Janusz Rybakowski’s final comment:
Half a Century of Inspiring Lithium Controversy

Barry Blackwell: The lithium controversy: A historical autopsy
Collated by Olaf Fjetland

In the next year, a half century will have passed after publication of the famous Lancet paper by Blackwell and Shepherd, “Prophylactic lithium: another therapeutic myth?” During this period, a number of important developments have occurred to debunk the myth.

Lithium has been firmly established as the first-choice drug for preventing mood episodes in bipolar disorders, meeting all requirements of the Evidence-Based Medicine (Severus et. al., 2014). Concomitantly, in this half century, other drugs with mood-stabilizing properties have been introduced. They are defined as drugs that: (1) reduce or ameliorate manic and/or depressive symptoms; (2) act to prevent recurrent manic and/or depressive episodes; and (3) do not induce or worsen manic or depressive episodes. Recently, a classification of mood stabilizers (MS) was proposed, based on the chronology of their introduction into the psychiatric armamentarium (Rybakowski, 2007). Description of the long-term mood stabilizing properties of lithium, valproate and carbamazepine were published in 1960-70 (Hartigan, 1963; Lambert et. al,, 1971; Okuma et. al., 1973), and the first observations that atypical antipsychotic drugs, such as clozapine, may exert mood-stabilizing effects was advanced in the 1990s (Zarate et al., 1995). Subsequently, other atypical antipsychotics such as olanzapine, quetiapine and aripiprazole have been found to have MS properties (Rybakowski, 2007; 2008). A suggestion that the anticonvulsant lamotrigine may also have such characteristics was proposed in 2002 (Ketter and Calabrese, 2002). Because lithium, valproates and carbamazepine preceded these newer agents by several decades, convention has grouped these agents as 1^st generation MSs while the newer agents are designated as 2^nd generation MSs (Rybakowski, 2007).

Although a number of drugs with mood-stabilizing properties already exist, none has so far surpassed lithium as far as prophylactic efficacy in bipolar illness is concerned, not even to mention a duration of such prophylaxis. This has been happening even though lithium is “an orphan drug” with no interest for backing it by any major pharmaceutical company. In the first decade of 2010, an intensive promotion of valproate as a prophylactic agent in bipolar illness lead to a significant increase of the use of this drug at the expense of lithium usage. However, in a 2010 Lancet issue, the results of an excellent BALANCE study were published showing unquestionable superiority of lithium over valproate for the prevention of recurrences in bipolar disorder (BALANCE investigators and collaborators, 2010). Recently, we, in the Poznan center, reported on five excellent lithium responders receiving the drug, mostly as monotherapy, for 40 years or more (Permoda-Osip et. al., 2016).

An important indication for lithium is augmentation of antidepressant drugs in treatment-resistant depression. Such procedure has proved very effective in both unipolar and bipolar depression (Crossley and Bauer, 2007), although more so in bipolar one (Rybakowski and Matkowski, 1992). This may also relate to an issue named in this discussion as "hidden bipolars," i.e. subjects with major depression having some bipolar characteristics. In contemporary literature, such patients with major depression are termed as having subclinical bipolar symptoms or belonging to the bipolar spectrum. They may account to about 1/3 of patients with a diagnosis of unipolar depression (Angst et. al., 2011). In the Polish TRES-DEP study including 1,051 patients with major depressive disorder, using the Hypomania Checklist-32, developed by Jules Angst, the features of bipolarity were found in 37.5% of the patients and connected with worse effects of antidepressant drugs (Rybakowski et. al., 2012). Therefore, the features of bipolarity can make the patient more resistant to a pharmacotherapy with antidepressant drugs and a concomitant usage of MS agents (lithium in the first place) may be of therapeutic value (Rybakowski, 2012).

Apart from therapeutic potential in mood disorder, a number of interesting lithium properties have been revealed. Therapeutic efficacy of lithium against herpes infections in the clinical setting had been already mentioned in my previous essay (Rybakowski and Amsterdam, 1991). However, of paramount importance from a clinical point of view is the anti-suicidal effect of lithium which significantly decreases the mortality rate of treated patients. Important evidence for this effect came from a collaborative study by the International Group for the Study of Lithium-treated patients (IGSLI), with Mogens Schou as a co-author (Müller-Oerlinghausen et. al., 1992). Lithium has now been regarded as the mood-stabilizing drug with best evidenced anti-suicidal properties. They are most pronounced after two years or more of lithium prophylaxis and not directly related to lithium prevention of mood episodes (Lewitzka et. al., 2015). Concerning lithium and suicidality, intriguing epidemiological studies should be also mentioned showing inverse correlation between suicidal rate and lithium concentration in drinking water (Oghami et. al., 2009; Kapusta et. al., 2011).

Last but not least, a subject of great interest has recently been a possible neuroprotective effect of lithium. This has been supported by clinical findings of increased volume of some brain structures, such as prefrontal cortex and hippocampus in lithium-treated patients, demonstrated also by the IGSLI group (Moore et. al., 2009; Hajek et. al., 2014). The Danish epidemiological studies showed that the continued treatment with lithium was associated with a reduced rate of dementia, in contrast to anticonvulsants, antidepressants and antipsychotics drugs (Kessing et. al., 2008, 2010). Although the results of clinical studies have brought mixed results, a potential use of lithium in neurodegenerative disorders remains still an open issue (Rybakowski, 2011).

References

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BALANCE investigators and collaborators, Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010; 375: 385-395.

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August 17, 2017