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

Janusz Rybakowski’s reply to Hector Warnes’ comment


       Thanks to Hector Warnes for his thoughtful comments on my essay on the 120th anniversary of the Kraepelinian dichotomy. They mostly pertain to a relationship between continuum vs. subdivision concepts of psychiatric disorders and intermediate areas in this dichotomy.

       In the paper published in Current Psychiatry Reports, I dedicated a subchapter to a continuum concept of psychiatric disorders, the epitome of this being Wilhelm Griesinger’s (1817-1868) theory of “unitary psychosis” (Einheitspsychose). As Hector points out, this issue was widely discussed in the paper of Berrios and Beer (1994) and also a recent essay by Tom Ban (2018). Griesinger argued that madness was the consequence of a single disease of the brain. According to his conception the manifold symptoms of madness were not the result of different diseases but different stages of a single disease process (Griesinger 1845). Griesinger took over the idea of the “unitary psychosis”  from his mentor Ernst Albrecht von Zeller (1804-1877). According to Zeller, the continuum or staging of mental disorders begins with melancholia, further progressing to mania, paranoia and dementia (Zeller 1837).

       The most important continuum concept of mood disorders and schizophrenia in the 20th century was that of a British psychiatrist Timothy Crow. According to him, the continuum extends from unipolar, through bipolar affective illness and schizoaffective psychosis, to typical schizophrenia, with increasing degrees of the neuropsychological defect (Crow 1986). In his comments, Hector supports Crow’s distinction between type I and type II schizophrenia (Crow 1980).  As the cognitive impairment is significantly more marked in type II, this type of schizophrenia should be placed on the extreme position on this continuum.

       Hector Warnes, discussing the Kraepelinian division, raises the interesting issue of the intermediate areas both between the piers of this dichotomy and within them, i.e., between schizophrenia and bipolar disorder, and between bipolar disorder and major depressive disorder. In connection with this, the most interesting would be the concept of “bipolar spectrum disorder” including, on the one end, the phenomenon of schizoaffective disorder, first such named by Kasanin (1933), and on the other major depressive disorder with bipolar features.   

       The schizoaffective disorder could be included in a spectrum of bipolar and related disorders on account of its periodic course and the long-term use of the first and second generation mood-stabilizers (Rybakowski 2018) in its treatment.

       On the other hand, a proportion of patients with major depressive disorder with bipolarity features can be also identified for a spectrum of bipolar and related disorders. A diagnostic conversion from depression into bipolar disorder in the course of the illness was shown by Angst, Sellaro, Stassen and Gamma (2005) in 1.5% of depressive patients per year. Similar figures were obtained in a Polish study (Dudek, Siwek, Zielińska et al. 2013) (1.7%) and in the meta-analysis of Baldessarini, Faedda, Offidani et al. (2013) (1.79%). Furthermore, using the tools for measuring bipolarity, such as the Hypomania Checklist-32 and the Mood Disorder Questionnaire, bipolarity features were demonstrated in a proportion of patients with major depression (Rybakowski, Dudek, Pawłowski et al. 2011). Such subjects are characterized, among others, by the worse response to antidepressant drugs (Rybakowski 2012).   Coming back to Kraepelin's concept, it should be also mentioned that in recent years a neo-Kraepelinian approach to mood disorders has emerged where the most cyclic and recurrent forms of unipolar depression can be regarded as a part of a bipolar spectrum (Saggese, Lieberman and Goodwin 2006). This was also reflected in the second edition of the Goodwin-Jamison 2007 book titled Manic-depressive illness. Bipolar disorders and recurrent depression.

       Hector also supports Brian Leonard’s (2007) concept considering inflammation as a common factor of mood disorders to dementia, and especially, the factor connected with progressing from mood disorder to dementia. It is conceivable that in both categories, i.e., bipolar and major depressive patients with severe neurocognitive impairment, a proposition to create a “neurocognitive” or “dementia” spectrum could be made.  

       I should like to end up with the results of my ketamine infusion study in bipolar depression. The study included 53 patients (13 men, 40 women), aged 22-81 years (mean 47±12.6 years) with a bipolar depressive episode. The average age at illness onset was 31 years (±13) and the average length of the depressive episode was 4.9 (±2.0) months. Before the ketamine infusion, patients were hospitalized for, on average, 21 days (±5). All the patients received at least one 1st or 2nd  generation mood-stabilizing drug: lithium carbonate - 35 patients; quetiapine - 36 patients; valproate – 11 patients; carbamazepine - 8 patients; lamotrigine - 17 patients; aripiprazole – 4 patients; and topiramate - 1 patient (Rybakowski 2018). All the patients had previously been treated with antidepressant drugs without sufficient improvement. The last antidepressant used before the infusion of ketamine was, venlafaxine in 20 patients; in 14 - paroxetine; in 9 - bupropion and sertraline; in 6 – mirtazapine; in 3 – clomipramine; and in 2 – reboxetine, fluvoxamine, fluoxetine, mianserin, escitalopram, citalopram, duloxetine or amitriptyline. All antidepressants were discontinued for at least 7 days before infusion. On the day of the study, each patient received a 40-minute infusion of ketamine, 0.5mg/kg body weight. Psychometric evaluation was performed using the 17-item Hamilton Depression Rating Scale – HDRS.

       The intensity of depression in patients before intravenous administration of the drug, measured on the HDRS, was 23.4+4.6 points. After administration of ketamine, a significant decrease in the HDRS score was observed. This fell to 15.6+7.4 points after 24 hours; to 14.2+7.2 points on the 3rd day; to 12.5±7.7 points on the 7th day; and 11.8±8.1 points two weeks following ketamine infusion. The criteria for the response (a reduction of ≥50% on the HDRS compared with baseline) at 24 h were met by 13 patients (24,5%) and at day 7 by 27 patients (51%). The criteria for remission (intensity of depression ≤7 points on HDRS) at 24 h were met by eight patients (15%) and at day 7 by 14 patients (26%).

       In this group of patients, intravenous ketamine was relatively well tolerated. A transient increase in blood pressure occurred in about 1/3 of patients and did not correlate with the response. Also, psychiatric side effects, such as depersonalization and derealization, were experienced by 1/3 of patients only during the infusion, were not severe and did not correlate with the response to ketamine. None of the patients had a hypomanic switch within the 7 days after ketamine infusion.

       Although the study was neither randomized nor controlled we suggest that its results may show that adding single ketamine infusion to mood stabilizers rapidly improves depression scores in inpatients with treatment-resistant bipolar depression (Rybakowski, Permoda-Osip and Bartkowska-Sniatkowska 2017).

       I am, by no means, a proponent of long-term ketamine administration. However, I think that it may constitute an acute option for treatment-resistant depression, thus proving that NMDA antagonistic action may have antidepressant properties.



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April 23, 2020