The Historical Development of Immunoendocrine Concepts of Psychiatric Disorders and Their Therapy

Abstract

Relationships between the central nervous, immune and endocrine systems are a focus of psychiatric research, particularly in depression and schizophrenia. The field has long antecedents. Observed phenomena attributable to these relationships date back to the Neolithic era. Immunoendocrine theories in the broadest sense are recorded in antiquity. In the 19th century, Kraepelin and Wagner-Jauregg reported pioneering clinical observations in psychiatric patients. Von Basedow, Addison and Cushing described psychiatric symptoms in patients suffering from endocrine diseases. The 20th century opened with the identification of hormones, the first, adrenaline, chemically isolated independently by Aldrich und Takamine in 1901. Berson and Yalow developed the radioimmunoassay (RIA) technique in 1959 making it possible to measure levels of hormones and cytokines. These developments have enabled great strides in psychoimmunoendocrinology. Contemporary research is investigating diagnostic and therapeutic applications of these concepts, for example by identifying biomarkers within the endocrine and immune systems and by synthesizing and testing drugs that modulate these systems and show antidepressant or antipsychotic properties.

Keywords: cytokines; depression; history of psychiatry; hormones; immune system; schizophrenia.

Figure 1

German neuropsychiatrist Paul Julius Möbius (1853–1907) made several contributions to endocrine processes underlying both human behavior and certain illnesses. (Reproduced with permission from: Archives for the History of Psychiatry in Leipzig).

Figure 2

The Austrian neuropsychiatrist Julius Wagner-Jauregg (1857–1940) is the most outstanding researcher in psychiatric immunology. His observation that a vaccination with malaria produced a relief in symptoms or even cure in progressive paralysis was a first landmark in psychiatric therapy by influencing the immune system (Reproduced with kind permission from: Österreichische Nationalbibliothek/Austrian National Library, ID 66321–B).

Figure 3

The principle of flow cytometry to differentiate the individual cellular components of the blood: The Forward Scatter (FSC) measures the acute-angular diffraction of the light and depends on the cell’s volume. The Sideward Scatter (SSC) measures the rectangular diffraction of the light and depends on the granularity of the cell, the size and structure of its core, and the amount of vesicles contained in it. With the help of FSC and SSC, the individual cells contained in the blood can be differentiated. For further sub-differentiation, e.g., by the sub-type of cell or its functional status, marker molecules on the surface of the cells, the so-called cluster of differentiation (CD), are used. In this figure, a granulocyte passes the laser light (left part of the figure). After sorting by cell size and granularity according to the light detected by the FSC and the SSC as displayed in the right part of the figure, the granulocyte could then be further analyzed for the frequency of CD4 on its surface by the signal of fluorescent (FL) antibodies against CD4.

Figure 4

Immune hypothesis of schizophrenia: The type 2 cytokines interleukins (IL)-4, IL-5 and IL-10 activate astrocytes and inhibit microglia. Astrocytes, in turn, produce the glutamate antagonist kynurenic acid which leads to a reduction of glutamate signaling accompanied by disturbances of the dopamine system. For details see text. Abbreviations: kynurenine aminotransferase (KAT), kynurenine (3)-monooxygenase (KMO), indoleamine (2,3)-dioxygenase (IDO), N-methyl-d-aspartate (NMDA).

Figure 5

Mechanisms through which TNF-α could contribute to the emergence of a depression: activation of the hypothalamus-pituitary-adrenal (HPA) axis, induction of apoptosis, stimulation of the serotonin reuptake and induction of the IDO. For details see text. Abbreviations: tryptophan hydroxylase (TPH), aromatic l-amino acid decarboxylase (AAAD), indoleamine (2,3-)dioxygenase (IDO), tumor necrosis factor-α (TNF-α).