Barry Blackwell:  The Lithium Controversy. A Historical Autopsy


Janos Radó’s reply to Gordon Johnson’s comment on Janos Radó’s (January 25, 2018) final comment


         I would like to thank Gordon Johnson for his comments on my  final comment on the collated document of Barry Blackwell’s Lithium controversy project. I am especially grateful for his comments because it was from his reports that we learned the natural history of renal function changes in patients under lithium therapy (Johnson, Glenn, Hunt et al. 1984; Johnson 1998).

         In some patients treated for 10-20 years urinary concentrating ability studied during administration of vasopressin decreased below plasma osmolality (300mosm/Kg). This observation was confirmed later by many investigators. Thus, the development of nephrogenic diabetes insipidus as a consequence of long-term lithium treatment is no longer a rarity. In some cases withdrawal of lithium resulted in improved renal function, while in others lithium-induced nephrogenic diabetes insipidus remained irreversible, e.g., “permanent” (Radó and Zdravkova 1991,1993).  Even in these cases therapy is not absolutely hopeless. Several therapeutic options are available, by which the patient’s rest during night can be somewhat secured by decreasing the polyuria with thiazide diuretics, indomethacine, amiloride, desmopressin and, most importantly, combinations of them (Croft, Bedford, Leader and Walker 2018; Mizuno, Fujimoto, Sugiyama et al. 2003; Radó 2018, 2019; Stasior, Kikeri, Duel and Seifter 1991; Weinstock and Moses 1990).

         Although lithium-induced permanent nephrogenic diabetes insipidus is “by definition” a vasopressin-resistant condition, vasopressin resistance in many cases is not absolute (Canfield, Tamarappoo, Moses et al.1997; Moses, Scheinman and Oppenheim 1984). When we started our studies with desmopressin a “supramaximal” dose was 300 mcg given intranasally. In these early human pharmacology investigations 320 mcg was given as a quasi “single dose” during one hour to patients with neurohypophyseal (central) diabetes insipidus (Radó 1975). When we used desmopressin for nephrogenic diabetes insipidus 300 mcg was given during 24 hrs (Radó and Zdravkova 1991,1993). In the meantime, however, it became known that desmopressin may be effective also in hematologic disorders. In these disorders, in certain cases, desmopressin was given in very extreme doses

         The industry produced desmopressin preparations containing very high concentrations of desmopressin which acted on the blood clotting mechanism for bleeding disorders. By using such a preparation (Octim Nasal Spray Ferring Pharmaceuticals Ltd) administration of 300 mcg (150 mcg into each nostril) as a single dose is easily feasible.

         To the best of my knowledge this preparation has not been tried, up to now, in the combination therapy (with indomethacine or other compounds) of the lithium-induced permanent nephrogenic diabetes insipidus. Nevertheless, Gordon Johnson’s statement, based on his studies, is valid  also at present: “the results confirm the safety of lithium administration in the majority of patients.” This wise sentence has been corroborated since many times (Aiff, Attman P, Aurell et al. 2014; Blackwell  2014; Bendz Schön, Attman and Aurell 2010; Croft, Bedford, Leader and Walker 2018; Radó 2018, 2019; Rybakowski 2017; Severus 2014; Shine, McKnight, Leaver and Geddes 2015).



Aiff H, Attman P, Aurell M, Bendz H, Schön S, Svedlund J. The impact of modern treatment principles may have eliminated lithium-induced renal failure. Journal of Psychopharmacology. 2014;28 (2):151-154. 

Bedford JJ, Weggery S, Ellis G, McDonald FJ, Joyce PR, Leader JP, Walker RJ. Lithium-induced nephrogenic diabetes insipidus: renal effects of Amiloride. Clin J Am Soc Nephrol 2008/a; 3: 1324–31.

Bendz H, Schön S, Attman P, Aurell M. Renal failure occurres in chronic lithium treatment but is uncommon. Kidney International 2010; 77:219-224.

Blackwell B. Lithium Controversy. A historical autopsy. June 19, 2014.

Canfield MC, Tamarappoo BK, Moses AM, Verkman AS, Holtzman EJ. Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response. Hum Mol Genet. 1997 Oct;6(11):1865-71.

Croft, PK, Bedford, J. J., Leader, JP, Walker RJ: Amiloride modifies the progression of lithium-induced renal interstitial fibrosis. Nephrology (Carlton). 2018; 23(1):20-30. 

Johnson G. Lithium--early development, toxicity, and renal function. Neuropsychopharmacology 1998; 19:200-5.

Johnson G, Glenn E, Hunt G, Duggin G, Horvath JS, Tiller DJ. Renal function and lithium treatment: initial and follow-up tests in manic-depressive patients. J. Affective Disorders 1984; 6: 249-63 1984.

Johnson G. Comment on Janos Radó’s (January 25, 2018) final comment. (Barry Blackwell Lithium July 5, 2018.

Mizuno H, Fujimoto S, Sugiyama Y, Kobayashi M, Ohro Y, Uchida S, Sasaki S, Togari H. Succesful treatment of partial nephrogenis diabetes insipidus with thiazide and desmopressin. Horm Res. 2003; 59(6) :297-300.

Moses AM, Scheinman SJ, Oppenheim A. Marked hypotonic polyuria resulting from nephrogenic diabetes insipidus with partial sensitivity to vasopressin. J Clin Endocrinol Metab.1984; 59: 1044–9.

Radó J. Final comment on Barry Blackwell: The lithium controversy. A historical autopsy. Collated by Olaf Fjetland. Use of modern antidiuretic agents in the treatment of permanent lithium-induced nephrogenic diabetes insipidus (Administration of excessive doses of desmopressin resulted in clinically relevant antidiuresis, enhanced by indomethacine and abolished by calcitonine). January 25, 2018.

Radó JP, Marosi J, Fischer J, Tako J, Kiss N. Relationship between the dose of 1-deamino-8-d-arginine vasopressin (ddavp) and the antidiuretic response in man. Endokrinologie 1975; 66: 184-95.

Radó JP, Zdravkova S. Lithium-induced chronic water-metabolism disorder (nephrogenic diabetes insipidus)]. Orv Hetil. 1991;132, 1987-90.

Radó JP, Zdravkova S. Effect of Indomethacine and Calcitonin During Administration of 1-Deamino-8-D-Arginin-Vasopressin (dDAVP) on Free Water Clearance in Nephrogenic Diabetes Insipidus (NDI). XIIth International Congress of Nephrology. June 13–18, 1993 Jerusalem, Israel.

Radó J. Renal Toxicity of Lithium in Historical Perspective with Special Reference To Nephrogenic Diabetes Insipidus and its Treatment.  May 2, 2019. 

Rybakowski J. Final comment: Half a Century of Inspiring Lithium Controversy. Barry Blackwell: The Lithium controversy: A historical autopsy. Collated by Olaf Fjetland. collated. August 17, 2017.

Shine B, McKnight RF, Leaver L, Geddes JR. Long term effects of lithium on renal, thyroid, and parathyroid function: retrospective analysis of laboratory data. The Lancet 215; 386:461-468.

Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, Bauer M, Geddes JR. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord. 2014; 2:15.

Stasior DS, Kikeri D, Duel B, Seifter JL. Nephrogenic diabetes insipidus responsive to indomethacine plus dDAVP. New Eng J Med 1991; 324: 850-1. 

Weinstock RS, Moses AM. Desmopressin and indomethacine therapy for nephrogenic diabetes insipidus in patients receiving lithium carbonate. South Med J 1990; 83: 1475-7.


July 11, 2019