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Monday, 12.04.2021

Janusz Rybakowski: Lithium The Amazing Drug in Psychiatry 


Janusz Rybakowski’s reply to Barry Blackwell’s comments


       Many thanks to Barry Blackwell for his thoughtful comments on my book. He also raised several important contemporary issues connected with lithium therapy. My adventure with lithium started two years after his famous paper in Lancet. It seems that parallel to my career, Barry experienced a significant conversion of his views, becoming the advocate of lithium treatment which he is now. In connection with his excellent essay, I should like to reiterate some topics which were touched upon in the book and also by him:


1. Lithium as an essential trace element.        

       A possibility that lithium is an essential trace element was raised by John Cade in his seminal paper starting the introduction of lithium in modern psychiatry when he remarked, “The effect on patients with pure psychotic excitement – that is, true manic attacks – is so specific that it inevitably leads to speculation as to the possible etiological significance of a deficiency in the body of lithium ions in the genesis of this disorder” (Cade 1949). For many years, as the dose of lithium used for treatment exceeded 200-fold its endogenous amount, such a concept has not received much attention. Its revival came only in the recent decade due to the two lines of evidence. Firstly, a negative association between some mental deviations and lithium in drinking water was observed. An inverse correlation between suicides and lithium concentration in drinking water was demonstrated in research performed in Japan (Ohgami, Terao, Shiotsuki  et al. 2009), Austria (Kapusta, Mossaheb, Etzersdorfer et al. 2011), the USA (Blüml, Regier, Hlavin et al. 2013) and Greece (Giotakos, Nisianakis, Tsouvelas and Giakalou 2013). In subsequent years, such a negative association between tap water lithium and dementia was also observed (Kessing, Gerds, Knudsen et al. 2017; Fajardo, Fajardo, LeBlanc et al. 2018). These findings resulted even in a suggestion of drinking water supplementation with lithium in the areas of its low level. The second line of evidence was based on the findings of therapeutic efficacy of very low doses of lithium. The most conspicuous in this respect is the paper of Brazilian authors (Nunes, Viel and Buck 2015) in which they showed a beneficial effect of lithium micro-doses (300 µg/day) on a decline of performance in patients with Alzheimer’s disease. Recently Gadh (2020) assessed the effectiveness of 150 mg of lithium carbonate in a residential addiction treatment center. He found many beneficial results such as reduction buprenorphine-naloxone use by 50%, benzodiazepines by 99%, atypical antipsychotics by 70% and smoking cessation increased by 300%. The completion rate of those who took low-dose lithium improved by almost 100%. Therefore it seems that the concept of lithium as a trace element formulated by a Japanese researcher, Takeshi Terao in 2015 (Terao 2015) has gained significant support in the last five years.


2. The anti-suicidal activity of lithium.          

       The anti-suicidal activity of lithium mentioned already in the above research of drinking water has been amply demonstrated in clinical studies. This is one of the most valuable experiences concerning long-term use of lithium in mood disorders and the evidence has been accumulated that among mood-stabilizing drugs, the use of lithium results in the biggest reduction of suicides and suicide attempts. As suicides are the most common cause of death of people with mood disorders, this property of lithium translated greatly into its beneficial clinical effect.

       The antisuicidal effect of lithium was confirmed by the meta-analyses performed in the 21st century. Baldessarini, Tondo, Davis et al. (2006) showed that the risk of committing suicide was five times lower among patients taking lithium than those subjected to other forms of treatment. Cipriani, Hawton, Stockton and Geddes (2013) concluded that lithium was significantly better than a placebo in reducing the number of suicides and general mortality, both in bipolar disorder (BD) and in unipolar depression, and superior to other mood-stabilizers and antidepressants. The discontinuation of lithium significantly increases suicide risk. According to German researchers, the anti-suicidal effect of lithium is not correlated with the quality of prevention of mood recurrences which points to the specificity of such an effect of lithium (Lewitzka, Severus, Bauer et al. 2015).

       Therefore, it seems important to recommend considering using lithium in every patient with a mood disorder where risk of suicide is present. An assessment of such risk factors should include, among others, family history of suicidal behavior, the occurrence of suicidal behavior during the current course of the illness and the patient's present life situation and clinical condition. In the case of patients whose clinical course corresponds with the profile of excellent lithium responders, the use of lithium monotherapy is sufficient to prevent suicidal behavior. In other patients with a high risk of suicidal behavior, lithium should be used as an essential component of a combined mood-stabilizing treatment.

       The researchers of the anti-suicidal effect of lithium postulate its broader use to possibly save the lives of people with mood disorders, which was also the case in the above-mentioned paper of Cipriani, Hawton, Stockton and Geddes (2013). However, as a rebuttal to this claim, Olfson (2015) in his infamous paper stated: “The high frequency and clinical severity of adverse events associated with lithium should be considered among calls to expand lithium treatment in bipolar disorder.” No wonder this outraged Barry, and I concur with him in this respect.


3. Augmentation by lithium of antidepressant drugs.           

       Treatment-resistant depression has become one of the most important therapeutic problems in psychiatry nowadays. An important application of lithium could be the augmentation of antidepressant drugs in treatment-resistant depression in the course of both bipolar and recurrent depression. In my opinion, the augmentation by lithium of antidepressants can make the second indication for lithium use after the prevention of mood episodes. We showed that significant clinical amelioration assessed after 28 days of lithium administration takes place in at least a half of the patients, is greater in BD than in unipolar disorder and in patients with rapid improvement (within several days after lithium introduction) occurs  (Rybakowski and Matkowski 1987, 1992). When introducing lithium to potentiate the effect of antidepressants in treatment-resistant depression, the desired drug concentration is 0.6-0.8 mmol/l and the drug should be continued for four weeks. After that time, a clear improvement can be expected in at least 50% of patients. In about 1/4 of patients, the effect can be observed very quickly, within a few days after initiating the administration of the drug. If no significant improvement is observed within four weeks, lithium can be stopped. However, if a good therapeutic effect is achieved, to prevent the recurrence of depression, the drug should be continued for at least one year (Bauer, Adli, Ricken et al. 2014). The side-effects are rare, most frequently hand tremor. If lithium is added to the SSRI drugs, the risk of serotonin syndrome is low. Lithium augmentation can be successfully used in the elderly, where the efficacy can be even better in people over 65 years of age (Buspavanich, Behr, Stamm et al. 2010).

       Recently, intranasal ketamine was introduced by the Janssen company as a possible tool for the augmentation of antidepressants in treatment-resistant depression. In Poland, the price of one shot of intranasal ketamine is $250 (US). Given using this drug twice weekly, the price for monthly therapy is $2,000 (US). This also refers to Barry’s remark of the cost of therapy. No direct comparison of lithium and intranasal ketamine augmentation of antidepressants have been done so far.


4. Underutilization of lithium

       One of the reasons for the underutilization of lithium is the introduction and active promotion of other mood-stabilizing drugs, both first and second generation (Rybakowski 2018a). Lithium is an “orphan drug” which, due to the low cost of production, is not promoted by any drug company. Another motive may be the perception of lithium as a “toxic” drug due to its adverse effects, mainly on thyroid, renal and cognitive functions. This perception is common not only among doctors of different specialties but also among some psychiatrists.

       Insufficient usage of lithium can be reflected by trends in the prescription of mood-stabilizers in recent decades. They have indicated a significant increase for the new mood-stabilizing drugs, while lithium has been on a similar level or slightly decreased. A study performed in Poland showed that during 2004-2010, the prescription of lithium in Poland rose by 4% while in 2011-2017 this increase amounted to 16%. However, in the second half of 2017, the prescriptions of lithium were surpassed nearly 3-fold by valproate and about 2-fold by quetiapine, olanzapine and lamotrigine (Rybakowski and Checinska 2018).

       Two years ago, the eminent specialist on BD, Robert Post, deplored that lithium is greatly underutilized in the USA, even more than in Europe. He pointed to the multiple assets of lithium and argued that the fear of lithium’s adverse effects can be exaggerated (Post 2018). In the same year, I wrote a paper titled “Challenging the negative perception of lithium and optimizing its long-term administration,” in which I indicated the advantage of lithium over other mood-stabilizing drugs and possibilities of effective management of lithium side-effects (Rybakowski 2018b). Whereas in one of the latest editorials of the journal Bipolar Disorders, titled “Make lithium great again,” psychiatrists lead by the Chief Editor of the journal, Gin Malhi, call upon a better utilization of lithium’s therapeutic potential and the most frequent use of the drug (Malhi, Bell, Boyce et al. 2020).

       It is to be hoped that all these claims will not remain the voice of one crying in the wilderness and can make some effects in favor of lithium.



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February 4, 2021