Schizophrenia: An Overview

A homeless man arrives at the emergency room, reporting that his brother is a space alien who is trying to take over the world. The man claims to hear voices and feel the presence of aliens in his body that are controlling his thoughts and actions. Such bizarre presentations are often seen among psychotic patients diagnosed as having schizophrenia. Physicians beginning to practice psychiatry are often drawn to the field after seeing patients with dramatic psychotic symptoms and soon learn that the illness is quite complex. Schizophrenia is a chronic psychiatric illness characterized by positive symptoms (delusions, hallucinations, and grossly disorganized speech and behavior), negative symptoms (apathy, social isolation, and diminished affect), and cognitive impairment (1). Any combination of these symptoms can lead to marked disruption in behavior and significant negative effects on functioning and an increased risk for the development of many comorbid health problems, suicide risk, and substance use disorders. Despite advances in epidemiology, genetics, and neuroimaging, psychiatrists still rely on a comprehensive history, physical exam, and laboratory studies to diagnose schizophrenia. The exact etiologic factors remain elusive. It is by definition a diagnosis made after the exclusion of other possible conditions such as a mood disorder, substance abuse, or certain medical conditions. We begin by discussing historical foundations of this illness, and DSM-5 criteria, and we review the epidemiologic, genetic, and neuroanatomical markers seen in this disease.

Historical Foundations

In 1911, the Swiss psychiatrist Eugene Blueler chose the Greek roots “schizo” (split) and “phrene” (mind) to describe the disorganized thinking of people with schizophrenia. Arnold Pick had noted in 1891 both psychotic and cognitive deficits among those with this disorder and called it “dementia praecox.” More notably, Emil Kraepelin in 1893 differentiated the episodic nature of psychosis seen in manic-depression from dementia praecox (2). Kurt Schneider tried to distinguish various forms of psychotic symptoms that he thought had special value in distinguishing schizophrenia from psychosis resulting from other disorders. These are known as Schneider's “first-rank” symptoms. They include passivity experiences, such as bizarre delusions of being controlled by an external force, thought insertion or withdrawal, and thought broadcasting. He used the German term gedankenlautwerden to describe the auditory hallucinations in schizophrenia as voices that are heard aloud. These voices could comment on an individual’s thoughts or behavior. The individual could also hear third-person conversations with other hallucinated voices talking to each other (3). Blueler, Kraepelin, Schneider, and other pioneers of psychiatry based schizophrenia’s classification on the observation that many psychotic symptoms tend to occur together. Despite such elegant descriptions, extensive diagnostic evaluations and follow-up have shown that there are no specific psychotic symptoms that are pathognomonic for schizophrenia. Schizophrenia was also traditionally subclassified into disorganized, catatonic, paranoid, residual, or undifferentiated types. These subtypes have not been shown to be reliable or predictive of outcome of the disorder and were eliminated in DSM-5 (4). The box on this page highlights the DSM-5 criteria for schizophrenia. If the full criteria are met but the duration of illness is less than six months, the diagnosis of schizophreniform disorder should be diagnosed.

Psychosis is generally defined as a break in reality testing either by abnormal sensory experiences, such as hallucinations, or by holding fixed false beliefs (delusions) that are not accepted by most people. Impairment is also commonly seen in thought and speech patterns. An individual with schizophrenia may develop disorganized speech that makes maintaining discourse during an interview difficult (formal thought disorder) (5). A few minor changes were made to the diagnostic criteria for schizophrenia from DSM-IV to DSM-5. Five cardinal symptoms (delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms) are all still recognized in criterion A. However, two of the first three (delusions, hallucinations, and disorganized speech) are now required to make the diagnosis. The concept of bizarre hallucinations or commenting voices was given more credence in earlier diagnostic criteria, but the phenomena are no longer given special consideration (as Schneider believed they should) in DSM-5 (6).

Despite these changes in diagnostic criteria, it is imperative for clinicians to screen patients for the cardinal signs of psychosis and to clinically elicit the classical symptoms of the disorder. This often requires a careful mental status examination and the collection of external sources of information such as records and interviews of family members (1, 7).

Epidemiology

The prevalence of schizophrenia is around 1% (0.3% to 0.7%) worldwide (1, 8). The incidence is about 1.5 per 10,000 individuals. The male:female ratio is 1.4:1. The increased risk among men has been of interest to researchers. Some have suggested that this may result from higher drug use among men or a possible protective effect from contraceptive use among women (8, 9). On the basis of a large genomewide association study, the genetic basis of schizophrenia is similar among males and females. Females are often diagnosed later than males, and males typically have a worse outcome (1, 10). About 20% of patients with schizophrenia attempt suicide. There is a 5%−6% lifetime prevalence rate of completed suicide, making this a life-threatening disorder. However, most individuals with schizophrenia die of natural causes and have a mortality rate that is two to three times greater than the rest of the population. The disease often strikes patients in the prime of their young adult life. The adult incidence curve increases until it reaches its highest point in the mid-20s, then declines. A second, much smaller peak of increased incidence of schizophrenia is seen in the 40s, which is more common in females (1, 11).

Individuals with schizophrenia are much more vulnerable to becoming homeless than are people with no mental illness. Some of the highest rates of schizophrenia are found in the chronically homeless population. A large public mental health system study found that 15% were homeless at the time of at least one service encounter in a one-year period. Male gender, African American ethnicity, presence of substance use disorder, and a lack of Medicaid insurance were associated with homelessness of patients diagnosed as having schizophrenia. Patients often develop a complex array of social, medical, psychiatric, and financial issues. High levels of general medical comorbidities are commonly found among patients with schizophrenia and add a tremendous burden to the health care needs and cost in this population. Earlier diagnosis and treatment may be of great importance to prevent a declining health and psychosocial course (10, 12, 13).

Genetic Studies

Schizophrenia is often thought to be a number of disorders sharing a similar presentation (1, 14). This is because no specific gene or environmental factor explains the etiology for all of the affected individuals (15). Genetic research has not revealed a robust understanding of the etiology of schizophrenia. Instead, genomewide association studies (GWAS) have revealed only a few weak-effect associations, which account for only a small part of the genetic risk. A complex interplay of genes and environment is likely responsible for the similar presentations of schizophrenia. The total heritable risk for schizophrenia is 70%−80% (14–16). A large number of statistical analyses are needed to estimate the genetic and environmental aspects of variance. Estimates are sometimes obtained with large data sample sets from individuals with a close genetic relationship—such as twins and siblings—rather than from more distantly related individuals. It has been determined that the monozygotic twin concordance rate is 40%−50% and that the dizygotic twin concordance rate is 10%−15%. Offspring of the unaffected monozygotic twin are at increased risk of schizophrenia, and there is a high incidence of disease among adopted children whose biological mothers have a diagnosis of schizophrenia (15). The following are some genes that have been of interest to schizophrenia researchers: catechol O-methyltransferase (COMT), DAO/G30, DISC 1, DTNB 1, GABRB2, NRG 1, and ZNF804A. Rare deletions at 15q13 and 22q11 (DiGeorge syndrome) regions may also predispose individuals to schizophrenia (15–17). There is genetic support for the existence of common DNA variants (single nucleotide polymorphisms) that influence risk of both bipolar disorder and schizophrenia, differing from Kraeplin’s model, which assumes that these are two very separate entities (17).

GWASs have a greater power to detect weak associations to common variants. In 2014, the largest molecular genetic study of schizophrenia ever conducted was published by the schizophrenia genetics consortium. In this landmark schizophrenia GWAS, 108 conservatively defined loci met genomewide significance (18). Associations found that were relevant to hypotheses of the etiology and treatment of schizophrenia included DRD2 (the target of antipsychotic drugs) and multiple genes (e.g., GRM3, GRIN2A, SRR, GRIA1) involved in glutamatergic neurotransmission and synaptic plasticity. Epidemiological studies have also long hinted at a role for immune dysregulation involving the MHC in schizophrenia; the findings also provided genetic support for this hypothesis.

Another large multisite study was recently conducted to characterize 12 neurophysiological and neurocognitive endophenotypic measures in schizophrenia. Several genes of potential interest were identified: HTR6 on chromosome 1p36 (emotion recognition), ZNF804A on 2q32 (sensorimotor dexterity), ATXN7 on 3p14 (the antisaccade task), DAT on 5p15 (prepulse inhibition), GRIN2B on 12p12 (face memory), and YWHAE on 17p13 (multivariate cognitive phenotype) (19). Many of the candidate genes are involved in neurotransmission, synaptic plasticity, and brain development. Genetic markers involving the MHC along chromosome 6 are of great interest (20). The complement activation cascade is normally integral to the immune system’s ability to eliminate pathogens. However, excessive complement, particularly component 4 mediated synapse elimination, may play a role in the development of schizophrenia. In the brain, microglia are phagocyte immune cells that express complement receptors. Inappropriate or intense synaptic pruning may be explained by this aberrant immunological function (21, 22). Advanced paternal age has also been linked to schizophrenia, possibly implicating de novo mutations in paternal germ cells. One study found that the odds of schizophrenia occurring among offspring of fathers 45 years old or older were 2.8 times as great as among offspring of fathers ages 20–24 years (23). However, in a large meta-analysis, increased genetic risk from the mother was thought to explain the association between advanced paternal age and psychosis and argued against the de novo mutation hypothesis. Instead, assortative mating may contribute to the observed association between advanced paternal age and maternal schizophrenia (24).

Gestational, Nutritional, and Immune System Factors

A host of environmental factors are also implicated in the development of schizophrenia. These include maternal factors such as immigration, perinatal factors (infections, inflammation, obstetrical complications, maternal stress, and fetal hypoxia), and winter births (25–27). Evidence of vascular involvement, including enlarged retinal venule calibers, are possibly related to genes regulated by hypoxia, altered cerebral blood flow, and mitochondrial dysfunction (26). Higher winter birth rates may be associated with gestational infections such as influenza or vitamin D deficiency. Famines leading to malnutrition during neurodevelopment are also implicated in schizophrenia (26, 27). Folate deficiency in particular has been identified as a risk factor for schizophrenia in epidemiologic and gene-association studies. Low serum folate levels are correlated with negative symptoms of patients with schizophrenia. Elevated concentrations of homocysteine in the third trimester of maternal serum was correlated with a twofold risk of schizophrenia for the offspring. The low functioning 677C>T (222Ala>Val) variant in the methylenetetrahydrofolate reductase gene is overrepresented among patients with schizophrenia. Misvariants in three other genes that regulate 1-carbon metabolism—folate hydrolase 1 (FOLH1), methionine synthase (MTR), and COMT—are correlated with negative, but not positive, symptoms in schizophrenia. On the basis of preliminary trials, folate plus vitamin B12 supplementation may improve negative symptoms of schizophrenia for such genetically susceptible individuals (28).

Cytokines are signaling molecules of the immune system that exert effects in the periphery and the brain. They are produced by both immune and nonimmune cells and exert their effects by binding specific cytokine receptors on a variety of target cells. There is evidence of an increased prevalence of aberrant cytokine levels among patients with schizophrenia. Infection may induce maternal immune activation, which subsequently leads to a cytokine-mediated inflammatory response in the fetus. The timing of the insult to the developing fetus may also play an important role. Associations between schizophrenia and second-trimester influenza, rubella, respiratory infection, polio, measles, and varicella-zoster have been implicated (29). Toxoplasma gondii (a protozoan) infection of pregnant women may cause congenital deafness, retinal damage, seizures, and mental retardation. In addition, serum antibodies to Toxoplasma gondii were also found to be a risk factor for the development of schizophrenia (30). The following are some cytokines and inflammatory pathways that have been studied and found to be potentially associated with schizophrenia: tumor necrosis factor (TNF) and interleukin 1 (IL-1), IL-6, and IL-8 (31, 32). Aside from their effects on neurotransmission, particularly dopamine, antipsychotics may additionally have a balancing effect on immune responses, perhaps accounting for the delayed response seen in many cases (33). For instance, antipsychotic treatment has been found to modulate plasma levels of soluble IL-2 receptors and to reduce the plasma levels of IL-1β and interferon-γ (IFN-γ) (33, 34). Anti-inflammatory effects of aspirin, N-acetylcysteine, and estrogens have also been found to be beneficial in treating schizophrenia (35). In a recent meta-analysis, some cytokines (IL-1β, IL-6, and transforming growth factor-β [TGF-β]) were hypothesized to be state markers for acute exacerbations, whereas others (IL-12, IFN-γ, TNF-α, and soluble IL-2 receptor) may be trait markers (36).

Brain Injury, Traumatic Events, Cannabis, and Immigration

Environmental insults, such as traumatic brain injury, childhood traumatic events, and cannabis use, are also implicated in schizophrenia (25, 37). Compared with native-born populations, immigrant populations, particularly those that face discrimination, have a considerable risk of schizophrenia. However, the exact mechanism of the environmental contribution to this risk remains poorly understood (38). Traumatic histories are common among patients with schizophrenia, and childhood traumatic events are associated with the development of schizophrenia. Patients diagnosed as having comorbid schizophrenia and posttraumatic stress disorder have worse symptoms, higher rates of suicidal thoughts, and more frequent hospitalizations (39).

Neurotransmitters and Receptors

In 1975, Seeman et al. discovered that haloperidol bound to dopamine sites with higher potency than did other neurotransmitters. These sites were named antipsychotic/dopamine receptors (now called D2 receptors). The research team further delineated antipsychotics by a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients. They found that a minimum occupancy (65%) of D2 receptors was needed for antipsychotic benefit (40). The “dopamine hypothesis” was thus born and has long been used to describe the underlying pathophysiology of schizophrenia. However, mounting research implicates the dysregulation of other pathways such as glutamatergic, opioid, GABA-ergic, serotonergic, cholinergic, and possibly other systems (41).

The N-methyl-d-aspartate (NMDA) receptor is a glutamatergic receptor that has been of great interest to schizophrenia researchers, particularly with regard to recently discovered receptor subunits. NMDA receptors may be involved in brain overactivity caused by withdrawal of sedatives such as alcohol, resulting in agitation and seizures. The NMDA antagonists phencyclidine and ketamine induce a psychosis among healthy individuals that can mimic schizophrenia (42, 43). In addition, neuroimaging studies using magnetic resonance spectroscopy have linked GABA and NMDA receptors to abnormal brain connectivity of individuals with schizophrenia (44). Reduced NMDA receptor activity can lead to sensory deficits, generalized cognitive deficits, impaired learning and memory, thought disorder, negative symptoms, positive symptoms, gating deficits, executive dysfunction, and dopamine dysregulation (45). NMDA receptor sites have now been identified with sophisticated three-dimensional crystallographic studies. These subunits may help lead to new discoveries, because endogenous ligands or pharmacological substances are known to modulate NMDA receptor activity in a subunit selective fashion (46). GABA-ergic inhibitory function is also of great interest for novel drug development (47).

Neuroimaging

Expanding data in neuroimaging has found evidence that individuals with schizophrenia have enlarged ventricles and cortical tissue loss of about 5% of brain volume (48). Some affected structures include the hippocampus, superior temporal cortex, and the prefrontal cortex. Functional MRI studies have found evidence of hyperactivity in the hippocampus and the dorsal lateral prefrontal cortex, leading some researchers to believe that a loss of inhibitory neuron function may be responsible for some of the symptoms in schizophrenia. A combination of structural and functional imaging strategies is currently being investigated to look for patterns of brain connectivity, particularly around the time when clinically high-risk individuals transition into full-blown psychosis (49). Progressive brain changes over time have been associated with a poorer prognosis. Some studies also suggest that antipsychotic medications have a subtle but measurable influence on brain tissue loss over time (50).

Prodromal State and Synaptic Pruning

Approximately 80%−90% of patients with schizophrenia have a “prodrome” lasting up to one year, characterized by “attenuated” psychotic symptoms that appear to be on a continuum with softer forms of psychotic symptoms such as delusions and hallucinations. These symptoms may include unusual, odd, or overvalued beliefs, guardedness, or auditory hallucinations. Schizophrenia is thought to derive primarily from deficits in dendritic spines that arise during development, thus posing another challenge to researchers (51).

From embryonic development to about the age of two years, new neurons and synapses are formed rapidly. This results in far more neurons and synapses than are needed. Synaptic pruning is the process by which these extra synapses are eliminated, thereby increasing the efficiency of the neural network. The entire process continues up until approximately 10 years of age, by which time nearly 50% of the synapses present at two years of age have been eliminated. The pattern and timeline of pruning may differ in various regions of the brain (51). This process of “editing” of brain connections—in which excess material is discarded—is a mechanism that remains elusive. The cytokine and microglial mediated synaptic pruning and dendritic retraction provide a hypothesis for the disease mechanism seen in the brains of individuals with schizophrenia (52).

Illness Course

Adolescent or young adult patients often present with the prodrome of symptoms described above in which patients function below their baseline level prior to meeting the full criteria for schizophrenia. This time period is also sometimes referred to as an “at-risk mental state.” It can be challenging to differentiate this from a mood disorder, substance abuse, attentional disorders, or maladaptive personality features (25, 53). There are also studies revealing overlaps between autism spectrum disorders and schizophrenia. Childhood-onset schizophrenia is a rare subtype. Genomewide copy number variation studies have identified rare mutations that are strong risk factors for both autism spectrum disorders and schizophrenia. Nevertheless, early intervention is considered vital in reducing adverse outcomes (25, 54).

Expressed Emotions and Recidivism

Numerous studies have demonstrated that high levels of expressed emotions (EE) in families of patients with schizophrenia are associated with relapses. Researchers since the 1950s have found that EE is an important environmental stressor that can worsen psychopathology and can often contribute to recidivism. For example, families or caregivers may use a negative tone of voice to convey their feelings of hostility (anger, criticism, rejection, irritability, ignorance, etc.), which ultimately can lead to patient decompensation. Case management interventions such as psychoeducation, improved communication skills, and healthy coping strategies, along with medication adherence, can be effective strategies in reducing high EE and decreasing recidivism (55, 56).

Prognostic Considerations

Because the disease is variable, schizophrenia researchers over the past several decades have been examining prognostic indicators. In general, prognostic outcomes are considered better for females and with higher premorbid levels of social adjustment (e.g., being married, higher education levels, occupational status), rapid as opposed to slow onset of psychotic symptoms, positive as opposed to negative symptoms, and having a family environment with low EE scores. Indicators for higher risk of relapse are a genetic history of schizophrenia, a baseline schizoid personality disorder, earlier age of onset, higher levels of negative symptoms, and longer inpatient treatment (57). Religious, spiritual, artistic, and cultural issues are often pertinent to explore in interactions with patients, and psychiatrists and other clinicians should make efforts to use a person-centered approach during rapport building and treatment. However, aggressively challenging delusions is not generally effective and may agitate or create mistrust among patients with psychosis (58). Occasionally, patients can incorporate caregivers into their delusional system and thus pose a serious challenge to treatment.

Patients with schizophrenia have a lower overall life expectancy in comparison with that of the general population. This is likely due to a lack of overall quality of health and behavioral issues such as high blood pressure, diabetes, cancer, poor diet, lack of exercise, and cardiopulmonary diseases. Half of all patients with schizophrenia smoke cigarettes, a major contributor to comorbid health problems (59).

Comorbidity Issues

Teasing apart schizophrenia symptoms from those of other comorbid disorders can be difficult. Multiple studies worldwide have found that depression, anxiety, and substance abuse are found more often among patients with schizophrenia than in the general population (60, 61). It is difficult to know whether these problems are part of the syndrome of schizophrenia or a result of having the illness. For example, if a young patient is also abusing substances, a first episode of psychosis can present a challenging clinical problem. One study suggested that 44% of such patients turned out to have had a drug-induced psychosis and that 56% of patients later developed schizophrenia as their primary diagnosis (61, 62). Adolescents with a polymorphism (Val¹⁵⁸Met) of the COMT gene may be especially vulnerable to developing schizophrenia after cannabis abuse (62).

Obsessive-compulsive disorder (OCD) also has been found at an increased rate (up to 12.5-fold) in schizophrenia. Conversely, there is a 3.77-fold increased risk of schizophrenia among patients with OCD. For some patients, depression and OCD are part of a prodrome for schizophrenia (61, 63).

Legal and Ethical Issues

Contrary to popular belief, the proportion of violent crimes committed by people diagnosed with a severe mental illness is small. Despite portrayals in mass media, strangers are at a lower risk of being violently attacked by someone who has a severe mental disorder than by someone who is mentally healthy (64). However, the presence of substance abuse, treatment nonadherence, and persecutory delusions are associated with a greater risk of violence. Family members and friends are at the highest risk of being victimized by a violent patient who has a severe mental illness (64, 65). The presence of psychosis from a severe mental illness is a common basis for the insanity defense used in criminal law in most states and in the federal jurisdiction of the United States. Forensic psychiatrists often reconstruct the accused individual’s lifelong history to determine whether a severe mental illness such as schizophrenia or some other condition, including malingering (faking), is present (66).

Patients with schizophrenia may become severely disabled by their symptoms. Examples include an inability to care for themselves (e.g., maintaining proper sustenance, shelter, or medical care) or a risk of harming themselves or others. The legal system is often involved to advocate for treatment and is balanced against the patient’s individual freedom and autonomy. For example, a guardian or surrogate decision maker may be legally appointed to make financial or medical decisions on the patient’s behalf. It may also become necessary for patients to be held involuntarily (civilly committed) for a period in an inpatient treatment facility or residential care facility. Medications may be forced on patients in some jurisdictions, usually on the basis of imminent harm criteria such as risk of harm to self or others. The use of injectable medications may become useful in the treatment of nonadherent patients. Obtaining consent for treatment can be challenging with patients who lack insight into their illness. Information should be titrated gradually to ethically treat the patient while revealing important potential harmful side effect issues as the patient regains the capacity to understand them (66–68). Patients with severe mental illnesses, including schizophrenia, have long been the subject of oppression, imprisonment, and even genocide under the Nazi regime. It is therefore critically important for psychiatry to maintain proper ethical codes of conduct with respect to the research and treatment of its most vulnerable populations (69).

Conclusions

Schizophrenia is a complex and chronic disorder with profound effects on patients, families, and communities. There is no unifying single feature of schizophrenia; psychiatrists have long hypothesized that schizophrenia is a multifactorial disease (or diseases) of the brain, which has in common similar symptoms and effects on functioning. Important advances in genetics, immune function, neuroanatomical markers, and neurodevelopment have increased our understanding of the underlying pathophysiology associated with the illness. In the coming years, we hope that further elucidating the pharmacogenetics, immunological aspects, and neurodevelopmental aspects of schizophrenia will allow for the discovery of novel treatments targeted to individual patients, ideally very early in the course of the illness.