@usp.br
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Declaration of interest

None. Funding detailed in Acknowledgements.

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References
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Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder

  • Paula V. Nunes (a1), Orestes V. Forlenza (a1) and Wagner F. Gattaz (a1)
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eLetters

Lithium and dementia

Sara V Ormerod, Psychiatrist
07 September 2007

Dear Sir

Nunnes et al (2007), suggested “that lithium might reduce the risk ofdementia in patients with bipolar disorder.” There is a wealth of data regarding lithium toxicity and side effects. Between 1963 and 2006 there have been 44 yellow cards reporting lithium causing a confusional state but there is no comment on Lithium levels( href="http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=287" target="_blank">http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=287).Lithium has been demonstrated to cause mild impairment of psychomotor speed and several studies have also demonstrated a mild decline in verbal memory associated with treatment (Patchet et al (2003)). It has been reported that lithium can cause neurotoxicity, which may present with a dementia type syndrome even when lithium levels are within the normal therapeutic range (Padladini et al (1995)). We have recently treated a 71year old gentleman for treatment resistant depression. At the time of commencing lithium treatment he had mild renal impairment (urea= 8.8umol/Land creatinine 162umol/L) and his MMSE prior to Lithium was 21/30. In addition he was being treated with Mirtazepine 45mg and Olanzapine 15mg (the doses of which had not been altered for 3 months) He was also taking Digoxin 125 micrograms (digoxin level 1.1 ug/L), Domperidone 10mg TDS, Diltiazem LA 200mg OD and Lactulose 10ml BD for physical health problems. Our patient took Lithium for 12 weeks. During this time he developed increasing cognitive impairment including disortientation, dressing apraxia, expressive dysphasia and myocloninc jerks. His MMSE scores demonstrated a progressive reduction to a lowest of 10/30. No other causefor the deterioration could be identified despite investigations and review by a geriatrician and neuropsychiatrist. Throughout his lithium treatment levels remained within therapeutic limits (range <0.1-0.68 mmol/L) and his renal impairment remained approximately stable. An EEG ontreatment demonstrated no alpha activity, dominated by a mixture theta anddelta activity. Discontinuing lithium therapy his MMSE returned to his pre-treatment level of 23/30 within 2 weeks.

It is important to highlight our experience, particularly if psychiatrists are considering using lithium as a preventative agent for the development of dementia, they must be aware it may cause a dementia like syndrome within therapeutic range. Importantly this syndrome appearsreversible with discontinuation of lithium.

Sara Ormerod MBChB, MRCPscyh, DGMGeorge Tadros MBChB, PGDip, MRCPsych, MD

Queen Elizabeth Psychiatric Hospital, Off Vincent Drive, Edgbaston, Birmingham B15 2QZEmail: george.tadros@bsmht.nhs.uk

Declaration of interests: None

Nunnes, P.V. Forlenza, O.V. Gattaz, W.G. (2007) Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br.J. Psychiatry, 190:359-60Padladini, D. Cinti, A. De-Dominicis, L. Pucci, E. Giuliani, G. (1995) Lithium carbonate intoxication: Demental syndrome with normal serum lithium levels. Rivista di Neurobilogia, 41(5), 731-739Patchet, A.K. Wisniewski, A.M. (2003) The effects of lithium on cognition:an updated review. Psychopharmacology, 170, 225-234 ... More

Conflict of interest: None Declared

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Re: Lithium for Alzheimer's prevention

Takeshi Terao, Professor of Neuropsychiatry
08 May 2007

Thank you very much for Professor Gattaz et al�fs reply to my commenton their paper (Nunes et al 2007). I agree with them in their opinion thatit is important to further investigate the potential protective effect of lithium in Alzheimer�fs disease.

Although Professor Gattaz et al cited in their letter that 14% of bipolar and 16% of unipolar elderly patients developed dementia (MMSE<24) as compared to 3.4% of age-matched controls (Kessing 1998), Kessing and Andersen (2004) subsequently reported that proportion developing dementia during follow-up was 97 (2.3%) of 4,248 patients with bipolar disorder and 337 (1.8%) of 18,726 patients with depressive disorder. These percentages seem to be lower, but the rate of dementia increased on average 13% with every episode leading to admission for patients with depressive disorder and 6% with every episode leading to admission for bipolar patients, when adjusted for differences in ages and sex. If this is the case, there is a possibility that lithium may indirectly prevent dementia via its prophylactic effects of mood disorders. Another possibility is that lithium can directly prevent dementia via its inhibition of glycogen synthase kinase (GSK) 3 alpha (Phiel et al 2003) and GSK 3 beta (Phiel and Klein 2001). Although Professor Gattaz et al did not find significant differences in the number of previous depressive and manic episodes between the lithium and the non-lithium groups in their sample (Nunes et al 2007), at the moment, both possibilities should be kept in mind while investigating lithium effects for preventing dementia.

Kessing LV, Andersen PK (2004): Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? Journal of Neurology, Neurosurgery,and Psychiatry 75:1662-1666.

Nunes PV, Forlenza OV, Gattaz WF (2007): Lithium and risk for Alzheimer�fs disease in elderly patients with bipolar disorder. British Journal of Psychiatry 190:359-360.

Phiel CJ, Klein PS (2001): Molecular targets of lithium action. Annual Review of Pharmacology and Toxicology 41:789-813.

Phiel CJ, Wilson CA, Lee VM-Y, Klein PS (2003): GSK-3 alpha regulatesproduction of Alzheimer�fs disease amyloid-beta peptides. Nature 423:435-439.
... More

Conflict of interest: None Declared

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Lithium for Alzheimer�s prevention

Wagner F. Gattaz, Professor of Psychiatry
18 April 2007

We read with interest the comments of Dr. T. Terao on our findings that lithium reduced the risk of Alzheimer´s disease(Nunes et al 2007), incontrast with the work by Dunn et al. (2005), who identified from the General Practice Research Database in the UK all cases diagnosed as "dementia" between 1992 and 2002 (n = 9954) and compared the number of prescriptions of lithium to these individuals with a control group of patients without a diagnosis of dementia (n = 9374). They found that moredemented patients (n = 47; 0.47%) than controls (n = 40; 0.43%) were exposed to lithium. We feel that this finding does not allow conclusions to be drawn as to whether lithium protects or not against dementia, because it has been shown that demented patients have an increased risk ofdeveloping mania and depression (Nilsson et al. 2002) and are thus more prone to receive treatment for it, including lithium. Conversely, affective disorders itself seem to increase risk for dementia. In a series of outstanding studies based on data from the Danish psychiatric case register, Kessing and co-workers found that 14% of bipolar and 16% ofunipolar elderly patients developed dementia (MMSE < 24) as compared to3.4% of age-matched controls (Kessing 1998). Even within a younger sampleof psychiatric patients (mean age ~ 50 years), Kessing et al. (1999) reported that patients with bipolar disorder had the highest risk of receiving a diagnosis of dementia, followed by patients with unipolar affective disorder, patients with schizophrenia and patients with neuroses. Thus, if affective disorders do increase both the risk of dementia and the likelyhood of receiving lithium treatment, than due to the sampling method used by Dunn et al. one could expect to find more lithium treatment within elderly individuals with dementia. Actually Dunnet al. themselves discussed this alternative explanation to their findingsas a “reverse causation” possibility.

We think that it is important to investigate further the potential protective effect of lithium in Alzheimer´s disease, as this could represent a low-cost, patent-free and universally available strategy to reduce the prevalence of the disease.

References:

Dunn N, Holmes C, Mullee M (2005): Does lithium therapy protect against the onset of dementia? Alzheimer Dis Assoc Disord 19:20-22

Kessing LV (1998): Cognitive impairment in the euthymic phase of affective disorder. Psychol Med 28(5):1027-1038.

Kessing LV, Olsen EW, Mortensen PB, Andersen PK (1999): Dementia in affective disorder: a case-register study. Acta Psychiatr Scand 100(3):176-185.

Nilsson FM, Kessing LV, Sorensen TM, Andersen PK, Bolwig TG (2002): Enduring increased risk of developing depression and mania in patients with dementia. J Neurol Neurosurg Psychiatry 73:40-44.

Nunes PV, Forlenza OV, Gattaz WF (2007): Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder. Br J Psychiatry 190: 359-360
... More

Conflict of interest: None Declared

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Lithium for Dementia Prevention

Takeshi Terao, Professor
11 April 2007

Nunes et al (2007) reveal that the prevalence of Alzheimer�fs diseasein the group on continuous lithium treatment was significantly less than that in the group without recent lithium therapy. After controlling for age, lithium use remained associated with a smaller risk of Alzheimer�fs disease (age-adjusted OR=0.079, 95% CI 0.020-0.321) and they suggest that lithium may prevent Alzheimer�fs disease. Conversely, Dunn et al (2005) show that patients who received lithium had a significantly higher risk ofdementia compared with those who did not (age-adjusted OR=1.8, CI 1.1-2.8)and the finding does not support the use of lithium for preventing dementia.

Nunes et al (2007) also found no differences between the lithium and the comparison group in the assessment of neuropsychological performance after excluding patients with Alzheimer�fs disease. This is in accordance with our study where Mini-Mental State Examination (MMSE) scores were not different between patients receiving lithium and patients without lithium after excluding patients with dementia (Terao et al, 2006). Our study, however, shows that patients having the present and/or the past history oflithium treatment had significantly better MMSE scores than patients without any history of lithium treatment (Terao et al, 2006).

At present, it is yet to be determined whether lithium can prevent dementia, but prospective studies with a large number of patients are warranted to investigate this very important effect.

Dunn, N., Holmes, C., Mullee, M. (2005) Does lithium therapy protect against the onset of dementia? Alzheimer Disease and Associated Disorders,19, 20-22.

Nunes, P.V., Forlenza, O.V., Gattaz, W.F. (2007) Lithium and risk forAlzheimer�fs disease in elderly patients with bipolar disorder. British Journal of Psychiatry, 190, 359-360.

Terao, T., Nakano, H., Inoue, Y., et al (2006) Lithium and dementia: a preliminary study. Progress in Neuro-Psychopharmacology & BiologicalPsychiatry, 30, 1125-1128.
... More

Conflict of interest: None Declared

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