This article is about the recently published article Dr Aftab and I have published in the Psychiatric Times: Future Proofing Lithium Pharmacokinetic Research

I know that lithium pharmacokinetics is not exactly the sexiest subject in the world. I definitely know that the proper use of notation isn’t.

However, improper (or lack of) use of notations in research can cause an otherwise good research paper to be uninterpretable.

This has consequences. Confusion reigns and scientific progress stalls. In the recently published Psychiatric Times article I’ve written with Dr Awais Aftab of Psychiatry at the margins 1 we highlight the absence of temporal information for lithium blood serum concentrations (the 12 hour level) in the academic literature. And the many problems this causes for current and future lithium pharmacokinetic research.

This excerpt sets out the fundamental issue:

consider this extract from Nolen et al2:

“For maintenance treatment of BD several reviews recommend differing minimum effective lithium serum levels ranging from 0.40 mmol/L and 0.50 mmol/L or 0.60 mmol/L…to as high as 0.80 mmol/L.”

The author has given the equivalent of a place (a lithium serum concentration range) without a time. How can we accurately interpret these values without knowing when they were taken, how long it has been since the last dose of lithium, and what the dosing schedule is?

You might also be wondering now, how common is this problem in the psychiatric literature?

Unfortunately, the answer is that nearly every psychiatric research paper that mentions a lithium serum concentration neglects to mention a time.

Future Proofing Lithium Pharmacokinetic research (For Nolen Reference, see in text)

If you have ten minutes, please do give the article a read.

As an anonymous writer, without any reputation to fall back on, one has to go to rather significant lengths to prove a point. When submitting the article, I made an effort to show just how widespread the lack of 12 hour level notation is.

Well, I think it is best if I just show you what I did…

Examples of lithium serum concentration without temporal information (i.e. lack 12 hour serum lithium level notation)

Note: Each entry has a unique first author. 4 examples are given per year over the past 20 years. For lithium serum concentrations, the units mM = mmol/L = mEq/L.

2023

  1. Hidalgo-Mazzei et al [1]:
    “More recently, even potential neuroprotective as well as antiviral effects were proposed when used in lower doses than those recommended in BD maintenance treatment (i.e., 0.60–0.80 mmol/L)”

  2. Zorrilla et al [2]:
    “Although there is consensus on the standard therapeutic range (0.6–1.2), the ideal therapeutic level has been reduced to 0.60–0.80 mmol/L. In case the patient shows good response, this range can be reduced to 0.40–0.60 mmol/L to minimize side effects”

  3. Golic et al [3]:
    “Possible explanations for these findings are the rather high compliance (75–93%) and comparable lithium levels (0.58 – 0.64 mmol/l)”

  4. Davis et al [4]:
    “Considering the most current available literature regarding lithium at therapeutic levels, these risks are of similar or greater magnitude to lithium maintained within a therapeutic window of <0.8 mmol/L”

2022

  • Nielsen et al. [5]:
    “when serum lithium levels between 0.8 and 1.2 mmol/L were recommended”

  • Sampogna et al. [6] (“standard lithium serum level” mentioned without 12 hours):
    “According to the recent recommendations issued by the ISBD/IGSLI Task Force on treatment with lithium in adult patients with bipolar disorder, the standard lithium serum level should be 0.60-0.80 mmol/L, with the option to reduce it to 0.40-0.60 mmol/L in case of good response but poor tolerance, or to increase to 0.80-1.00 mmol/L in case of insufficient response and good tolerance”

  • Heald et al. [7]:
    “Serum lithium concentrations were grouped into four categories: (a) LO, <0.40 mmol/L (below the British National Formulary (BNF) recommended therapeutic range); (b) BNF/NICE, 0.40–0.79 mmol/L (within BNF and/or NICE ranges); (c) BNF/ NICE relapse, 0.80–0.99 mmol/L (within BNF range, but where more frequent monitoring is recommended when a previous relapse has occurred or where there are subsyndromal symptoms); and (d) HI, ≥1.00 mmol/L (above both BNF and NICE ranges, where there is an increased risk of toxicity)”

  • Chakraborty et al. [8]:
    “Maintenance level of plasma lithium greater than 1.0 mmol/l should be avoided if possible”

2021

  • Severus et al. [9]:
    “There is a significant number of patients who do not respond to or do not tolerate the usually recommended therapeutic serum concentrations of 0.6 – 0.8 mmol/L”

  • Pérez de Mendiola et al. [10]:
    “50% of the participants use serum lithium levels between 0.6 and 0.8 mmol/L for the maintenance phase of BD. 21% consider adequate any concentration within the therapeutic range established between 0.6 and 1.2 mmol/L. Another 20% utilizes higher lithium serum levels between 0.8 and 1 mmol/L to prevent relapse or recurrence in BD”

  • Parfitt et al. [11] (I think the authors are referencing the mean 12 hour standardised lithium serum level out of a sample of multiple patients?):
    “In our study, the mean serum lithium concentration was found to be around 0.6 mmol/L across all three centres. This is at the lower end of the NICE recommended range”

  • Hsu et al. [12]:
    “This study aimed to predict serum lithium levels at a therapeutic level of 0.6–1.2 mmol/L (binary prediction) and blood concentration value (continuous prediction)”

2020

  1. Rybakowski [13]:
    “In a manic state, lithium carbonate can be initiated at a dose of 750-1000 mg per day to achieve a concentration of more than 0.8 mmol/l. Some researchers believe that this concentration may be as high as 1.2 mmol/l in the manic state because such patients tolerate it well”

  2. Schoot et al. [14]:
    “The recommendation of the ISBD/IGSLI task force for the therapeutic range in the maintenance treatment of bipolar disorder is 0.6–0.8 mmol/L”

  3. Ossani et al. [15] (An example of how a lack of 12 hour lithium serum concentration notation can cause confusion when other metrics are used):
    “In contrast, in a retrospective analysis of laboratory data, median serum lithium concentrations higher than the overall median (0.60 mmol/L) were associated with an eGFR < 60 mL/ min/1.73 m2”

  4. Barroilhet and Ghaemi [16]:
    “It is our general practice and viewpoint that lower levels can be sufficient, and clinicians should be flexible to allow for possible efficacy at lower levels, in the 0.4-0.8 mmol/L range”

2019

  1.  Fountoulakis et al. [17]:
    “We report the case of a 68-year old female suffering from Bipolar disorder (DSM-5), treated with lithium (Li) monotherapy 600 mg per day (serum levels 0.6) for the last 15 years”

  2. Imaz et al. [18]:
    “The target plasma level for lithium in acute treatment is 0.8–1.2 mEq/L in young subjects, while in maintenance treatment, the most common optimal plasma concentration range is 0.5–0.8 mEq/L”

  3. Xu et al. [19]:
    “Figure 2 shows the distribution of the serum lithium concentration in patients with BD. These data ranged from 0.11 to 1.34 (mean = 0.60, SD = 0.23) mmol/L”

  4. Soni [20]:“Lithium neurotoxicity is a well-recognised problem, usually identified clinically and confirmed by lithium levels above 1.0mmol/L”

2018

  • Nederlof et al. [21]:
    “Recommendations regarding optimal lithium serum levels differ among clinical practice guidelines, with the most common range being between 0.6 and 0.8  mmol/L for maintenance treatment”

  • Smith et al. [22]:
    “the mean once-daily dose of Priadel™ was 1000 mg ± 151 mg and the average serum lithium concentration was 0.88 ± 0.12 mmol/L”

  • Yoshida et al. [23] (The authors incorrectly refer to the 12 hour standardised serum concentration level as a “trough” – this is only the case for a twice daily dosing regimen):
    “Although lithium has extensively been used for the treatment of affective disorders, including bipolar disorder…its narrow therapeutic window for serum concentrations of 0.6-1.2 mmol/L at trough…requires routine therapeutic drug monitoring (TDM)”

  • Sun et al. [24]:
    “Clinical experience suggests that serum lithium concentrations > 0.8 mmol/L are likely to produce significant adverse effects or toxicity in those patients aged > 75 years”

2017

  • Zivanovic [25]:
    “The original recommendation to sustain lithium levels of at least 0.6 mmol/L…”

  • Malhi et al. [26]:
    “Of the 12 that gave recommendations regarding lithium dose, 10 stipulated a therapeutic plasma concentration range, with the most common optimal plasma concentration range being identified as between 0.6 and 0.8 mmol/L”

  • Gupta and Khastgir [27]:
    “Studies suggest a relationship between impaired renal function and either persistent high serum lithium levels (>0.6 mmol/L v. <0.6 mmol/L) or a serum lithium measure of > 1.0 mmol/L”

  • De Fazio et al. [28]:
    “Twenty-six percent of patients treated with lithium showed evidence of toxicity; their plasma concentration of lithium ranged from 1.4 to 2.6 mEq/L”

2016

  • Machado-Viera et al. [29]:
    “Mean lithium dose at endpoint was 710.5 ± 110 mg/day (range = 600–900 mg/day), and mean plasma lithium levels were 0.49 ± .0.2 mEq/l (0.23–1.04)”

  • Gitlin [30]:
    “In the most severe cases, defined by extraordinarily high lithium levels (>4.0  mmol/l)…”

  • Castro et al. [31]:
    “Finally, we observed increasing risk with greater lithium trough levels, such that odds of renal failure are more than twofold greater among individuals with lithium levels of 0.8 mEq/l or greater”

  • Girardi et al. [32]:
    “Lithium-associated toxicity and adverse events are related to serum concentrations of lithium and normally occur at concentrations >1.5–2.0 mmol/L”

2015

  • Haussman et al. [33]:
    “The effective dose range of lithium is 0.6 – 1.0  mmol/l, while in prolonged administration it may be toxic at 1.2  mmol/l or greater”

  • Clos et al. [34]:
    “Our patient population for this study is a well-monitored cohort on lithium maintenance therapy, in whom 91% of lithium levels are up to a maximum of 0·8 mmol/L and the mean lithium plasma level is 0·56 mmol/L”

  • Bocchetta et al. [35]:
    “This may not be the case with our lithium cohort, dating no further back than 1980 and maintained within a therapeutic range between 0.5 and 1.0 mmol/L”

  • Azab et al. [36]:
    “She was stable for many years on lithium 900 mg/day, with blood levels of 0.5–0.6 mEq/L”

2014

  • Kirkham et al. [37]:
    “The range of levels suggested for a safe and effective therapeutic target for lithium within the UK has changed since the initial discovery of its narrow therapeutic range and now lies between 0.4 and 1.0 mmol/L”

  • Forlenza et al [38]:
    “Oral doses of lithium carbonate (mean serum levels ranging from 0.4 to 0.8 mmol/L) or placebo were continuously administered for 18 months”

  • Oruch et al. [39]:
    “The therapeutic range is 0.5–1.0 mmol/l (higher levels are needed to treat acute mania)”

  • Bschor [40] (12 hour time to collect patient blood samples mentioned, but in a later section of the paper):
    “A cumulative meta-analysis revealed that presumably usual therapeutic serum concentrations in the range of 0.6–0.9 mmol/L are needed for effective augmentation”

2013

  • Carter et al. [41]:
    “At day 42, lithium serum levels were significantly higher in the SDD group (0.93 mmol/L SDD, compared with 0.79 mmol/L BID, P < 0.001)”

  • Bretaudeau Deguigne et al. [42]:
    “Therapeutic plasma lithium levels range from 0.6 to 1.2 mEq/L.”

  • Erden et al. [43]:
    “His serum lithium level was 2.7 mmol/L (therapeutic range 0.6–1.2 mmol/L)”

  • Rittmannsberger and Malsiner-Walli [44]:
    “Mean lithium serum levels were 0.67 mmol/L in the depressive states, 0.39 mmol/L in the manic states (t = 4.11, p = 0.001 versus depression), and 0.40 mmol/L in the euthymic states (t = 3.58, p = 0.003 versus depression)”

2012

  • Radhakrishnan et al. [45]:
    “The recommended serum lithium level at steady state (Css) is from 0.5–1.2 mEq/L for acute treatment of bipolar disorder…and 0.6 and 0.8 mEq/L for prophylaxis…A serum level below 0.4 mEq/L is found to be no better than placebo and greater than 1.5 mEq/L is associated with potential toxicity.”

  • Shetty et al. [46]:
    “Blood, saliva, and urine samples were collected from 50 patients, and estimation of serum, salivary, and urine lithium was done using an atomic absorption spectrophotometer. Mean serum lithium was 0.75 ± 0.25 mEq/L, mean salivary lithium was 1.91 ± 0.80 mEq/L, and mean urine lithium was 7.16 ± 4.84 mEq/L”

  • Gentile [47]:
    “Nevertheless, it is not possible to exclude that some of these events (such as cardiac rhythm dysfunctions) could occur even in the presence of neonatal serum lithium concentrations not higher than 0.4 mEq/L”

  • Netto and Phutane [48]:
    “In most cases, the therapeutic serum lithium levels were less than or equal to 1.5 mEq/L (P < .001), and dosage regimens were less than 2,000 mg/day”

2011

  • Singh et al. [49] (standardised twelve hour lithium serum concentration is mentioned, but after the lithium serum concentration value in the next sentence):
    “the total daily dose of lithium carbonate per kilogram body weight required to obtain a serum lithium level of 0.91 mEq/L was calculated and the dose adjusted to the nearest multiple of 150 mg. Twelve-hour (6 30 minutes) serum lithium level estimation was done after 1 week using ion selective electrode system (EasyLyte; Medica, Bedford, MA) and the dose was adjusted accordingly in the therapeutic range by the treating team.”

  • Wijeratne and Draper [50] (Authors do give the definition of the standardised 12 hour lithium serum concentration with reference to the Amdisen 1977 paper, however, the abstract does not contain 12 hour notation, example given below):
    “For most patients, a target serum lithium concentration range of 0.5–0.8 mmol/L, varying according to clinical indication, age and concurrent physical status, seems most appropriate in enhancing efficacy and minimizing adverse effects”

  • D’Souza et al. [51]:
    “In contrast, the therapeutic threshold was comparable between old and young patients, as older patients with a lithium level below 0.4 mmol/L were more likely to relapse than those with a higher level”

  • Findling et al. [52]:
    “Typically, the target maximum lithium serum concentration in adults is 1.3 mEq/L, with 1.5 mEq/L representing the lower limit for toxicity”

2010

  • Collins et al. [53]:
    “Lithium is generally ineffective when the serum level is below 0.4 mmol/L, and very few patients will benefit from levels greater than 1.0 mmol/L”

  • Oliviera et al. [54]:
    “However, despite such great success, lithium has a narrow therapeutic index, with therapeutic serum levels between 0.6 and 1.5 mEq/L”

  • Dunne [55]:
    “The optimal steady-state concentration of lithium for maintenance treatment of bipolar disorder is generally considered to be 0.6–1.0 mEq/litre (mmol/litre)”

  • Shulman [56]:
    “Lithium dosing ranged from 300 to 900 mg/day, with a serum concentration ranging from 0.5 to 1.0 mmol/L”

2009

  • Lembke [57]:
    “One of the earlier studies to examine the optimal dose of lithium in the treatment of symptoms of acute mania advocated a serum lithium concentration between 0.9 mEq/L and 1.4 mEq/L”

  • Grandjean and Aubry [58] (Authors do give the definition of the standardised 12 hour lithium serum concentration in the abstract):
    “Typically, it has been considered that lithium concentrations should be maintained between 0.6 and 1.0 mmol/L”

  • W. Young [59]:
    “The effective dose range for lithium is 0.6–1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5–2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage”

  • Grünfeld and Rossier [60]:
    “Toxic intracellular levels of lithium could, therefore, build up quickly in cells of the collecting duct that are exposed to therapeutic concentrations of lithium (0.6– 1.2mmol/l)”

2008

  • Ljubicic et al. [61]:
    “Lithium therapy is titrated to achieve plasma concentrations between 0.5 and 1.2 mEq/L”

  • Lima et al. [62]:
    “Lithium’s therapeutic window for human clinical use is between: 0.6 to 1.2 mmol/L serum levels”

  • Huang et al. [63]:
    “The mean ± SD of lithium daily dose and actual concentrations were 940 ± 204 mg ⁄ day (range: 600–1200 mg) and 0.6 ± 0.2 mEq ⁄ L (range: 0.21–1.0 mEq ⁄ L) respectively”

  • Abou-Auda et al. [64]:
    “The purpose of these methods is eventually to maintain steady-state therapeutic levels of 0.6–1.2 mmol ⁄ L.”

2007

  • A.H. Young and Hammond [65]:
    “Patients prescribed lithium for the first time should have serum lithium for the first time should have serum lithium levels measured once a week until levels have stabilised between 0.6 and 0.8 mmol/l”

  • Wilting et al. [66]:
    “Its narrow therapeutic window (0.6–1.2 mmol/L), together with high intra- and interindividual variability in pharmacokinetics and interindividual sensitivity to adverse drug reactions, necessitates regular monitoring of lithium serum levels”

  • Waring [67]:
    “At the most recent assessment, 15 months after discharge from hospital, the patient was well, with a normal electrocardiograph, and serum sodium of 143 mmol/l, potassium of 4.1 mmol/l, bicarbonate of 21 mmol/l, urea of 8 mmol/l, creatinine of 157 µmol/l, lithium of 0.9 mmol/l, and plasma osmolality of 292 mOsm/kg”

  • Mohandas and Rajmohan [68]:
    “Guidelines for serum lithium concentrations are based on limited evidence; and a recent study recommends a low mean serum lithium concentration (approximately 0.5 mmol/L), which may be achieved using a mean dose of just over 400 mg/day in a single-dose regimen”

2006

  • Ferrier et al. [69]:
    “Participants received treatment for at least 3 months and blood serum lithium concentrations ranged from 0.5 to 1.4 mmol/l.”

  • Ketter et al. [70]:
    “Plasma lithium concentrations ranging from 0.6 to 1.2 mEq/L were considered within normal limits.”

  • Bellesi et al. [71]:
    “The lithium serum level (0.5 mmol/l) and other routine laboratory parameters were in the normal range”

  • Dunkelmann et al. [72]:
    “The serum lithium levels on day seven of treatment varied between 0.50 and 0.89 mmol/l, the psychiatric therapeutic range was 0.51-1.2mmol/l.”

2005

  • Mamiya et al. [73]:
    “The efficacy and toxicity of lithium are closely related to serum lithium concentration, with its therapeutic range reported to be 0.6 to 1.2 mEq/L”

  • Ramaprasad [74]:
    “Because it is toxic over a certain dose, the blood Li is maintained in a narrow range (0.5–1.2 meq/L) which is considered therapeutic”

  • Colom et al. [75]:
    “Optimal serum lithium levels (0.8–1.0 mmol/L) may enhance psychosocial outcome”

  • Kleindienst et al. [76]:
    “Lithium seems effective at preventing depression at a mean serum level of 0.73 mEq/l…and seems efficacious in preventing manic or mixed states in the range of 0.8 to 1.1 mEq/l”

2004

  • Leboulanger et al. [77]:
    “Lithium concentrations were in the range typical of patients being treated at the Geneva University Hospital, with ~75% having steady-state concentrations between 0.5 and 0.9 mmol/L”

  • Chen et al. [78]:
    “Many minor side-effects may occur at serum levels of 0.6–1.2 mEq/L, although serum lithium concentrations ranging from 0.6 to 1.2 mEq/L have been demonstrated to be efficacious in the treatment of bipolar patients.”

  • Kafantaris et al. [79]:
    “Any patient who developed adverse effects that interfered with his or her functioning or whose serum levels exceeded 1.2 mEq/L had his or her lithium dose reduced”

  • Yeung and Chan [80]:
    “Although the dermatological reactions appear to be dose related, their presence does not indicate systemic toxicity as most of the eruptions arise within the therapeutic range of plasma lithium levels (0.5–1.5 mEq/L).”

Honourable mention

A 2017 paper by Baird-Gunning et al. [81] gives post dose temporal information with lithium serum concentrations and highlights the importance of doing so.


References

[1]          D. Hidalgo-Mazzei et al., ‘Clinicians’ preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders around the world: a survey from the ISBD Lithium task force’, International Journal of Bipolar Disorders, vol. 11, no. 1, p. 20, May 2023, doi: 10.1186/s40345-023-00301-y.

[2]          I. Zorrilla et al., ‘Lithium levels and lifestyle in patients with bipolar disorder: a new tool for self-management’, International Journal of Bipolar Disorders, vol. 11, no. 1, p. 11, Mar. 2023, doi: 10.1186/s40345-023-00291-x.

[3]          M. Golic et al., ‘The low risk for early renal damage during lithium treatment has not changed over time’, J Psychopharmacol, vol. 37, no. 3, pp. 318–324, Mar. 2023, doi: 10.1177/02698811221123054.

[4]          R. A. Davis, T. Branagan, C. D. Schneck, J. D. Schold, T. Thant, and B. Kaplan, ‘Lithium and the living kidney donor: science or stigma?’, American Journal of Transplantation, May 2023, doi: 10.1016/j.ajt.2023.05.022.

[5]          R. E. Nielsen, L. V. Kessing, W. A. Nolen, and R. W. Licht, ‘Lithium and Renal Impairment: A Review on a Still Hot Topic’, Pharmacopsychiatry, vol. 51, no. 5, pp. 200–205, Sep. 2018, doi: 10.1055/s-0043-125393.

[6]          G. Sampogna et al., ‘Why lithium should be used in patients with bipolar disorder? A scoping review and an expert opinion paper’, Expert Review of Neurotherapeutics, vol. 22, no. 11–12, pp. 923–934, Nov. 2022, doi: 10.1080/14737175.2022.2161895.

[7]          A. H. Heald et al., ‘Can we check serum lithium levels less often without compromising patient safety?’, BJPsych Open, vol. 8, no. 1, p. e18, Jan. 2022, doi: 10.1192/bjo.2021.1027.

[8]          A. Chakraborty, R. Biswas, and A. Kumar, ‘Lithium and Nephrotoxicity’, Bengal Journal of Psychiatry, Aug. 2022, doi: 10.51332/bjp.2022.v27.i1.116.

[9]          E. Severus, W. A. Nolen, and M. Bauer, ‘Lithium: The best current treatment for the well-informed bipolar patient’, Bipolar Disorders, vol. 23, no. 1, pp. 92–92, 2021, doi: 10.1111/bdi.13007.

[10]       X. Pérez de Mendiola, D. Hidalgo-Mazzei, E. Vieta, and A. González-Pinto, ‘Overview of lithium’s use: a nationwide survey’, Int J Bipolar Disord, vol. 9, p. 10, Mar. 2021, doi: 10.1186/s40345-020-00215-z.

[11]       C. Parfitt et al., ‘Serum lithium test requesting across three UK regions: an evaluation of adherence to monitoring guidelines’, BMC Psychiatry, vol. 21, no. 1, p. 32, Jan. 2021, doi: 10.1186/s12888-020-03023-y.

[12]       C.-W. Hsu et al., ‘Predicting Serum Levels of Lithium-Treated Patients: A Supervised Machine Learning Approach’, Biomedicines, vol. 9, no. 11, Art. no. 11, Nov. 2021, doi: 10.3390/biomedicines9111558.

[13]       J. Rybakowski, ‘Lithium treatment – the state of the art for 2020’, Psychiatr Pol, vol. 54, no. 6, pp. 1047–1066, Dec. 2020, doi: 10.12740/pp/128340.

[14]       T. S. Schoot, T. H. J. Molmans, K. P. Grootens, and A. P. M. Kerckhoffs, ‘Systematic review and practical guideline for the prevention and management of the renal side effects of lithium therapy’, European Neuropsychopharmacology, vol. 31, pp. 16–32, Feb. 2020, doi: 10.1016/j.euroneuro.2019.11.006.

[15]       G. P. Ossani, A. M. Uceda, N. R. Lago, and D. J. Martino, ‘Relationship between serum lithium concentration and kidney damage in a preclinical model’, Bipolar Disorders, vol. 22, no. 3, pp. 281–285, 2020, doi: 10.1111/bdi.12854.

[16]       S. A. Barroilhet and S. N. Ghaemi, ‘When and how to use lithium’, Acta Psychiatrica Scandinavica, vol. 142, no. 3, pp. 161–172, 2020, doi: 10.1111/acps.13202.

[17]       K. N. Fountoulakis, T. Tegos, and V. Kimiskidis, ‘Lithium monotherapy-induced tardive dyskinesia’, Journal of Affective Disorders, vol. 244, pp. 78–79, Feb. 2019, doi: 10.1016/j.jad.2018.10.094.

[18]       M. L. Imaz, M. Torra, D. Soy, L. García-Esteve, and R. Martin-Santos, ‘Clinical Lactation Studies of Lithium: A Systematic Review’, Frontiers in Pharmacology, vol. 10, 2019, doi: 10.3389/fphar.2019.01005.

[19]       Y.-Y. Xu et al., ‘Factors related to lithium blood concentrations in Chinese Han patients with bipolar disorder’, Neuropsychiatric Disease and Treatment, vol. 15, pp. 1929–1937, Jul. 2019, doi: 10.2147/NDT.S205780.

[20]       S. Soni, ‘Lithium neurotoxicity presenting as dementia with therapeutic serum lithium levels’, BMJ Case Reports CP, vol. 12, no. 1, p. bcr, Jan. 2019, doi: 10.1136/bcr-2018-227741.

[21]       M. Nederlof et al., ‘Monitoring of patients treated with lithium for bipolar disorder: an international survey’, Int J Bipolar Disord, vol. 6, no. 1, p. 12, Apr. 2018, doi: 10.1186/s40345-018-0120-1.

[22]       F. E. Smith, P. E. Thelwall, J. Necus, C. J. Flowers, A. M. Blamire, and D. A. Cousins, ‘3D 7Li magnetic resonance imaging of brain lithium distribution in bipolar disorder’, Mol Psychiatry, vol. 23, no. 11, Art. no. 11, Nov. 2018, doi: 10.1038/s41380-018-0016-6.

[23]       K. Yoshida et al., ‘Prediction Model of Serum Lithium Concentrations’, Pharmacopsychiatry, vol. 51, no. 3, pp. 82–88, May 2018, doi: 10.1055/s-0043-116855.

[24]       M. Sun, N. Herrmann, and K. I. Shulman, ‘Lithium Toxicity in Older Adults: a Systematic Review of Case Reports’, Clin Drug Investig, vol. 38, no. 3, pp. 201–209, Mar. 2018, doi: 10.1007/s40261-017-0598-9.

[25]       O. Zivanovic, ‘Lithium: A classic drug—Frequently discussed, but, sadly, seldom prescribed!’, Aust N Z J Psychiatry, vol. 51, no. 9, pp. 886–896, Sep. 2017, doi: 10.1177/0004867417695889.

[26]       G. S. Malhi, D. Gessler, and T. Outhred, ‘The use of lithium for the treatment of bipolar disorder: Recommendations from clinical practice guidelines’, Journal of Affective Disorders, vol. 217, pp. 266–280, Aug. 2017, doi: 10.1016/j.jad.2017.03.052.

[27]       S. Gupta and U. Khastgir, ‘Drug information update. Lithium and chronic kidney disease: debates and dilemmas’, BJPsych Bull, vol. 41, no. 4, pp. 216–220, Aug. 2017, doi: 10.1192/pb.bp.116.054031.

[28]       P. De Fazio et al., ‘Lithium in late-life mania: a systematic review’, Neuropsychiatric Disease and Treatment, vol. 13, pp. 755–766, Mar. 2017, doi: 10.2147/NDT.S126708.

[29]       R. Machado-Vieira et al., ‘A Selective Association between Central and Peripheral Lithium Levels in Remitters in Bipolar Depression: A 3T-7Li Magnetic Resonance Spectroscopy Study’, Acta Psychiatrica Scandinavica, vol. 133, no. 3, pp. 214–220, 2016, doi: 10.1111/acps.12511.

[30]       M. Gitlin, ‘Lithium side effects and toxicity: prevalence and management strategies’, International Journal of Bipolar Disorders, vol. 4, no. 1, p. 27, Dec. 2016, doi: 10.1186/s40345-016-0068-y.

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