Age has been shown to induce increasing activity of the TNFα and IL-6 system (Haack et al 1999
). In contrast, IL-6 levels have been reported to be elevated in younger schizophrenic patients, but not in patients older than 35 years (Maes et al 1994
). In our study, we did not find a correlation between age and cytokine levels in elderly schizophrenic patients or healthy controls, and age did not differ between groups. Thus, the correlation between age and IL-6 levels in elderly subjects is questionable. However, only elderly patients were included in the sample. In order to find a correlation, a sufficient degree of age variance is necessary, which may not be present in our selected sample.
In our study, schizophrenic patients had lower MMSE scores than healthy controls. Thus, differences in cytokine levels may be affected by coexisting dementia. However, MMSE scores correlated negatively with serum levels of antipsychotics and may be influenced by medication effects such as sedation. Post-mortem studies of plaques, tangles, and cytokine levels may elucidate the correlation between dementia and cytokines.
Despite the absence of significant correlations between psychopathology and cytokine levels, state of the illness may have an influence on cytokine levels, since all our patients had a chronic course of the disorder. IL-6 levels have been reported to be higher during the acute state of the disease and to decline after remission (Naudin et al 1996
; Frommberger et al 1997
). Additionally, elevated IL-1β levels have been reported in acute but not in chronic schizophrenic patients (Katila et al 1994
). Our study sample consisted of chronic patients with persisting positive and negative symptoms as well as neurocognitive deficits. Thus, our results in chronic patients confirm higher serum IL-6 levels in treatment-resistant schizophrenic patients than in healthy controls and patients without treatment resistance (Lin et al 1998
). However, in our elderly study group with persisting symptoms and long-term duration of the disease we did not investigate treatment resistance. Nor did we confirm correlations between IL-6 levels and negative symptoms or correlation with duration of illness measured in younger schizophrenic patients (Ganguli et al 1994
; Kim et al 2001
Sex-related differences found previously in psychiatric patients, such as higher TNFα levels in women than in men (Baker et al 1996
) and higher IL-6 levels in males (Ganguli et al 1994
), could not be confirmed by our study. In addition, we did not find higher IL-6 levels in males than in females. In accordance with other studies in medicated chronic schizophrenia (Naudin et al 1996
), we did not confirm elevated TNFα levels in mostly unmedicated schizophrenic patients compared with healthy controls (Monteleone et al 1997
; Theodoropoulou et al 2001
Although differences have not been detected between patients on and off neuroleptic medication (Katila et al 1994
; Theodoropoulou et al 2001
), treatment effects may have affected TNFα in our patients, leading to control levels. Clozapine has been reported to decrease TNFα to normal levels without effects on IL-6 after a 10-week treatment period (Monteleone et al 1997
). In contrast, short-term clozapine treatment has been shown to increase TNFα levels (Pollmacher et al 1996
; Hinze-Selch et al 2000
). Additionally, typical neuroleptics such as haloperidol and perazine decreased the release of TNFα and IL-1β from monocytes to control levels (Kowalski et al 2001
). Inhibitory effects of chlorpromazine on TNFα production have also been observed (Bertini et al 1993
). Thus, normal TNFα levels of schizophrenic patients in our study may be the consequence of long-term treatment with clozapine and typical neuroleptics. However, there was no correlation of serum clozapine, clozapine metabolite, and haloperidol levels with IL-1β or TNFα. Furthermore, we did not detect differences in IL-6 and IL-1β levels between treatment groups, suggesting no specific long-term treatment effects on these levels. However, in our naturalistic study design, patients were not treated with haloperidol as monotherapy, and other typical neuroleptics such as perazine, chlorprothixene, thioridazine, and promethazine could have influenced cytokine levels. Thus, additional studies using monotherapy are warranted.
Clozapine has been shown to increase plasma IL-6 levels only in vitro and after 2 weeks of treatment, but not during longer treatment periods (Maes et al 1994
; Hinze-Selch et al 1998
). Thus, clozapine may have short-lasting immunomodulatory effects that are associated with clozapine-induced fever and agranulocytosis (Pollmacher et al 2000
). Our results suggest that effects of long-term clozapine treatment differ from short-term effects. In contrast, our results confirm previous studies reporting no effects of haloperidol treatment on IL-6 levels (Kim 1986
; Pollmacher et al 1997
). In addition, we did not detect effects of smoking on proinflammatory cytokines and did not confirm a study of smoking effects on IL-6 levels (Haack et al 1999
To date, there is only one post-mortem study reporting decreased gene and protein expression of the IL-1β inhibiting IL-1 receptor antagonist, but no diagnosis effects on IL-1β expression in the prefrontal cortex of schizophrenic patients (Toyooka et al 2003
). Since microglia produces cytokines upon activation (Kreutzberg 2000
) and microglial dysfunction may be involved in the pathophysiology of schizophrenia (Munn 2000
; Radewicz et al 2000
), gene and protein expression studies in post-mortem brains are warranted to elucidate regulation of cytokines in the CNS.
Expression and signaling of cytokines may be influenced by environmental factors such as stress, infection, and brain activity (Nawa et al 2000
). A number of environmental factors have been implicated in schizophrenia, including hypoxia (Cannon et al 2002
; Van Erp et al 2002
), maternal viral infection (Buka et al 2001
), nutritional deficiency (Susser et al 1996
), and season of birth (Pulver et al 1981
). All of these could influence cytokine levels. Proinflammatory cytokines are increased during CNS ischemia (Saito et al 1996
; Orzylowska et al 1999
). Season of birth, however, has no apparent effects on cytokine levels in schizophrenia (Altamura et al 2003
). By contrast, in keeping with the neurodevelopmental hypothesis, animal studies revealed schizophrenia-related behavioral abnormalities such as latent inhibition in adult animals after immune activation during pregnancy (Zuckerman et al 2003
). In embryonic cell culture, IL-1β and IL-6 induced decreases in the number of neurons immunoreactive for microtubule-associated protein 2, suggesting decreased neuronal survival (Marx et al 2001
). Moreover, cytokines are known to influence behavior such as food and water intake, social interaction, learning and cognitive function, sexual behavior, sleep, and anhedonia (Larson and Dunn 2001
). Comedication of schizophrenic patients with the cyclo-oxygenase-2 inhibitor celecoxib showed greater improvement in psychopathological scores than antipsychotic treatment alone, suggesting that immune dysfunction in schizophrenia is somehow linked to the pathomechanisms of the disorder (Muller et al 2002
). Thus, increased IL-1β and IL-6 levels may be associated with schizophrenia-related behavior. Further neurodevelopmental animal studies could clarify the relationship between adult cytokine levels and schizophrenia-associated behavior.
In summary, elevated IL-1β and IL-6 levels may be related to chronic schizophrenia even in old age. Confounding factors such as age, sex, smoking, and antipsychotic medication have not been shown to affect these serum cytokine levels. However, we have investigated only a small sample size related to the quantity of confounding variables, and correlations may become significant in a larger sample. In addition, some factors such as additional treatment with benzodiazepines or anticholinergic medication have not been investigated. Further studies should investigate cytokine expression in post-mortem brains. To clarify the effect of neurodevelopmental disturbances on immune function and schizophrenia-related behavior, investigations of animal models are warranted.