Two compelling case reports provide additional evidence for potential mechanistic associations between the immune system and schizophrenia.
SIGNIFICANCE FOR PRACTICING PSYCHIATRISTS
TABLE. Considerations for adjunctive monoclonal antibody immunotherapy in schizophrenia
The investigation of immune system abnormalities in schizophrenia, though ongoing for decades, has received significant renewed interest, stimulated in part by our increased understanding of brain-immune interactions that occur in other chronic medical disorders. Two compelling case reports provide additional evidence for potential mechanistic associations between the immune system and schizophrenia.
Immune dysfunction in schizophrenia
Sommer and colleagues1 described the case of an elderly male with leukemia but no psychiatric history who presented with new-onset psychosis after undergoing an allogenic peripheral blood stem cell transplant from a brother with chronic schizophrenia.
Conversely, Miyaoka and colleagues2 reported on a young male who experienced prolonged remission of treatment-resistant psychosis, in the absence of antipsychotic medication, after a bone marrow transplant for leukemia. Of course, it is challenging to establish a causal link between the immune system and schizophrenia, but the bidirectional nature of these case reports provides new lines of evidence supporting the plausibility of such an association.
Indeed, schizophrenia is associated with immune system abnormalities throughout the lifespan (see Goldsmith and Miller3 for a comprehensive review). Briefly, genes involved in the regulation of the immune system are associated with increased risk of schizophrenia. Prenatal maternal infection with a variety of different infectious agents is a replicated risk factor for the development of schizophrenia in the offspring. Moreover, there is evidence for bidirectional associations between schizophrenia and severe infections and autoimmune disorders.4
Patients with schizophrenia have immune abnormalities in the blood, cerebrospinal fluid, and CNS, including immune cell numbers, inflammatory markers, and antibody titers.3,5 There is also evidence for immune abnormalities in the blood and an increased prevalence of autoimmune disorders in the relatives of patients with schizophrenia.6 Acutely ill patients with schizophrenia appear to have an increased prevalence of certain comorbid infections (eg, lower urinary tract infections). Schizophrenia is also associated with increased mortality from infectious diseases, including pneumonia and influenza.
Although there are a number of well-replicated findings in this area, the effect sizes are small to moderate for many associations, and there are also negative studies. There are many potential explanations for these discrepancies, including small sample sizes, stage of illness, medication status, comorbid conditions, and potential confounding or moderating factors such as obesity and smoking. Another important potential explanation for these heterogeneous findings is that immune system dysfunction occurs in only a subset of patients with schizophrenia. This may reflect an inherent limitation of our phenomenologically based nosology.
Adjunctive anti-inflammatory agents in schizophrenia
Importantly, findings indicate that treatment with NSAIDs as adjuncts to antipsychotics may be associated with significant improvement in psychopathology in schizophrenia.7-9 Additionally, baseline blood levels of cytokines-key signaling molecules that regulate inflammation-may predict treatment response to these agents.
Nitta and colleagues8 analyzed 8 studies (N = 774 patients) of adjunctive NSAIDs (6 trials of celecoxib and 2 trials of aspirin), including 3 unpublished reports. They found that NSAIDs were associated with a small, trend-level reduction in total psychopathology, and a small, significant reduction in positive psychopathology. The effects of adjunctive NSAIDs were greater in inpatients and patients with first-episode psychosis.
In an analysis of 26 double-blind trials of various agents with anti-inflammatory properties, Sommer and colleagues10 found significant effects for aspirin, estrogens, and the antioxidant N-acetylcysteine in patients with schizophrenia.
Results from an analysis of 8 randomized controlled trials (N = 548 patients) show that adjunctive minocycline, a second-generation tetracycline antibiotic with good CNS penetration, was associated with significant improvements in total, positive, and negative psychopathology.11 Taken together, these findings provide important empirical support for the hypothesis that immune dysfunction, namely increased inflammation, may be involved in the pathophysiology of schizophrenia.
The small-to-moderate effect sizes for the efficacy of adjunctive NSAIDs most likely reflects that immune dysfunction occurs in only a subset of patients with schizophrenia. Two important limitations of these studies are that: NSAIDs have relevant off-target (ie, non-immune) effects and evidence of immune dysfunction (eg, the presence of increased inflammation in the peripheral blood, as measured by C-reactive protein [CRP]) was not an inclusion criterion, which may have decreased the signal-to-noise ratio in these trials.
In contrast with NSAIDs, monoclonal antibodies, also termed biologic agents or “biologics,” target specific inflammatory cytokines or cytokine receptors. These agents are used in the treatment of certain chronic diseases, including hepatitis C, malignant melanoma, and autoimmune disorders such as rheumatoid arthritis and multiple sclerosis. Intriguingly, monoclonal antibody immunotherapy for these chronic medical disorders has been associated with a range of neuropsychiatric adverse effects, most commonly depression and psychosis.12 That immunotherapy may be associated with psychosis (albeit rarely) indirectly supports the plausibility that immunotherapy with other, different cytokines may be a potential treatment for psychosis.
There are several major potential advantages of monoclonal antibody immunotherapy over NSAIDs or other anti-inflammatory agents as adjunctive treatments for schizophrenia (Table). Monoclonal antibodies do not have any off-target effects, they act only on specific cytokines. Therefore, improvements in psychopathology in response to monoclonal antibody immunotherapy would further (and directly) implicate these inflammatory pathways in the pathophysiology of schizophrenia.
Compared with NSAIDs, monoclonal antibodies have more potent anti-inflammatory properties. Indeed, NSAIDs have minimal efficacy in conditions with significant inflammation, such as autoimmune disorders. The small-to-moderate effect sizes for improvements in psychopathology with adjunctive NSAIDs may also suggest that more potent anti-inflammatory agents are needed for more robust effects. Presently, most monoclonal antibodies are administered by intravenous (IV) infusion (although some agents can be given subcutaneously or orally), typically once a month. From a research perspective, this is advantageous in terms of obviating issues of medication adherence that may confound findings.
Early studies of adjunctive monoclonal antibody immunotherapy in schizophrenia
In parallel with the evolution of mono- clonal antibody immunotherapy in other chronic disorders, there are nascent studies of these agents in schizophrenia. GrÃ¼ber and colleagues13 reported that two patients with treatment-resistant schizophrenia had significant improvement in psychopathology during open-label adjunctive treatment with recombinant human interferon gamma-1b (IFN-Î³-1Î²).
In an 8-week open-label trial of adjunctive tocilizumab (an anti-interleukin [IL]-6 receptor [IL-6R] mAb) in 6 stable outpatients with schizophrenia, our group found significant improvements in cognition.14
A randomized controlled trial in 36 patients found that adjunctive tocilizumab did not improve psychopathology or cognition in stable patients with schizophrenia.15 Several aspects of this very important negative trial warrant further consideration.
1. Although the authors found that baseline CRP did not predict treatment outcome, evidence of inflammation was not an inclusion criterion. Therefore, the number of subjects with evidence of inflammation who received tocilizumab was small, and the study may have been underpowered to detect such an association.
2. Subjects in this trial were clinically stable at study entry. Previous meta-analyses suggest that response to adjunctive NSAIDs may be more robust in acutely ill patients.
3. Baseline assessments were completed within 2 weeks of the first infusion of study drug. It is possible, therefore, that some clinical improvement in this trial was not captured due to this modest delay in assessment.
Considerations in schizophrenia immunotherapy
These early studies highlight some of the challenges and complexities of trials of monoclonal antibody immunotherapy in schizophrenia.
Monoclonal antibodies that target the cytokines IL-1, IL-6, IL-12/23, IL-17, and TNF-Î±, the cell adhesion molecule Î±4-integrin, and B-cell activation are approved for use in autoimmune and inflammatory disorders.16
A number of trials of adjunctive treatment with these agents in schizophrenia are planned or ongoing. These trials will largely focus on patients with evidence of baseline inflammation (eg, elevated blood CRP), as this approach may increase both the likelihood of response as well as the study’s signal-to-noise ratio. Studies will investigate canakinumab (anti-IL-1Î² mAb; https://www.neura.edu.au/project/cana kinumab-add-treatment-schizophrenia-cats-study-2), natalizumab (mAb against the cell adhesion molecule Î±4-integrin)12, siltuximab (anti-IL-6 mAb; NCT02796859), and tocilizumab (NCT02874573).
Several other important considerations in the design and implementation of monoclonal antibody immunotherapy clinical trials include the timing and duration of therapy during the course of schizophrenia. In a meta-analysis, we found increases in some inflammatory markers during periods of acute psychosis, but not during periods of clinical stability.3 Therefore, future trials should consider acutely ill (eg, hospitalized) and clinically stable patients separately.
Illness phase and duration of treatment are also important considerations. For example, is it pragmatic to expect improved psychopathology in patients with chronic illness, or should immunotherapy be considered in earlier phases of illness? The majority of previous trials of adjunctive NSAIDs were of shorter (<12 weeks) duration and in acutely ill patients. Thus, it is not clear whether anti-inflammatory treatments help patients reach a new, lower baseline level of symptoms, or if they accelerate the speed of response to psychotropic medications during periods of acute illness.
The risk of serious adverse effects due to profound immunosuppression, including demyelinating disorders, ulcers, and malignancy with long-term monoclonal antibody immunotherapy, must also be considered (Table). Although adverse effects of NSAIDs are generally more benign, there is also increased risk of gastrointestinal bleeding and cardiovascular mortality with prolonged use of these agents.
The high cost of adjunctive monoclonal antibody immunotherapy (potentially >$1000 per dose) is another important factor that may limit use. Furthermore, the IV route of administration poses a myriad of logistical issues for patients and clinicians in terms of time, facilities, and equipment to perform infusions, as well as monitoring for patient safety (eg, risk of anaphylaxis during and after the infusion).
The available data do not support the widespread clinical utility of measuring inflammatory markers such as blood CRP levels in patients with schizophrenia and prescribing adjunctive NSAIDs or monoclonal antibody immunotherapy for those with evidence of abnormality. Nevertheless, there is a compelling rationale for well-designed, carefully conducted trials of monoclonal immunotherapy in schizophrenia, which will permit direct testing of the hypothesis that immune dysfunction, including inflammation, plays a causal role in psychopathology. It will be interesting to observe whether such highly selective strategies will pay off and whether the therapeutics of schizophrenia will broaden to encompass immune-based approaches. These studies, regardless of outcome, will provide valuable insights into the effects of the immune system on brain and behavior, and represent an important potential step towards more personalized medicine for patients with schizophrenia.
Dr Miller is Associate Professor of Psychiatry, Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia.
Dr Miller reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.
1. Sommer I, van Bekkum D, Klein H, et al. Severe chronic psychosis after allogeneic SCT from a schizophrenic sibling. Bone Marrow Transplant. 2015;50:153-154.
2. Miyaoka T, Wake R, Hashioka S, et al. Remission of psychosis in treatment-resistant schizophrenia following bone marrow transplantation: a case report. Front Psychiatry. 2017;8:174.
3. Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Molec Psychiatry. 2016;21:1696-1709.
4. Benros ME, Pedersen MG, Rasmussen H, et al. A nationwide study on the risk of autoimmune diseases in individuals with a personal or a family history of schizophrenia and related psychosis. Am J Psychiatry. 2014;171:218-226.
5. Kirkpatrick B, Miller BJ. Inflammation and schizophrenia. Schizophr Bull. 2013;39:1174-1179.
6. Eaton W, Byrne M, Ewald H, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry. 2006;163:521-528.
7. Nitta M, Kishimoto T, MÃ¼ller N, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013;39:1230-1241.
8. Muller N Ulmschneider M, Scheppach C, et al. COX-2 inhibition as a treatment approach in schizophrenia: Immunological considerations and clinical effects of celecoxib add-on therapy. Eur Arch Psychiatry Clin Neurosci. 2004;254:14-22.
9. Laan W, Grobbee DE, Selten JP, et al. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010;71:520-527.
10. Sommer I, van Westrhenen R, Begemann M, et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014;40:181-191.
11. Xiang YQ, Zheng W, Wang SB, et al. Adjunctive minocycline for schizophrenia: a meta-analysis of randomized controlled trials. Eur Neuropsychopharmacol. 2017;27:8-18.
12. Miller BJ, Buckley PF. The case for adjunctive monoclonal antibody immunotherapy in schizophrenia. Psych Clin N Am. 2016;39:187-198.
13. GrÃ¼ber L, Bunse T, Weidinger E, et al. Adjunctive recombinant human interferon gamma-1b for treatment-resistant schizophrenia in 2 patients. J Clin Psychiatry. 2014;75:266-267.
14. Miller BJ, Dias JK, Lemos HP, et al. An open-label, pilot trial of adjunctive tocilizumab in schizophrenia. J Clin Psychiatry. 2016;77:275-276.
15. Girgis RR, Ciarleglio A, Choo T et al. A randomized, double-blind, placebo-controlled clinical trial of tocilizumab, an interleukin-6 receptor antibody, for residual symptoms in schizophrenia. Neuropsychopharmacol. 2018;43:1317-1323.
16. Miller AH, Haroon E, Felger JC. Therapeutic implications of brain-immune interactions: treatment in translation. Neuropsychopharmacol. 2017;42:334-359. â