Janusz Rybakowski: The Kraepelinian dichotomy in historical perspective 


Hector Warnes’ response to Janusz Rybakowski’s reply


        I am grateful for Janusz Rybakowski’s reply to my comments. I admire his open-mindedness and provisional statements over so many uncertainties that are vexing our field. Before addressing the newest compound with anti-depressant properties only to be used for refractory depressions I would like to raise two issues.

        In my experience I have the impression that endogenous depression is more responsive to anti-depressants than neurotic stormy depressions (not the reactive ones) particularly those with pre-morbid personality disorders and a history of childhood broken home or abuse.

        I would further add that the more severe psychomotor retardation and hopelessness and a sense of emptiness and hollowness the less is the suicidal risk which increases when the patient starts improving or when the depression is agitated (olanzapine or quetiapine may be used) or has co-morbidities plus serious precipitating events. The so-called atypical depressions (clinophylia, hyperphagia and hypersomnolence) are less likely to present a suicidal risk. It would seem that the antidepressants are potentially acting on the etiology of the illness unlike the anti-psychotics which control the symptoms but (most of them) do not act on the negative symptoms and follow a deteriorating and chronic course.

        The diagnostic group of schizophreniform psychosis with a precipitating event, disturbances of consciousness and normal premorbid personality, are likely to respond very well to anti-psychotic agents but should they relapse in two or three years showing affective symptoms the diagnosis becomes a problematic one because of the cyclic endogenous or schizoaffective nature.

        We are coming to a consensus on the definition of pseudo-resistance to anti-depressants in a severe unipolar depression:

· Insufficient doses of the drug, not given for at least three months and or in combination with other anti-depressants with different modes of action in at least two or more clinical essays;

· Non-compliance;

· Pharmacogenetic profiles; and

· Many times, the close relative of a patient who responded well to an anti-depressant in the past is likely to respond positively to the same anti-depressant in the present. 

        Co-morbidity (patients who are likely to take adrenergic beta blockers, corticosteroids, who are addicted, have a metabolic syndrome, inflammatory auto-immune disease, diabetes mellitus, etc.) may inhibit the plasma levels of the drug or induce drug interactions with collateral side effects and so on.

        A multi-center European study (Souery, Amsterdam, de Montigny et al. 1999) showed treatment resistance is associated with:

· Comorbidity with anxiety, phobias and or panic disorder;

· Higher risk of suicidal intentionality;

· Severity of the episode;

· Higher number of previous admissions to psychiatric centers in terms of number of recurrences;

· Early onset and psychotraumatic events;

· Characteristic symptoms of severe endogenous or melancholic traits;

· Background of lack of response to antidepressants; and or

· Pre-morbid personality disorder.

        It is likely that refractory severe depression is more responsive to Electro-Convulsive Therapy in a higher percentage of cases than to an antidepressant with a consistent protocol outlined in the best centers.

        Professor Rybakowski wrote on the promising results of a new anti-depressant, ketamine, for the treatment of refractory depression. It appears that the modulation of glutamate, an excitatory neurotransmitter, is involved. Ketamine is an antagonist of the glutamatergic NMDA and an agonist of the AMPA receptors. In 2000, Berman, Cappiello, Anand, et al. tried ketamine on nine major unipolar depressives using intravenous doses of 0.5 mg/kg; all patients except two improved significantly in less than an hour but the effect ceased after 72 hours.

        In 2018  Daly, Sing, Fedgchin et al. studied 126 adults diagnosed as bipolar disorder and a history of non-responsiveness to two or more antidepressants. Sixty-seven were screened in a randomized  fashion and 60 were able to complete both double-blind periods.  Intranasal Esketamine showed a rapid onset of a  favorable response, which was dose related,  lasting for about two months. The authors suggested further trials because of the promising outcome.



Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 2000; 47(4):351-4. 

Daly EJ, Sing JB, Fedgchin M, Cooper K, Lim P, Shelton RC, Thase ME, Winokur A, Nueten LV, Manji H, Drevets WC. Efficacy and safety of intranasal esketamine adjuntive to oral antidepressant therapy in treatment-resistant depressions: A randomized clinical trial.  JAMA Psychiatry 2018; 75(2):139-48. 

Souery D, Amsterdam J, de Montigny C, Lecrubier, Montgomery YS, Lipp O, Racagni G, Zohar J, Mendlewicz J. Treatment resistant depression: methodological overview and operational criteria. Eur. Neuropsychopharmacol 1999; 9(1-2):83-91. 


October 29, 2020