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

Nassir Ghaemi’s comments


        The commentary by my colleague Dr. Rybakowski applies classic diagnostic validators to Kraepelin’s basic dichotomy of dementia praecox (schizophrenia) versus manic-depressive illness (MDI: bipolar illness plus unipolar depression): genetics, pathophysiology and treatment response.

        Let’s take these one by one:

1. Genetics:  As noted, much of the current GWAS studies find a good deal of overlap between schizophrenia and bipolar illness, as defined by DSM-IV and 5.  But they do not find them to be identical. Thus, they do not invalidate the Kraepelinian dichotomy, although at least in those with psychosis (which is a minority of bipolar illness), there is overlap.  It should be noted that the same GWAS studies find notable overlap between bipolar illness and DSM-defined “major depressive disorder” (which is a conglomeration of many different depressive states). Thus, genetic research today can be seen as refuting the DSM-III/IV/5 anti-Kraepelinian refusal to combine bipolar illness and “MDD” together as one disease (manic-depressive illness).

2. Pathophysiology: A common error is to view similar pathophysiology as arguing for one diagnosis or disease. This is the false assumption of the Wernicke tradition, as well also of the current National Institute of Mental Health Research Domain criteria (NIMH-RDoC).  The falsity of this idea has to do with the fact that the body functions as a final common pathway for many disease etiologies. Thus, streptococcal pneumonia and pneumococcal pneumonia both have a similar pathophysiology – lung inflammation – yet are different diseases. So too schizophrenia and MDI  have common pathways in the limbic system and with monoamine or glutamate neurotransmitters, but that does not mean they are the same diseases or diagnoses.  The same principles apply to cognitive sequelae.

3. Treatment response: This is by far the weakest validator of a diagnosis, because drugs are nonspecific. Yet many clinicians focus a lot on this factor, as does Dr. Rybakowski.  Drugs are nonspecific: aspirin works for 27 different diseases, as does propranolol.  So we really should not emphasize this validator. But speaking to the examples given, lithium works in MDI, meaning both unipolar depression and bipolar illness; dopamine blockers (so-called “antipsychotics”) work for mixed states and thus for both depressive and manic symptoms – and thus both examples support Kraepelin’s concept of MDI, as opposed to the DSM anti-Kraepelinian and pro-Leonhardian bipolar/MDD dichotomy.

        On the issue of the supposed efficacy of dopamine blockers in maintenance efficacy of bipolar illness, our colleague, like most clinicians and researchers, takes the word of the FDA and the pharmaceutical industry uncritically.  It is an unfortunate fact that most of the profession still does not realize that the claim to maintenance efficacy with randomized discontinuation trials (RDTs) is invalid scientifically.  In RDTs, patients are preselected to respond already to a drug and then they are assessed again for response. If you like chocolate cake, but not vanilla cake, you are randomized to chocolate cake again or vanilla, and, not surprisingly, chocolate cake always wins.  There never has been a RDT which disproves efficacy: whatever drug is “enriched” always works. If you preselect for acute placebo response, placebo is better than any drug in maintenance treatment of anything.  I’ve written about this matter elsewhere (Ghaemi and Selker 2017; Goodwin, Whitham and Ghaemi 2011; Ghaemi 2019). In short, I think the claims about dopamine blocker efficacy in bipolar illness based on RDTs cannot be believed; those agents are not proven effective, in my view, because the RDT design upon which such claims are based is invalid.

In summary, I think the newest research, properly analyzed, supports Kraepelin’s basic nosology, by and large, and it contradicts the DSM-III to 5 Wernicke/Leonhardian nosology.



Ghaemi SN. Clinical Psychopharmacology. Oxford University Press. 2019.

Ghaemi SN, Selker HP. Maintenance efficacy designs in psychiatry: Randomized discontinuation trials - enriched but not better. J Clin Transl Sci. 2017;1(3):198-204.

Goodwin FK, Whitham EA, Ghaemi SN. Maintenance treatment study designs in bipolar disorder: do they demonstrate that atypical neuroleptics (antipsychotics) are mood stabilizers? CNS Drugs. 2011;25(10):819-27.


February 6, 2020