Despite its virtually universal acceptance as the gold standard in treating bipolar disorder, prescription rates for lithium have been decreasing recently. Although this observation is multifactorial, one obvious potential contributor is the side effect and toxicity burden associated with lithium. Additionally, side effect concerns assuredly play some role in lithium nonadherence. This paper summarizes the knowledge base on side effects and toxicity and suggests optimal management of these problems. Thirst and excessive urination, nausea and diarrhea and tremor are rather common side effects that are typically no more than annoying even though they are rather prevalent. A simple set of management strategies that involve the timing of the lithium dose, minimizing lithium levels within the therapeutic range and, in some situations, the prescription of side effect antidotes will minimize the side effect burden for patients. In contrast, weight gain and cognitive impairment from lithium tend to be more distressing to patients, more difficult to manage and more likely to be associated with lithium nonadherence. Lithium has adverse effects on the kidneys, thyroid gland and parathyroid glands, necessitating monitoring of these organ functions through periodic blood tests. In most cases, lithium-associated renal effects are relatively mild. A small but measurable percentage of lithium-treated patients will show progressive renal impairment. Infrequently, lithium will need to be discontinued because of the progressive renal insufficiency. Lithium-induced hypothyroidism is relatively common but easily diagnosed and treated. Hyperparathyroidism from lithium is a relatively more recently recognized phenomenon.
In older studies, with data collected during a time when more (but certainly not all) patients were seemingly treated with lithium monotherapy, the majority of lithium-treated patients report at least one side effect with estimates ranging between 67 and 90% (Johnston et al. 1979; Bone et al. 1980; Vestergaard et al. 1980; Gitlin et al. 1989). Thus, only a relative small fraction of lithium-treated patients are side effect free. Most patients have more than one side effect attributed by the patient to lithium (Vestergaard et al. 1980; Gitlin et al. 1989).
Diarrhea increases in prevalence in patients through the first 6 months of treatment and is seen in up to 10% of lithium-treated patients (Vestergaard et al. 1988). Serum lithium levels >0.8 mEq/l are associated with higher rates of diarrhea (Vestergaard et al. 1988). Some, but not all studies, suggest higher rates of diarrhea with sustained release lithium preparations, presumably due to more distal absorption of the drug (Edstrom and Persson 1977). As with vomiting, lithium intoxication can be associated with diarrhea. The presence or absence of other toxic symptoms and a serum lithium level will help guide the clinician as to whether further evaluation for toxicity should be considered.
Proposed risk factors for the renal effects leading to polyuria/polydipsia include: duration of treatment, higher serum lithium levels, repeated episodes of lithium intoxication and the ingestion of other psychotropic medications, especially antipsychotics (Gitlin 1999; Azab et al. 2015).
Tremor, primarily of the hands, is among the most common lithium side effects, seen in approximately one quarter of treated patients (Gelenberg and Jefferson 1995). Lithium tremor is generally symmetric and is indistinguishable from essential or physiologic tremor. Thus, it is most apparent with intentional posture, such as writing or holding a coffee cup (Baek et al. 2014). It is distinct from the parkinsonian tremor associated with dopamine-blocking agents. Patients treated with D2 blockers and lithium may present with a complex tremor from multiple etiologies. The severity of lithium-induced tremor is additive to other forms of physiologic tremor from etiologies such as anxiety, alcohol withdrawal, caffeine ingestion or idiopathic, familial tremor. Some studies have found additive effects from other medications such as some antidepressants (Bone et al. 1980; Vestergaard et al. 1988).
Lithium-induced tremor typically presents early in treatment but may emerge at any time. When it occurs later, additional etiologies should be considered such as those noted above. At times, lithium tremor seems to improve spontaneously after years of treatment. Lithium tremors are more common with older age, presumably due to the additive effects of age-related essential tremor. The type of lithium preparation does not alter tremor prevalence but higher lithium levels correlate with greater risk of tremor (Vestergaard et al. 1988).
Suggested treatment strategies for weight gain are all based on common sense and nonspecific approaches. First, the likelihood of weight gain should be discussed before lithium treatment is initiated since prevention is easier than treatment. Patients should be encouraged to drink low or noncaloric drinks to treat their thirst. General diet and exercise strategies should, of course, be encouraged. If the patient is taking multiple medications, switching from a treatment with high weight gain liability (such as olanzapine or quetiapine) to another with less weight gain (e.g., aripiprazole or lurasidone) should be considered. Finally, if these strategies are insufficient, the use of adjunctive weight-losing medications, such as topiramate may be tried (Chengappa et al. 2001).
In contrast to most of the other potential side effects surveyed in this paper, sexual dysfunction from lithium has been relatively neglected as a topic of clinical inquiry. A recent literature review found only thirteen papers on the topic (Elnazer et al. 2015). Problems in interpreting the little data that exist include a lack of control groups since sexual dysfunction in epidemiological samples is considerable (Laumann et al. 1999); the negative effect of other psychotropic medications (especially antidepressants and antipsychotics) on sexual function; the potential effect of depressed mood and depressive symptoms on sexuality. An earlier study suggested that sexual dysfunction in lithium-treated patients was seen only in patients also taking benzodiazepines (Ghadirian et al. 1992). In one of the few studies using a control group of age-matched healthy controls, stable bipolar patients on lithium showed decreased libido and sexual satisfaction (Zuncheddu and Carpiniello 2006). Both the onset of bipolar disorder and the institution of lithium seemed to have independent negative influences on sexuality. In the most recent study, 37% of euthymic bipolar patients on lithium acknowledged sexual dysfunction across multiple sexual domains (Grover et al. 2014).
Given the paucity of data in this area, unsurprisingly, few treatment approaches to lithium-associated sexual dysfunction have been suggested. In the only controlled trial, aspirin 240 mg daily was more effective than placebo in reducing overall sexual dysfunction and in improving erectile dysfunction (Saroukhani et al. 2013). Phosphodiesterase 5 inhibitors, which have been demonstrated as effective in treating SSRI-induced sexual dysfunction in both men and women (Nurnberg et al. 2008, 2003), should be considered for those with lithium-associated sexual difficulties, especially if diminished arousal plays an important role.
Exact prevalence rates of dermatological disorders from lithium are not available. Both new cases and exacerbation of pre-existing acne and psoriasis due to lithium have been described (Pfennig et al. 2006) with one study suggesting a significantly higher risk in men (Chan et al. 2000). The latter finding may reflect the higher prevalence of acne in young men vs. young women, presumably due to the influence of testosterone. Moderate to severe psoriasis should be considered a relative contraindication to lithium. Dermatological effects of lithium may be related to lithium levels.
Thus, a first therapeutic strategy for lithium-associated acne would be to consider lowering the lithium dose. In mild cases of acne, usual dermatological remedies should be considered. A small placebo-controlled trial found a positive effect of inositol 6 g daily in decreasing the severity of psoriatic lesions in lithium-treated patients (Allen et al. 2004). However, if the skin lesions are moderate to severe, do not respond to conventional remedies and/or are associated with substantial social self-consciousness (especially in young people), switching from lithium to another mood stabilizer may be necessary.
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).
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