An observational study of 110 elderly lithium-treated patients followed up for 6 years with particular reference to renal function
Bocchetta et al. Int J Bipolar Disord
An observational study of 110 elderly lithium-treated patients followed up for 6 years with particular reference to renal function
Alberto Bocchetta 0 2
Francesca Cabras 2
Martina Pinna 2
Antonio Poddighe 1
Claudia Sardu 3
Raffaella Ardau 0
Caterina Chillotti 0
Maria Del Zompo 0 2
0 Unit of Clinical Pharmacology, Azienda Ospedaliero-Universitaria di Cagliari, “San Giovanni di Dio” Hospital , Via Ospedale 54, 09124 Cagliari , Italy
1 Neurology Outpatient Unit, Local Health Agency , Cagliari , Italy
2 Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sci- ences, University of Cagliari , Cagliari , Italy
3 Department of Medical Science and Public Health, University of Cagliari , Cagliari , Italy
Background: Recent observational studies have focused on lithium treatment in the elderly, with particular reference to safety in terms of thyroid and renal functions. The purpose of this study was to compare the clinical characteristics of patients starting lithium treatment before (N = 79) or after (N = 31) the age of 65 years. Patients were followed up for 6 years with focus on renal function and prescription of levothyroxine and methimazole. Results: At baseline, median lithium serum concentration was 0.55 mmol/l. The estimated glomerular filtration rate was lower than 60 ml/min/1.73 m2 in 43 (39%) patients. In a multiple regression analysis controlling for age and gender, we found a significant effect of duration of lithium treatment on estimated glomerular filtration rate (−0.85 ml/ min/1.73 m2 per year of prior exposure). The annual decline during follow-up was 2.3 ml/min/1.73 m2. Two patients were prescribed levothyroxine, and two were prescribed methimazole for the first time during follow-up. Conclusions: Median lithium serum concentration in this cohort of elderly patients with mainly bipolar disorders was lower than the therapeutic range indicated for younger adults. The decline in glomerular filtration rate may be accelerated by long-term lithium use. Thyroid and renal functions continue to require close monitoring throughout the course of lithium treatment.
Mood disorders; Bipolar disorders; Depression; Lithium; Elderly; Creatinine; Kidney; Lithium; Nephrotoxicity; Thyroid
Reviews published over the last two decades continue to
recommend lithium treatment in elderly patients with
bipolar disorder (Young et al. 2004; Aziz et al. 2006;
Shulman 2010). There is also evidence that lithium
combined with antidepressants may be effective in the
prophylactic therapy of elderly patients with unipolar
depression (Wilkinson et al. 2002). Prescription
patterns have shifted in favor of valproic acid over lithium
for elderly patients with bipolar disorder, but this shift
may not be completely evidence based (Shulman et al.
2003). Current national and international guidelines
for bipolar disorder are incorporating emerging
information, but the majority of guidelines do not have
sections that pertain specifically to older adults (Dols
et al. 2016). Research into the use of lithium in old age
is very limited, because elderly subjects are frequently
excluded from randomized clinical trials. One
exception is the trial that has been performed specifically in
late-life mania, but the key results for which are yet to
be published (Young et al. 2010). Observational
studies of elderly lithium patients continue to provide
useful information, and recently, research has reported on
thyroid and renal functions (Kraszewska et al. 2015;
© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.
Permoda-Osip et al. 2016; Rej et al. 2013a, 2014a),
and cognitive function and brain abnormalities
(Gildengers et al. 2015; Zung et al. 2016) in these elderly
Kraszewska et al. (2015) studied thyroid function in a
cross-sectional sample of 66 patients with bipolar
disorder receiving lithium over a period of between 10 and
44 years (mean age = 62 years). Of the 45 women in the
sample, seven were receiving levothyroxine replacement
therapy and an additional three had elevated thyrotropin
concentrations. Therefore, some features of
hypothyroidism occurred in 22% of their female sample.
Permoda-Osip et al. (2016) studied kidney, thyroid,
and other organ functions after 40 years or more of
lithium therapy in five patients (age range = 64–79 years).
The three women in the sample had asymptomatic
stage 2 chronic kidney disease (CKD) with an
estimated Glomerular Filtration Rate (eGFR) ranging from
60 to 75 ml/min/1.73 m . One male had stage 3 CKD
(eGFR = 45–49 ml/min/1.73 m2), and the other had stage
2/3 CKD (59 ml/min/1.73 m2). One woman had severe
thyroid dysfunction (Hashimoto’s disease) with extremely
high levels of antithyroid peroxidase antibodies and
antithyroglobulin antibodies and was receiving
thyroxine. However, cognitive functions in all five patients were
comparable to those in healthy people of similar gender,
age, and education.
Rej et al. (2013b) conducted a retrospective study of 27
lithium-using geriatric patients (mean age = 81.6 years)
with eGFR ≤60 ml/min/1.73 m2 on ≥2 occasions
within ≥3 months. Patients were divided into those who
continued lithium use ≥2 years following CKD and those
who discontinued lithium. Changes in eGFR between
continuers and discontinuers after 60 months were not
statistically significant. However, clinically important
decreases in eGFR occurred in the majority of continuers
but in none of the discontinuers.
A Canadian population-based cross-sectional study
of 2480 lithium users aged 70 years or above measured
prevalence of CKD, acute kidney injury, and nephrogenic
diabetes insipidus. The 6-year prevalence rate of CKD
was 13.9%. Lithium use for more than 2 years was one
of the variables independently associated with CKD (Rej
et al. 2014a).The purpose of the present study was to
follow up a cohort of 110 cross-sectional lithium patients
studied since 2010, when they were at least 65 years old.
Our aims were (1) to compare patients who had become
old during long-term lithium treatment with those who
had been first prescribed lithium in old age, with
particular regard to psychiatric diagnosis, and concurrent
psychiatric and non-psychiatric medication; and (2) to
follow up patients with regard to status of lithium
treatment, and thyroid and renal functions.
Out of the 350 patients treated with lithium who had
attended the Unit of Clinical Pharmacology, Azienda
Ospedaliero-Universitaria, Cagliari, at least once between
January and August 2010, we selected those born in 1945
or earlier (N = 110; 80 women, 30 men).
The Unit of Clinical Pharmacology has been one of the
reference centers for lithium monitoring in the Cagliari
area since its introduction in the 1970s. Lithium may be
prescribed by any psychiatrists in this area, but elderly
patients eligible for mood stabilizing treatment are often
sent in by neurologists or general practitioners. Patients
may continue to be followed by the referring specialist or
may be managed by the lithium clinic staff alone.
The best estimate lifetime psychiatric diagnoses in the
clinic are based on: direct interviews using the
Schedule for Affective Disorders and Schizophrenia-Lifetime
Version (SADS-L) (Endicott and Spitzer 1978), medical
records, and information from relatives and referring
Once the initial treatment has stabilized, the usual
interval between visits and lithium serum measurements
in young adults goes from 8 to 12 weeks, but elderly
patients are monitored more frequently. Routine visits
for lithium patients include: (a) medical evaluation; (b)
psychiatric evaluation; (c) completion of a checklist of
side effects and concurrent medications; (d)
measurement of serum concentrations of lithium 12 ± 1 h after
the last dose. On admission and on a yearly basis
thereafter, we require routine laboratory tests, thyroid function
tests, electrocardiogram, and a visit by a cardiologist.
Our therapeutic range for lithium maintenance in elderly
patients is widened to 0.40–0.80 mmol/l compared to the
0.60–0.80 mmol/l range indicated for younger adults.
For the purpose of the present study, we extracted the
following variables from patients’ charts: demographic
characteristics, psychiatric diagnosis, history of
maintenance treatments prior to lithium, current lithium dose,
concurrent medications, and data on renal and thyroid
Patients were followed up for 6 years (last evaluation,
August 31, 2016), with particular emphasis on status of
lithium treatment, concurrent medications, and thyroid
and renal functions.
Serum creatinine concentrations were taken from the
panel of laboratory tests requested on an annual basis.
The traditional standardization method for serum
creatinine was used.
The estimated Glomerular Filtration Rate (eGFR) was calculated from serum creatinine values using the
equation proposed by the Modification of Diet in Renal
Disease (MDRD) Study Group (Levey et al. 1999;
Earley et al. 2012), with the ‘186’ correction factor, which
also takes into account age, gender and ethnicity. The
following categories of eGFR were considered: higher than
90 ml/min/1.73 m2 (G1); 60–89 ml/min/1.73 m2 (G2);
45–59 ml/min/1.73 m2 (G3a); 30–44 ml/min/1.73 m2
(G3b); 15–29 ml/min/1.73 m2 (G4); lower than 15 ml/
min/1.73 m2 (G5). The abbreviations and ranges recall
those used by KDIGO (2013) 2012 Clinical Practice
Guidelines for the Evaluation and Management of Chronic
Kidney Disease (CKD) (2012), but it must be noted that
KDIGO CKD stages are also based on albuminuria
categories, which were not included in the present study.
We used the following statistical tests: (a) unpaired or
paired Student’s t test to compare means; (b)
nonparametric Mann–Whitney test to compare medians; (c)
Fisher’s exact test to analyze contingency tables: (d) multiple
regression analysis to study the effects on renal function
of age, gender and years of lithium treatment at
inception and during follow-up, using eGFR or eGFR decline
as the dependent variable; (e) a generalized linear model
for repeated measures to analyze the influence of age
and gender on eGFR variation during the 6-year
followup; (f ) Cox regression analysis was performed to analyze
time between the start of the study and achievement of
eGFR <45 ml/min/1.73 m2, as a function of age, gender
and duration of prior lithium exposure.
Cross‑sectional data at start
At the start of the study, median serum concentration
of lithium in the 110 patients was 0.55 mmol/l. Patients
were taking regularly the following medications: N = 80
(73%) benzodiazepines, N = 57 (52%) ACE inhibitors,
sartans, and/or thiazides, N = 21 (19%) oral
hypoglycemic agents or insulin, and N = 34 (31%) hypolipidemic
Mean daily doses of lithium carbonate were
significantly lower in patients taking ACE inhibitors,
sartans, and/or thiazides (384 ± 187 versus 464 ± 196 mg;
P = 0.03).
Regarding thyroid function, N = 33 (30%) were taking
levothyroxine, and N = 2 (2%) were taking methimazole.
With regard to renal function, 43 (39%) had an eGFR
lower than 60 ml/min/1.73 m2.
Demographic and clinical characteristics of patients
according to the age of their first lithium prescription are
shown in Table 1.
After correcting for the effects of age and gender,
duration of lithium treatment was associated with lower eGFR
values (Table 2).
Compared to the remaining patients, the subgroup
(N = 31) starting lithium for the first time during old
Table 1 Demographic and clinical characteristics at baseline by age at first lithium prescription
Patients who started
lithium at age <65 (n = 79)
Patients who started
lithium at age ≥65 (n = 31)
2010 2011 2012 2013 2014 2015 2016
Fig. 1 Attrition rate of patients during 6-year follow-up. Number of
patients studied, deceased, or otherwise lost to follow-up over the
6 years of the study
age (≥65 years) included greater proportions of patients
with the following characteristics: N = 14 (41%) had been
referred to the lithium clinic by a neurologist; N = 10
(32%) had a diagnosis of bipolar disorder not elsewhere
defined; N = 8 (26%) had previously been exposed to
chronic antidepressants; N = 10 (32%) had undergone
neuroimaging (CAT or NMR); and N = 13 (42%) were
taking antiplatelets or oral anticoagulants.
At the end of the 6-year follow-up, 58 (53%) patients were
still on lithium (Fig. 1), including 7 patients who had
continued lithium but were not able to come into the clinic
because of physical disability. Of the remaining patients,
32 (29%) were lost to follow-up, while 20 (18%) had died
due to intervening diseases (Fig. 1).
Death occurred at a median age of 76 years for the
following causes: 6 malignancies, 2 respiratory diseases, 6
cardiovascular diseases (including 5 cerebrovascular), 2
renal diseases, 3 neurologic diseases, and 1 complications
Two patients were prescribed levothyroxine and two
methimazole for the first time during follow-up.
In the 48 patients (9 men and 39 women) who had
serum creatinine measured at the end of follow-up,
eGFR had declined from a mean of 66.4 to a mean of
52.6 ml/min/1.73 m2 (Student’s t test for paired
samples; P = 7 × 10−9), corresponding to an annual decline
Table 2 Multiple regression analysis of eGFR at baseline
A ri on rate
of 2.3 ml/min/1.73 m2. The generalized linear model for
repeated measures confirmed that eGFR decreased from
66.4 ml/min/1.73 m2 (95% CI 61.0–71.8) to 52.6 ml/
min/1.73 m2 (95% CI 47.5–57.9) during the 6-year
follow-up, corresponding to a mean variation of 13.8 ml/
min/1.73 m2 (95% CI 9.8–17.7). The model did not detect
effects of age and gender, but the small sample size is
to be taken into account. In a Cox regression analysis,
incidence rate of eGFR <45 increased by 0.61% (95% CI
0.17–1.06%) for each year of prior lithium exposure, with
no influence of age and gender.
Dosing and maintenance of serum concentrations
Maintenance doses in this elderly cohort (median 450 mg
of lithium carbonate daily) were much lower compared
to the usual dosage of 900–1500 mg of lithium carbonate
per day used in younger adults (Baldessarini and Tarazi
2006). Such doses are consistent with the results from
the McGill Geriatric Lithium-Induced Diabetes Insipidus
Clinical Study (Rej et al. 2014b) reporting that the lithium
dose required to achieve a given serum concentration
decreases threefold from middle to old age. With regard
to the therapeutic range, serum concentrations are not
well established in the elderly. In our lithium clinic, the
lower end of the range for elderly patients is reduced to
0.40 mmol/l compared to the 0.60 mmol/l generally
indicated for younger adults (Bauer and Gitlin 2016),
principally to prevent episodes of lithium toxicity associated
with reduced renal function, drug interactions, and risk
of dehydration, all of which are typical of old age.
Moreover, there is evidence that the ratio between
serum and brain concentration may decrease with age
(Moore et al. 2002).
The high proportion of patients from this cohort taking
regularly psychiatric and non-psychiatric medications
warrants some comments. For example, it is perhaps
surprising that 3/4 of our patients were on long-term
benzodiazepines. It is possible that the specialists prioritized
the need to control anxiety and/or sleep disorders over
the widely known detrimental side effects of
benzodiazepines on cognition (Larson et al. 1987). Another point of
note is that medications that are theoretically
contraindicated in lithium patients (ACE inhibitors, sartans, and
thiazides) were taken regularly by more than half of the
patients in this cohort. The likely explanation here is that
hypertension must be treated even in lithium patients,
provided that the doses are reduced adequately. This
notion is corroborated by the fact that patients in this
cohort treated with ACE inhibitors or sartans were taking
significantly lower lithium doses. Moreover, with regard
to cases with reduced eGFR, the decision to treat patients
with ACE inhibitors or sartans was often taken by the
nephrologist, based on the evidence that these drugs may
slow the progression of CKD (Ruggenenti et al. 2012).
We have not included data on other nephrotoxic drugs,
namely NSAIDs, because they were not taken regularly
but only when needed.
A subgroup of patients in this cohort who began
taking lithium when elderly recalls the case series of 10
patients described by Hagop Akiskal’s group of “elderly
patients with late-onset mood and related behavioral
symptomatology and cognitive decline without past
history of clear-cut bipolar disorder”. The authors reported
that “symptoms were often refractory to or aggravated by
antidepressants…, whereas mood stabilizers and/or
atypical antipsychotics were beneficial, promoting behavioral
improvement in all treated patients and marked
cognitive recovery in five”. Only one case had been treated with
lithium (Ng et al. 2008). We did not measure cognition
in the present study, but the above-mentioned subgroup
had a history of behavioral dysregulation, mood lability,
and cognitive symptoms that improved after
withdrawing long-term antidepressant treatment and starting
lithium. According to referring specialists, their choice
of prescribing lithium was also based on its
neuroprotective properties (Bauer et al. 2003). Interestingly, a longer
duration of lithium treatment has been reported to be
related to higher white matter integrity among elderly
patients with bipolar disorder (Gildengers et al. 2015).
In another study using voxel-based morphometry, Zung
et al. (2016) found an increased left hippocampal volume
in the lithium-treated group compared with the
nonlithium-treated group, and decreased left hippocampal
volume in the nonlithium group relative to controls.
One-third of patients from this cohort were taking
thyroid hormone replacement therapy, including two
patients who were prescribed levothyroxine for the first
time during follow-up. It has long been known that
lithium is associated with hypothyroidism, and that
middle-aged women are at higher risk (Johnston and Eagles
1999). In the aforementioned cross-sectional study
of thyroid function by Kraszewska et al. (2015), of 45
women receiving long-term lithium (mean age, 63 years),
seven (16%) were receiving levothyroxine replacement
therapy. In three patients, this drug had been introduced
within the 1st year of lithium therapy, and in the
remaining four patients after 8, 11, 12, and 33 years.
Hyperthyroidism requiring antithyroid medication was
less frequent in patients from this cohort (4%), and
manifested for the first time during follow-up in two cases.
Therefore, we conclude that thyroid function
continues to require close monitoring throughout lithium
The problem of lithium-associated renal dysfunction
has recently been addressed by several research studies
and reviews (Rej et al. 2012, 2015). With regard to old
patients, a series of studies from the University of Toronto
have provided several pertinent results. In a 4-year
retrospective cohort study of 42 patients, lithium levels did
not correlate with change in eGFR, suggesting that
levels up to 0.8 mmol/l are safe in geriatric patients without
pre-existing chronic renal failure (Rej et al. 2013a). In a
5-year retrospective cohort study of 27 geriatric patients
with eGFR lower than 60 ml/min/1.73 m2, changes in
eGFR in patients who continued lithium for at least
2 years and those who discontinued lithium did not differ
significantly. However, clinically important decreases in
eGFR occurred in the majority of continuers but in none
of the discontinuers (Rej et al. 2013b). In a 4-year
retrospective cohort study of 82 patients, geriatric psychiatry
patients were found at higher risk for clinically important
decreases in eGFR than 200 psychotropic-naïve similarly
aged controls. Multivariate analyses of potential risk
factors for renal dysfunction (including age, hypertension,
diabetes, diuretics, and duration of lithium treatment),
suggested that lithium is an important factor when eGFR
is lower than 60 ml/min/1.73 m2 (Rej et al. 2014c). In a
population-based cross-sectional study of 2480 lithium
users aged ≥70 years, lithium use for >2 years was one of
the factors independently associated with CKD, together
with hypertension, diabetes mellitus, ischemic heart
disease, nephrogenic diabetes insipidus, acute kidney injury,
and use of loop diuretics, hydrochlorothiazide, or
atypical antipsychotics (Rej et al. 2014b).
We have previously reported that duration of lithium
treatment is to be added to advancing age as a risk
factor for reduced glomerular filtration rate (Bocchetta et al.
2013, 2015). In a retrospective regression analysis of the
last available eGFR regarding 953 (596 women, 357 men)
patients of any age, eGFR was found lower in women
(by 3.47 ml/min/1.73 m2), in older patients (0.73 ml/
min/1.73 m2 per year of age), and in patients with longer
lithium treatment (0.73 ml/min/1.73 m2 for each year)
(Bocchetta et al. 2015). In the present study, the effects
of sex and age were not significant because of the small
sample size and the limited age range.
The decline attributable to lithium was 0.85 ml/
min/1.73 m2 per year of prior exposure. During
followup, the decline was faster, corresponding to an annual
decline of 2.3 ml/min/1.73 m2. It must be noted that
39% of patients had already an eGFR lower than 60 ml/
min/1.73 m2 at baseline, and the initial mean eGFR in
patients followed up for 6 years was 66.4 ml/min/1.73 m2.
There are data suggesting that, once CKD is established,
eGFR further declines irrespective of lithium withdrawal
(Bendz et al. 2010; Bocchetta et al. 2015). A similar
pattern of decline is also observed in the general
population: for example, a longitudinal analysis performed
on 4074 subjects from the Sardinia study cohort (Pani
et al. 2014) revealed that eGFR declined by 1.87 ml/
min/1.73 m2 per year in individuals with a baseline eGFR
of <60 ml/min/1.73 m2 compared to a decline of 0.80 ml/
min/1.73 m2 per year in individuals with a baseline eGFR
of ≥60 ml/min/1.73 m2.
In a 2-year randomized, placebo-controlled trial
followed by single-blind extension, lithium treatment was
not associated with renal dysfunction (Aprahamian et al.
2014). The trial was carried out in the context of a study
of long-term lithium treatment for amnestic mild
cognitive impairment in the elderly (Forlenza et al. 2011). It
must, however, be noted that the target of lithium
concentrations was low (0.25–0.50 mmol/l), and subjects
with CKD might have been excluded from the trial,
because enrollment was reliant on the approval of the
A recent population-based study concluded that, after
adjustment for several confounders (including
comorbidities, co-prescriptions, and episodes of lithium
toxicity), the decline attributable to lithium was not
significant (Clos et al. 2015). However, this study did not
include patients older than 64 years, and patients with an
eGFR <60 ml/min/1.73 m2 represented only 1% of their
Limitations of the study
The noninterventional nature of this study implies
several limitations. Apart from ordinary clinical procedures,
no specific instruments were used to evaluate response
to treatment or side effects. Cognition was not
measured, and neuroimaging was not performed
systematically. With regard to the role of lithium exposure in the
decline of renal function, the absence of a control group
has to be taken into account. Moreover, several potential
risk factors for CKD (such as hypertension, diabetes,
comedications) that can be detected in population-based
samples were not adjusted for because of the small size of
this clinical sample.
This observational study provides some clues
regarding lithium treatment in the elderly. As comorbidity and
polypharmacy may increase the risk of adverse events
and drug interactions, median lithium serum
concentration in this cohort was lower than the therapeutic range
indicated for younger adults. Decline in glomerular
filtration rate may be accelerated by long-term lithium use.
Thyroid and renal functions continue to require close
monitoring throughout lithium treatment.
AB conceived the study, took care of patients’ treatment and follow-up, and
prepared the manuscript. FC contributed to the literature search and clinical
management. MP took care of patients’ treatment and follow-up. AP carried
out and interpreted the neurologic aspects. CS performed the statistical
analysis. RA took care of patients’ treatment and follow-up. CC coordinated the
clinical work and took care of patients’ treatment and follow-up. MDZ supervised
the clinical work, interpreted the results, and reviewed the manuscript. All the
authors read and approved the final manuscript.
AB is an Assistant Professor at the Department of Biomedical Sciences, the
University of Cagliari and works at the lithium clinic as a specialist in Psychiatry
and Clinical Pharmacology since 1979; FC has graduated in Medicine after
an internship at the lithium clinic and part of this work is part of her doctoral
thesis; MP is a specialist in Psychiatry and is currently attending the School of
Specialty in Clinical Pharmacology and Toxicology at the University of Cagliari;
AP is a specialist in Psychiatry and Neurology; CS is an Associate Professor at
the Department of Medical Science and Public Health, the University of
Cagliari; RA is a specialist in Clinical Pharmacology and works at the lithium clinic
since 2001; CC is a specialist in Clinical Pharmacology and works at the lithium
clinic since 2001; MDZ is Full Professor at the Department of Biomedical
Sciences, the University of Cagliari, and works at the lithium clinic as a specialist
in Neurology since 1976.
Partial accounts of this work were presented at the 24th IGSLI Conference
(Cagliari, 1–3 October 2010) and at the 30th IGSLI Conference (Cagliari, 29
September–2 October 2016).
The authors declare that they have no competing interests.
Availability of data and supporting materials
Please contact author for data requests.
The study was approved by the Ethics Committee of the “Azienda
Ospedaliero-Universitaria di Cagliari” (Ref Number NP/2013/3836) on June 24, 2013.
Aprahamian I , Santos FS , dos Santos B , Talib L , Diniz BS , Radanovic M , Gattaz WF , Forlenza OV . Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension . J Clin Psychiatry . 2014 ; 75 : e672 - 8 .
Aziz R , Lorberg B , Tampi RR . Treatment for late-life bipolar disorder . Am J Geriatr Pharmacoterapy . 2006 ; 4 : 347 - 64 .
Baldessarini RJ , Tarazi FI . Pharmacotherapy of psychosis and mania . In: Brunton LL, Lazo JS , Parker KL, editors. Goodman and Gilman's the pharmacological basis of therapeutics . 11th ed. New York : McGraw-Hill ; 2006 . p. 461 - 500 .
Bauer M , Alda M , Priller J , Young LT , International Group For The Study Of Lithium Treated Patients (IGSLI). Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders . Pharmacopsychiatry . 2003 ; 36 (Suppl 3): S250 - 4 .
Bauer M , Gitlin M. The essential guide to lithium treatment . Berlin: Springer ; 2016 .
Bendz H , Schön S , Attman PO , Aurell M. Renal failure occurs in chronic lithium treatment but is uncommon . Kidney Int . 2010 ; 77 : 219 - 24 .
Bocchetta A , Ardau R , Carta P , Ligas F , Sardu C , Pani A , Del Zompo M. Duration of lithium treatment is a risk factor for reduced glomerular function: a cross-sectional study . BMC Med . 2013 ; 11 : 33 .
Bocchetta A , Ardau R , Fanni T , Sardu C , Piras D , Pani A , Del Zompo M. Renal function during long-term lithium treatment: a cross-sectional and longitudinal study . BMC Med . 2015 ; 13 : 12 .
Clos S , Rauchhaus P , Severn A , Cochrane L , Donnan PT . Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study . Lancet Psychiatry . 2015 ; 2 : 1075 - 83 .
Dols A , Kessing LV , Strejilevich SA , Rej S , Tsai SY , Gildengers AG , Almeida OP , Shulman KI , Sajatovic M , International Society for Bipolar Disorders Task Force for Older Adults with Bipolar Disorder . Do current national and international guidelines have specific recommendations for older adults with bipolar disorder? A brief report . Int J Geriatr Psychiatry . 2016 ; 31 : 1295 - 300 .
Earley A , Miskulin D , Lamb EJ , Levey AS , Uhlig K. Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review . Ann Intern Med . 2012 ; 156 : 785 - 95 .
Endicott J , Spitzer RL. A diagnostic interview: the schedule for affective disorders and schizophrenia . Arch Gener Psychiatry . 1978 ; 1978 (35): 873 - 943 .
Forlenza OV , Diniz BS , Radanovic M , Santos FS , Talib LL , Gattaz WF . Diseasemodifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial . Br J Psychiatry . 2011 ; 198 : 351 - 6 .
Gildengers AG , Butters MA , Aizenstein HJ , Marron MM , Emanuel J , Anderson SJ , Weissfeld LA , Becker JT , Lopez OL , Mulsant BH , Reynolds CF 3rd. Longer lithium exposure is associated with better white matter integrity in older adults with bipolar disorder . Bipolar Disord . 2015 ; 17 : 248 - 56 .
Johnston AM , Eagles JM . Lithium-associated clinical hypothyroidism. Prevalence and risk factors . Br J Psychiatry . 1999 ; 175 : 336 - 9 .
Kidney Disease : Improving Global Outcomes (KDIGO) CKD Work Group . KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease . Kidney Int Suppl . 2013 ; 3 : 1 - 150 .
Kraszewska A , Chlopocka-Wozniak M , Abramowicz M , Sowinski J , Rybakowski JK. A cross-sectional study of thyroid function in 66 patients with bipolar disorder receiving lithium for 10-44 years . Bipolar Disord . 2015 ; 17 : 375 - 80 .
Larson EB , Kukull WA , Buchner D , Reifler BV . Adverse drug reactions associated with global cognitive impairment in elderly persons . Ann Intern Med . 1987 ; 107 : 169 - 73 .
Levey AS , Bosch JP , Lewis JB , Greene T , Rogers N , Roth D , Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation . Ann Intern Med . 1999 ; 130 : 461 - 70 .
Moore CM , Demopulos CM , Henry ME , Steingard RJ , Zamvil L , Katic A , Breeze JL , Moore JC , Cohen BM , Renshaw PF. Brain-to-serum lithium ratio and age: an in vivo magnetic resonance spectroscopy study . Am J Psychiatry . 2002 ; 159 : 1240 - 2 .
Ng B , Camacho A , Lara DR , Brunstein MG , Pinto OC , Akiskal HS. A case series on the hypothesized connection between dementia and bipolar spectrum disorders: bipolar type VI? J Affect Disord . 2008 ; 107 : 307 - 15 .
Pani A , Bragg-Gresham J , Masala M , Piras D , Atzeni A , Pilia MG , Ferreli L , Balaci L , Curreli N , Delitala A , Loi F , Abecasis GR , Schlessinger D , Cucca F. Prevalence of CKD and its relationship to eGFR-related genetic loci and clinical risk factors in the Sardinia Study Cohort . J Am Soc Nephrol . 2014 ; 25 : 1533 - 44 .
Permoda-Osip A , Abramowicz M , Kraszewska A , Suwalska A , ChlopockaWozniak M , Rybakowski JK . Kidney, thyroid and other organ functions after 40 years or more of lithium therapy: a case series of five patients . Ther Adv Psychopharmacol . 2016 ; 6 : 277 - 82 .
Rej S , Herrmann N , Shulman K. The effects of lithium on renal function in older adults - a systematic review . J Geriatr Psychiatry Neurol . 2012 ; 25 : 51 - 61 .
Rej S , Abitbol R , Looper K , Segal M. Chronic renal failure in lithium-using geriatric patients: effects of lithium continuation versus discontinuation-a 60-month retrospective study . Int J Geriatr Psychiatry. 2013a; 28 : 450 - 3 .
Rej S , Looper K , Segal M. The effect of serum lithium levels on renal function in geriatric outpatients: a retrospective longitudinal study . Drugs Aging. 2013b; 30 : 409 - 15 .
Rej S , Beaulieu S , Segal M , Low NC , Mucsi I , Holcroft C , Shulman K , Looper KJ . Lithium dosing and serum concentrations across the age spectrum: from early adulthood to the tenth decade of life . Drugs Aging. 2014a; 31 : 911 - 6 .
Rej S , Li BW , Looper K , Segal M. Renal function in geriatric psychiatry patients compared to non-psychiatric older adults: effects of lithium use and other factors . Aging Ment Health. 2014b; 18 : 847 - 53 .
Rej S , Shulman K , Herrmann N , Harel Z , Fischer HD , Fung K , Gruneir A. Prevalence and correlates of renal disease in older lithium users: a populationbased study . Am J Geriatr Psychiatry. 2014c; 22 : 1075 - 82 .
Rej S , Elie D , Mucsi I , Looper KJ , Segal M. Chronic kidney disease in lithiumtreated older adults: a review of epidemiology, mechanisms, and implications for the treatment of late-life mood disorders . Drugs Aging . 2015 ; 32 : 31 - 42 .
Ruggenenti P , Cravedi P , Remuzzi G. Mechanisms and treatment of CKD . J Am Soc Nephrol . 2012 ; 23 : 1917 - 28 .
Shulman KI . Lithium for older adult with bipolar disorder . Should it still be considered a first line agent? Drug Aging . 2010 ; 27 : 607 - 15 .
Shulman KI , Rochon P , Sykora K , Anderson G , Mamdani M , Bronskill S , Tran CT. Changing prescription patterns for lithium and valproic acid in old age: shifting practice without evidence . BMJ . 2003 ; 326 : 960 - 1 .
Wilkinson D , Holmes C , Woolford J , Stammers S , North J. Prophylactic therapy with lithium in elderly patients with unipolar major depression . Int J Geriatr Psychiatry . 2002 ; 17 : 619 - 22 .
Young RC , Gyulai L , Mulsant BH , Flint A , Beyer JL , Shulman KI , Reynolds CF 3rd. Pharmacotherapy of bipolar disorder in old age: review and recommendation . Am J Geriatr Psychiatry . 2004 ; 12 : 342 - 57 .
Young RC , Shulberg HC , Gildengers AG , Sajatovic M , Mulsant BH , Gyulay L , Beyer J , Marangell L , Kunik M , Ten Heve T , Bruce ML , Gur R , Marino P , Evans JD , Reynolds CF 3rd, Alexopoulos GS . Conceptual and methodological issues in designing a randomized, controlled treatment trial for geriatric bipolar disorder: GERI-BD . Bipolar Disord. 2010 ; 12 : 56 - 67 .
Zung S , Souza-Duran FL , Soeiro-de-Souza MG , Uchida R , Bottino CM , Busatto GF , Vallada H. The influence of lithium on hippocampal volume in elderly bipolar patients: a study using voxel-based morphometry . Transl Psychiatry . 2016 ; 6 : e846 .