Lithium: An American Perspective

American psychiatry (like the country itself) seems to be branded by those outside my country with the adjectives associated with children or superficial, easily distracted adults…”enamored by whatever is new and shiny” [1]. With regard to lithium, we are accused of being out of step with the rest of the psychiatric world, prescribing lithium less frequently, distracted by pharmaceutical marketing of proprietary medications or unduly swayed by the direct to consumer (DTC) marketing, unable to resist our patients’ requests to be prescribed whatever medication they saw advertised on late night television.

It is certainly true that lithium prescriptions in the United States are lower than one might anticipate given its extraordinary efficacy over many decades of clinical use [2]. Yet, this picture of the United States as uniquely resistant to lithium is a simplistic cartoon. First, lithium is, of course, still prescribed regularly in the US. Second, rates of lithium prescriptions have been decreasing in other countries too such as Denmark [3] and Sweden [4]although the decrease in the US has been greater than has been observed elsewhere. Third all the medications commonly used as mood stabilizers other than lithium-lamotrigine, valproate, quetiapine, risperidone, olanzapine, aripiprazole-have all been available as generic medications for years and there has been no marketing on their behalf since then. Therefore, is it not possible that American psychiatrists-and American patients- are using other mood stabilizers for legitimate reasons?

These reasons comprise the usual criteria that are used in making clinical prescribing decisions-efficacy, side effects and potential toxicities, and ease of administration. These reasons are detailed in greater depth elsewhere [5]. As acknowledged in the Global Perspective in this Journal issue [1], only a quarter to one third of lithium treated patients respond robustly. Should we not be prescribing other mood stabilizers (sometimes in conjunction with lithium) for the other two thirds to three quarters of our bipolar patients? As an example, the results of two studies have suggested the somewhat greater efficacy of lamotrigine compared to lithium in preventing depression, which is both the dominant pole of bipolar disorder and the pole most associated with functional impairment among bipolar individuals [6]. With the appropriately increased attention towards optimal treatment of bipolar II patients for whom depression is even more dominant [7], lamotrigine’s greater efficacy in preventing depression becomes even more relevant.

Additionally, lithium’s side effect burden is significant. Only a relatively small fraction of lithium treated patients are side effect free [8]. Additionally, side effects are an important factor (but certainly not the only one) in predicting nonadherence to lithium, a critical problem in long term mood stabilizer treatment. In the one study with a non-enriched design (this criterion is essential since enriched designs are biased towards greater tolerability in the experimental treatment) comparing lithium with lamotrigine, the latter was associated with fewer side effects than lithium [9], consistent with clinical experience.

Potential toxicities are another area of legitimate concern when considering the algorithm of mood stabilizers. Of course, no medication is devoid of potential toxicities-either short term in the case of immunologically based rashes with lamotrigine-or long term such as tardive dyskinesia with antipsychotics or hepatic toxicity with valproate. Nonetheless, the potential long term toxicities with lithium-renal and parathyroid-are legitimate concerns. (I am ignoring lithium’s thyrotoxicity since it is so easily monitored, diagnosed and treated). Despite the conflicting data about the extent of the risk of developing end stage renal disease from lithium [10], it is difficult to dismiss these concerns given the inherent morbidity of either dialysis or renal transplantation. Given the lifetime nature of bipolar disorder and the lifetime needs of bipolar individuals to be treated with mood stabilizers, even ten year follow-up studies on lithium’s renal effects are not sufficiently reassuring. These worries are analogous to the legitimate concerns about tardive dyskinesia associated with the long term use of antipsychotics. We should not stop prescribing either lithium or antipsychotics, but we need to be open and mindful of the long terms risks. The recent data on lithium’s effect on calcium levels and parathyroid levels are also concerning [11]. I have already consulted on a long term (twenty years) lithium-treated bipolar patient whose hypercalcemia could not be effectively managed medically and had a (successful) parathyroidectomy in order to continue on lithium. Unfortunately, she needed to discontinue lithium later on due to progressive renal insufficiency.

Finally, the obligatory rituals of treatment which, with lithium, include regular, albeit infrequent venipuncture to monitor lithium levels, and thyroid, renal and parathyroid function parameters are burdens for many patients, especially when some other mood stabilizers have no such requirements.

My comments are not meant to discourage the prescription of lithium. I have prescribed lithium for forty years, regularly and with gratitude. With a subgroup of bipolar individuals, lithium can be extraordinarily effective, even life saving. Additionally, lithium may have other positive effects that are not seen with other mood stabilizers, such as its antisuicidal effects [12], its efficacy as an adjunctive antidepressant in unipolar depression [13] and its potential to decrease the risk of neurodegenerative disorders such as some forms of dementia [14]. But, as experts in the treatment of bipolar disorder, we need to be honest with ourselves, the community of clinicians and with patients as to the risks and benefits of all our mood stabilizers. I am grateful to be able to prescribe lithium. I am equally grateful for the availability of other mood stabilizers which have different but equally relevant advantages and different liabilities.

So, the American perspective may be more reasonably described as appreciative of the long term mainstays of treatment (in this case, lithium) but rather open to other newer modalities which yield more therapeutic options. This plethora of choice is a boon to patients, their families and doctors alike.

• References

• 1 Lithium MalhiG. A global perspective. Pharmacopsychiatry 2018; 51: 220-221
• 2 Blanco C, Laje G, Olfson M. et al. Trends in the treatment of bipolar disorder by outpatient psychiatrists. American Journal of Psychiatry 2002; 159: 1005-1010
• 3 Kessing L, Vradi E, Anderson PK. Nationwide and population-based prescription patterns in bipolar disorder. Bipolar Disorder 2016; 18: 174-182
• 4 Karanti A, Kardell M, Lundberg U. et al. Changes in mood stabilizer prescription patterns in bipolar disorder. Journal of Affective Disorders 2016; 195: 50-56
• 5 Gitlin MJ. (2016a) Why isn’t lithium prescribed more often? Here are the reasons. Journal of Psychiatry and Neurological Services 2016; 29: 293-297
• 6 Gitlin MJ, Miklowitz DJ. The difficult lives of individuals with bipolar disorder: A review of functional outcomes and their implications for treatment. Journal of Affective Disorders 2017; 209: 147-154
• 7 Judd LL, Akiskal HS, Schettler PJ. et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60: 261-269
• 8 Gitlin MJ. (2016b) Lithium side effects and toxicity: Prevalence and management strategies. Int J Bipolar Disord 2016; 4: 27
• 9 Licht R, Nielsen J, Gram L. et al. Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of Danish university andtidepressant group (DUAG-6). Bipolar Disorder 2010; 12: 483-493
• 10 Aiff H, Attman P, Aurell M. et al. Effects of 10-30 years of lithium treatment on kidney function. Journal of Psychopharmacology 2015; 29: 608-614
• 11 McKnight R, Adida M, Budge K. et al. Lithium toxicity profile: A systematic review and meta-analysis. Lancet 2012; 379: 721-728
• 12 Cipriani A, Hawton K, Stockton S. et al. Lithium in the prevention of suicide in mood disorders: Updated systematic review and meta-analysis. BMJ 2013; 246: f3646
• 13 Nelson JC, Baumann P, Delucchi K. et al. A systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression. Journal of Affective Disorders 2014; 168: 269-275
• 14 Morris G, Beck M. The putative use of lithium in Alzheimer’s disease. 2016; 13: 853-861