Psychoimmunological alterations in schizophrenia: how do confounding variables influence the findings?

Abstract

Several groups have contributed to the progress of immunological research in schizophrenia. Early studies demonstrated partly divergent results. The recently improved control concerning confounding variables has lead to increasingly consistent findings. The influence of psychotropic medication, serum cortisol levels, different immunological techniques, sex differences and psychopathology on psychoimmunological findings in schizophrenia is discussed.

Novel findings due to technical advances have strengthened the hypothesis that immunological dysfunction may contribute towards the multifactoral etiology of schizophrenia (Kirch, 1993; Syvälahti, 1994; Wright et al, 1993). Since the early work of Bruce and Peebles (1904) who reported increased leukocyte counts, especially during the acute phase of illness, numerous studies have focused on the role of cellular immunity in schizophrenia. One particular line of research has focused on investigating the numbers of immunocompetent cells. Nyland et al. (1980) showed a decreased number of T-lymphocytes in acute but not in chronic schizophrenics. An elevated number of T-cells was reported by two groups (Henneberg et al., 1990; Ackenheil et al., 1991; Müller et al., 1991, 1993) while others (including ours) demonstrated no changes in T-cell numbers (Villemain et al., 1989; Masserini et al, 1990; Achiron et al, 1994; Sasaki et al, 1994; Hornberg et al, 1995; Wilke et al, 1996). Inconsistent results have also been reported concerning several T-lymphocyte subtypes, B-lymphocytes and natural killer cells (NK-cells).

Another approach has focused on cytokine production. Cytokines are produced by leukocytes; they regulate the differentiation and acti- vation of immunologically active cells and control the communication between the immunocompetent cells. The production of cytokines after mitogen stimulation can be regarded as a functional marker of cellular immunity.

Research on cytokines in schizophrenia has yielded increasingly consistent results. In response to mitogen stimulation, Kolyaskina (1983) showed a reduced proliferative activity of T-lymphocytes while serum levels of interleukin-2 (IL-2) were found to be unchanged (Barak et al., 1995; Gattaz et al., 1992). Furthermore, several groups (including our own) have reported that the production of IL-2 by lymphocytes after mitogen stimulation is significantly lower in schizophrenics than it is in non-psychotic controls (Villemain et al, 1989; Hornberg et al., 1995; Bessler et al, 1995; Ganguli and Rabin, 1989; Ganguli et al, 1992,1995; Rothermundt et al, 1996). The decreased IL-2 production after mitogen Stimulation of acutely ill schizophrenics compared to patients in remission suggests that IL-2 is a state rather than a trait marker for the acute illness (Ganguli and Rabin, 1993; McAllister et al, 1995; Arolt et al, 1997). In a functional sense, interferon gamma (IFN-γ) and IL-2 are closely related since the production of IFN-γ is stimulated by IL-2. Despite this relationship the results concerning IFN-γ in schizophrenia have so far been less impressive than those regarding IL-2. Serum levels of IFN-γ are not on the whole elevated (Gattaz et al., 1992; Becker et al, 1990; Schindler et al., 1986) although higher levels were reported by Preble and Torrey (1985). A tendency towards decreased production after stimulation has been reported on several occasions (Hornberg et al., 1995; Katila et al., 1989; Moises et al, 1985). In a group of psychotic patients which included schizophrenics and depressed patients, Inglot et al. (1994) showed a decreased production of IFN-3. p]For a correct interpretation of the at least partially inconsistent immunological findings in schizophrenia it remains an important task to distinguish the influence of the following interfering variables that might influence the results and complicate interpretations:

• 1. Cortisol levels

• 2. Medication

• 3. Immunological technique

• 4. Sex differences

• 5. Psychopathology