Hector Warnes’ Final Comment


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


            I congratulate Professor Blackwell for his outstanding review of the many hurdles that the therapeutic use of lithium have encountered since 1949.  His review has a great deal of autobiography by examining his own scientific development,  at times being candid, other times being ironical or self-critical.

            Lithium was finally accepted as a mood stabilizer in Bipolar Disorders, as a useful drug in the treatment of Manic excitement and perhaps as a useful antidepressant that lowers the suicidal rate in Bipolar patients. The latter has not been confirmed. 

            I shall cite a paragraph in Barry’s essay that cannot be disputed: “...that more scrupulous analysis of the phenomenology, genetics and neurochemistry might reveal what SUBTYPES respond specifically to lithium, imipramine or valproic acid (Grof).”  We are really raising the issue of subtypes of Bipolar Disorders or Bipolar Spectrum disorders which would include Schou’s hidden bipolar disorders, the rapid cycling, the treatment resistant or refractory bipolar disorders, the vital depressions and a host of other manifestations either somatic, neurovegetative, psychological or behavioural (e.g., some  addictive disorders, compulsive gambling, acting out and anniversary reactions).  I am seeing patients with cycles every two years, others have cycles every five years, others every 10 years and, invariably, the same month or season of the year. Others have only manic or hypomanic episodes, often  a continuation  of the so-called  hypomanic personality.  Most cases have a family history of Major Depression or Bipolar Disorder.

            I would support Barry’s eclecticism regarding the overrating of the therapeutic effect of lithium. In order to explain myself, I shall put forward the point that it is rather an individual response specificity which depends on family history, pharmacogenetics, co-morbidity, drug-drug-interactions resulting in unresponsiveness to treatment, life events and  pharmacological history of previous response to a specific compound. Most bipolar patients have other medical pathologies for which they are receiving treatment.

            The more the therapeutic window is narrowed for any drug the more the side effects or the risk of severe adverse reactions.  We must not forget as well that there are patients who show positive placebo genesis to any new drug and others who show negative placebo genesis to the same drug.  But we know by now that there is no panacea (cure-all) drugs. Most placebo studies (when they were allowed) showed that up to 30% of patients respond favorably to an inert substance, particularly if the there is a good doctor-patient relationship and if the doctor (as Barry puts it) shows enthusiasm.   Most psychotropic drugs, including anti-depressants, are effective in about 40 to 70% of well selected patients.

            Lithium site of action on the first and second messenger, on gene expression, on calcium regulation, on the inositol monophosphatase, on the phospholipase C and on neuro-plasticity are not to be dismissed lightly. Liping Hou, Urs Heilbronner, Franziska Degenhardt, et al. (2016) have shown that single nucleotide polymorphism on chromosome 21 is associated with lithium response; carriers of the response associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles.

            Finally, Barry raised the theme of serendipity which has, at times, led to great discoveries. We cannot forget that in 1952 some tuberculous patients treated with isoniazid became hypomanic and it was attributed that this MAOI had antidepressant properties. It was withdrawn from the market because of hepatotoxicity.  Another extraordinary discovery was that of Alexander Fleming who, in 1928, accidentally observed that a culture of staphylococci became contaminated with a fungus of the Penicillum genus. The colonies of staphylococci surrounding the fungus were annihilated.



Hou L, Heilbronner U, Degenhardt F, Alda M, Rietschel M, McMahon FJ and Schulze TZ . Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study. Lancet. 2016; 387 (10023): 1085-93.


July 27, 2017