CNS Spectrums What is the neurobiology of schizophrenia?

www.cambridge.org/cns
Michael A. Cummings1,2 , Ai-Li W. Arias1,2 and Stephen M. Stahl3,4
1
University of California, Irvine, CA, USA; 2University of California, Riverside, CA, USA; 3University of California, San
Diego, CA, USA and 4University of Cambridge, Cambridge, UK

Review
Abstract
Cite this article: Cummings MA, Arias A-LW,
Schizophrenia spectrum disorders are brain diseases that are developmental dementias (dementia
and Stahl SM (2024). What is the neurobiology
of schizophrenia? CNS Spectrums praecox). Their pathology begins in utero with psychosis most commonly becoming evident in
https://doi.org/10.1017/S1092852924000518 adolescence and early adulthood. It is estimated they afflict the U.S. population at a prevalence rate
of approximately 0.8%. Genetic studies indicate that these brain diseases are about 80% deter-
Received: 06 May 2024
mined by genes and about 20% determined by environmental risk factors. Inheritance is polygenic
Accepted: 24 June 2024
with some 270 gene loci having been identified as contributing to the risk for schizophrenia.
Keywords: Interestingly, many of the identified gene loci and gene polymorphisms are involved in brain
Neurobiology; schizophrenia; developmental formation and maturation. The identified genetic and epigenetic risks give rise to a brain in which
dementia; dementia praecox; brain changes; neuroblasts migrate abnormally, assume abnormal locations and orientations, and are vulnerable
dopamine; glutamate
to excessive neuronal and synaptic loss, resulting in overt psychotic illness. The illness trajectory of
Corresponding author: schizophrenia then is one of loss of brain mass related to the number of active psychotic
Michael A. Cummings; exacerbations and the duration of untreated illness. In this context, molecules such as dopamine,
Email: Michael.Cummings@DSH.CA.GOV glutamate, and serotonin play critical roles with respect to positive, negative, and cognitive
domains of illness. Acutely, antipsychotics ameliorate active psychotic illness, especially positive
signs and symptoms. The long-term effects of antipsychotic medications have been debated;
however, the bulk of imaging data suggest that antipsychotics slow but do not reverse the illness
trajectory of schizophrenia. Long-acting injectable antipsychotics (LAI) appear superior in this
regard. Clozapine remains the “gold standard” in managing treatment-resistant schizophrenia.

Schizophrenia spectrum disorders are a cluster of psychotic brain diseases that afflict approxi-
mately 0.4% to nearly 2.0% of persons in various worldwide populations.1,2 In 2019, the direct and
indirect annual costs of schizophrenia were estimated at $343.2 billion in the United States alone.3
Moreover, in addition to a substantial economic burden on society as a whole, the schizophrenia
spectrum disorders impose a variety of devastating personal and familial burdens, including but
not limited to social isolation, disruption of education, unemployment, homelessness, intrafami-
lial violence, entanglement in the legal system, incarceration, increased injury and illness, and a
shortened life span.4,5 Given the costly and disastrous effects of the schizophrenia spectrum
disorders, Emil Kraepelin, who first characterized these psychotic disorders, described them as
dementia praecox or early dementia.6 In the remainder of this review, we will consider the
neurobiology underlying a cluster of brain diseases that can be conceptualized under an umbrella
as a group of developmental dementias with similar core pathologies but heterogeneous variations
in clinical detail.
The human genome was first published in 2001.7 Since then, researchers have been working
to identify protein-coding genes. The number of such genes is presently estimated at
between 19,000 and 20,000.8 Within the human genome, some 270 gene loci have been
associated with schizophrenia spectrum disorders, with 108 risk genes being identified as single
nucleotide polymorphisms.9 The most obvious genetic associations have been with genetic
variations in the major histocompatibility complex. Besides polymorphisms, structural variants
in the form of copy number variants, such as microdeletions and microduplications have a very
high impact in a subset of patients. These variations are mainly microdeletions on 1q21.1, 2p16.3,
3q29, 15q13.3, and 16p11.2, as well as a large deletion on 22q11.21 and a microduplication
on 16p11.2.10 Importantly, many of the genes and gene loci implicated in schizophrenia are
© The Author(s), 2024. Published by Cambridge involved in areas such as cell differentiation, cell regulation, cell maturation, cell migration,
University Press. This is an Open Access article, orientation of cells, the structure of cell receptors, cell adhesion, and, in the case of neurons,
distributed under the terms of the Creative development of neural networks.11,12 Additionally, those gene foci that are part of the histo-
Commons Attribution licence (http://
compatibility complex play critical roles in immune identity and control of inflammatory
creativecommons.org/licenses/by/4.0), which
permits unrestricted re-use, distribution and processes.8,13,14
reproduction, provided the original article is Although schizophrenia spectrum disorders are heavily genetically determined, it is thought
properly cited. that about 20% of the risk for overt illness is determined by environmental factors such as
maternal stress during pregnancy, in utero infection exposure, childhood illnesses, childhood
adversity, and childhood or adolescent exposure to drugs such as methamphetamine or canna-
bis.1,15 Many of these environmental risk factors may influence the occurrence and phenotypic

https://doi.org/10.1017/S1092852924000518 Published online by Cambridge University Press

 2 Michael A. Cummings, Ai-Li W. Arias and Stephen M. Stahl

development of schizophrenia via epigenetic processes, such as selected environmental risk factors hold promise for altering the
gene promotion or inhibition of other genes using small peptides phenotypic presentation of schizophrenia, as well as risk of overt
or short ribonucleic acid (RNA) sequences, methylation of deox- illness in both present and future generations.18,19
yribonucleic acid (DNA), or modulation of the acetylation of The human central nervous system begins as a simple tube
histone (protein involved in the winding and unwinding of DNA formed from neural crest cells. This relatively simple structure,
strands for copying).16,17 Moreover, while no gene therapies cur- however, then undergoes a complex and elegant series of steps to
rently exist for schizophrenia spectrum disorders, interventions in become the brain and spinal cord.20 The brain is formed by

Figure 1. Ventricular enlargement/brain atrophy.

openbooks.lib.msu.edu (open access).

Figure 2. Mesostriatal dopaminergic hyperactivity.

Stahl, S. Stahl’s Essential Psychopharmacology, 5th Edition, Chapter 4, p. 93.

https://doi.org/10.1017/S1092852924000518 Published online by Cambridge University Press

 CNS Spectrums 3

Figure 3. 5HT2A serotonergic hyperactivity.

Stahl, S. Stahl’s Essential Psychopharmacology, 5th Edition, Chapter 4, p. 136.

overfolding of the cephalad portion of the neural tube with glial cells nervous system, along with their associated astrocytes, oligodendro-
laying down the structural form of the brain and providing trails of gliocytes, and microglia, as well as other cell types, become the adult
chemical markers for motile neuroblasts to follow to their cortical brain and spinal cord.21,24,25
and subcortical positions.21 During the second trimester of preg- In contrast, brain development and maturation in schizophre-
nancy, neuroblasts (immature motile forms of later neurons) nia spectrum disorders is clearly abnormal. To begin, many of the
undergo rapid mitosis deep in the forming brain near the lateral neuroblasts produced during the second trimester of pregnancy fail
ventricles. These neuroblasts then crawl to their later positions to reach their correct positions, instead being found in post-
following neurotrophic markers and organize themselves into mortem studies isolated deep within the white matter of the
orderly neural assemblies.20 They then form neural networks by brain.26,27 Then, across childhood and adolescence individuals in
sprouting axons and dendrites. Initially, the number of connections the premorbid phase of schizophrenia exhibit excessive loss of
is 2 to 5 times greater than the connections present in the mature neurons and synaptic connections, such that by the onset of overt
brain. That is, exposure to the environment and the process of psychosis some one-third to one-half exhibit clear atrophic changes
learning selects those pathways that will be reinforced and those and enlargement of the lateral ventricles on brain imaging.28,29
that will be allowed to atrophy as the brain matures.22-24 The primary Ventricular enlargement, reflecting loss of brain tissue in schizo-
visual cortex is the first to mature at about 1 year of age, while the last phrenia, is illustrated below (Figure 1).
areas to mature are the frontal and temporal lobes at between 18 the Following the onset of overt illness, loss of brain mass con-
25 years of age. Thus, the roughly 100 billion neurons of the central tinues and appears to be correlated with the duration of untreated

https://doi.org/10.1017/S1092852924000518 Published online by Cambridge University Press

 4 Michael A. Cummings, Ai-Li W. Arias and Stephen M. Stahl

Figure 4. Mesocortical dopaminergic hypoactivity.

Stahl, S. Stahl’s Essential Psychopharmacology, 5th Edition, Chapter 4, p. 95.

illness and the number of psychotic exacerbations.1,29,30 At least a the cell bodies of the relevant mesostriatal dopamine neurons.41,44
portion of the brain tissue loss associated with psychotic exacer- This is illustrated as follows (Figure 2).
bations or longer durations of untreated active psychosis appears Excessive serotonin (5-hydroxytryptamine) stimulation of
to be mediated by inflammatory processes, including activation of 5HT2A receptors may add to positive psychotic signs and symptoms,
microglia and invasion of the brain by macrophages.14,31,32 Inter- especially visual hallucinations, in schizophrenia.41,45 This is illus-
estingly, treatment of high-risk children (i.e., having 2 parents trated as follows (Figure 3).
with schizophrenia spectrum disorders) with low-dose antipsy- Finally, it appears that in addition to previously described devel-
chotic medications may reduce the rate of conversion to overt opmental pathologies and atrophic changes, inadequate stimulation
illness in adolescence.33 Nevertheless, it should be noted that of frontal lobe D1 and D3 dopamine receptors contributes to the
some subsequent studies have failed to find evidence that anti- negative symptoms and cognitive impairments of schizophrenia
psychotic treatment during the premorbid phase of schizophrenia spectrum disorders, including anosognosia (unawareness of ill-
is protective with respect to later development of overt schizo- ness).41,46 This is illustrated as follows (Figure 4).
phrenia.34 Better established appear to be observations that con- Importantly, all antipsychotic medications appear capable of
sistent antipsychotic treatment (eg, with LAIs) slows but does not ameliorating psychotic symptoms, with the largest effects being on
reverse the deterioration of the brain in schizophrenia spectrum positive signs and symptoms.47 In particular, LAIs appear superior
disorders.35-37 in preventing relapse and, thereby, illness progression, morbidity,
Clinically, the signs and symptoms of schizophrenia have been and mortality.35,48 In the near future, a new class of antipsychotics
divided into positive, negative, and cognitive deficit domains.1,38 likely starting with xanomeline/trospium may be able to presyn-
Positive signs and symptoms include hallucinations/illusions, delu- aptically modulate dopamine release in mesostriatal projections by
sional ideation, illogical thoughts and behavior, hyperactivity/agi- targeting the M4 acetylcholine auto-receptor.44 Among the anti-
tation, and thought disorder.1,38 Negative signs and symptoms psychotics, clozapine remains the “gold standard” of treatment in
include apathy, lethargy, abulia, avolition, and social withdrawal.39 several areas, that is, management of treatment-resistant illness,
Cognitive deficits in schizophrenia spectrum disorders include reduction of violence, reduction of suicide risk, and enhancement
deficits in attention, concentration, memory organization and of cognitive executive functions.49,50 Clozapine also appears to be
recall, language processing, and executive functions such as self- unique in that it likely acts by exerting effects upstream of the
awareness and social judgment.38, 40 In addition to the develop- mesostriatal dopamine neurons by improving glutamate signal
mental abnormalities and atrophic brain changes described earlier transduction.51,52
in this article, 2 neuromodulatory molecules, that is, dopamine and Summary: Schizophrenia spectrum disorders are a group of
serotonin, appear to play important functional roles in schizophre- related psychotic developmental dementias (dementia praecox)
nia spectrum disorders.41,42 Below, we will consider 3 neural net- characterized by positive, negative, and cognitive signs and symp-
works with respect to the positive, negative, and cognitive domains toms usually beginning in adolescence or early adulthood. Illness is
of schizophrenia. mediated by a combination of developmental and atrophic changes
Positive signs and symptoms appear to arise in part from in brain structure and defects in the signal transductions of gluta-
excessive dopamine stimulation of mesostriatal projections to tem- mate, gamma amino butyric acid (GABA), acetylcholine, dopa-
poral lobe association cortices and related structures (formerly mine, and serotonin. Importantly, defects in neurotransmitter
termed the mesolimbic pathway).41,43 This excessive stimulation signal transduction provide targets for pharmacotherapy with
of limbic D2 dopamine receptors, in turn, appears to arise from a antipsychotic medications. Critically, failure to provide consistent
failure of inhibition by gamma aminobutyric (GABA) interneurons antipsychotic treatment early in the course of illness (eg, with LAIs)
in the frontal cortex. And failure of M4 acetylcholine receptors on promotes atrophic brain pathology and deterioration of the illness

https://doi.org/10.1017/S1092852924000518 Published online by Cambridge University Press

 CNS Spectrums 5

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