Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations

Norbert Müller


Schizophr Bull. 2018;44(5):973-982. 

In This Article

Anti-inflammatory Treatment in Schizophrenia

The finding that anti-inflammatory medication is beneficial in schizophrenia provides perhaps the most convincing evidence that inflammation is involved in schizophrenia. A detailed overview on the efficacy of anti-inflammatory treatment in schizophrenia has been published elsewhere.[104] This summary focuses on cyclooxygenase (COX) inhibitors. The most broadly studied COX inhibitor is the COX-2 inhibitor celecoxib. A 6-week prospective, randomized, double-blind study in patients with an acute exacerbation of schizophrenia compared celecoxib as an add-on to risperidone with risperidone and a placebo add-on.[105] Outcome was significantly better in the celecoxib add-on group (n = 25) than in the group receiving only the antipsychotic (n = 25),[105] whereby the effects on cognition were especially pronounced.[106] Data from this study were pooled with data from another 6-week study of risperidone and celecoxib add-on, and the resulting group of n = 90 cases was analyzed. The analysis found that patients who had been ill for 2 years or less benefited from the celecoxib add-on, whereas patients with longer disease duration did not differ from the placebo add-on group (see Figure 2).

Figure 2.

Comparison of disease duration on the effects of celecoxib add-on therapy to risperidone. Patients with disease duration <2 years and celecoxib treatment had a better outcome than patients with a disease duration >2 years and placebo and both groups of patients with a disease duration of more than 2 years (results not statistically significant). Adapted from Ref.127

This finding indicates that treatment of schizophrenia patients with a COX-2 inhibitor is most beneficial in the initial period of the disease process. Support for this hypothesis is provided by a study that found no benefit of celecoxib in chronic schizophrenia.[107] To further test this hypothesis, my group studied celecoxib as an add-on to amisulpride in first-manifestation schizophrenia.[108] We found positive effects of celecoxib add-on treatment on the Positive and Negative Syndrome Scale (PANSS) positive, negative, and total scores and on the general psychopathology score.[108,109] A caveat with regard to the COX-2 inhibitors is the increased risk of adverse cardiovascular events.

Acetylsalicylic acid (ASA), another anti-inflammatory agent, has also shown positive effects in schizophrenia spectrum disorders.[110] A meta-analysis of five double-blind studies of nonsteroidal anti-inflammatory drugs in schizophrenia (four studies of celecoxib and one of ASA) found significant effects of the drugs on overall symptoms and both positive and negative symptoms.[111] However, a meta-analysis of eight studies (six of celecoxib and two of ASA) in schizophrenia found significant effects in first-episode but not chronic patients and in inpatients but not outpatients.[112]

The studies described above indicate that the efficacy of anti-inflammatory treatment is associated with the disease stage, ie, such treatment shows less efficacy in chronic schizophrenia (which may be related to the degree of neuroprogression). The negative impact of chronification on the outcome of schizophrenia in general is well known from studies of first- and second-generation antipsychotics. Nevertheless, so far anti-inflammatory treatment has been evaluated in schizophrenia only in short-term studies lasting a few weeks at the most. Of relevance in this context is that short-term anti-inflammatory treatment also shows only weak effects in chronic inflammatory diseases. Longer term anti-inflammatory treatment may have more positive effects in chronic schizophrenia.[113]

Possible predictors for a better treatment response to anti-inflammatory treatment require further study. All the studies on the link between inflammation and clinical outcomes in psychosis found that higher inflammation is associated with poorer response to antipsychotics.[114–117] Whether high levels of inflammation predict a better outcome to anti-inflammatory treatment—as could be shown in major depression for anti-TNF treatment and for celecoxib[118,119]—has to be proven. To date, no immune-related prediction markers have been identified for anti-inflammatory treatment.

Of importance in this context, however, is that several nonsteroidal anti-inflammatory drugs, such as COX-2 inhibitors, probably also have nonimmune-mediated effects,[120] although their effects are most likely due to their common denominator, ie, their effects on inflammation. More convincing evidence for a pathophysiological role of inflammation in schizophrenia would be provided by monoclonal antibodies against targets in the immune system because these antibodies do not have any other direct or indirect effects on neurotransmitters.