15.4: Biological Basis of Schizophrenia Spectrum Disorder

Learning Objectives

• Describe the principal features of schizophrenia spectrum disorders.
• Identify the difference between positive and negative symptoms in schizophrenia.
• Identify the biology thought to underlie the etiology of schizophrenia.
• Describe the dopamine and glutamate hypotheses of schizophrenia.
• Explain the key elements of the neurodevelopmental theory of schizophrenia
• Evaluate the influence of the prefrontal cortex in the etiology and symptoms of schizophrenia

Overview

Schizophrenia spectrum and other psychotic disorders are a category of psychological disorders encompassing an incredibly diverse range of characteristics, including distortions in perception, impairments in cognition, and abnormal motor activity. In addition, the symptoms vary greatly among individuals, as there are rarely two cases similar in presentation, course, or responsiveness to treatment (APA, 2013).

This category also includes schizophreniform disorder (a briefer version of schizophrenia), schizoaffective disorder (a mixture of psychosis and depression/mania symptoms), delusional disorder (the experience of only delusions), and brief psychotic disorder (psychotic symptoms that last only a few days or weeks). However, as many of the symptoms of these disorders overlap with schizophrenia, this disorder is the primary focus of this section.

Schizophrenia Symptomology

Originally termed dementia praecox (Latin for premature dementia), schizophrenia involves a diverse and complex set of symptoms, such as delusions, hallucinations, disorganized speech and behavior, abnormal motor behavior (including catatonia), anhedonia/amotivation and blunted affect/reduced speech (APA, 2013). Given this diversity of symptoms, and the fact that the presentation of symptoms can vary widely from case to case, it has been difficult for researchers and clinicians to precisely define schizophrenia as a disorder (Tandor, 2013). Growing evidence suggests that schizophrenia represents a broad and heterogenous syndrome, rather than a specific disorder, and is better classified along a psychosis spectrum (APA, 2013, Cuthbert & Morris, 2021).

When considering the symptoms of schizophrenia, it is common practice to divide the symptoms into positive symptoms (symptoms that demonstrate an excess of function) and negative symptoms (symptoms that represent a loss or reduction in function) (see Figure \(\PageIndex{1}\)).

Figure \(\PageIndex{1}\): Schizophrenia symptoms are often classified as positive (an excess of typical function) or negative (a loss/reduction in typical function). (CC BY-SA 4.0; Amy E. Coren, Ph.D.)

The most common positive symptoms are delusions and hallucinations. Delusions are “fixed beliefs that are not amenable to change in light of conflicting evidence” (APA, 2013, pp. 87). An individual suffering from delusions remains convinced in their belief, even when presented with clear, contradicting evidence. Researchers believe that delusions primarily relate to the social, emotional, educational, and cultural background of the individual (Arango & Carpenter, 2010). For example, an individual with schizophrenia who comes from a highly religious family is more likely to experience religious delusions (delusions of grandeur) than another type of delusion.

Hallucinations are perceptual experiences with no external stimulus (such as hearing voices when no one else is present). Hallucinations can occur in any sensory modality: auditory, visual, olfactory (smell), gustatory (taste), or somatic (touch), however the most common type are auditory hallucinations (APA, 2013). The content of these auditory hallucinations is frequently negative, making critical comments (“you’re worthless”) or telling the person what to do.

Negative symptoms typically involve an impairment in functions – cognitive, physical, and/or emotional. For example, anhedonia reflects a lack of apparent drive to engage in social or recreational activities. Importantly, this does not seem to reflect a lack of enjoyment in pleasurable activities or events (as is often seen in Depressive Disorders) (Llerena, et al., 2012) but rather a reduced drive or ability to take the steps necessary to obtain the potentially positive outcomes (Barch & Dowd, 2010). Flat affect and reduced speech (alogia) reflect a lack of showing emotions through facial expressions, gestures, and speech intonation, as well as a reduced amount of speech and increased pause frequency and duration.

Genetics and Epigenetics in Schizophrenia

Numerous family and twin studies have provided evidence that genetics play a significant role in an individual’s risk of developing schizophrenia (Henriksen, et al., 2017). However, as is the case with many psychological disorders, the genetics underlying schizophrenia have proven to be highly complex, heterogeneous, and polygenic. Furthermore, the wide variations in symptoms among cases (i.e., one individual may demonstrate only negative symptoms, while another may present only positive symptoms) makes it even more challenging to identify specific genes associated with risk for schizophrenia.

Genome-wide studies have identified more than 70 genes suspected of playing a role in producing schizophrenia (Flint & Munafò, 2014), and it is believed that the development of schizophrenia involves the cumulative effects of multiple genes, with most of these having only a small effect by themselves.

While our understanding of the genetic basis underlying schizophrenia is still developing, recent research has noted several genes associated with various aspects of brain development, including myelination and synaptic transmission (Smigielski, et al. 2020), that are also associated with an increased susceptibility to schizophrenia (Gürel, et al. 2020). It is now believed that this genetic susceptibility may be triggered by early environmental factors, through epigenetic mechanisms, and alter the course of neural development, leading to the later development of schizophrenia. (Gürel, et al. 2020.) This theory is sometimes referred to as the Neurodevelopmental Hypothesis of schizophrenia since it requires epigenetic activation of genes during early development to set the stage for latter presentation of the disorder. "The influential neurodevelopmental hypothesis of schizophrenia proposes that pathological neurodevelopmental processes, beginning as early as the first and second trimesters, result in neuronal circuits that are primed to generate psychotic symptoms during adolescence or young adulthood, often in the context of heightened biological and psychological stress" (Nour and Howes, 2015). See the section below on the Neurodevelopmental Hypothesis for more details.

The Role of Neurotransmitters in Schizophrenia

Since the 1960s, it has been believed that many of the symptoms of schizophrenia were the result of an overactivity of dopamine. As with many of the psychological disorders, it is now understood that the biochemistry underlying schizophrenia is complex and involves multiple biological systems.

Dopamine Hypothesis of Schizophrenia

Although the first antipsychotic drugs appeared in the 1950s, it was not well understood how these drugs were alleviating some of the symptoms of schizophrenia, nor why they also produced side effects, similar to those seen in patients with Parkinson’s disease (muscular rigidity, tremors, decrease in voluntary movement). It wasn’t until the late 1960s when further research made the notable discovery that the striatums of individuals with Parkinson’s disease were completely depleted of dopamine (Goetz, 2011). This discovery led researchers to further speculate that antipsychotic drugs might be producing their rigidity and tremor side effects by reducing dopamine activity, which then implied that many of the psychotic symptoms alleviated by these drugs were being caused by the overactivity of dopamine in the brain. These speculations developed into what eventually became known as the dopamine theory of schizophrenia (see Brisch, et al., 2014).

Almost since this theory became accepted, the development of newer antipsychotics had generally followed the dopamine hypothesis. In other words, since patients with schizophrenia were assumed to have increased dopaminergic activity, dopamine antagonist drugs, particularly those that targeted the dopamine D2 receptor could treat their symptoms.

The antagonism of dopamine D2 receptors in the mesolimbic pathway is thought to be the main mode of action of antipsychotic medication in treating psychotic symptoms. See Figure \(\PageIndex{2}\). In addition to the mesolimbic brain areas, dopamine dysregulation has also been observed in the amygdala and prefrontal cortex, which are important for emotional processing, and differences in dopamine contents in the prefrontal cortex, cingulate cortex, and hippocampus between schizophrenia patients and healthy control subjects (Patel, et al., 2010). In particular, the dopamine system in the hippocampus is overactive in schizophrenia patients (Grace, 2012).

However, a dopamine receptor antagonist is not clinically effective at treating cortical-related symptoms, such as cognitive deficits, in schizophrenia. Although the exact mechanism underlying these cognitive deficits remains largely unknown, factors such as deficits in cortical dopamine function , dysfunction in the glutamate, NMDA receptor, or synaptic elimination are likely to play a contributing role.

Molecular imaging studies have supported an association of increased subcortical dopamine transmission with the positive symptoms of schizophrenia with some exceptions. Although hyperactivity in subcortical dopaminergic function most likely contributes substantially to positive symptoms, the original dopamine hypothesis must be extended to include contributions of other neurotransmitter systems in the pathophysiology of schizophrenia [13].

As researchers came to better understand the biological complexities of schizophrenia, the original version of the dopamine hypothesis no longer fit with our understanding of the disorder. This has led to the “revised dopamine hypothesis” (Brisch, et al., 2014). This revised hypothesis proposes that the increased dopamine transmission in the mesocorticolimbic areas (see Figure \(\PageIndex{2}\)) and decreased dopamine transmission in the prefrontal cortex seen in individuals with schizophrenia account for many of their symptoms. (Pogarell, et al. 2012).

Figure \(\PageIndex{2}\): The mesocorticolimibic dopamine pathway. The revised dopamine hypothesis proposes that many of the symptoms of schizophrenia arise from dopamine dysfunction in this pathway. (CC BY-SA 4.0; BruceBlaus via Wikimedia Commons)

Glutamate Hypothesis of Schizophrenia

As noted above, schizophrenia has been primarily associated with dopamine dysfunction, and treatments have been developed that target the dopamine pathway in the central nervous system. However, accumulating evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid (GABA) systems. This broad range of dysfunction may lead to the diverse cognitive, behavioral, and social alterations observed in this disorder (Yang & Tsai, 2017)

Glutamate is one of the excitatory and most abundant neurotransmitters in the brain. Glutamate pathways link to the cortex, the limbic system, and the thalamus regions, all of which have been implicated in schizophrenia. The association of glutamate dysfunction with schizophrenia could originate from the observation that the cerebrospinal fluid of patients with schizophrenia had decreased glutamate levels . Furthermore, patients who abuse certain glutamate antagonists, such as phencyclidine or ketamine, frequently show psychotic symptoms. Dysfunction of glutamate action can be a promising treatment target for its essential role in the pathophysiology of schizophrenia, especially in terms of negative symptoms and cognitive impairment (Yang & Tsai, 2017).

Neurodevelopment Hypothesis of Schizophrenia

Almost three decades ago Weinberger proposed a neurodevelopmental hypothesis for the etiology of schizophrenia. Weinberger’s hypothesis synthesized emerging findings from the field of schizophrenia research, attaching particular importance to the observation that symptoms of the disease often surface in adolescence and are associated with stressful life events. Weinberger suggested that ‘…a fixed ‘lesion’ from early in life may interact with normal brain maturational events that occur much later.’ This vision of the pathogenesis of schizophrenia was prescient. At the time, the field of neuropathology in schizophrenia was in its infancy. The only evidence for structural brain pathology was the finding of enlarged ventricular volume in patients with schizophrenia. There was not yet any hard evidence linking early brain insult to schizophrenia, and the concept that the late adolescent maturational process of synaptic elimination might contribute to schizophrenia had only recently been proposed (Selemon & Zecevic, 2015)

In the ensuing years, a wealth of evidence has accumulated from epidemiologic studies to indicate that prenatal and perinatal factors contribute to the risk of developing schizophrenia, leading to virtual universal acceptance of schizophrenia as a neurodevelopmental disease. Over this same period, neuroimaging studies of schizophrenia subjects have found widespread cortical gray matter loss due to impoverished neural connectivity that is particularly pronounced in certain areas such as the prefrontal cortex. Taken together, these diverse research findings strengthen the basic tenets of the neurodevelopmental hypothesis: (1) that schizophrenia is a disease associated with early abnormal brain development and (2) that schizophrenia-associated neuropathology, for example, reduction of neuropil in the prefrontal cortex, could be unmasked by the late adolescent process of synaptic pruning. (Selemon & Zecevic, 2015)

Neural Structures in Schizophrenia

There is a long and reliable history of research into the neural basis of schizophrenia. Neuroimaging studies have found a significant reduction in overall and specific brain region volumes, as well as tissue density of individuals with schizophrenia compared to healthy controls (Brugger & Howes, 2017). Additionally, there has been evidence of ventricle enlargement (See Figure \(\PageIndex{3}\)) as well as volume reductions in the medial temporal lobe, which contains such structures as the amygdala (involved in emotion regulation), the hippocampus (involved in memory), as well as the neocortical surface of the temporal lobes (processing of auditory information) (Kurtz, 2015). Additional studies also indicate a reduction in the orbitofrontal regions of the brain, a part of the frontal lobe that is responsible for response inhibition (Kurtz, 2015).

Figure \(\PageIndex{3}\): The enlarged ventricles are often seen in the brains of individuals diagnosed with Schizophrenia. (CC BY-SA 4.0; BruceBlaus via Wikimedia Commons)

Focus on Prefrontal Cortex Alterations in Schizophrenia

One of the brain regions most consistently implicated in the pathophysiology of schizophrenia is the dorsolateral prefrontal cortex (See Figure \(\PageIndex{4}\)). Dysfunction of the dorsolateral prefrontal cortical is thought to be an underlying substrate for thought disorder in schizophrenia. Patients with schizophrenia perform poorly on an array of cognitive tasks that depend on prefrontal cortical function, for example, Continuous Performance (attention), Stroop (cognitive inhibition), Wisconsin Card Sort (cognitive flexibility), Delayed Response (working memory) and N-Back (working memory) tasks. Moreover, a meta-analysis of magnetic resonance imaging findings has reaffirmed that the dorsolateral prefrontal cortex is a hotspot for gray matter volume deficit in the brains of schizophrenia patients. (Selemon & Zecevic, 2015)

Figure \(\PageIndex{4}\): Dorsolateral Prefrontal Cortex - A major component of the frontal lobe involved with higher cognitive functions and shown to be altered in studies of schizophrenia. From Zahr, N.M.., Sullivan, E.V., (2008) Translational Studies of Alcoholism Bridging the Gap. Alcohol Research & Health, 31 (3). NIH, Public Domain.

Interestingly, a review of recent research confirms the influence of the neurodevelopmental hypothesis on prefrontal cortex development, especially in terms of two developmental periods, early gestation and adolescence, that have been implicated in the etiology of schizophrenia. Guided by knowledge of basic human neurodevelopment, this research has identified two developmental processes, cell proliferation in early gestation and synaptic pruning in adolescence, that are prominent during these critical time periods and are essential to normative prefrontal cortical development. The results of this body of research suggests that diverse environmental insults may converge on these processes and perturb normal development of the prefrontal cortex, resulting in a heightened risk of schizophrenia. (Selemon & Zecevic, 2015)

References

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Brisch, R., Saniotis, A., Wolf, R., Bielau, H., Bernstein, H. G., Steiner, J., Bogerts, B., Braun, K., Jankowski, Z., Kumaratilake, J., Henneberg, M., & Gos, T. (2014). The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Frontiers in psychiatry, 5, 47. https://doi.org/10.3389/fpsyt.2014.00047.

Brugger SP, Howes OD. (2017). Heterogeneity and Homogeneity of Regional Brain Structure in Schizophrenia: A Meta-analysis. JAMA Psychiatry. 74(11):1104-1111. doi:10.1001/jamapsychiatry.2017.2663. PMID: 28973084; PMCID: PMC5669456.

Cuthbert B.N. & Morris S.E. (2021). Evolving Concepts of the Schizophrenia Spectrum: A Research Domain Criteria Perspective. Frontiers in Psychiatry. 12. DOI=10.3389/fpsyt.2021.641319

Flint J, Munafò MR. (2014) Genetics: finding genes for schizophrenia. Curr Biol., 24(16), R755-7. doi: 10.1016/j.cub.2014.07.018.

Grace A. A. (2012). Dopamine system dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia. Neuropharmacology, 62(3), 1342–1348. https://doi.org/10.1016/j.neuropharm.2011.05.011.

Gürel C, Kuşçu GC, Yavaşoğlu, A, Avcı, CB. (2020). The clues in solving the mystery of major psychosis: The epigenetic basis of schizophrenia and bipolar disorder. Neuroscience & Biobehavioral Reviews. 113. 51-61. https://doi.org/10.1016/j.neubiorev.2020.03.005.

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Nour, M., Howes, O. (2015). Interpreting the neurodevelopmental hypothesis of schizophrenia in the context of normal brain development and ageing. Biological Sciences, 112 (21) E2745 https://doi.org/10.1073/pnas.1502170112

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Selemon, L., Zecevic, N. (2015) Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry 5, e623 . https://doi.org/10.1038/tp.2015.115

Smigielski L, Jagannath V, Rössler W, Walitza S, Grünblatt E. (2020). Epigenetic mechanisms in schizophrenia and other psychotic disorders: a systematic review of empirical human findings. Mol Psychiatry. 25(8). 1718-1748. doi: 10.1038/s41380-019-0601-3. Epub 2020 Jan 6. PMID: 31907379.

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Yang, A., & Tsai, S.-J. (2017). New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. International Journal of Molecular Sciences, 18(8), 1689. MDPI AG. Retrieved from http://dx.doi.org/10.3390/ijms18081689

Zahr, N.M.., Sullivan, E.V., (2008) Translational Studies of Alcoholism Bridging the Gap. Alcohol Research & Health, 31 (3).

Attributions

Biological Bases of Schizophrenia Spectrum and other psychotic disorders. Original material written by Amy E. Coren, PhD, Pasadena City College, is licensed under CC BY-NC-SA 4.0. Adapted by Alan Keys, Ph.D., Sacramento City College, Sacramento, CA

Neural Structures in Schizophrenia adapted from Alexis Bridley & Lee W. Daffin Jr., Essentials of Abnormal Psychology, 6.1 Schizophrenia Spectrum and Other Psychotic Disorders by Washington State University licensed under CC-BY-NC-SA 4.0 International License. Retrieved from: https://opentext.wsu.edu/abnormalpsy...g-information/

Sections on the Dopamine and Glutamate Hypotheses of Schizophrenia were adapted by Alan Keys, Ph.D. from original material produced by Amy Coren, Ph.D., Pasadena City College, Pasadena, CA. and Yang, A., & Tsai, S.-J. (2017). New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. International Journal of Molecular Sciences, 18(8), 1689. MDPI AG. Retrieved from http://dx.doi.org/10.3390/ijms18081689. CC BY 2.0

Sections on the Neurodevelopmental Hypothesis of Schizophrenia and Focus on Prefrontal Cortex adapted from Selemon, L., Zecevic, N. (2015) Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry 5, e623 . https://doi.org/10.1038/tp.2015.115. CC BY-SA 4.0

Figure \(\PageIndex{1}\) CC BY-SA 4.0, Amy E. Coren, Ph.D. via original creation

Figure \(\PageIndex{2}\) CC BY-SA 4.0; BruceBlaus via Wikimedia Commons

Figure \(\PageIndex{3}\) CC BY-SA 4.0; BruceBlaus via Wikimedia Commons