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Does Lithium protect against dementia?

By Kessing LV, Forman JL, Andersen PK, Journal of Bipolar Disorder Feb 2010
Bipolar Disord 2010 Feb; 12(1):87-94.


  • Studies suggest that BD is associated with increased risk of dementia, and the risk increases with every new affective episode
  • Lithium may have neuroprotective abilities, reduce the risk of developing dementia by inhibiting glycogen synthase kinase-3, a key enzyme in the metabolism of amyloid precursor protein and in the phosphorylation of tau protein involved in the pathogenesis of Alzheimer’s Disease


  • To investigate whether continued treatment with Lithium in patients with mania or bipolar disorder is associated with reduced risk of developing dementia, and whether continued treatment with anticonvulsants, antidepressants and antipsychotics were eventually associated with a decreased rate of developing dementia


  • The population sample was obtained by linking Danish population-based registers, Danish Medical Register, Danish National Hospital Register and Danish Psychiatric Central Register from January 95 to December 05, with a diagnosis of manic or mixed episode or bipolar disorder (ICD-10 codes).
  • Patients with a diagnosis of dementia or schizophrenia were excluded.
  • Study design: non-randomized,
  • Statistical analysis: Poisson regression analyses were conducted with a diagnosis of dementia as outcome and with the number of prescriptions of lithium, anticonvulsants, antidepressants and antipsychotics, respectively at the end of study period (December 05). Data were analyzed accordingly including effect of various drugs severity of bipolar disorder, multiple prescription, sex and age on rate of dementia.


  • A total of suitable patients of 4856 were exposed to any of the drugs of interest at least once during the study period
  • 2449 (50.4%) were exposed to lithium, 1781 (36.7%) to anticonvulsants, 4280 (88.1%) to antidepressants and 3901 (80.3%) to antipsychotic.
  • A total of 4856 patients (4.5%) had a diagnosis of dementia.
  • Most prevalent combinations of drugs include
    i) Lithium, antidepressant and antipsychotic (20.7%),
    ii) Antidepressants and antipsychotics (19.7%)
    iii) All 4 types (16.8%)
    iv) Anticonvulsants, antidepressants and antipsychotic (12.4%)
  • Purchase of 2 or more prescription of Lithium was associated with significantly decreased rate of dementia compared with the rate during the period with one purchase prescription of lithium.
  • For other types of drugs, the rate of dementia during multiple prescription periods did not differ significantly from the rate during prescription period one.


  • Among patients with bipolar disorder or mania, continued use of lithium was associated with a decreased rate of dementia. However, continued treatment with other medication was not associated with a significantly decreased rate of dementia
  • There is a dose-response relationship between the severity of bipolar disorder and the risk of developing dementia. It confirms that the risk of developing dementia increases with the number of prior affective episodes.


  • Diagnoses were made by clinicians and were not research based. Validity of the ICD-10 diagnoses of bipolar disorder has not been investigated, clinicians may have heterogeneous ways of handling diagnoses
  • A majority of patients included in the study used drugs from or more different types of 4 drug types, which might reduce the possibility of finding effects related to individual types of drugs.
  • The finding of a decreased rate of dementia in relationship to continued use of lithium could be the result of a number of potential relationship:
    1. Treatment with lithium may not be given to patients who the clinician believes will develop dementia later on e.g. patients with mild cognitive impairment as this might induce confusion. Continued treatment with lithium may not be given to patients with cardiac or renal insufficiency which may be related eventually to increased risk of dementia.
    2. Patients who continue taking lithium for longer periods may presumably be good compliers with less alcohol use and a healthier lifestyle associated with decreased risk of alcohol use.
    3. Anticonvulsants have been associated with neuroprotective abilities in much the same way as lithium, among others, including inhibition of glycogen synthase kinase-3. It is not possible from the present study to determine whether lithium has a protective effect against dementia due to increased neurogenesis or due to mood-stabilizing abilities preventing from recurrences of affective episodes or other treatment related factor.


Among patient with mania or bipolar disorder, continued use of lithium was associated with a decreased rate of dementia. In contrast, no significant associations were found between continued treatment with anticonvulsants, antidepressants or antipsychotics respectively. However, methodological reasons for these findings cannot be excluded due to non-randomized nature of data.

Resources Centre Literature Review Does Lithium protect against dementia?