Presentation

Risk factors and clinical features of lithium intoxication are described in Table 2. The symptoms of lithium intoxication relate to its pattern – acute, acute-on-chronic or chronic intoxication – with chronic intoxication occurring with established lithium concentrations and being associated with more severe sequelae (Baird-Gunning Reference Baird-Gunning, Lea-Henry and Hoegberg2017). Overdose is a pertinent cause of lithium intoxication and can be intentional or unintentional. A review using data from the US national poisons information database reported that intentional overdose caused 18% of documented cases of lithium intoxication in the USA in 2013 (Baird-Gunning Reference Baird-Gunning, Lea-Henry and Hoegberg2017).

TABLE 2

Lithium toxicity: risk factors and clinical features

NSAIDs, non-steroidal anti-inflammatory drugs; ACE, angiotensin-converting enzyme; SILENT, syndrome of irreversible lithium-effectuated neurotoxicity.

Sources: Adityanjee (Reference Adityanjee1989); Baird-Gunning et al (Reference Baird-Gunning, Lea-Henry and Hoegberg2017); Murphy et al (Reference Murphy, Redahan and Lally2023).

Lithium intoxication can present with a range of symptoms of varying severity, but can also be detected with confirmed elevated serum levels indicating toxicity in the absence of clinical features. Central nervous system (CNS) manifestations (Table 2) are characteristic of chronic intoxication, with gradual accumulation of lithium in the nervous system.

Higher functions can be impaired on a continuum, ranging from impaired concentration to significant confusion and disorientation, and ultimately seizures and coma. Significant CNS involvement increases the risk of lasting neurological complications. The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) was first described in 1987 and refers to persistent neurological damage secondary to lithium intoxication. This was initially characterised by predominating signs of cerebellar dysfunction such as ataxia, dysarthria, coarse tremor and dysdiadochokinesis (Adityanjee Reference Adityanjee1989).

The clinical presentation of SILENT has been further characterised since its initial description and can also include extrapyramidal movements, dementia with deficits in multiple cognitive domains, signs of upper motor neuron damage such as hyperreflexia and spasticity, bowel and bladder incontinence and fundoscopic abnormalities (Munshi Reference Munshi and Thampy2005).

Management

The management of lithium intoxication (Table 2) relies on accurate recognition and prompt intervention. Lithium should be withheld in all cases of probable intoxication supported by clinical features while serum levels are awaited. Any lithium-treated patient who develops vomiting, altered level of consciousness, gross tremor or cerebellar signs should be considered to have lithium intoxication and managed accordingly until the situation is clarified, even when therapeutic serum levels are found, given the association of these clinical features with lithium toxicity. Dose reduction may be undertaken in asymptomatic cases with serum levels approaching 1.5 mmol/L.

Hospital admission should be considered in certain cases (Table 2). Mild cases often resolve with lithium cessation, as symptoms tend to be concentration dependent. Chronic intoxication often occurs with intravascular volume depletion and is managed by restoration of corporeal fluid balance, usually with normal saline infusion.

In severe intoxication, rapid removal of lithium from systemic circulation is appropriate. The method of choice for this is intermittent haemodialysis (Box 5), to which lithium is particularly amenable (Okusa Reference Okusa and Crystal1994).

Lithium re-initiation should be a medical decision with multidisciplinary input and consideration of the cause of intoxication, its chronicity, treatment tolerability, patient preference and physical comorbidity (Murphy Reference Murphy, Redahan and Lally2023). Lithium rechallenge after intentional overdose should be subject to a comprehensive risk assessment, considering imminent and historical risk factors for suicide and bearing in mind lithium’s recognised unique anti-suicidal effects. Risk-mitigating strategies such as controlled or supervised dispensing and close psychiatric monitoring as practised in in-patient or day hospital services may be helpful when rechallenging with lithium in this context.

Hypothyroidism

Treatment with lithium frequently affects the thyroid gland, resulting in overt/subclinical hypothyroidism, thyroid nodules or goitre. The majority of those who develop a thyroid disorder on lithium develop subclinical hypothyroidism or goitre. The prevalence of lithium-associated hypothyroidism is approximately 10–20%, with a calculated annual incidence of new-onset hypothyroidism of 2.17% in women and 0.68% in men (Kibirige Reference Kibirige, Luzinda and Ssekitoleko2013). Most thyroid dysfunction manifests within 3 years (Duce Reference Duce, Duff and Zaidi2023). Lithium concentration in the thyroid gland is 3–4 fold higher than in plasma, where it inhibits thyroid hormone release, the principal mechanism in the development of hypothyroidism and goitre. This inhibitory effect is secondary to alterations in tubulin polymerisation and inhibition of action of thyroid-stimulating hormone (TSH) on cyclic adenosine monophosphate (cAMP) (Kibirige Reference Kibirige, Luzinda and Ssekitoleko2013). The inhibition of thyroid hormone release promotes a higher TSH secretion, which results in an increased thyroid volume.

Thyroid function should be checked before commencing lithium and every 6 months. More frequent monitoring is indicated if there is evidence of impaired thyroid function or an increase in mood symptoms (NICE 2014). Lithium-induced hypothyroidism is usually subclinical (TSH 6–10 mU/L, with normal tri-iodothyronine (T3) and/or thyroxine (T4) levels) and asymptomatic (Kibirige Reference Kibirige, Luzinda and Ssekitoleko2013). Subclinical hypothyroidism, particularly when identified in the initial months of treatment with lithium, may be transient and self-resolving (Duce Reference Duce, Duff and Zaidi2023). More frequent monitoring may be an appropriate initial approach. Although up to 40% of lithium-induced hypothyroidism could be reversible on discontinuation (Haissaguerre Reference Haissaguerre and Vantyghem2022), the identification of hypothyroidism and/or goitre during lithium therapy does not indicate a need for lithium discontinuation and it is acceptable to continue treatment with lithium (Gitlin Reference Gitlin2016).

The decision to treat subclinical hypothyroidism with levothyroxine is outlined in Table 3. Levothyroxine can be initiated by a psychiatrist or general practitioner, with referral to an endocrinologist if symptoms persist or the treatment response is suboptimal. Dosing may be decided in consultation with an endocrinologist. To enhance absorption, levothyroxine should be taken on an empty stomach at least 30 min before eating and, insofar as possible, not within 4 h of using antacids, proton-pump inhibitors or iron supplements. A flexible approach to treatment is required, and debate continues about defining subclinical/clinical hypothyroidism. Treatment with levothyroxine should aim to maintain TSH levels within the reference range (Table 3). If symptoms of hypothyroidism persist, dose adjustment should be considered while avoiding doses that cause TSH suppression or thyrotoxicosis (NICE 2019a). It should be kept in mind that the TSH level can take up to 6 months to return to the reference range for people who had a very high level prior to treatment or a prolonged period of untreated hypothyroidism.

TABLE 3

Endocrine, metabolic and renal side-effects of lithium and management interventions in bipolar disorder

TSH, thyroid-stimulating hormone; T4, thyroxine; BMI, body mass index; SGAs, second generation antipsychotics; GLP-1, glucagon-like peptide-1; ACR, albumin/creatinine ratio.

Sources: Vestergaard et al (Reference Vestergaard, Poulstrup and Schou1988); Keck & McElroy (Reference Keck and McElroy2003); McKnight et al (Reference McKnight, Adida and Budge2012); NICE (2014); Shapiro & Davis (Reference Shapiro and Davis2015); Gitlin (Reference Gitlin2016); Praharaj (2016); NICE (2019a, 2019b); Mifsudet et al (Reference Mifsud, Cilia and Mifsud2020); Schoot et al (Reference Schoot, Molmans and Grootens2020); Duce et al (Reference Duce, Duff and Zaidi2023); Ferensztajn-Rochowiak & Rybakowski (Reference Ferensztajn-Rochowiak and Rybakowski2023); Gitlin & Bauer (Reference Gitlin and Bauer2023); Kong et al (2024).

Hyperthyroidism

Lithium-induced hyperthyroidism is rare and is increasingly thought not to be consequential to lithium treatment (Shine Reference Shine, McKnight and Leaver2015). The onset of hyperthyroidism during lithium treatment merits investigation for Grave’s disease or Hashimoto’s thyroiditis, which are much more prevalent conditions, and would indicate the need for endocrinology referral and assessment. Increased antibodies targeting the TSH receptor thyroid-stimulating immunoglobulin or thyroid-binding inhibitory immunoglobulin are found in Grave’s disease.

Hyperparathyroidism and hypercalcaemia

Lithium-associated hyperparathyroidism (LAH) consists of a spectrum of biochemical abnormalities, ranging from overt hyperparathyroidism to hypercalcaemia with inappropriately normal parathyroid hormone levels and normocalcaemia with raised parathyroid hormone levels (Mifsud Reference Mifsud, Cilia and Mifsud2020). Estimates of prevalence of LAH vary between studies, but may be as high as 5–15% (Lally Reference Lally, Lee and McDonald2013; Shine Reference Shine, McKnight and Leaver2015). Most people with LAH tend to have mild hypercalcaemia and are usually asymptomatic (Mifsud Reference Mifsud, Cilia and Mifsud2020).

Lithium promotes calcium reabsorption and increased parathyroid hormone release. In the initial stages of treatment with lithium, hypercalcaemia occurs as a result of lithium’s inhibition of the calcium-sensing receptor (CaSR) and glycogen synthase kinase-3 (GSK-3). In the parathyroid gland, inhibition of CaSR results in reduced sensitivity of parathyroid cells to serum calcium levels, while in the kidney, it leads to increased renal tubular calcium reabsorption. Inhibition of GSK-3, which is responsible for inhibition of parathyroid hormone gene transcription, leads to overproduction of parathyroid hormone (Mifsud Reference Mifsud, Cilia and Mifsud2020). Long-term lithium treatment may lead to changes in the parathyroid glands, either by revealing hyperparathyroidism in individuals with a subclinical parathyroid adenoma or potentially by triggering multiglandular hyperplasia leading to hyperparathyroidism.

Calcium levels should be checked before commencing lithium treatment, 6-monthly thereafter (NICE 2014) and more frequently if symptoms of hypercalcaemia occur (Table 3). It has been suggested that hypercalcaemia in LAH is often less symptomatic than in primary hyperparathyroidism, but the relative incidence of symptomatic versus asymptomatic presentations in lithium-associated cases has not been well established (Shapiro Reference Shapiro and Davis2015). Where hypercalcaemia is identified (corrected serum calcium ≥2.6 mmol/L on two separate occasions), its aetiology should be confirmed by undertaking further investigations (Table 3). Individuals with chronic kidney disease (CKD) can have secondary hyperparathyroidism with elevated parathyroid hormone levels, but with hypocalcaemia along with hyperphosphataemia.

In cases of severe or symptomatic hyperparathyroidism, discontinuation of lithium should be considered, although this may not lead to normalisation of calcium levels in all cases. Discontinuation should be accompanied by close monitoring of calcium levels and for resolution of symptoms. Beyond consideration of cessation of lithium, the guidelines for managing primary hyperparathyroidism provide a framework for the management of LAH (Mifsud Reference Mifsud, Cilia and Mifsud2020) (Table 3). Patients who are symptomatic and/or have corrected serum calcium levels ≥2.6 mmol/L on two separate occasions should be referred for input from a specialist (NICE 2019b). Specialist referral for those with corrected serum calcium ≥2.85 mmol/L should include referral to a surgeon with expertise in parathyroid surgery (NICE 2019b). In the majority of cases of LAH (67–100%), parathyroidectomy achieves normocalcaemia (Mifsud Reference Mifsud, Cilia and Mifsud2020).

In those with contraindications to surgery and serum calcium levels ≥2.85 mmol/L with symptoms or ≥3.0 mmol/L with or without symptoms, the use of calcimimetic therapy such as cinacalcet may be considered as an alternative (NICE 2019b).

Of note, lithium does not cause osteoporosis and may have osteoprotective effects, reducing fracture risk in people with bipolar disorder (Köhler-Forsberg Reference Köhler-Forsberg, Rohde and Nierenberg2022). Similarly, lithium does not increase the risk of nephrolithiasis, unless the patient develops a parathyroid adenoma or hyperplasia (Lehmann Reference Lehmann and Lee2013).

Management

Assessment of weight gain in lithium-treated patients should consider baseline weight and body mass index (BMI), diet, activity levels, medical comorbidities and their influence on behaviours further affecting physical health. Weight should be monitored at regular intervals during the maintenance phase, bearing in mind that most weight gain is believed to occur within the first 2 years of lithium treatment. Watchful waiting can be practised, given ultimate weight stabilisation in most cases. Various co-prescribed psychotropics (Table 3) are possible contributors to lithium-associated weight gain.

The expertise of appropriate allied health professionals, when available, should be availed of to guide patients in lifestyle modifications. Specific dietary advice based on individual eating habits has been shown to reduce the risk of weight gain (>5 kg) in patients newly initiated on lithium. This can be implemented by a variety of health professionals in different settings and is both inexpensive and effective (Keck Reference Keck and McElroy2003).

If additional psychotropics are indicated in lithium-treated bipolar depression, cariprazine, lurasidone or lamotrigine may be preferable, as they are associated with less weight gain compared with olanzapine, quetiapine or sodium valproate. Pharmacological management of lithium-associated weight gain (Table 3) may involve treating other lithium-induced conditions, such as hypothyroidism. There is little evidence for pharmacological treatment of lithium-associated weight gain.

Management

Monitoring renal function while on lithium treatment is important for early identification and intervention, particularly as lithium-induced nephropathy is typically asymptomatic (Box 4). NICE guidelines recommend measuring eGFR before commencing lithium and 6-monthly thereafter (NICE 2014). If a decline in eGFR is noted, frequency of monitoring should be increased. Increased monitoring should be accompanied by screening for and treating comorbid medical conditions that may contribute to renal insufficiency and medication review to identify other nephrotoxic medications (Box 4).

Referral to nephrology should be considered when patients are at high risk of progression, have significant proteinuria, show rapid decline in kidney function or have complex/secondary causes of CKD (Table 3). The goal of referral would be to consider other aetiologies of impaired renal function, such as hypertension and type 2 diabetes mellitus.

Cessation of lithium may be considered, once other possible aetiologies of nephropathy have been considered and addressed. The decision to discontinue lithium should take into account current renal function, duration of treatment and lithium response. Discontinuation of lithium will not always result in stabilisation of kidney function, and patients with advanced renal insufficiency frequently show continued deterioration of renal function even after lithium discontinuation (Gitlin Reference Gitlin and Bauer2023).

Management

The decision on whether to treat polyuria should be made on the basis of symptom severity as well as associated distress or impact on functioning. Equally NDI does not always require treatment and may be self-limiting. An overview of management steps is provided in Table 3. Polyuria and NDI are not typically indications for cessation of lithium in patients who are benefitting from it, and once-daily dosing reduces polyuria risk.

Polyuria and NDI may be associated with electrolyte disturbances such as hypernatraemia, which should be screened for and corrected in accordance with conventional guidelines. Once the underlying factors have been addressed, pharmacological treatment can be considered: amiloride (off-label) is the most promising option (Schoot Reference Schoot, Molmans and Grootens2020) (Table 3). A treatment goal may be reduction of distressing thirst and excessive urination, with or without corrected osmolality. Amiloride is most likely to be effective when there is a mild to moderate urinary concentration deficit. Alternative drug treatments, such as a hydrochlorothiazide–triamterene combination, have shown some positive results, but there is currently insufficient evidence to recommend these agents (Gitlin Reference Gitlin2016).

Managment

Dose reduction can be considered, subject to thorough risk–benefit analysis, accounting for individual patient sensitivity to developing tremor at different serum lithium concentrations. It is best to allow up to 2 weeks before repeating serum concentrations and reassessing tremor severity, to allow time for steady state concentrations.

Pharmacological treatment of lithium-induced tremor is similar to that for essential tremor (Table 4). Propranolol has the strongest evidence base, at 80 mg/day divided into three or four equal doses in regular formulations; once-daily dosing of a sustained-release formulation is an option. Doses <100 mg/day are often effective, although doses of 60–320 mg/day have been used (Baek Reference Baek, Kinrys and Nierenberg2014).

If propranolol is intolerable (side-effects include fatigue, sedation, bronchospasm, hypoglycaemia) or contraindicated because of respiratory disease, atenolol can be trialled. Topiramate has previously shown moderate benefit in the treatment of essential tremor, but lacks evidence for use in lithium-induced tremor and may pose tolerability problems in lithium-treated individuals. Primidone is effective in treating essential tremor, with case report evidence in treating combined lithium-tricyclic induced tremor (Baek Reference Baek, Kinrys and Nierenberg2014). Doses start at 50–75 mg daily, with 50 mg increases every 3–4 days. Best responses occur at doses <200–250 mg/day. Fatigue may influence tolerability. Clonazepam (0.5–6 mg daily) and alprazolam (0.5–3 mg daily) are thought to be effective owing to their anxiolytic effect, but use is cautioned because of side-effects and abuse potential (Baek Reference Baek, Kinrys and Nierenberg2014).

Management

In managing lithium-associated nystagmus, other potential aetiologies should be considered and investigated (Table 4). Magnetic resonance imaging (MRI) should be considered to rule out structural brain lesions, particularly where there are additional neurological findings on physical examination. A serum lithium level and screening for other signs of lithium toxicity should be done. Where lithium toxicity is identified, it should be managed accordingly (see section ‘Lithium toxicity’).

Lithium-induced nystagmus may resolve with discontinuation, but can be irreversible, even with cessation of lithium (Halmagyi Reference Halmagyi, Lessell and Curthoys1989). Early identification will increase the likelihood of reversibility on cessation. There is a single case report of response to baclofen (20 mg three times a day) in lithium-induced nystagmus (Lee Reference Lee and Lessell2003).

Management

To date, there are no definitive treatments for lithium-associated symptoms of cognitive impairment (Table 4). Watchful waiting can be practised in the initial treatment phase, with affect stabilisation itself (particularly from mania or hypomania) potentially leading to improvement in cognition and emotional blunting.

Psychoeducation regarding adaptation to euthymia and absence of hypomanic mood states is important. Reducing the lithium dose may be effective as some patients experience higher CNS levels compared with others at equivalent serum concentrations, given the evidence for individual differences in cerebral lithium concentrations, particularly in older patients. This may be more relevant if cognitive symptoms occur after titration to a higher serum lithium concentration or at established higher serum concentrations. Dose reduction can be attempted when comorbid causes of cognitive dysfunction, such as mood symptoms, medical conditions and concurrent medications, are ruled out.

Psychostimulants are potentially beneficial for individuals experiencing cognitive impairment, although they have not been rigorously evaluated for this purpose in the context of lithium treatment.

Management

ECG monitoring (Table 4) is particularly indicated in those at higher risk for supratherapeutic lithium levels, such as those with reduced renal function.

T-wave inversion and sinus bradycardia are generally not indications for dose reduction or action beyond continuation of routine monitoring. However, changes that have higher risk for arrhythmias and fatal cardiac outcomes – for example, sinoatrial blocks, ST-segment changes and Brugada pattern – need to be addressed, including referral to cardiology services. Dose adjustment may be required, given the dose-dependent association. ECG changes are often reversible on discontinuation and this is a consideration for potentially serious changes (Mehta Reference Mehta and Vannozzi2017).

Management

It is an important to address sexual dysfunction in lithium-treated patients as its presence may curtail global levels of functioning and reduce treatment adherence (Elnazer Reference Elnazer, Sampson and Baldwin2015). Treating sexual dysfunction in lithium users may therefore improve quality of life and treatment concordance, which can be considered major therapeutic goals.

Assessment and management in lithium users require knowledge of premorbid (when in psychiatric remission) and baseline sexual function. Lifestyle and psychological factors, along with medical and psychiatric comorbidities, should be examined and addressed (Table 4).

Watchful waiting is an option in mild and non-distressing sexual dysfunction. Active symptom management should be considered only in conjunction with managing the above factors. Changes to lithium dosage or schedule are not presently recommended. It is unclear to what extent sexual dysfunction in lithium users persists, but its identification in lithium maintenance treatment cohorts suggests that it can.

Pharmacological strategies include phosphodiesterase-5 inhibitors, which have displayed effectiveness in sexual dysfunction in populations treated with antidepressants, antipsychotics and lithium in combination with other psychotropics (Gitlin Reference Gitlin2016; Sheibani Reference Sheibani, Ghasemi and Dehpour2022).