Neuroimmunopathology of Schizophrenia

Neuroimmunopathology of Schizophrenia
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Image courtesy of Psychiatric News

Schizophrenia is a complex psychiatric disorder characterized by disorganized thought and behaviour, distortions of reality, and other cognitive and emotional deficits. Although symptoms of the disorder vary by patient, they typically include hallucinations, delusions, mood disturbances, and impaired motivation.[1] Schizophrenia affects about 1 in 100 people and often leads to considerable social and occupational dysfunction. Treatment is most commonly in the form of drug-therapy, however a lack of understanding of the disorder has resulted in inconsistent efficacy of these drugs.[1] While it is clear that schizophrenia results from interplay between genetic and environmental factors, much of the biological basis of the illness is still unknown. In recent years, however, increasing evidence has suggested a role of the immune system in the pathogenesis of the disorder. Studies have shown that maternal infections during pregnancy increase the chance of schizophrenia in the offspring in both humans and mice.[2] Moreover, serum cytokine levels have been shown to be elevated in patients with schizophrenia, likely implicating inflammation as a contributing factor.[2] Overall, the immunological perspective of schizophrenia provides a novel angle from which researchers can approach this mysterious disorder and develop more effective treatment options.

1.1 Symptoms

Patients with schizophrenia may present with a wide array of symptoms depending on their personal circumstances and the stage of their illness.[3] Onset of symptoms typically occurs in late adolescence (15-19 years of age), often beginning as a prodromal phase – the first stage of the disorder characterized by the gradual emergence of symptoms.[4] These early symptoms include social withdrawal, anhedonia, and sudden fits of anger.[3] The transition from the prodromal phase to the active phase of schizophrenia is marked by the appearance of more severe symptoms such as psychosis. These symptoms can be classified as positive, negative, or cognitive.

Living with Schizophrenia
An incredible view into the mind of someone living with schizophrenia
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1.1a Positive and negative

Positive symptoms are those that result from an excess of normal brain function, and notably include hallucinations and delusions.[3] Hallucinations are false sensory experiences created solely by the mind and perceived as real.[5] The most common type of hallucination experienced by patients with schizophrenia is the auditory hallucination, which involves voices that speak to the patient or narrate their actions.[3] Delusions are false beliefs held by patients even after they have been shown strong evidence of the falsehood of these beliefs.[5] Other positive symptoms include disorganized speech and repetitive movements.

Negative symptoms are those that result from deficits in normal function, and include anhedonia, alogia (inability to speak), social withdrawal, and depleted motivation.[3] These symptoms are not only harder to treat, but they can also often lead to misdiagnosis of schizophrenia as depression.[3]

1.1b Cognitive

Cognitive symptoms in schizophrenia include disorganized thinking, impaired executive functioning, impaired working memory, and an inability to focus.[3] These symptoms present an enormous challenge in the everyday lives of patients, as they often make daily mundane activities such as getting dressed or preparing a meal very difficult.[3]

1.2 Diagnosis

To be clinically diagnosed with schizophrenia, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) requires that at least two Criterion A symptoms (for a summary, see Table 1) be present in the individual for a 1-month period, and at least one of these symptoms must be either delusions, hallucinations, or disorganized speech.[6] Prodromal symptoms must have persisted for six months, and social as well as occupational functioning must be significantly impaired. Importantly, the DSM-5 eliminated the use of subtypes in schizophrenia and instead emphasized capturing symptom severity as a way of dealing with the heterogeneity of the disorder.[6]

Table 1. DSM-5 Criteria for Schizophrenia
Criterion A. Two or more of the following symptoms, each present for 1 month. At least one of these should include 1-3.
  1. Delusions
  2. Hallucinations
  3. Disorganized speech
  4. Grossly disorganized or catatonic behaviour
  5. Negative symptoms (i.e., diminished emotional expression or avolition)
Criterion B. Social/occupational dysfunction.
Criterion C. Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms.
Criterion D. Exclude schizoaffective and major mood disorder.
Criterion E. Exclude substance/general mood condition.
Criterion F. If there is a history of autism spectrum disorder or other communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations are also present for at least 1 month.
Table adapted from Tandon et al.[6]

1.3 Causes

Schizophrenia is known as a complex psychiatric disorder, meaning that it results from the intermingling of both genetic and environmental factors.[7] Researchers are still attempting to untangle the intricate web that underlies the disorder, and as such, the etiology of the schizophrenia remains unclear. However, the last several decades of research have produced two major hypotheses concerning the neurobiology of the disorder: the dopamine hypothesis and the glutamate hypothesis, both depicted in Figure 1.

  1. The dopamine hypothesis postulates that a hyperactive mesolimbic dopaminergic pathway is responsible for the positive symptoms of schizophrenia, while hypoactivity in the same pathway results in the negative symptoms.[8]
  2. The glutamate hypothesis proposes that a cortical glutamate pathway that is responsible for inhibiting the mesolimbic dopamine neurons is underactive, and can lead to both the positive and negative symptoms seen in the disorder.[8]

Figure 1. Dopamine & Glutamate Hypotheses of Schizophrenia
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Left: Hyperactivation of the mesolimbic dopamine pathway leads to positive symptoms
Right: Dopaminergic signalling is inhibited by GABAergic signalling, which in turn is activated by glutamatergic signalling. Thus, hypoactivation of glutamatergic signalling leads to positive symptoms.
NOTE: Mechanisms behind negative symptoms not shown. See source (where image has been obtained from) for details[8]

In addition to these two possible mechanistic explanations for schizophrenia, a general model explaining the development of the disorder – the two-hit hypothesis – has gained traction in the past decade.[9]

1.3a The Two-Hit Hypothesis

The two-hit hypothesis proposes that schizophrenia is the result of two ‘hits’ (see Figure 2 below):

  1. The first hit occurs during perinatal period, when multiple genetic factors as well as environmental insults can perturb the early development of the central nervous system (CNS), leading to abnormal signalling pathways. This early disruption will not result in any clinical manifestations, but instead will make the individual more vulnerable to a future second hit.[10]
  2. The second hit would likely occur during adolescence (the typical age of onset for schizophrenia), and would be in the form of some environmental stimulus such as social stress, isolation, or drug abuse. It is this second hit that is the immediate cause of the disorder, but because the first hit has rendered the individual more vulnerable to the second, the combination of both hits is required for the onset of schizophrenia.[9]

Figure 2. The Two-Hit Hypothesis of Schizophrenia
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The first hit (composed of genetic and environmental factors) "loads the gun": it makes the individual more susceptible to the second hit by altering brain development.
The second hit (environmental factor) "pulls the trigger": it leads to actual onset of the disorder.
Image obtained and modified from:

1.4 Immunopathology

In recent years, researchers have gained a newfound appreciation for the intimate link between the immune system and the development of the CNS. Indeed, immunological disturbances have been linked to several CNS disorders, including autism spectrum disorders, fetal alcohol spectrum disorder, amyotrophic lateral sclerosis, and schizophrenia. Epidemiological and clinical studies have demonstrated that maternal infections during pregnancy increase the chance of schizophrenia in the offspring.[11] Specifically, infections of influenza, Toxoplasma gondii, and herpes simplex virus type 2 have been implicated.[11] Moreover, animal models of gestational infection have produced offspring that have phenotypes and abnormalities similar to those seen in schizophrenia.[11] Altogether this suggests that the immune system may contribute to the first ‘hit’ in the two-hit hypothesis (see above). Although the causal mechanisms behind these findings are unclear, evidence strongly suggests that cytokines may be key players.[11]

1.4a Role of cytokines

Cytokines are soluble peptides that act as cell signal molecules to mediate the immune response.[2] Clinical studies have shown that elevated maternal levels of the cytokines interleukin-8 (IL-8)[12] and tumour necrosis factor alpha (TNF-a)[13] are associated with increased risk of schizophrenia in offspring. These cytokines, along with IL-6 are known to have pro-inflammatory functions in the body.[2] Further work using animal models of maternal infection suggest that increased inflammation during early neurodevelopment may result in permanently increased inflammation once the offspring become adults.[14] Indeed, several studies have reported increased blood concentrations of cytokines in individuals with schizophrenia (see Figure 3).[15]

Figure 3. Hedges' g plot indicating blood cytokine levels in schizophrenia
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Overall, blood levels for most cytokines are higher (bars going to right; positive effect sizes) in patients who have experienced their first episode of psychosis (blue) or are in acute relapse of psychosis (red),
compared to control. For the the post-treatment data (green), bars indicate whether cytokine levels increased (positive effect size) or decreased (negative effect size) following antipsychotic treatment.
FEP: First episode psychosis. Image obtained from Miller et al.[15]

The significance of elevated cytokine levels remains largely unclear, however several studies have linked interleukin levels to both dopaminergic and glutamatergic transmission, supporting the two classic hypotheses (see above] ).[10] Furthermore, Ellman and colleagues showed that in humans, fetal exposure to IL-8 resulted in brain morphology changes that included increased ventricular cerebrospinal fluid (CSF).[16] Interestingly, ventricular enlargement is a hallmark anomaly in schizophrenia, so it is possible that IL-8 is a contributing factor here.[16] Other structural alterations found in this study were decreased volume of both the left entorhinal cortex, which is involved in memory, and the right superior temporal gyrus, which is involved in speech.[16] Both of these functions are impaired in schizophrenia.

1.4b Maternal Immune Activation models

Maternal immune activation (MIA) models are animal models of gestational infection that have provided tremendous insight into the influence of the immune system on the brain. MIA models entail administration of immune-activating substances such as polyinosinic:polycytidylic acid (poly I:C), lipopolysaccharide, or IL-6 into pregnant mice, followed by examination of the offspring of these mice.[2] In 2007, Smith and colleagues reported that poly I:C injection into pregnant mice, which induced elevated IL-6 levels, resulted in offspring that had impairments in both social interaction and prepulse inhibition, very similar to what is observed in schizophrenia.[17] Interestingly, these abnormalities were not seen when the mothers were simultaneously given poly I:C and anti-IL-6 antibodies, indicating a crucial role for IL-6. In fact, Freda Miller and colleagues have suggested a possible mechanism by which IL-6 might interfere with brain development. Her group showed that maternal administration of IL-6 resulted in an enlarged pool of neural stem cells, which in turn led to abnormally increased neurogenesis in adult offspring.[18] It may be possible that the increase in neuron production causes an imbalance in neurotransmission (e.g. dopaminergic or glutamatergic) that may lead to schizophrenia-like abnormalities, presenting an intriguing avenue of research to explore.

1.5 Treatment

Treatment of schizophrenia is primarily in the form of drug-therapy, although a holistic approach involving family therapy and cognitive therapy is often most effective.[3] Family therapy in particular has been associated with increased adherence to medications, reduced rates of relapse, and lessening of symptoms in patients.[3] However, pharmacological treatment remains the most effective course of action when treating schizophrenia.[3]

1.5a Current medications

First-generation antipsychotic medications, or neuroleptics, were introduced in the 1950s but were overtaken by atypical (or second-generation antipsychotics) some 40 years later.[3] Atypical antipsychotics are favoured over the first-generation alternatives because they are less likely to produce the severe neurological side effects that include dystonia, bradykinesia, and tardive dyskinesia.[3] Still, however, the efficacy of drug-therapy varies by patient; the heterogeneity of schizophrenia confers heterogeneity in treatment response.[3]

Figure 4. Change in PANSS Score with Adjunctive Aspirin or Adjunctive Placebo Treatment
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After 2 months of treatment, the antipsychotic/aspirin adjunctive regime was superior in reducing PANSS scores
than the antipsychotic/placebo regime. PANSS = Positive and Negative Syndrome Scale. Image obtained from Laan et al.[19]

1.5b Immune-based therapy

In order to increase the effectiveness of drug-therapy for schizophrenia, several groups have asked whether combination treatment of antipsychotics and anti-inflammatory drugs is more beneficial for patients than antipsychotics alone. One such group is that of Laan and colleagues, who in 2010 conducted a randomized, double-blind, placebo-controlled study to determine whether adjunctive aspirin therapy was beneficial for patients taking antipsychotics. The group used the well-established positive and negative syndrome scale (PANSS) to measure symptom severity in both the treatment and control group (antipsychotic + placebo). As illustrated in Figure 4, it was found that an antipsychotic with aspirin was superior to an antipsychotic with placebo, as the PANSS score of those in the aspirin group was significantly lower after three months.[19] While promising, sufficient replication of these findings is needed before anything definite can be concluded. Nevertheless, this study bolsters the case for the immunological perspective on brain disturbances.

1. Kirkpatrick, B., & Miller, B. J. (2013). Inflammation and schizophrenia. Schizophrenia bulletin, 39(6), 1174–9. doi:10.1093/schbul/sbt141
2. Girgis, R. R., Kumar, S. S., & Brown, A. S. (2014). The cytokine model of schizophrenia: emerging therapeutic strategies. Biological psychiatry, 75(4), 292–9. doi:10.1016/j.biopsych.2013.12.002
3. Schultz, S. H., North, S. W., & Shields, C. G. (2007). Schizophrenia: a review. American family physician, 75(12), 1821–9. Retrieved from
4. Paus, T., Keshavan, M., & Giedd, J. N. (2008). Why do many psychiatric disorders emerge during adolescence? Nature reviews. Neuroscience, 9(12), 947–57. doi:10.1038/nrn2513
5. Freeman, D., & Garety, P. a. (2003). Connecting neurosis and psychosis: the direct influence of emotion on delusions and hallucinations. Behaviour Research and Therapy, 41(8), 923–947. doi:10.1016/S0005-7967(02)00104-3
6. Tandon, R., Gaebel, W., Barch, D. M., Bustillo, J., Gur, R. E., Heckers, S., … Carpenter, W. (2013). Definition and description of schizophrenia in the DSM-5. Schizophrenia research, 150(1), 3–10. doi:10.1016/j.schres.2013.05.028
7. Sullivan, P. F., Kendler, K. S., & Neale, M. C. (2014). Schizophrenia as a Complex Trait. JAMA Psychiatry, 60(1), 1187-1192.
8. Stahl, S. M. (2007). Beyond the dopamine hypothesis to the NMDA glutamate receptor hypofunction hypothesis of schizophrenia. CNS spectrums, 12(4), 265.
9. Maynard, T. M., Sikich, L., Lieberman, J. a, & LaMantia, a S. (2001). Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia. Schizophrenia bulletin, 27(3), 457–76. Retrieved from
10. Feigenson, K. a, Kusnecov, A. W., & Silverstein, S. M. (2014). Inflammation and the two-hit hypothesis of schizophrenia. Neuroscience and biobehavioral reviews, 38, 72–93. doi:10.1016/j.neubiorev.2013.11.006
11. Brown, A. S., & Derkits, E. J. (2010). Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. The American journal of psychiatry, 167(3), 261–80. doi:10.1176/appi.ajp.2009.09030361
12. Brown, A. S., Hooton, J., Schaefer, C. A., Zhang, H., Petkova, E., Babulas, V., … & Susser, E. S. (2004). Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. American Journal of Psychiatry, 161(5), 889-895.
13. Buka, S. L., Tsuang, M. T., Torrey, E. F., Klebanoff, M. A., Wagner, R. L., & Yolken, R. H. (2001). Maternal cytokine levels during pregnancy and adult psychosis. Brain, behavior, and immunity, 15(4), 411-420.
14. Kirkpatrick, B., & Miller, B. J. (2013). Inflammation and schizophrenia. Schizophrenia bulletin, 39(6), 1174-1179.
15. Miller, B. J., Buckley, P., Seabolt, W., Mellor, A., & Kirkpatrick, B. (2011). Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biological psychiatry, 70(7), 663-671.
16. Ellman, L. M., Deicken, R. F., Vinogradov, S., Kremen, W. S., Poole, J. H., Kern, D. M., … & Brown, A. S. (2010). Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8. Schizophrenia research, 121(1), 46-54.
17. Smith, S. E., Li, J., Garbett, K., Mirnics, K., & Patterson, P. H. (2007). Maternal immune activation alters fetal brain development through interleukin-6. The Journal of Neuroscience, 27(40), 10695-10702.
18. Gallagher, D., Norman, A. a, Woodard, C. L., Yang, G., Gauthier-Fisher, A., Fujitani, M., … Miller, F. D. (2013). Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating an endogenous self-renewal pathway. Cell stem cell, 13(5), 564–76. doi:10.1016/j.stem.2013.10.002
19. Laan, W., Grobbee, D. E., Selten, J.-P., Heijnen, C. J., Kahn, R. S., & Burger, H. (2010). Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. The Journal of clinical psychiatry, 71(5), 520–7. doi:10.4088/JCP.09m05117yel

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