Optimal timing for lithium levels

Kevin J Black

doi:10.12688/f1000research.122507.2

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Revised

Optimal timing for lithium levels

[version 2; peer review: 2 approved, 1 approved with reservations]

Kevin J Black

PUBLISHED 16 Sep 2024

Author details Author details

Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, MO, 63110, USA

Kevin J Black
Roles: Conceptualization, Writing – Original Draft Preparation

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REVIEWER STATUS

Abstract

Reddy and Reddy (2014) discuss the optimal timing for lithium levels in patients taking once-daily extended-release lithium formulations. They argue for blood sampling 24 h after the previous dose rather than the standard 12 h. I interpret the data quite differently. The authors start with the assumption that the clinician wants a trough level. I disagree. What one wants is to be able to compare a patient’s lithium level to the large body of published knowledge about lithium dosing. Almost all of that data comes from standard 12-h blood draws with plain (immediate-release) lithium carbonate or lithium citrate. So, the real question of interest is, with extended-release lithium formulations, at what time point does one draw the lithium level to compare most accurately with a standard 12-h blood draw with plain lithium carbonate?

The answer is not obvious because extended-release formulations affect only the absorption and not the excretion of lithium. Their primary benefit is reducing the transient peak lithium serum concentration, not delaying the (already relatively slow) elimination of lithium.

Emami and colleagues (2004) provide the needed data. First they show that 90% of the administered dose of a commercial extended-release formulation (Eskalith CR^®) is absorbed by 4 h after a dose, and ~100% is absorbed by 8 h (their Figure 2A). Second, they show that at 12 h after a dose, the blood levels for immediate and extended release formulations are essentially identical (their Figure 3). Thus 12 h after the previous dose is the ideal time for drawing blood levels for extended-release lithium tablets.

Keywords

lithium, pharmacology, administration & dosage, pharmacokinetics, blood level, concentration

Corresponding author: Kevin J Black

Competing interests: A previous version of this article appeared as a comment on the now-discontinued PubMed Commons.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2024 Black KJ. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Black KJ. Optimal timing for lithium levels [version 2; peer review: 2 approved, 1 approved with reservations]. F1000Research 2024, 11:779 (https://doi.org/10.12688/f1000research.122507.2) First published: 12 Jul 2022, 11:779 (https://doi.org/10.12688/f1000research.122507.1) Latest published: 16 Sep 2024, 11:779 (https://doi.org/10.12688/f1000research.122507.2)

Revised Amendments from Version 1

The reviewer agreed with my conclusions about the timing of lithium levels, but raised the question of why this article exists. The raison d'être for this article is that resident physicians kept finding this article when they searched PubMed for information on when to draw blood levels for slow-release lithium formulations. I wanted to point future trainees who found the same article to a different (and more standard) viewpoint. Unfortunately, the journal the original article appeared in does not accept late correspondence, the NLM sadly ended their PubMed Commons experiment, and few physicians use PubPeer (https://pubpeer.com/publications/B9D70BCDC05E3FD3503A6C35331D0A). In short, I saw no solution other than to publish this letter so that a "Comment in:" link pointing to this letter would appear on the PubMed page for the 2014 paper.

See the author's detailed response to the review by Mehak Pahwa
See the author's detailed response to the review by Dean MacKinnon

Reddy and Reddy (2014) discuss the optimal timing for lithium levels in patients taking once-daily extended-release lithium formulations. They argue for blood sampling 24 h after the previous dose rather than the standard 12 h. Trainees searching for information on timing of lithium blood sampling have been influenced by that paper’s conclusions. Unfortunately, the journal the original article appeared in does not accept late correspondence, the NLM sadly ended their PubMed Commons experiment, and few physicians use PubPeer. This short note is intended to provide on the 2014 article’s PubMed page a “Comment” link to a more traditional viewpoint.

Reddy and Reddy start with the assumption that the clinician wants a trough level. Rather, what one wants is to be able to compare a patient’s lithium level to the large body of published knowledge about lithium dosing. Almost all of that data comes from standard 12-h blood draws with plain (immediate-release) lithium carbonate or lithium citrate. So, the real question of interest is, with extended-release lithium formulations, at what time point does one draw the lithium level to compare most accurately with a standard 12-h blood draw with plain lithium carbonate?

Emami et al. (2004) provide the needed data. First they show that 90% of the administered dose of a commercial extended-release formulation (Eskalith CR^®) is absorbed by 4 h after a dose, and ~100% is absorbed by 8 h (their Figure 2A). Second, they show that at 12 h after a dose, the blood levels for immediate and extended release formulations are essentially identical (their Figure 3). Thus 12 h after the previous dose is the ideal time for drawing blood levels for extended-release lithium tablets.

Data availability

There are no data associated with this article.

References

Emami J, Tavakoli N, Movahedian A: Formulation of sustained-release lithium carbonate matrix tablets: influence of hydrophilic materials on the release rate and in vitro-in vivo evaluation. J Pharm Pharm Sci. 2004; 7(3): 338–344. PubMed Abstract
Reddy DS, Reddy MS: Serum lithium levels: ideal time for sample collection! Are we doing it right? Indian J Psychol Med. 2014; 36(3): 346–347. PubMed Abstract | Publisher Full Text

Comments on this article Comments (1)

Version 2

VERSION 2 PUBLISHED 16 Sep 2024

Revised

Author Response (F1000Research Advisory Board Member) 10 Sep 2025

Kevin J Black, Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, 63110, USA

10 Sep 2025

Author Response F1000Research Advisory Board Member

Nolen et al 2019 report a literature review and Delphi process with expert consensus statements on lithium dosing. Sections 4.3-4.4 and Table 5 (item 4) in their report agree that ... Continue reading Nolen et al 2019 report a literature review and Delphi process with expert consensus statements on lithium dosing. Sections 4.3-4.4 and Table 5 (item 4) in their report agree that in clinical practice, blood sampling for lithium concentration should happen at 12 ± 1 hours after the last dose regardless of immediate- vs. delayed-release formulation.
This consensus is consistent with the discussion above and the comments of the three reviewers. (Still, I can't help noting that this F1000Research note does cite data, from Emami et al.)

Nolen WA, Licht RW, Young AH, Malhi GS, Tohen M, Vieta E, Kupka RW, Zarate C, Nielsen RE, Baldessarini RJ, Severus E, The ISBD/IGSLI Task Force on the Treatment with Lithium. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord. 2019 Aug;21(5):394-409. doi: 10.1111/bdi.12805. Epub 2019 Jun 20. PMID: 31112628; PMCID: PMC6688930.
Nolen et al 2019 report a literature review and Delphi process with expert consensus statements on lithium dosing. Sections 4.3-4.4 and Table 5 (item 4) in their report agree that in clinical practice, blood sampling for lithium concentration should happen at 12 ± 1 hours after the last dose regardless of immediate- vs. delayed-release formulation.
This consensus is consistent with the discussion above and the comments of the three reviewers. (Still, I can't help noting that this F1000Research note does cite data, from Emami et al.)

Nolen WA, Licht RW, Young AH, Malhi GS, Tohen M, Vieta E, Kupka RW, Zarate C, Nielsen RE, Baldessarini RJ, Severus E, The ISBD/IGSLI Task Force on the Treatment with Lithium. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord. 2019 Aug;21(5):394-409. doi: 10.1111/bdi.12805. Epub 2019 Jun 20. PMID: 31112628; PMCID: PMC6688930.
Competing Interests: [not a competing interest, but apparently I omitted the citation from the previous, not-yet-approved version of this comment.] Close
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Author details Author details

Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, MO, 63110, USA

Kevin J Black
Roles: Conceptualization, Writing – Original Draft Preparation

Competing interests

A previous version of this article appeared as a comment on the now-discontinued PubMed Commons.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (2)

version 2

Revised

Published: 16 Sep 2024, 11:779

https://doi.org/10.12688/f1000research.122507.2

version 1

Published: 12 Jul 2022, 11:779

https://doi.org/10.12688/f1000research.122507.1

© 2024 Black KJ. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Black KJ. Optimal timing for lithium levels [version 2; peer review: 2 approved, 1 approved with reservations]. F1000Research 2024, 11:779 (https://doi.org/10.12688/f1000research.122507.2)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Key to Reviewer Statuses VIEW HIDE

ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions

Version 2

VERSION 2

PUBLISHED 16 Sep 2024

Revised

Views

Reviewer Report 27 Jan 2025

Seyyed Nassir Ghaemi, Harvard Medical School, Tufts University, Boston, USA

Approved

https://doi.org/10.5256/f1000research.171732.r356872

I fully agree with Dr Black's analysis and description. The prior article by Reddy and Reddy was mistaken and misleading. No revision is needed of this correct critique.

The half life of lithium does not change whether it is immediate release or extended release. In both cases it is about 24 hours. Yet the level is done at 12 hours based on 75 years of research using that timing to correlate with clinical toxicity.

Is the rationale for commenting on the previous publication clearly described?

Yes
Are any opinions stated well-argued, clear and cogent?

Yes
Are arguments sufficiently supported by evidence from the published literature or by new data and results?

Yes
Is the conclusion balanced and justified on the basis of the presented arguments?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Bipolar illness, psychopharmacology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Version 1

VERSION 1

PUBLISHED 12 Jul 2022

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Reviewer Report 28 Jun 2024

Dean MacKinnon, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Approved

https://doi.org/10.5256/f1000research.134501.r286092

This is a brief correspondence to address somewhat dated reports that suggest altering practice with regard to the timing of therapeutic lithium levels. The author addresses a pharmacologic conjecture that a 24 hour level rather than the standard 12 hour level might be preferable, countering that conjecture with a sensible argument based on clinical utility and data to back it up. A previous commenter had reservations because the critique seemed untimely and thought there could be more data to back it up. While these points are true, I do not see it as my role to question the timing of indexing, and I think the data are sufficient to confirm a point that is consistent with standard clinical practice already.

Is the rationale for commenting on the previous publication clearly described?

Yes
Are any opinions stated well-argued, clear and cogent?

Yes
Are arguments sufficiently supported by evidence from the published literature or by new data and results?

Yes
Is the conclusion balanced and justified on the basis of the presented arguments?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Mood disorders, psychiatric genetics, education, history

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

CITE

Report a concern

Author Response (F1000Research Advisory Board Member) 28 Jun 2024

Kevin J Black, Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, 63110, USA

28 Jun 2024

Author Response F1000Research Advisory Board Member

Thank you for your thoughtful review and clear feedback.
Competing Interests: No competing interests were disclosed.
Thank you for your thoughtful review and clear feedback.
Thank you for your thoughtful review and clear feedback.
Competing Interests: No competing interests were disclosed. Close
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COMMENTS ON THIS REPORT

Author Response (F1000Research Advisory Board Member) 28 Jun 2024

Kevin J Black, Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, 63110, USA

28 Jun 2024

Author Response F1000Research Advisory Board Member

Thank you for your thoughtful review and clear feedback.
Competing Interests: No competing interests were disclosed.
Thank you for your thoughtful review and clear feedback.
Thank you for your thoughtful review and clear feedback.
Competing Interests: No competing interests were disclosed. Close
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Reviewer Report 23 Nov 2022

Mehak Pahwa, Department of Psychiatry and Behavioral Sciences, University of Louisville, Louisville, KY, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.134501.r154972

I agree with the argument of measuring the level at 12 hrs after the last dose of both immediate release and extended-release. However, I don't understand why the correspondence is on a paper published in 2014 and there is only ... Continue reading

Is the rationale for commenting on the previous publication clearly described?

Yes
Are any opinions stated well-argued, clear and cogent?

Partly
Are arguments sufficiently supported by evidence from the published literature or by new data and results?

Partly
Is the conclusion balanced and justified on the basis of the presented arguments?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Mood disorders, women mental health, geriatric psychiatry, bipolar disorder

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response (F1000Research Advisory Board Member) 30 Nov 2022

Kevin J Black, Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, 63110, USA

30 Nov 2022

Author Response F1000Research Advisory Board Member

I thank Dr. Pawha for agreeing with my main point and for her thoughtful question about why this article exists. Please let me explain. The raison d'être for this article ... Continue reading I thank Dr. Pawha for agreeing with my main point and for her thoughtful question about why this article exists. Please let me explain. The raison d'être for this article is that residents kept pulling out the referenced paper by Reddy and Reddy from PubMed to justify drawing lithium levels later for patients taking slow-release formulations. So how could I get an opposing view to future clinicians who searched PubMed to answer this question? The journal the original article appeared in does not accept late correspondence, the NLM sadly ended their PubMed Commons experiment, and few physicians use PubPeer. In short, I saw no solution other than to publish a letter like this one that PubMed would index and show as a "Comment in" link under the original abstract.
I thank Dr. Pawha for agreeing with my main point and for her thoughtful question about why this article exists. Please let me explain. The raison d'être for this article is that residents kept pulling out the referenced paper by Reddy and Reddy from PubMed to justify drawing lithium levels later for patients taking slow-release formulations. So how could I get an opposing view to future clinicians who searched PubMed to answer this question? The journal the original article appeared in does not accept late correspondence, the NLM sadly ended their PubMed Commons experiment, and few physicians use PubPeer. In short, I saw no solution other than to publish a letter like this one that PubMed would index and show as a "Comment in" link under the original abstract.
Competing Interests: No competing interests were disclosed. Close
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COMMENTS ON THIS REPORT

Author Response (F1000Research Advisory Board Member) 30 Nov 2022

Kevin J Black, Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, 63110, USA

30 Nov 2022

Author Response F1000Research Advisory Board Member

I thank Dr. Pawha for agreeing with my main point and for her thoughtful question about why this article exists. Please let me explain. The raison d'être for this article ... Continue reading I thank Dr. Pawha for agreeing with my main point and for her thoughtful question about why this article exists. Please let me explain. The raison d'être for this article is that residents kept pulling out the referenced paper by Reddy and Reddy from PubMed to justify drawing lithium levels later for patients taking slow-release formulations. So how could I get an opposing view to future clinicians who searched PubMed to answer this question? The journal the original article appeared in does not accept late correspondence, the NLM sadly ended their PubMed Commons experiment, and few physicians use PubPeer. In short, I saw no solution other than to publish a letter like this one that PubMed would index and show as a "Comment in" link under the original abstract.
I thank Dr. Pawha for agreeing with my main point and for her thoughtful question about why this article exists. Please let me explain. The raison d'être for this article is that residents kept pulling out the referenced paper by Reddy and Reddy from PubMed to justify drawing lithium levels later for patients taking slow-release formulations. So how could I get an opposing view to future clinicians who searched PubMed to answer this question? The journal the original article appeared in does not accept late correspondence, the NLM sadly ended their PubMed Commons experiment, and few physicians use PubPeer. In short, I saw no solution other than to publish a letter like this one that PubMed would index and show as a "Comment in" link under the original abstract.
Competing Interests: No competing interests were disclosed. Close
Report a concern

Comments on this article Comments (1)

Version 2

VERSION 2 PUBLISHED 16 Sep 2024

Revised

Author Response (F1000Research Advisory Board Member) 10 Sep 2025

Kevin J Black, Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, 63110, USA

10 Sep 2025

Author Response F1000Research Advisory Board Member

Nolen et al 2019 report a literature review and Delphi process with expert consensus statements on lithium dosing. Sections 4.3-4.4 and Table 5 (item 4) in their report agree that ... Continue reading Nolen et al 2019 report a literature review and Delphi process with expert consensus statements on lithium dosing. Sections 4.3-4.4 and Table 5 (item 4) in their report agree that in clinical practice, blood sampling for lithium concentration should happen at 12 ± 1 hours after the last dose regardless of immediate- vs. delayed-release formulation.
This consensus is consistent with the discussion above and the comments of the three reviewers. (Still, I can't help noting that this F1000Research note does cite data, from Emami et al.)

Nolen WA, Licht RW, Young AH, Malhi GS, Tohen M, Vieta E, Kupka RW, Zarate C, Nielsen RE, Baldessarini RJ, Severus E, The ISBD/IGSLI Task Force on the Treatment with Lithium. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord. 2019 Aug;21(5):394-409. doi: 10.1111/bdi.12805. Epub 2019 Jun 20. PMID: 31112628; PMCID: PMC6688930.
Nolen et al 2019 report a literature review and Delphi process with expert consensus statements on lithium dosing. Sections 4.3-4.4 and Table 5 (item 4) in their report agree that in clinical practice, blood sampling for lithium concentration should happen at 12 ± 1 hours after the last dose regardless of immediate- vs. delayed-release formulation.
This consensus is consistent with the discussion above and the comments of the three reviewers. (Still, I can't help noting that this F1000Research note does cite data, from Emami et al.)

Nolen WA, Licht RW, Young AH, Malhi GS, Tohen M, Vieta E, Kupka RW, Zarate C, Nielsen RE, Baldessarini RJ, Severus E, The ISBD/IGSLI Task Force on the Treatment with Lithium. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord. 2019 Aug;21(5):394-409. doi: 10.1111/bdi.12805. Epub 2019 Jun 20. PMID: 31112628; PMCID: PMC6688930.
Competing Interests: [not a competing interest, but apparently I omitted the citation from the previous, not-yet-approved version of this comment.] Close
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Mehak Pahwa, University of Louisville, Louisville, USA
Dean MacKinnon, Johns Hopkins University School of Medicine, Baltimore, USA
Seyyed Nassir Ghaemi, Harvard Medical School, Tufts University, Boston, USA

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27 Jan 2025 | for Version 2

Seyyed Nassir Ghaemi, Harvard Medical School, Tufts University, Boston, USA

8 Views Cite this report Responses(0)

Approved

Is the rationale for commenting on the previous publication clearly described?

Yes
Are any opinions stated well-argued, clear and cogent?

Yes
Are arguments sufficiently supported by evidence from the published literature or by new data and results?

Yes
Is the conclusion balanced and justified on the basis of the presented arguments?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Bipolar illness, psychopharmacology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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28 Jun 2024 | for Version 1

Dean MacKinnon, Johns Hopkins University School of Medicine, Baltimore, MD, USA

17 Views Cite this report Responses(1)

Approved

Is the rationale for commenting on the previous publication clearly described?

Yes
Are any opinions stated well-argued, clear and cogent?

Yes
Are arguments sufficiently supported by evidence from the published literature or by new data and results?

Yes
Is the conclusion balanced and justified on the basis of the presented arguments?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Mood disorders, psychiatric genetics, education, history

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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43 Views

23 Nov 2022 | for Version 1

Mehak Pahwa, Department of Psychiatry and Behavioral Sciences, University of Louisville, Louisville, KY, USA

43 Views Cite this report Responses(1)

Approved With Reservations

Is the rationale for commenting on the previous publication clearly described?

Yes
Are any opinions stated well-argued, clear and cogent?

Partly
Are arguments sufficiently supported by evidence from the published literature or by new data and results?

Partly
Is the conclusion balanced and justified on the basis of the presented arguments?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Mood disorders, women mental health, geriatric psychiatry, bipolar disorder

Respond to this report

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Author Response F1000Research Advisory Board Member

30 Nov 2022

Kevin J Black, Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, 63110, USA

I thank Dr. Pawha for agreeing with my main point and for her thoughtful question about why this article exists. Please let me explain. The raison d'être for this article is that residents kept pulling out the referenced paper by Reddy and Reddy from PubMed to justify drawing lithium levels later for patients taking slow-release formulations. So how could I get an opposing view to future clinicians who searched PubMed to answer this question? The journal the original article appeared in does not accept late correspondence, the NLM sadly ended their PubMed Commons experiment, and few physicians use PubPeer. In short, I saw no solution other than to publish a letter like this one that PubMed would index and show as a "Comment in" link under the original abstract.

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Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

[1] Emami J, Tavakoli N, Movahedian A: Formulation of sustained-release lithium carbonate matrix tablets: influence of hydrophilic materials on the release rate and in vitro-in vivo evaluation. J Pharm Pharm Sci. 2004; 7(3): 338–344. PubMed Abstract

[2] Reddy DS, Reddy MS: Serum lithium levels: ideal time for sample collection! Are we doing it right? Indian J Psychol Med. 2014; 36(3): 346–347. PubMed Abstract | Publisher Full Text

Optimal timing for lithium levels

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