This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Letter to the Editor

Drs Aprahamian and Forlenza Reply

Ivan Aprahamian, MD, and Orestes V. Forlenza, MD, MPhil, PhD

Published: February 25, 2015

See Letter by Lozano and Article by Aprahamian et al

Drs Aprahamian and Forlenza Reply

To the Editor: In his letter commenting on our recent article,1 Dr Lozano accurately reinforced the risk of renal and neurologic complications secondary to chronic lithium use. These adverse events are well known to most clinicians and have been clearly reported in the medical literature. Nonetheless, the use of lithium salts still represents an important strategy for the treatment of complex neuropsychiatric disorders, namely bipolar disorder, which invariably requires long-term management. Lithium represents a first-line therapeutic strategy or an adjunctive approach in the pharmacotherapy of mood disorders. Good clinical practice dictates that the clinician will perform a rigorous risk-benefit assessment prior to prescribing lithium and that safety and tolerability will be actively monitored throughout the treatment. This recommendation may be critical for the treatment of elderly patients and other individuals with comorbid medical or neurologic conditions that might increase the risk for such complications.

We agree with Dr Lozano’s concerns about the safety limits of long-term lithium use. But perhaps his reading of our article1 missed a few important points. First, rather than as a mood stabilizer, we addressed the potential of lithium as a candidate drug for the treatment of neurocognitive disorders, such as Alzheimer’s disease,2 amyotrophic lateral sclerosis,3 and multiple system atrophy.4 For this purpose, the putative disease-modifying effects may rely on serum concentrations of lithium much lower than those required for the treatment of bipolar disorder. In our study, the therapeutic range of lithium carbonate was set to yield concentrations of 0.25 to 0.5 mEq/L. This low-dose regimen is presumably associated with a better tolerability profile and a smaller incidence of adverse events and systemic complications.

Second, the author of the letter was concerned about the duration of the trial, which might have been too short to warrant a definitive conclusion. We partially agree with that, but this limitation of the study design must be balanced by the many advantages of conducting a randomized controlled trial (RCT), particularly with respect to the level of evidence provided. The duration of follow-up is one of the most important methodological constraints in any RCT. Most of the available evidence on lithium safety is derived from observational, naturalistic, and uncontrolled studies; retrospective analyses of patient charts; case reports and small case series; and a few short-duration case-control studies.5,6 Very little of the information on the topic is derived from RCTs, of which there is considered to be an acute paucity by most authors in this field.6 The study we conducted was double-blinded in the first 2 years of follow-up and single-blinded in the extension phase of up to 4 years. To the best of our knowledge, this was the longest such trial of lithium ever conducted. We understand that the onset of renal impairment may be far beyond our endpoint; however, it is practically and financially impossible to conduct a controlled trial with a duration of follow-up close to the one suggested by Dr Lozano.

Third, our study was not designed to detect subtle impairments of urinary osmolality reflecting initial impairment of renal tubular function, although we agree that this set of data should be included in future studies with low-dose lithium treatment. In our protocol, safety and tolerability variables were captured by means of a thorough medical examination (physical, neurologic, and psychiatric), in addition to a comprehensive neuropsychological assessment. None of our subjects presented with clinically relevant polyuria or other related symptoms. Signs of severe neurologic impairments were also not detected. In fact, participants receiving lithium (as compared to placebo) presented with significant improvements in global cognitive function, memory, and attention.2

Finally, diuretic use was an exclusion/withdrawal criterion in our study, as were any other medications with known potential drug interaction with lithium.


1. Aprahamian I, Santos FS, dos Santos B, et al. 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(7):e672-e678. PubMed doi:10.4088/JCP.13m08741

2. Forlenza OV, Diniz BS, Radanovic M, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198(5):351-356. PubMed doi:10.1192/bjp.bp.110.080044

3. Morrison KE, Dhariwal S, Hornabrook R, et al; UKMND-LiCALS Study Group. Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2013;12(4):339-345. PubMed doi:10.1016/S1474-4422(13)70037-1

4. Saccí  F, Marsili A, Quarantelli M, et al. A randomized clinical trial of lithium in multiple system atrophy. J Neurol. 2013;260(2):458-461. PubMed doi:10.1007/s00415-012-6655-7

5. Paul R, Minay J, Cardwell C, et al. Meta-analysis of the effects of lithium usage on serum creatinine levels. J Psychopharmacol. 2010;24(10):1425-1431. PubMed doi:10.1177/0269881109104930

6. McKnight RF, Adida M, Budge K, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721-728. PubMed doi:10.1016/S0140-6736(11)61516-X

Ivan Aprahamian, MD

Orestes V. Forlenza, MD, MPhil, PhD

Author affiliations: Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.

Potential conflicts of interest: None reported.

Funding/support: Funding sources for the study discussed in this letter are listed at the end of the original article [J Clin Psychiatry 2014;75(7):e672-e678].

Related Articles

Volume: 76

Quick Links: