Background
Despite its place as the gold standard for maintenance treatment in bipolar disorder, prescription patterns from a number of (but not all) countries demonstrate a decreasing use of lithium (Karanti et al.
2016; Kessing et al.
2016; Parabiaghi et al.
2015). Assuredly, this phenomenon reflects a number of factors that influence both physician and patient behaviors including the number of other mood stabilizers available, the need for regular monitoring via venipuncture with lithium, the marketing of other patent-protected mood stabilizers and so forth. Beyond the decision as to which mood stabilizer should be prescribed, some of these same factors are likely to play a role in predicting adherence to maintenance lithium.
Side effects are another important variable in both prescription patterns and adherence. Surprisingly, the exact role of side effects in predicting lithium nonadherence—which averages >40% (Perlick et al.
2004)—is still unclear (Goodwin and Jamison
2007). Clinicians may view side effects as more important in nonadherence than do patients (Jamison et al.
1979). Additionally, patients’ perception of or apprehension of side effects, as opposed to the actual presence of side effects may contribute more to nonadherence (Scott and Pope
2002). Specific side effects—such as cognitive dulling—may also be more associated with nonadherence than the total number of side effects (Gitlin et al.
1989). Complicating the issue is the frequent misattribution of symptoms as side effects with a common example being cognitive dullness as a symptom of depression, attributed to the mood stabilizer, as a side effect. Nonetheless, it seems self-evident that side effects play at least some role in lithium nonadherence.
Because of this, knowledge of lithium side effects and education about these with patients remains an essential part of clinical practice. Additionally, managing these side effects remains a critical element in psychiatrists’ optimal treatment of bipolar disorder. This paper reviews the most common side effects of lithium and reviews treatment strategies for them. It also reviews the potential toxic effects of lithium on organ function since managing these risks is also essential in long-term lithium therapy.
Lithium and the kidneys
The polyuria discussed above reflects lithium’s effect on the renal tubular system. Concerns that this might reflect structural irreversible damage, as opposed to simply reversibly interfering with tubular function, began with the first reports of biopsy-proven interstitial nephritis in lithium-treated patients almost 40 years ago (Hestbech et al.
1977). All studies examining renal morphology in lithium-treated patients have consistently found the same results: focal nephron atrophy, and interstitial fibrosis with relative preservation of glomeruli (Gitlin
1999). This is consistent with the clinical features of lithium-associated nephropathy—obligate polyuria—but without marked decrease in filtering capacity of the kidneys as measured by eGFR and secondarily by serum creatinine. (The latter measure is less accurate than eGFR since it also reflects muscle mass which decreases with age. Thus, an older person may have substantially diminished eGFR but a relatively normal serum creatinine.) Polyuria correlates only weakly with reduced kidney function with the former rather common and the latter unusual (Azab et al.
2015).
Although lithium-treated patients have, in general, a lower eGFR than those not treated, the eGFR does not correlate with time on lithium suggesting that it is not progressive within groups. However, a subgroup of lithium-treated patients does show progressive renal insufficiency. This is manifested by “creeping creatinine” (Jefferson
1989) with a gradual rise in serum creatinine and a decrease in creatinine clearance over years. This phenomenon occurs in approximately 20% of lithium-treated patients (Lepkifker et al.
2004). In one study, approximately 1/3 of lithium-treated patients had an eGFR <60 ml/min while 5% showed an eGFR of <30 ml/min (Aiff et al.
2015).
An even smaller subgroup of lithium-treated patients progresses towards end-stage renal disease (ESRD) and ultimately dialysis and/or renal transportation. The prevalence of ESRD associated with lithium is difficult to estimate. One study found the risk to be almost eightfold compared to the general population (Aiff et al.
2014a). In contrast, another study found risk for renal insufficiency but not ESRD (Kessing et al.
2015) while a third study found no differences in the rate of eGFR declines in lithium-treated patients vs. those treated with other psychotropic agents (Clos et al.
2015). In the most recent study, compared to patients treated with other mood stabilizers such as valproate, olanzapine or quetiapine, lithium was associated with higher rates of chronic renal disease (eGFR <60 ml/min) but not more severe renal disease (eGFR <30 ml/min) (Hayes et al.
2016). Since lithium-associated ESRD is virtually exclusively seen in patients treated for a very long term—in one study, the average time on lithium for those with ESRD was 27 years (Aiff et al.
2014a), studies of only 10–15 years may not show the increase in ESRD.
Some recent studies have suggested both lower rates of ESRD in lithium-treated patients over the last thirty years when mean therapeutic lithium levels are lower than before (Aiff et al.
2014b) and less effect on renal function in general with lower levels (Aprahamian et al.
2014). However, the largest study of unselected patients continued to find significant rates of renal damage and ESRD in a lithium-treated population (Aiff et al.
2015).
Risk factors for lithium-induced nephropathy are length of treatment, age, and prior episodes of lithium toxicity (Aiff et al.
2015; Bocchetta et al.
2015; Clos et al.
2015). Whether the lithium regimen—once-daily vs. multiple doses—predicts differential rates of ESRD is unclear.
Some evidence exists that progressive renal impairment continues even after lithium discontinuation, (Bocchetta et al.
2015). In one study, patients with a serum creatinine >2.5 mg/dl (220 ml/l) at the time of lithium discontinuation were far more likely to progress to ESRD (Bendz et al.
2010). In another study, further deterioration of renal function was more likely if the creatinine clearance was <40 ml/min (Presne et al.
2003).
General guidelines for minimizing the risk of significant renal damage in lithium-treated patients are: monitor serum creatinine and eGFR regularly during lithium treatment at intervals of every 6 months to 1 year; avoid episodes of lithium toxicity, keep mean lithium levels within the low therapeutic range when possible, and consider once-daily dosing. When the serum creatinine rises to 1.6 mg/dl (140 mmol/l), consultation with a nephrologist is appropriate and consideration for lithium discontinuation should be discussed with the patient (Gitlin
1993). Since the progression of renal damage is slow, if discontinuing lithium is deemed necessary, the second mood stabilizer should be added, titrated to full dose and only then should the lithium be tapered and discontinued gradually over 4–8 weeks.
Lithium and thyroid function
First recognized in the late 1960s when goiters were discovered in a cohort of lithium-treated patients (Schou et al.
1968), antithyroid effects of lithium are now well established. Multiple mechanisms are probably involved. The most important of these is inhibition of thyroid hormone release from the thyroid gland; however, lithium may also decrease iodine trapping with the gland and inhibit synthesis of thyroid hormones (Lazarus
2009; Kibrige et al.
2013).
The prevalence of thyroid dysfunction in lithium-treated patients varies substantially across studies, reflecting both different populations and varying definitions of hypothyroidism. As examples, lithium has been associated with overt hypothyroidism (manifest symptoms of hypothyroidism plus high thyroid-stimulating hormone [TSH] and low T4) vs. subclinical hypothyroidism (asymptomatic plus high TSH with normal T4) vs. goiter without reference to biochemical markers. Overt hypothyroidism is estimated as having a prevalence of 8–19% with subclinical hypothyroidism showing rates up to 23% (Kleiner et al.
1999). Many patients with goiter are euthyroid in that the enlarged gland has been sufficiently stimulated to synthesize and release adequate amounts of thyroid hormone.
The most important risk factors for lithium-induced hypothyroidism are the presence of antithyroid antibodies, which increases the risk by eightfold (Bocchetta et al.
2007), female sex (which covaries with antithyroid antibody prevalence (Ozerdem et al.
2014; Kraszewska et al.
2015; Shine et al.
2015), older age and a family history of hypothyroidism (Kibrige et al.
2013).
Symptoms of lithium-induced hypothyroidism are the same as seen in primary cases of the disorder—lethargy, mental slowing, depression, weight gain, dry skin, and cold intolerance. Of course, a number of these symptoms overlap with depression symptoms as well as side effects from lithium or other psychotropic agents, making diagnosis difficult in the absence of thyroid function tests.
Given the substantial rates of thyroid dysfunction in lithium-treated patients, thyroid parameters should be checked before lithium is instituted and then monitored after 3–6 months initially and then every 6–12 months. The minimal test required both before and during lithium treatment is the thyroid-stimulating hormone (TSH) level. Peripheral thyroid hormone measurements T3 and T4 are recommended by some, as are antithyroid (TPO) antibodies and/or ultrasound of the thyroid gland.
The interpretation and recommendations for clinical management of thyroid abnormalities during lithium treatment varies. The most important clinical rule is that hypothyroidism never justifies lithium discontinuation. A reasonable middle ground approach of Kleiner et al. (
1999) suggests that TSH values >10 mU/L on two occasions should be interpreted as incipient thyroid gland failure and warrants administration of l-thyroxine even if the patient is asymptomatic. TSH levels between top normal and slightly high (usually 4–4.5 and 10 mU/L) should be treated if the patient has refractory depression or lassitude/fatigue. TSH levels between 4 and 10 mU/L in asymptomatic patients can be monitored closely without exogenous thyroid treatment, although some experts add l-thyroxine in these situations also. Thyroid hormones should be prescribed to bring TSH values within the normal range.
Although not systematically studied, patients with lithium-induced hypothyroidism who discontinue lithium can usually stop thyroid treatment. Occasionally, however, discontinuing l-thyroxine after lithium discontinuation results in the re-emergence of hypothyroidism. In these cases, it is assumed that lithium exacerbated a subclinical hypothyroidism which then continued after lithium discontinuation.
Lithium and parathyroid gland/calcium
Although evidence of increased calcium and serum parathyroid hormone (PTH) associated with lithium treatment has been available for decades, only recently has this effect been examined more systematically. Lithium increases renal calcium reabsorption and independently stimulates parathyroid hormone release (Shapiro and Davis
2015). A meta-analysis of relevant studies found that lithium treatment was associated with a 10% increase in blood calcium and PTH levels (McKnight et al.
2012). Studies published since then have mostly confirmed this finding (Albert et al.
2013,
2015; Shine et al.
2015). There is some evidence that lithium-associated hypercalcemia/hyperparathyroidism is associated with fewer clinical symptoms than are seen in primary hyperparathyroidism (Shapiro and Davis
2015). Classic symptoms of hypercalcemia include weakness, fatigue, renal stones, renal insufficiency and osteoporosis. Because of how recent these findings about lithium and calcium levels are, most Practice Guidelines with some exceptions (Yatham et al.
2013; Malhi et al.
2015) do not yet recommend regular monitoring of calcium and PTH levels with lithium-treated patients. However, measuring calcium levels both before the initiation of lithium treatment and yearly during treatment would seem to be prudent.
Treatment of lithium-associated hypercalcemia/hyperparathyroidism is the same as for primary cases (Shapiro and Davis
2015). Mild elevations of levels in asymptomatic patients can be simply monitored. With higher levels, switching from lithium to a different mood stabilizer, calcimimetic therapy with cinacalcet or local or subtotal parathyroidectomy are the reasonable treatment options.
Conclusion
Side effects and potential toxicities underlie at least part of the decreased utilization of lithium over the last decade or more. A number of these side effects—polyuria, thirst, nausea, tremor, sexual side effects—are typically either mild or no worse than annoying. Others such as weight gain and cognitive dullness/impairment are more distressing to patients and may be more associated with nonadherence. However, of note, in direct comparison studies, dropout rates due to other than relapse do not differ between lithium and anticonvulsant comparators (Severus et al.
2014). A number of basic nonspecific strategies, summarized in Table
1, may suffice for managing these side effects. In other circumstances, specific remedies, summarized in Table
2, may be implemented to diminish patients’ distress and to enhance the likelihood of treatment adherence.
Table 2
Managing lithium side effects: treatment strategies
Polyuria | Once-daily dosing diuretics |
Thirst/polydipsia | Sugarless gum glycerin-based oral moisturizers cholinergic mouthwashes |
Tremor | Beta-blockers primidone benzodiazepines Vitamin B6 |
Weight gain | Avoid high-calorie drinks exercise/diet topiramate |
Cognitive impairment | Stimulants |
Sexual dysfunction | Aspirin phosphodiesterase 5 inhibitors |
Skin lesion—acne–psoriasis | Usual remedies, inositol |
In most cases, lithium toxicity is preventable. Proper education and monitoring will certainly diminish the number of toxic episodes in lithium-treated patients.
Potential organ toxicity requires more vigilance both because of the need for laboratory monitoring of TSH, serum creatinine and eGFR and calcium levels and the potential consequence of these toxicities if and when they emerge. With proper monitoring, these concerns can be easily managed in the vast majority of lithium-treated patients. The small but measurable increased risk for ESRD in lithium-treated patients cannot be prevented completely but with the use of lower therapeutic lithium levels, monitoring of eGFR and judicious discontinuation of lithium when needed, this risk can be minimized and patients more effectively treated.