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onsdag, 01-12-2021

Janusz Rybakowski: 120 years of the Kraepelinian dichotomy of "endogenous psychoses" in historical perspective

Janusz Rybakowski’s reply to Samuel Gershon’s comment


        Many thanks to Sam Gershon for his positive attitude towards my essay on the 120th anniversary of the Kraepelinian dichotomy. In relation to this, it was also legitimate for him to ask, “Is there a specific drug for a specific disorder included in this dichotomy?  It could be defined as a drug which, if given, can totally correct underlying brain abnormality, making complete vanishing of symptoms, and resulting in entirely normal functioning in the long-term.”  In my opinion, such a drug exists - lithium - for a subgroup of patients with bipolar disorder specified as the “excellent lithium responders.”

        The term “excellent lithium responders” (ELR) was introduced by Paul Grof (1999), a Canadian psychiatrist of Czech origin, for patients who, while on monotherapy with lithium, experienced a dramatic change in their life as their mood episodes were totally prevented. In Poznan, we followed-up for 10 years 60 patients who started lithium prophylaxis in the 1970s, and 49 patients beginning this procedure in the 1980s. Those without mood episodes during this period (ELR) made up 35% of the first group and 27% of the second one, roughly one-third of bipolar subjects treated longitudinally with lithium (Rybakowski, Chłopocka-Woźniak and Suwalska 2001). Summarizing the issue after 10 years, Grof (2010) suggests that in ELR the illness can be characterized by distinct mood episodes, with full remissions between them, the absence of other psychiatric morbidity and frequent history of bipolar illness in their families, making an epitome of the illness, defined by Emil Kraepelin (1899) as “manisch-depressives Irresein.” In such a way, the issue closely relates to the Kraepelinian dichotomy.

        In ELR, due to the complete prevention of affective relapses, the progress of the illness is halted and their cognitive performance is not different from the matched healthy people (Rybakowski and Suwalska 2010). A decrease in serum brain-derived neurotrophic factor (BDNF) has been postulated as a marker of the later stage of bipolar disorder (Kauer-Sant’Anna, Kapczinski, Andreazza et al. 2009). However, in our study we found that ELR with a mean of 21 years of lithium treatment had normal serum BDNF levels (Rybakowski and Suwalska 2010).

        Recently, we described five patients (two men and three women, aged 64-79 years) with a good response to the ultra-long-term lithium treatment (40-45 years). Four of them (except for one female) met the criteria of ELR. Lithium prophylaxis usually begins within the first three years of the illness. Before starting lithium, the patient’s clinical characteristics of the illness were similar to those postulated by Grof (2010), i.e., distinct mood episodes with mania-depression-remission sequence, full non-symptomatic remissions and the absence of other psychiatric morbidity. Serum lithium in the group was in the range of 0.60-0.65 mmol/l, except for one male (0.7-0.8 mmol/l). Both males had impaired renal function with no progression in the last five years. One female (not meeting criteria for ELR), suffered from Hashimoto's disease and was treated with levothyroxine. In all patients, cognition and professional activity were at the level of healthy subjects of comparable age and education. Functioning in family and social roles was good. Therefore, in patients with favorable response to lithium, especially ELR, such a longitudinal administration of the drug can produce a satisfying performance in vocational and psychosocial areas and the management of potential adverse effects can be adequate (Permoda-Osip, Abramowicz, Kraszewska  et al., 2016).

        I have observed in my practice such an excellent response in some schizophrenia subjects treated with clozapine. However, I cannot figure out what were the common features of such patients before placing them on clozapine.


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Grof P. Excellent lithium responders: people whose lives have been changed by lithium prophylaxis.  In:  Birch  NJ,  Gallicchio  VS,  Becker  RW, editors.  Lithium:  50  Years  of  Psychopharmacology,   New   Perspectives   in   Biomedical   and   Clinical   Research.   Cheshire, Connecticut, Weidner Publishing Group, 1999:36-51.  

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Kauer-Sant’Anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Young LT, Yatham LN. Brain derived neurotrophic factor and inflammatory markers in patients with early vs. late stage bipolar disorder. Int J Neuropsychopharmacol 2009; 12: 447-58.

Permoda-Osip A, Abramowicz M, Kraszewska A, Suwalska A, Chłopocka-Woźniak M, Rybakowski JK. Kidney, thyroid and other organ functions after 40 years or more of lithium therapy: a case series of five patients. Ther Adv Psychopharmacol 2016; 6:277-82.

Rybakowski JK, Chłopocka-Woźniak M, Suwalska A. The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar Disord 2001; 3:63-7.

Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol 2010; 13:617-22.


April 23, 2020