Magda Malewska-Kasprzak, Agnieszka Permode-Osip and Janusz K. Rybakowski: Disturbance of the purinergic system in affective disorders and schizophrenia 

Hector Warnes’ response to Janusz Rybakowski’s reply


        It has been shown that dopamine interacts with glutamate and adenosine at different levels of the brain. Reduced striatal adenosine A2A receptors levels have been identified in a group of schizophrenics (Boison, Singer, Shen et al. 2008). Citing Professor Rybakowski: "The glutamatergic theory suggests a deficit of glutamatergic mechanisms, especially in in N-methyl-D-aspartate (NMDA) receptors in schizophrenia and an excess in depression." Does he refer to Dementia Praecox with a chronic and deteriorating evolution and multiple negative symptoms?

        Another question is regarding his assertion of an excess of glutamatergic activity in depression. The finding that glutamate has been shown to regulate neurogenesis, synaptogenesis and neuroplasticity in the hippocampus and stimulates neurotrophic factors such as BDNF (Mattson 2008) would not support this view. It would mean to me that, on the contrary, in major depression there is a deficiency, not an excess, of glutamatergic activity. In my opinion one of the many locus of action of the anti-depressant effect of Lithium would be a NMDA receptor blockade and an increase of adenosine-5-triphosphate.

        Finally, it has been shown that fast acting-antidepressants such as ketamine stimulate ERK signalling and BDNF release in neuronal cultures (Lepack, Bang, Lee et al. 2016) and that ketamine was effective in treatment resistant depression as you pointed out. More studies are required to confirm it due to the adverse side effects of the drug and the brevity of its efficacy (Murrough, Iosifescu, Chang et al. 2013).



Boison D, Singer P, Shen HY, Feldon J, Yee BK. Adenosine hypothesis of schizophrenia--opportunities for pharmacotherapy. Neuropharmacology. 2012; 62(3):1527-43.

Lepack AE, Bang E, Lee B, Dwyer JM, Duman RS. Fast acting-antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures. Neuropharmacology. 2016; 111:242-52.

Mattson MP. Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease. Ann N Y Acad Sci. 2008; 1144: 97-112.

Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes AL, Ali Shah A, Charney DS, Mathew SJ. Antidepressant efficacy of ketamine in treatment resistant major depression. Amer. J. Psychiat. 2013; 170:1134-42.


March 12, 2020