The 2017 International Society for Bipolar Disorders (ISBD) Task Force report on pediatric bipolar disorder (BD) cemented the concept that BD can have onset before the age 18, and that establishing the diagnosis should be based on symptoms of mania or hypomania, while chronic irritability by itself is not sufficient to establish a BD diagnosis [1, 2]. A 2010 study of 1566 patients from six international sites documented that approximately 5% of BD-1 and 5% of BD-2 cases had onset before the age of 20 (Figure 7.1), although the authors noted that only 34.1% of patients were evaluated at onset of their BD, so investigators had to rely on patient recall for two-thirds of the sample.

Acute Mania; Rapid Cycling Bipolar Disorder; Bipolar II Disorder and Bipolar Depression; Bipolar Disorder Prophylaxis, Response Predictors; Unipolar Depression; Suicidality; Aggressive or Impulsive Behavior in Child/Adolescent Patients with Conduct Disorder, in Borderline Personality Disorder or in Patients with Intellectual Disability; Neuroprotective Properties; Elevation of Neutrophil Counts; Mechanisms of Action

As clinical psychopharmacology moves into the twenty-first century, there is an emphasis on rational prescribing practices informed by pharmacokinetic principles and clinical dictates. Publications note that certain oral medications which historically were dosed more than once per day (e.g. most antipsychotics including clozapine) have comparable efficacy with nightly (QHS) dosing for the majority of patients [1–3].

Despite recent downward trends in lithium use for bipolar disorder (BD) [1], nearly every treatment guideline, meta-analysis or review published in the last decade has reinforced the notion that lithium remains the mood stabilizer of choice for acute or maintenance therapy in those with a history of mania (BD-1, schizoaffective disorder, bipolar type [SAD-BT]), and an important treatment option for other mood disorder spectrum patients (BD-2, unipolar major depressive disorder [MDD]) [2–4].

Medical journals from the late nineteenth and early twentieth centuries contained descriptions of lithium toxicity derived from animal experiments, some of which resulted in fatal outcomes; however, a 1903 paper reviewed this animal and human literature extensively and noted that, when lithium carbonate was used in daily doses of 975 mg – 1300 mg as a putative gout treatment, the adverse effects were quite modest and gastrointestinal in nature [2]. Perhaps emboldened by this finding, a Michigan physician, Dr. Clarence Cleaveland, decided in 1913 to experiment on himself by ingesting 14 grams (g) of lithium chloride (equivalent to 12,380 mg of lithium carbonate) in divided doses over a period of 28 h (2 g at 1 pm, 9 pm and 7 am, then 8 g at 7 pm) and document the outcome [3].

In a 1989 review entitled “Long-term treatment with lithium and renal function: A review and reappraisal,” the pioneering Danish psychopharmacologist Mogens Schou concluded: “The fear of eventual kidney insufficiency as a result of long-term lithium treatment can be set at rest” [1]. Despite the certainty advanced by the preeminent authority on lithium at that time – the man responsible for all of the early data on lithium’s efficacy and the first double-blind placebo-controlled trials – fear of lithium’s long-term renal adverse effects remains a significant concern to clinicians, a concern that is often disproportionate to the emerging data in this area.

There are numerous reasons for lithium discontinuation, some patient driven and others motivated by clinician concerns [1]. Focused and early attention to common adverse effects may forestall a certain proportion of somatic complaints leading to lithium refusal, but patients may also stop lithium due to the inconvenience of daily medication; diminished perceived need for lithium during periods of euthymia; a desire to remain in a hypomanic or even manic state (e.g. because they feel more creative or productive, or miss the elevated mood); comparative lack of efficacy for depressive episodes compared with the significant impact on mania; a wish not to be reminded of the illness itself; and not wanting their mood to be regulated by medication [2–4].

As reflected in the number of citations per year, the initial golden age of lithium discovery was indeed 1965–1990. Yet interest in lithium has not waned, and a renaissance in lithium related publications has occurred over the past 20 years (Figure 0.1). This literature is fueled by ongoing exploration of lithium’s unique mood stabilizing, anti-suicide and neuroprotective properties, a constellation of activities not seen in any single molecule [1–10]. Delving into how a simple ion conveys such benefits has opened important avenues of research into the neurobiology of both mood and degenerative brain disorders, and the molecular neuropharmacology of intracellular G-protein dependent and G-protein independent 2nd messenger systems [11, 12].

While the literature abundantly documents lithium’s unique efficacy profile and the limitations of non-lithium therapies, starting a patient on lithium requires the complete array of one’s clinical skills. One core ability relates to appropriate pharmacological use of lithium, including dosing, level monitoring, and management of drug interactions and adverse effects that lead to discontinuation [1]; however, it is facility in communicating with patients and eliciting their illness beliefs, their ideas about the need for any treatment, and their specific thoughts about lithium therapy that is crucial to minimizing nonadherence [2].