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


Janusz Rybakowski’s reply to Nassir Ghaemi’s comments


       Thanks to Nassir Ghaemi for his comments on my essay on the 120th anniversary of Kraepelin’s dichotomy, supporting my arguments on genetics and pathophysiology. As to the treatment response, I should like to elaborate, responding to his reservations. 

       The main psychopharmacological evidence against Kraepelinian dichotomy emerged after introducing in psychiatry the so-called atypical or new-generation antipsychotic drugs. These drugs, apart from being effective in schizophrenia, possess mood-stabilizing properties, evidenced by preventing affective recurrences (mostly manic) in bipolar disorder. They all act therapeutically in mania and some of them, such as quetiapine, lurasidone, and cariprazine, also exert, as monotherapy, significant therapeutic activity in bipolar depression (Rybakowski 2018).

       Recently, we proposed a definition of mood-stabilizer (MS) as a drug that, as monotherapy: (1) reduces or ameliorates manic and/or depressive symptoms; (2) acts prophylactically to prevent recurrent manic and/or depressive episodes which should be evidenced in the trial lasting at least one year; and, (3) does not induce or worsen manic or depressive episodes (Amsterdam and Rybakowski 2017).

       The first description of the long-term mood-stabilizing properties of lithium carbonate occurred in the early 1960s (Hartigan 1963). Beginning in the 1970s, other publications appeared describing the mood-stabilizing effects of anticonvulsant drugs such as valproate (Lambert, Borselli, Marcou et al. 1971) and carbamazepine (Okuma, Kishimoto and Inue 1973). Because lithium and the anticonvulsants preceded newer MS agents by several decades, I proposed to name them the first-generation MSs (Rybakowski 2007).

       The first observation that atypical antipsychotic drugs, such as clozapine, may exert MS effects was advanced in the mid-1990s (Zarate, Tohen, Banov et al.1995). Subsequently, other atypical antipsychotics such as olanzapine and quetiapine have been found to have MS properties. A suggestion that the anticonvulsant lamotrigine may also meet the criteria for MS was put forward in the early 2000s (Ketter and Calabrese 2002). Therefore these agents were proposed to be collectively named as the second-generation MSs (Rybakowski 2007). In subsequent years, meeting the criteria given above, other atypical antipsychotics such as aripiprazole (Keck, Calabrese, McIntyre et al. 2007), and risperidone (Quiroz, Yatham, Palumbo et al. 2010) have joined the family of the second-generation MSs.

       The concept of predominant polarity (i.e., manic or depressive) as the predominant prophylactic effect of an MS has been also proposed. For example, clozapine, which exerts a predominant antimanic and antipsychotic action, can be placed at the extreme antimanic end of the polarity continuum. Similarly, atypical antipsychotics such as olanzapine, aripiprazole, and risperidone may also be placed near the antimanic end of the polarity continuum. First-generation MSs also demonstrate greater antimanic than antidepressant activity. Among them, lithium appears to produce the greatest antidepressant action. Quetiapine exerts a balance of antimanic and antidepressant effectiveness and might best be considered to occupy the mid-position along the polarity continuum. Finally, lamotrigine may best be placed on the antidepressant pole of the polarity continuum (Popovic, Reinares, Goikolea et al. 2012).

       All antipsychotics collectively termed atypical or new-generation ones, are dopamine blockers. This property, similarly, as in the case of the first-generation antipsychotics, is connected with their therapeutic and also prophylactic efficacy in mania in bipolar disorder. However, a pharmacological spectrum of atypical antipsychotics is broader, most of them act on multiple receptors, including e.g., serotonergic 5-HT2 receptors. Furthermore, their effect on the dopaminergic system may go beyond dopaminergic blockade, e.g., aripiprazole is a partial dopaminergic receptor agonist. Atypical antipsychotics are not inducing depression (such as the first-generation antipsychotic drug, haloperidol, does) and some of them, exert a significant therapeutic and prophylactic effect on bipolar depression. The antidepressant property of quetiapine has been also attributed to blocking norepinephrine transporter (NET) by its main metabolite, norquetiapine (Cross, Widzowski, Maciag et al. 2016).

       The preventive effect of clozapine, olanzapine, quetiapine, aripiprazole and risperidone on affective recurrences has been demonstrated in many studies, although not always meet the criteria for a design of the randomized discontinuation trials, as Nassir postulates (Ghaemi and Selker 2017).

       As to lithium prophylaxis, the term “excellent lithium responders” (ER) was coined by the Canadian psychiatrist, Paul Grof (1999), for patients who on monotherapy with lithium experienced a dramatic change in their life as their mood episodes were prevented. We found that “excellent lithium responders can constitute about one-third of bipolar subjects treatedlongitudinally with lithium (Rybakowski, Chłopocka-Woźniak and Suwalska 2001). Grof(2010) suggests that lithium responders 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, reminding the aspects of the illness, defined by Emil Kraepelin(1899) as “manisch-depressives Irresein.”

       It is conceivable, that some bipolar patients could be excellent responders to  monotherapy with other mood stabilizers. The clinical characteristics of such patients would be different and a proportion of such responders could not be more than 30% of bipolar patients. Passmore, Garnham, Duffy et al. (2003) suggest that lamotrigine responders in contrast to lithium may have a chronic or rapid-cycling course of the illness, comorbid panic disorder or substance abuse, and more family history of schizoaffective disorder, major depression and panic attacks. Good response to clozapine can be connected with great severity of manic episodes when such prophylaxis starts. Also, the prophylactic (mostly antimanic) effect of olanzapine is stronger in patients in which olanzapine was effective during an acute manic episode.

       As a proportion of responders when a mood stabilizer is used in monotherapy is not high, a majority of bipolar patients is treated with combination therapy, usually with first- and second-generation mood stabilizers. Many studies have shown that a combination of lithium or valproates with quetiapine, olanzapine and aripiprazole is much better prophylactically that either of this drug alone. In the paper of Altamura, Mundo, Dell'Osso et al. (2005), it was shown that the efficacy of such combination doubles that of monotherapy. 

       Having said this, let me emphasize that the therapeutic and prophylactic activity of so-called atypical antipsychotic drugs both in schizophrenia and bipolar disorder, cannot blight a therapeutic specificity of the first-generation antipsychotics in schizophrenia and other psychotic disorders, and therapeutic specificity of diverse antidepressants in various kinds of depression (and also anxiety disorders). On the other hand, the first-generation mood-stabilizing drugs (lithium, carbamazepine, valproates) have been therapeutically effective in bipolar disorder, but not schizophrenia or other psychotic disorders. As to lithium, I have the most experience with, we found that its prophylactic efficacy has been negatively correlated with a feature of cognitive disorganization, connected with a predisposition to psychosis (Dembinska-Krajewska, Kliwicki, Chlopocka-Wozniak and Rybakowski 2012). Also, in a recent GWAS research, the polygenic score for schizophrenia was inversely correlated with lithium treatment response (International Consortium on Lithium Genetics 2018).           

       Therefore, despite widely using atypical antipsychotics in both schizophrenia and bipolar disorder, there is still a significant segment of psychopharmacology speaking in favor of the Kraepelinian dichotomy.




Altamura AC, Mundo E, Dell'Osso B, Tacchini G, Buoli M, Calabrese JR. Quetiapine and classical mood stabilizers in the long-term treatment of Bipolar Disorder: a 4-year follow-up naturalistic study. J Affect Disord 2008; 110:135-41.

Amsterdam JD, Rybakowski JK. Pharmacotherapy of bipolar disorder. In: The Oxford Handbook of  Mood Disorders (R J DeRubeis & D R Strunk, eds). Oxford University Press, New York, 2017; 385-97.

Cross AJ, Widzowski D, Maciag C, Zacco A, Hudzik T, Liu J, Nyberg S, Wood MW. Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models. Br J Pharmacol 2016; 173:155-66.

Dembinska-Krajewka D, Kliwicki S, Chlopocka-Wozniak M, Rybakowski J. The effectiveness of prophylactic use of lithium in bipolar disorder and schizotypal traits (in Polish). Pharmacother Psychiatry Neurol. 2012;  28:153-8.

Ghaemi SN, Selker HP. Maintenance efficacy designs in psychiatry: Randomized discontinuation trials - enriched but not better. J Clin Transl Sci. 2017; 1:198-204.

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

Grof P. Sixty years of lithium responders. Neuropsychobiology 2010; 62:27-35.

Hartigan G. The use of lithium salts in affective disorders. Br J Psychiatry, 1963; 109:810-14.

International Consortium on Lithium Genetics (ConLi+Gen), Amare AT, Schubert KO, Hou L, Clark SR, Papiol S et al. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: a genome-wide association study. JAMA Psychiatry 2018; 75:65-74.

Keck PE, Calabrese JR, McIntyre RS, McQuade R D, Carson WH, Eudicone JM, Carlson BX, Marcus RN, Sanchez R; Aripiprazole Study Group. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: A 100-week, double-blind study versus placebo. J Clin Psychiatry, 2007; 88:1480-91.

Ketter T, Calabrese JR. Stabilization of mood from below versus above baseline in bipolar disorder: A new nomenclature. J Clin Psychiatry, 2002; 63:146-51.

Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte. 6 Auflage. Barth, Leipzig, 1899.

Lambert PA, Borselli S, Marcou G, Bouchardy M, Cabrol G. Action thymoregulatrice a long terme de Depamide dans la psychose maniaco-depressive. Ann Med Psychol. 1971; 2:442-7.

Okuma T, Kishimoto A, Inue K. Anti-manic and prophylactic effect of carbamazepine (Tegretol) on manic depressive psychosis. Folia Psychiatr Neurol Japn 1973; 27:283-97.

Passmore MJ, Garnham J, Duffy A, MacDougall M, Munro A, Slaney C, Teehan A, Alda M. Phenotypic spectra of bipolar disorder in responders to lithium versus lamotrigine. Bipolar Disord. 2003; 5:110-14.

Popovic D, Reinares M, Goikolea JM, Bonnin CM, Gonzalez-Pinto A, Vieta E. Polarity index of pharmacological agents used for maintenance treatment of bipolar disorder. Eur Neuropsychopharmacol 2012; 22:339-46.

Quiroz JA, Yatham LN, Palumbo JM, Karcher K, Kushner S, Kusumakar V. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar disorder. Biol Pychiatry 2010; 68:156-62.

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. Two generations of mood stabilizers. Int J Neuropsychopharmacol 2007; 10:709-11.

Rybakowski JK. Meaningful aspects of the term 'mood stabilizer.' Bipolar Disord 2018; 20:391-2.

Zarate CA, Tohen M, Banov MD, Weiss M K, Cole JO. Is clozapine a mood stabilizer? J Clin Psychiatry, 1995; 56:108-12.


April 30, 2020