Understanding the Physiology of Schizophrenia

Brian Kirkpatrick, MD

Department of Psychiatry and Behavioral Science, Texas A&M College of Medicine, College Station

Insight into the physiology of schizophrenia is creating new treatment options and guiding research for this disabling mental disorder. Regardless of receiving pharmacologic treatment, many people with schizophrenia fail to experience substantial recovery.1 This low recovery rate may be because the treatment focus for schizophrenia has traditionally been on positive symptoms, but additional therapy must be explored to improve patients’ functioning and quality of life. Clinicians must also be aware of:


  • negative symptoms (eg, blunted affect, anhedonia, asociality, alogia, avolition, and apathy)
  • cognitive impairment (eg, abnormal memory, attention, and executive function)
  • medical comorbidities (eg, diabetes and inflammation).

For example, cognitive impairment is a core component of schizophrenia and is not secondary to psychotic symptoms. Understanding the physiology of schizophrenia will help clinicians to comprehensively assess and treat patients with schizophrenia.

Dopamine System

Schizophrenia is a complex disorder associated with both genetic and environmental risk factors.2 Because the syndrome has multiple consequences, its treatment should be multilayered. However, antipsychotics all have a similar mechanism of action: the inhibition of dopaminergic function.3 Because the original drugs that serendipitously lessened positive psychotic symptoms also blocked dopamine receptors, research on the physiology of schizophrenia historically has focused on specific neurotransmitter systems in the brain, especially the dopamine system.2 Evidence4,5 shows that patients with schizophrenia have abnormal dopaminergic functioning, which can affect the efficacy of antipsychotic drugs.6

AV 1. Hypofunction of NMDA Receptors in the Dopamine Pathways and the Resulting Schizophrenia Symptoms (00:41)

Based on Stahl8
Abbreviations are defined before the References

Antipsychotics reduce the positive symptoms of schizophrenia largely because they normalize dopamine hyperactivity. However, negative symptoms can be a side effect of this full antagonism.7 For example, overactivity of dopamine neurons in the mesolimbic dopamine pathway may result in positive symptoms, while underactivity in the mesocortical dopamine pathway may elicit negative and cognitive symptoms in schizophrenia (AV 1).8 Meta-analyses9 have suggested some new avenues for the management of negative symptoms, such as treatment with adjunctive α2-adrenergic antagonists. However, as useful as these treatments may be for decreasing positive and perhaps negative symptoms, many patients whose psychotic symptoms are mediated by antipsychotics still struggle with other symptoms that limit their social and occupational success.

Areas of physiologic abnormality that appear to contribute to dopamine abnormality include the glutamate system (especially NMDA), the serotonin system, and the acetylcholine system (especially nicotinic receptors). Some of these systems may also play a role in the impairment of cognitive functioning, which adds to impaired functioning, and may contribute to negative symptoms, which are major contributors to poor functioning and decreased quality of life in patients with schizophrenia.

Glutamate System

Glutamate receptors mediate excitatory synaptic transmission in the central nervous system and control processes in the brain, spinal cord, retina, and peripheral nervous system. The 2 broad classes of glutamate receptors are metabotropic and ionotropic. Metabotropic glutamate drugs received much attention as a promising therapy for schizophrenia, but a recent trial10 of pomaglumetad methionil, an agent that acts at mGlu2/3 receptors, was not superior to placebo in the treatment of positive symptoms. Interest is still high in ionotropic glutamate receptors, which include AMPA, kainate, and NMDA receptors.

Research11,12 into NMDA receptors, which regulate dopamine neurons, shows a link to the physiology of schizophrenia. Hypofunction of NMDA receptors may result in abnormal dopamine activity and produce symptoms of schizophrenia.12


In healthy individuals, low doses of NMDA receptor antagonists (such as ketamine13 and PCP14) can cause the negative symptoms and cognitive impairments associated with schizophrenia and, in patients with untreated schizophrenia, can exacerbate psychotic and cognitive symptoms. Agents that activate the glycine modulatory site on the NMDA receptor (glycine reuptake inhibitors) have reduced patients’ positive and negative symptoms of schizophrenia, as well as improved cognition.12 In addition, specific genes in the glutamate system, such as GRIN2B and SAP97, are implicated in the pathophysiology of schizophrenia and may be susceptibility factors for particular subgroups of patients.11,15

Serotonin System

Serotonin also appears to be involved in the pathophysiology of psychosis. When 5-HT2A receptors are blocked, dopamine is released in certain areas of the brain; the combination of 5-HT2A antagonism with partial D2 antagonism may improve not only positive symptoms but also negative and cognitive symptoms.7 Additionally, research16,17 has suggested that having certain serotonin-related genes, including TPH1 and 5-HTT variants, increases a person’s susceptibility to schizophrenia. Cognitive processes such as executive function and sustained attention may also be related to a 5-HTT polymorphism.18 As more genes are linked to the physiology of schizophrenia, pharmacologic treatments that target specific serotonin receptor subtypes could be developed.

Acetylcholine System

As stated, dopaminergic, glutamatergic, and serotonergic neuronal pathways are involved in the physiology of schizophrenia; these systems are also modulated by the α7-nicotinic acetylcholine receptor.19 In patients with schizophrenia, the α7-nicotinic acetylcholine receptor functions abnormally, causing abnormal hippocampal function, impairing cognition.20 Preliminary evidence20,21 suggests that α7-nicotinic receptor agonists can improve cognitive and negative symptoms in schizophrenia.

Physiologic Abnormalities

Along with the areas of brain dysfunction implicated in the physiology of schizophrenia, physiologic abnormalities outside the brain compound the illness. Patients with schizophrenia are at 2.5 times the risk of dying compared with the general population.22 These increased mortality rates are related not only to suicide but also to other contributors like diabetes and inflammation.

Diabetes. In addition to the risk of diabetes that accompanies some newer antipsychotics, people with schizophrenia may have a pre-existing vulnerability to diabetes. One study23 revealed abnormal glucose tolerance in antipsychotic-naïve patients with nonaffective psychosis, which could not be attributed to cortisol concentration, gender, ethnicity, socioeconomic status, neighborhood of residence, BMI, aerobic conditioning, smoking, or age. Other studies24–26 found similar results, with abnormal glucose tolerance and an increased risk of diabetes in patients with schizophrenia and their families, independent of access to health care, substance abuse, and diet/self-care. Based on these findings, clinicians should screen newly diagnosed patients with nonaffective psychosis for diabetes.

Inflammation. Increased inflammation has been implicated as another physiologic anomaly in the pathology of schizophrenia. As add-on therapy to antipsychotics, a COX-2 inhibitor and aspirin have both yielded positive effects on reducing schizophrenia symptoms.27,28

AV 2. The Possible Effect of Infection and Inflammation on the Physiology of Schizophrenia (00:36)

Reprinted with permission from Watanabe et al30
Abbreviations are defined before the References

Increased inflammation is consistent with the hypothesis that schizophrenia is a multisystem disease.29 A review30 of human studies and animal models examined how specific cytokines, which help control immune/inflammatory reactions and brain development, contribute to the abnormal brain function found in schizophrenia (AV 2).30 Further, inflammation may also be more prevalent in patients with negative symptoms than in those without.31


As research continues on the physiology of schizophrenia, areas of abnormality beyond that of the dopamine system are being explored. The glutamate, serotonin, and acetylcholine systems appear to be involved in causing dopamine abnormalities associated with schizophrenia. Besides abnormalities within the brain, physiologic anomalies (eg, diabetes, inflammation) may be involved in the etiology of the illness. Rather than focusing only on controlling positive psychotic symptoms, clinicians can work to alleviate other symptoms that impair patients’ function, especially negative and cognitive symptoms. The boundaries of schizophrenia research and treatment must continue to expand in order to help patients with schizophrenia achieve longer, more fulfilling lives.

For Clinical Use


  • In addition to positive symptoms, assess patients for negative symptoms, cognitive impairment, and physiologic anomalies such as inflammation
  • Screen for diabetes in patients with psychosis and monitor metabolic problems related to weight gain, glucose and lipids, blood pressure, and smoking


5-HT = 5-hydroxytryptamine (serotonin), 5-HTT = 5-hydroxytryptamine transporter, AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, BMI = body mass index, CNV = copy number variation, COX-2 = cyclo-oxygenase-2, EGF = epidermal growth factor, ErbB = epidermal growth factor receptor, gp130 = glycoprotein 130, GRIN2B = glutamate receptor ionotropic NMDA 2B, IL = interleukin, mGlu2/3 = metabotropic glutamate 2/3, NMDA = N-methyl-d-aspartate, NRG = neuregulin, PCP = phencyclidine, SAP97 = synapse-associated protein 97, SNP = single nucleotide polymorphism, TPH = tryptophan hydroxylase, VTA = ventral tegmental area

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