Schizophrenia spectrum disorders are a cluster of psychotic brain diseases that afflict approximately 0.4% to nearly 2.0% of persons in various worldwide populations.Reference Kahn, Sommer and Murray ^{1 ,} Reference McGrath, Saha, Chant and Welham ² In 2019, the direct and indirect annual costs of schizophrenia were estimated at $343.2 billion in the United States alone.Reference Kadakia, Catillon and Fan 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, intrafamilial violence, entanglement in the legal system, incarceration, increased injury and illness, and a shortened life span.Reference Gibb, Brewer and Bowden ^{4 ,} Reference Kennedy, Altar, Taylor, Degtiar and Hornberger 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.Reference Kendler 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.Reference Green, Watson and Collins 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.Reference Amaral, Carbonell-Sala and De La Vega 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.Reference Legge, Santoro, Periyasamy, Okewole, Arsalan and Kowalec 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.Reference Rujescu ¹⁰ Importantly, many of the genes and gene loci implicated in schizophrenia are involved in areas such as cell differentiation, cell regulation, cell maturation, cell migration, orientation of cells, the structure of cell receptors, cell adhesion, and, in the case of neurons, development of neural networks.Reference Stauffer, Bethlehem, Dorfschmidt, Won, Warrier and Bullmore ^{11 ,} Reference Owen, Legge, Rees, Walters and O’Donovan ¹² Additionally, those gene foci that are part of the histocompatibility complex play critical roles in immune identity and control of inflammatory processes.Reference Amaral, Carbonell-Sala and De La Vega ^{8 ,} Reference Debnath, Cannon and Venkatasubramanian ^{13 ,} Reference Khandaker, Cousins, Deakin, Lennox, Yolken and Jones ¹⁴

Although schizophrenia spectrum disorders are heavily genetically determined, it is thought 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 cannabis.Reference Kahn, Sommer and Murray ^{1 ,} Reference Stilo and Murray ¹⁵ Many of these environmental risk factors may influence the occurrence and phenotypic development of schizophrenia via epigenetic processes, such as gene promotion or inhibition of other genes using small peptides or short ribonucleic acid (RNA) sequences, methylation of deoxyribonucleic acid (DNA), or modulation of the acetylation of histone (protein involved in the winding and unwinding of DNA strands for copying).Reference Richetto and Meyer ^{16 ,} Reference Srivastava, Dada and Qian ¹⁷ Moreover, while no gene therapies currently exist for schizophrenia spectrum disorders, interventions in selected environmental risk factors hold promise for altering the phenotypic presentation of schizophrenia, as well as risk of overt illness in both present and future generations.Reference Xavier, Roman, Aitken and Nixon ^{18 ,} Reference Svrakic, Zorumski, Svrakic, Zwir and Cloninger ¹⁹

The human central nervous system begins as a simple tube formed from neural crest cells. This relatively simple structure, however, then undergoes a complex and elegant series of steps to become the brain and spinal cord.Reference Lu, Zhang and Lee ²⁰ The brain is formed by overfolding of the cephalad portion of the neural tube with glial cells laying down the structural form of the brain and providing trails of chemical markers for motile neuroblasts to follow to their cortical and subcortical positions.Reference Hendriks, Pagliaro and Andreatta ²¹ During the second trimester of pregnancy, neuroblasts (immature motile forms of later neurons) undergo rapid mitosis deep in the forming brain near the lateral ventricles. These neuroblasts then crawl to their later positions following neurotrophic markers and organize themselves into orderly neural assemblies.Reference Lu, Zhang and Lee ²⁰ They then form neural networks by sprouting axons and dendrites. Initially, the number of connections is 2 to 5 times greater than the connections present in the mature brain. That is, exposure to the environment and the process of learning selects those pathways that will be reinforced and those that will be allowed to atrophy as the brain matures.Reference Dambska and Laure-Kamionowska ^{22 -}Reference Forde, Ronan and Zwiers ²⁴ The primary visual cortex is the first to mature at about 1 year of age, while the last areas to mature are the frontal and temporal lobes at between 18 the 25 years of age. Thus, the roughly 100 billion neurons of the central nervous system, along with their associated astrocytes, oligodendrogliocytes, and microglia, as well as other cell types, become the adult brain and spinal cord.Reference Hendriks, Pagliaro and Andreatta ^{21 ,} Reference Forde, Ronan and Zwiers ^{24 ,} Reference Walhovd, Tamnes and Fjell ²⁵

In contrast, brain development and maturation in schizophrenia spectrum disorders is clearly abnormal. To begin, many of the neuroblasts produced during the second trimester of pregnancy fail to reach their correct positions, instead being found in post-mortem studies isolated deep within the white matter of the brain.Reference Connor, Crawford and Akbarian ^{26 ,} Reference Wu, Liu and Fang ²⁷ Then, across childhood and adolescence individuals in the premorbid phase of schizophrenia exhibit excessive loss of neurons and synaptic connections, such that by the onset of overt psychosis some one-third to one-half exhibit clear atrophic changes and enlargement of the lateral ventricles on brain imaging.Reference Chung and Cannon ^{28 ,} Reference Haukvik, Hartberg and Agartz ²⁹ Ventricular enlargement, reflecting loss of brain tissue in schizophrenia, is illustrated below (Figure 1).

Figure 1. Ventricular enlargement/brain atrophy.

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

Following the onset of overt illness, loss of brain mass continues and appears to be correlated with the duration of untreated illness and the number of psychotic exacerbations.Reference Kahn, Sommer and Murray ^{1 ,} Reference Haukvik, Hartberg and Agartz ^{29 ,} Reference Kubota, van Haren and Haijma ³⁰ At least a portion of the brain tissue loss associated with psychotic exacerbations or longer durations of untreated active psychosis appears to be mediated by inflammatory processes, including activation of microglia and invasion of the brain by macrophages.Reference Khandaker, Cousins, Deakin, Lennox, Yolken and Jones ^{14 ,} Reference Cai, Catts and Webster ^{31 ,} Reference Zhu, Webster and Murphy ³² Interestingly, treatment of high-risk children (i.e., having 2 parents with schizophrenia spectrum disorders) with low-dose antipsychotic medications may reduce the rate of conversion to overt illness in adolescence.Reference Yung and Nelson ³³ Nevertheless, it should be noted that some subsequent studies have failed to find evidence that antipsychotic treatment during the premorbid phase of schizophrenia is protective with respect to later development of overt schizophrenia.Reference Zhang, Xu and Tang ³⁴ Better established appear to be observations that consistent antipsychotic treatment (eg, with LAIs) slows but does not reverse the deterioration of the brain in schizophrenia spectrum disorders.Reference Horvitz-Lennon, Predmore and Orr ^{35 -}Reference Lawrie ³⁷

Clinically, the signs and symptoms of schizophrenia have been divided into positive, negative, and cognitive deficit domains.Reference Kahn, Sommer and Murray ^{1 ,} Reference McCutcheon, Reis Marques and Howes ³⁸ Positive signs and symptoms include hallucinations/illusions, delusional ideation, illogical thoughts and behavior, hyperactivity/agitation, and thought disorder.Reference Kahn, Sommer and Murray ^{1 ,} Reference McCutcheon, Reis Marques and Howes ³⁸ Negative signs and symptoms include apathy, lethargy, abulia, avolition, and social withdrawal.Reference Marder and Kirkpatrick ³⁹ Cognitive deficits in schizophrenia spectrum disorders include deficits in attention, concentration, memory organization and recall, language processing, and executive functions such as self-awareness and social judgment.Reference McCutcheon, Reis Marques and Howes ^{38 ,} Reference Javitt ⁴⁰ In addition to the developmental abnormalities and atrophic brain changes described earlier in this article, 2 neuromodulatory molecules, that is, dopamine and serotonin, appear to play important functional roles in schizophrenia spectrum disorders.Reference Stahl ^{41 ,} Reference Cumming, Abi-Dargham and Gründer ⁴² Below, we will consider 3 neural networks with respect to the positive, negative, and cognitive domains of schizophrenia.

Positive signs and symptoms appear to arise in part from excessive dopamine stimulation of mesostriatal projections to temporal lobe association cortices and related structures (formerly termed the mesolimbic pathway).Reference Stahl ^{41 ,} Reference Howes and Shatalina ⁴³ This excessive stimulation of limbic D₂ dopamine receptors, in turn, appears to arise from a failure of inhibition by gamma aminobutyric (GABA) interneurons in the frontal cortex. And failure of M₄ acetylcholine receptors on the cell bodies of the relevant mesostriatal dopamine neurons.Reference Stahl ^{41 ,} Reference Foster, Bryant and Conn ⁴⁴ This is illustrated as follows (Figure 2).

Figure 2. Mesostriatal dopaminergic hyperactivity.

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

Excessive serotonin (5-hydroxytryptamine) stimulation of 5HT_2A receptors may add to positive psychotic signs and symptoms, especially visual hallucinations, in schizophrenia.Reference Stahl ^{41 ,} Reference Preller, Burt and Ji ⁴⁵ This is illustrated as follows (Figure 3).

Figure 3. 5HT_2A serotonergic hyperactivity.

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

Finally, it appears that in addition to previously described developmental pathologies and atrophic changes, inadequate stimulation of frontal lobe D₁ and D₃ dopamine receptors contributes to the negative symptoms and cognitive impairments of schizophrenia spectrum disorders, including anosognosia (unawareness of illness).Reference Stahl ^{41 ,} Reference Howes and Kapur ⁴⁶ This is illustrated as follows (Figure 4).

Figure 4. Mesocortical dopaminergic hypoactivity.

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

Importantly, all antipsychotic medications appear capable of ameliorating psychotic symptoms, with the largest effects being on positive signs and symptoms.Reference Sabe, Pillinger and Kaiser ⁴⁷ In particular, LAIs appear superior in preventing relapse and, thereby, illness progression, morbidity, and mortality.Reference Horvitz-Lennon, Predmore and Orr ^{35 ,} Reference Taipale, Mittendorfer-Rutz and Alexanderson ⁴⁸ In the near future, a new class of antipsychotics likely starting with xanomeline/trospium may be able to presynaptically modulate dopamine release in mesostriatal projections by targeting the M₄ acetylcholine auto-receptor.Reference Foster, Bryant and Conn ⁴⁴ Among the antipsychotics, clozapine remains the “gold standard” of treatment in several areas, that is, management of treatment-resistant illness, reduction of violence, reduction of suicide risk, and enhancement of cognitive executive functions.Reference Meltzer and McGurk ^{49 ,} Reference Stahl ⁵⁰ Clozapine also appears to be unique in that it likely acts by exerting effects upstream of the mesostriatal dopamine neurons by improving glutamate signal transduction.Reference Nucifora, Woznica, Lee, Cascella and Sawa ^{51 ,} Reference McQueen, Sendt and Gillespie ⁵²

Summary: Schizophrenia spectrum disorders are a group of related psychotic developmental dementias (dementia praecox) characterized by positive, negative, and cognitive signs and symptoms usually beginning in adolescence or early adulthood. Illness is mediated by a combination of developmental and atrophic changes in brain structure and defects in the signal transductions of glutamate, gamma amino butyric acid (GABA), acetylcholine, dopamine, and serotonin. Importantly, defects in neurotransmitter signal transduction provide targets for pharmacotherapy with antipsychotic medications. Critically, failure to provide consistent antipsychotic treatment early in the course of illness (eg, with LAIs) promotes atrophic brain pathology and deterioration of the illness course. Finally, while all antipsychotic medications can ameliorate acute signs and symptoms, clozapine shows superior efficacy in treating the positive, negative, and cognitive signs and symptoms of the schizophrenia spectrum disorders, as well as treatment resistance, violence, and suicide.