Chapter 12

Schizophrenia Spectrum and Other Psychotic Disorders

Matilda Azis, Ivanka Ristanovic, Andrea Pelletier-Baldelli, Hanan Trotman, Lisa Kestler,
Annie Bollini, and Vijay A. Mittal

Chapter contents

History and Phenomenology 248

Conceptions and Classification of Psychosis 249
The Origins of Schizophrenia 255
Onset, Course, and Prognosis 259
Evidence-Based Interventions 264
Summary 268
References 269
248 | MATILDA AZIS E T AL.

Schizophrenia is among the most debilitating of mental illnesses. It is typically diagnosed between 20 and 25 years of age, a stage
of life when most people gain independence from parents, develop relationships, plan educational pursuits, and begin work or
career endeavors (De Lisi, 1992). Because the clinical onset usually occurs during this pivotal time, the illness can have a profound
negative impact on the individual’s opportunities for attaining social and occupational success, and the consequences can be devas-
tating for the patient’s life course, as well as for family members (Addington & Addington, 2005). Further, the illness knows no
national boundaries. Across cultures, estimates of the lifetime prevalence of schizophrenia range around 1% (Arajarvi et al., 2005;
Jongsma et al., 2018; Keith, Regier, & Rae, 1991; Kulhara & Chakrabarti, 2001; Torrey, 1987), although there is some research indi-
cating that the rate may be as low as 0.4% with more stringent measurement criteria (Saha, Chant, Welham, & McGrath, 2005).
Studies also suggest that the prognosis may differ among countries, with better outcomes in developing nations (Kulhara & Chakra-
barti, 2001), and there is strong evidence to suggest a link between migration and increased risk (Cantor-Graae & Selten, 2005).
However, more recent evidence suggests that variation in prognosis may not be that straightforward as there appear to be differences
within individual developing nations in course of illness, as well as discrepancies in measurement and access to care (Snowden &
Yamada, 2005). Access to treatment may be associated with better outcome across countries (Cohen, Patel, Thara, & Gureje, 2008;
Jorm, Patten, Brugha, & Mojtabai, 2017).
The origins of schizophrenia have continued to elude researchers, despite many decades of scientific research. To date, no single
factor has been found to characterize all patients with the illness. This holds for potential etiological factors, as well as clinical phe-
nomena. Patients with schizophrenia vary in symptom profiles, developmental histories, family backgrounds, cognitive function,
and even brain morphology and neurochemistry. Although this has led some to express dismay at the chances of ever finding the
cause of schizophrenia, research efforts have succeeded in revealing numerous pieces of what is now recognized as a complex puzzle
of etiological processes.
Based on findings from various lines of research, the consensus in the field is that:

1. Schizophrenia is a brain disease

2. Its etiology involves the interplay between genetic and environmental factors
3. Multiple developmental pathways eventually lead to disease onset
4. Brain maturational processes play a role in the etiological process.

In this chapter, we provide an overview of the current state of our knowledge about schizophrenia. We begin with a discussion of
history and phenomenology of the disorder, and then proceed to a description of some of the key findings which have shed light
on the risk factors, the development and the progression of this illness, and finally to a discussion of evidence-based
interventions.

History and Phenomenology

Written descriptions of patients experiencing psychotic symptoms (i.e., symptoms indicative of an inability to discern what is
reality), similar to those of what we now call schizophrenia, have been recorded since antiquity. However, because psychotic symp-
toms can be a manifestation of a variety of disorders, it is unclear whether schizophrenia, as we view it today, is an ancient or a
relatively new phenomenon. In the mid- to late-19th century, European psychiatrists were investigating the etiology, classification,
and prognoses of various types of psychosis. The term psychosis refers broadly to the presence of psychotic symptoms and may include
various diagnoses such as schizophrenia-related diagnoses, together with mood disorders with psychotic features. At that time, the
most common cause of psychosis was tertiary syphilis, although researchers were unaware that there was any link between psycho-
sis and syphilis (Kohler & Johnson, 2005). The psychological symptoms of tertiary syphilis frequently overlap with symptoms of
what we now call schizophrenia. The cause of syphilis was eventually traced to an infection with the spirochete, Treponema pal-
lidum, and antibiotics were found to be effective for prevention and treatment of the disorder. This important discovery served to
illustrate how a psychological syndrome can be produced by an infectious agent. It also sensitized researchers to the fact that similar
syndromes might be the result of different causes.
Emil Kraepelin (1856–1926), the medical director of the famous Heidelberg Clinic, was the first to differentiate schizophrenia,
which he referred to as dementia praecox (or dementia of the young) from manic-depressive psychosis (Kraepelin, 1913). He also
lumped together “hebephrenia,” “paranoia,” and “catatonia” (previously thought to be distinct disorders) and classified all of them
as variants of dementia praecox. He based this classification on their similarities in age of onset and the clinical feature of poor
prognosis. Kraepelin did not believe that any one symptom was diagnostic of dementia praecox, but instead focused on the total
clinical picture and changes in symptoms over time. If a psychotic patient deteriorated over an extended period of time (months/
years), the condition was assumed to be dementia praecox.
Many contemporary mental health professionals continue to expect negative outcomes in those afflicted with schizophrenia,
and this expectation infuses the mental health profession with an unfortunate sense of therapeutic nihilism. Yet, while it is true that
the majority of patients manifest a chronic course that entails lifelong disability, this bleak scenario is not inevitable (Carpenter &
 SCHIZOPHRENIA SPEC TRUM AND OTHER PSYCHOTIC DISORDERS | 249

Buchanan, 1994). The story of Dr. John Nash, professor and mathematician at Princeton, as told in the movie A Beautiful Mind, illus-
trates this point: Dr. Nash was able to function at a very high level in his academic field, despite his struggle with schizophrenia.

Conceptions and Classification of Psychosis

Early Conceptions of Schizophrenia

The term schizophrenia was introduced at the beginning of the 20th century by Eugen Bleuler (1857–1939), a Swiss psychiatrist and
the medical director of a mental hospital in Zurich (Howells, 1991, pp. xii, 95). The word is derived from two Greek words: schizo,
which means to tear or to split, and phren, which has several meanings: in ancient times, the word phren, meant “the intellect” or “the
mind”; phren also referred to the lungs and the diaphragm, which were believed to be the seat of emotions. Thus, the word schizo-
phrenia literally means the splitting or tearing of the mind and emotional stability of the patient.
Bleuler classified the symptoms of schizophrenia into fundamental and accessory symptoms. The fundamental symptoms of
schizophrenia are often reported in textbooks as the four As, although, in fact, there are five As and one D (Bleuler, 1950). These
fundamental symptoms are listed in Box 12.1. According to Bleuler, these symptoms are present in all patients, at all stages of the
illness and are diagnostic of schizophrenia.

Box 12.1 Bleuler’s Fundamental Symptoms of Schizophrenia

● Disturbances of association (loose, illogical thought processes).

● Disturbances of affect (indifference, apathy, or inappropriateness).
● Ambivalence (conflicting thoughts, emotions, or impulses which are present simultaneously or in rapid succession).
● Autism (detachment from social life with inner preoccupation).
● Abulia (lack of drive or motivation).
● Dementia (irreversible change in personality).

Bleuler’s “accessory symptoms” of schizophrenia included delusions, hallucinations, movement disturbances, somatic symp-
toms, and manic and melancholic states. In contrast to fundamental symptoms, he believed that these accessory symptoms were not
present in all patients with schizophrenia and often occurred in other illnesses. For these reasons, he assumed that the accessory
symptoms were not as diagnostic of schizophrenia.
Further refinements in the diagnostic criteria for schizophrenia were proposed by Kurt Schneider (1959) in the mid-1900s.
Like Bleuler, Kurt Schneider thought that certain “key” symptoms were diagnostic of schizophrenia. In his classification, he referred
to these diagnostic symptoms as “first rank symptoms” (see Box 12.2). He believed that, after medical causes of psychosis were
ruled out, one could make the diagnosis of schizophrenia if one or more first rank symptoms were present. Schneider’s descriptions
of the symptoms were more detailed and specific than were Bleuler’s fundamental symptoms. Subsequent diagnostic criteria for
schizophrenia have been heavily influenced by Schneider’s approach (Nordgaard, Arnfred, Handest, & Parnas, 2008).

Box 12.2 The Schneiderian “First Rank Symptoms”

● Thought echoing or audible thoughts (the patient hears his thoughts out loud).
● Thought broadcasting (patient believes that others can hear his thoughts out loud).
● Thought intrusion (patient feels that some of his thoughts are from outside; that is, not originating in his own mind).
● Thought withdrawal (patient believes that the cause of having lost track of a thought is that someone is taking his thoughts away).
● Somatic hallucinations (unusual, unexplained sensations in one’s body).
● Passivity feelings (patient believes that his thoughts, feelings, or actions are controlled by another or others).
● Delusional perception (a sudden, fixed, false belief about a particular everyday occurrence or perception.

Following longitudinal research in the 1960s, German researcher Gerd Huber laid out a list of symptoms that were evident
(through retrospective study) in the early course of illness as well as in the later stages of psychosis (Huber, Gross, Shuttler, & Linz, 1980).
These symptoms are termed “basic symptoms” and generally refer to symptoms reported by the patient himself and include impairment
in cognition, perception, motor function, will, initiative, level of energy, and tolerance of stress (Olson & Rosenbaum, 2006).
250 | MATILDA AZIS E T AL.

Moving Towards a Modern Conception of Schizophrenia

During the middle of the 20th century, different diagnostic criteria for schizophrenia became popular in different parts of the world.
The “Kraepelinian” tradition, with its longitudinal requirements for diagnosis, identified patients with poorer long-term prognosis.
In contrast, the Bleulerian and Schneiderian diagnostic systems allowed for a wider range of psychotic patients to be diagnosed with
schizophrenia. Thus, the patients diagnosed with these two systems tended to have a better prognosis than those diagnosed in the
more stringent Kraepelinian tradition. Because of these discrepancies, the use of multiple diagnostic systems had a detrimental effect
on research progress; research findings from countries using different diagnostic criteria were not comparable, thus limiting the
generalizability of the results.
The next generation of diagnostic systems evolved with the intent of achieving uniformity in diagnostic criteria and improving
diagnostic reliability. Among these were the “Feighner” or “St. Louis” diagnostic criteria (Feighner, Robins, & Guze, 1972), and the
Research Diagnostic Criteria developed by Robert Spitzer and his colleagues (Spitzer, Endicott, & Robins, 1978). These two
approaches to the diagnosis of schizophrenia strongly influenced modern-day diagnostic systems.

Updating Our Conceptions of Schizophrenia

While investigators have continued to focus on positive symptoms (excess of ideas, sensory experiences or behavior) such as hal-
lucinations, delusions, and bizarre behaviors, recently there has also been a renewed Bleulerian approach to core phenomenology,
including negative symptomatology, social processing dysfunction, and cognitive deficits.

Negative Symptoms
While most of the first-rank symptoms described by Schneider are also considered to be positive symptoms, negative symptoms,
in contrast, involve a decrease in behavior, such as blunted or flat affect and lack of motivation. A wide range of negative symptoms
such as anhedonia (lack of enjoyment), avolition (lack of volition), emotional withdrawal, social isolation, apathy (lack of interest),
and deterioration in role functioning are frequently reported in patients with schizophrenia (Bobes, Arango, Garcia-Garcia, & Rejas,
2010). Negative symptoms typically emerge several years prior to the onset of a psychotic disorder – in the prodromal phase. This
phase is characterized by attenuated symptoms: mild, less severe, or less frequent psychotic-like symptoms. Negative symptoms typ-
ically emerge before positive symptoms in this phase (Schmidt et al., 2017), they are associated with poor functional outcome
(Milev, Ho, Arndt, & Andreasen, 2005), they are highly debilitating to the patient, and they pose a substantial burden on the carers
and families of patients with schizophrenia and health-care systems. (Milev et al., 2005; Sicras-Mainar, Maurino, Ruiz-Beato, &
Navarro-Artieda, 2014). Compounding the importance of these symptoms, several studies have found that they are persistent (Haro
et al., 2018), associated with relapse (Bowtell, Ratheesh, McGorry, Killackey, & O’Donoghue, 2017), and associated with cognitive
decline (Sum, Tay, Sengupta, & Sim, 2018).
Due to these factors there has been a recent focus on the assessment and treatment of negative symptoms in schizophrenia.
A recent meta-analysis found few interventions focused on these symptoms, and most treatments were not clinically meaningful
(Fusar-Poli et al., 2015). Therefore, such symptoms can result in a dramatic reduction in quality of life.
A further route of exploration in this area has been to examine the concept of negative symptoms, how they can be defined,
and whether all symptoms fall under one category, or whether there are several different distinct constructs included under the
umbrella term of negative symptoms. A consensus has been reached to incorporate five domains of negative symptoms: blunted
affect, alogia, asociality, anhedonia, and avolition (Kirkpatrick, Fenton, Carpenter Jr., & Marder, 2006), and several studies have
confirmed the presence of two distinct dimensions within the five domains of negative symptoms: avolition–apathy and expressive
deficit (Blanchard & Cohen, 2005; Strauss et al., 2013). This distinction may contribute to our understanding of the pathophysio-
logical mechanisms underlying these symptoms and lead to new treatments for this debilitating facet of schizophrenia.

Social Processing Deficits

Among the core features of schizophrenia are social processing deficits (Savla, Vella, Armstrong, Penn, & Twamley, 2013). Studies of
social-cognitive abilities in schizophrenia patients have consistently shown that they are impaired in their ability to comprehend
and solve social problems, processing of emotions, social perception, attribution of events, and theory of mind (the ability to per-
ceive the judgments, beliefs, intentions, and emotions of others; Green & Horan, 2010; Hooley, 2010; Meherwan Mehta et al.,
2013; Penn, Corrigan, Bentall, Racenstein, & Newman, 1997; Tseng et al., 2015). These deficits also adversely affect functional
outcome in patients (Javed & Charles, 2018). Social-cognitive imaging studies consistently point to abnormalities in brain regions
and circuitry associated with social processing, adding to the evidence that social-cognitive impairment is a hallmark feature of
schizophrenia (Fujiwara, Yassin, & Murai, 2015; Modinos et al., 2015).
Deficits in social cognition may be partially due to limitations in more basic cognitive processes, such as memory and reasoning
(Kring & Elis, 2013). However, basic cognitive impairments do not account completely for the more pervasive and persistent social-
cognitive dysfunction observed in schizophrenia, and there is increasing evidence to support the idea that social cognition is a
separate construct (Meherwan Mehta et al., 2013). For example, imaging studies show that there is something unique in brain
 SCHIZOPHRENIA SPEC TRUM AND OTHER PSYCHOTIC DISORDERS | 251

activation when an individual is involved in a social versus strictly cognitive task (Viviano et al., 2018), and other research finds
that social cognitive and cognitive tasks often load on different domains when evaluated together using a statistical technique called
factor analysis (Billeke & Aboitiz, 2013).
One of the diagnostic criteria for schizophrenia is blunted or inappropriate affect. It is not surprising therefore, that patients
show abnormalities in the expression of emotion in both their faces and verbal communications (Zou et al., 2018). These abnor-
malities include less positive and more negative emotion, as well as emotional expressions that seem inconsistent with the social
context (termed inappropriate affect; Brozgold et al., 1998; Tremeau et al., 2005). Further, patients with schizophrenia are less
accurate than unaffected comparison subjects in their ability to label facial expressions of emotion, with a particular difficulty in
labeling fear and sadness (Amminger et al., 2012; Bigelow et al., 2006; Penn et al., 2000, Martin, Baudouin, Tiberghien, & Franck,
2005, Walker, 1981). Numerous studies have examined the link between social-cognitive impairments, such as emotional process-
ing and social functioning, indicating a strong relationship between poor social-cognitive ability and social difficulties (Moran,
Culbreth, & Barch, 2018; Salva et al., 2013). Specifically, research indicates that social cognition may be more closely tied to func-
tioning than other cognitive domains, suggesting that social cognition may be especially informative for understanding etiology
and developing treatment (Fett et al., 2011; Silberstein, Pinkham, Penn, & Harvey, 2018).
Patients with schizophrenia demonstrate deficits in motivation, decision-making, and learning that suggest impairments in
aspects of the reward system, the system responsible for generating a response to rewarding stimuli (Gold, Waltz, Prentice, Morris, &
Heerey, 2008). This is strongly related to negative symptoms such as anhedonia and apathy (Simon et al., 2010); however, several
studies have found no difference in self-reported anhedonia and apathy between patients with schizophrenia and healthy controls
(Taylor et al., 2012), and a review of the research found that motivational impairments may be associated with difficulty translating
reward information into motivated behavior rather than a deficit in hedonic experience (Strauss, Waltz, & Gold, 2014).

Cognitive Deficits
Among the most well-established aspects of schizophrenia are the cognitive impairments that accompany the illness (Nuechterlein,
Ventura, Subotnik, & Bartzokis, 2014). Neurocognitive deficits are found in the premorbid phase (the phase before the emergence
of symptoms, prior to the prodromal phase), in a substantial minority of youth who later develop schizophrenia, and these deficits
typically worsen over disease course. The degree of cognitive impairment has also been found to be strongly related to social and
role functioning in the illness (Seidman & Mirsky, 2017). Furthermore, research has shown that cognitive deficits persist during
symptomatic remission (Hoff et al., 1999). In fact, some experts argued that cognitive impairment should have been added as a
characteristic symptom in the DSM-5 (Keefe & Fenton, 2007). The DSM-5 Task Force decided against making this recommendation
because of its lack of diagnostic specificity.
Similar to negative symptoms, a consensus was reached by the National Institute of Mental Health’s (NIMH) Measurement and
Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, defining seven cognitive domains affected in
schizophrenia: processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem
solving, and social cognition (Nuechterlein et al., 2008). Patients with schizophrenia manifest performance deficits on a broad
range of cognitive tasks, from simple to complex (Elvevag & Goldberg, 2000; Keefe & Harvey, 2012), and a recent meta-analysis
examining the longitudinal prevalence of cognitive deficits over the disease course of schizophrenia found that deficits were present
before the prodromal phase, supporting a neurodevelopmental model of cognitive decline (Bora & Murray, 2014).
One of the most basic cognitive deficits present in the very earliest stages of the disease course is an impairment in visual
information-processing. Using a laboratory procedure called backward masking, researchers have shown that compared with both
healthy individuals and psychiatric controls, patients with schizophrenia are slower in the initial processing of stimuli (Green, Nuech-
terlein, Breitmeyer, & Mintz, 1999, 2006). Deficits also have been found in perceptual functioning. Individuals with schizophrenia
tend not to be susceptible to optical illusions such as perceiving two-dimensional objects in three-dimensional form. This type of
perceptual impairment can actually produce superior performance on certain tasks such as depth inversion illusions, in which concave
faces appear as convex (Keane, Silverstein, Wang, & Papathomas, 2013). Of note, there is some evidence that nicotine is beneficial to
such cognitive impairments, and there is ongoing work evaluating its effectiveness in clinical trials (Gee et al., 2017; Kem et al., 2018).
There is current debate as to whether the cognitive deficits present in schizophrenia are part of a single broad impairment
(Dickinson, Goldberg, Gold, Elvevag, & Weinberger, 2011; Dickinson, Iannone, Wilk, & Gold, 2004), or whether the deficits are
present in specific domains (Repovs, Csernansky, & Barch, 2011). Growing evidence supports the theory that both general and
specific cognitive deficits are present (Fornito, Yoon, Zalesky, Bullmore, & Carter, 2011; Sheffield et al., 2014).

Current Approaches to Classification

The two diagnostic systems currently in use for schizophrenia and other mental disorders are the Diagnostic and Statistical Manual of Mental
Disorders (DSM), used predominantly in the United States (American Psychiatric Association, 2013) and the International Statistical Clas-
sification of Diseases and Related Health Problems (ICD) used predominantly in Europe (World Health Organization, 1992). Dimensional
approaches such as the NIMH’s Research Domain Criteria (RDoC) are not diagnostic systems, but provide a framework for the
integration of basic behavioral and neuroscience research with our current understanding of mental disorders (Insel et al., 2010).
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Diagnostic and Statistical Manual of Mental Disorders (DSM)

The fifth edition of DSM was published in 2013. Schizophrenia is included with a group of disorders under the category of “Schiz-
ophrenia Spectrum and Other Psychotic Disorders,” reflecting a dimensional understanding of psychosis (Johns & van Os, 2001;
Barch et al., 2013); there are six criteria needed to meet the threshold for diagnosis (Table 12.1). DSM-5 criterion A states that there
must be two characteristic symptoms present from:

1. Hallucinations
2. Delusions
3. Disorganized speech (e.g., frequent derailment or incoherence)
4. Grossly disorganized or catatonic behavior
5. Negative symptoms (i.e., affective flattening, alogia, or avolition).

This is different from previous versions of the DSM, owing to the elimination of allowing for only one of these symptoms to
be sufficient if it is bizarre in nature or if it is a Schneiderian first-rank auditory hallucination (e.g., multiple voices conversing with

Table 12.1 DSM-5 Criteria for Schizophrenia

Criterion Category Description

A Characteristic Two (or more) of the following, each present for a significant portion of time during a 1-month period
symptoms (or less if successfully treated). At least one of these should include 1, 2, or 3.
1. Delusions
2. Hallucinations
3. Disorganized speech
4. Grossly disorganized or catatonic behavior
5. Negative symptoms (i.e., diminished emotion expression or avolition)
B Social/occupational For a significant portion of the time since the onset of the disturbance, level of functioning in one
dysfunction or more major areas, such as work, interpersonal relations, or self-care, are markedly below the level
achieved prior to the onset (or when the onset is in childhood or adolescence, failure to achieve
expected level of interpersonal, academic, or occupational achievement).
C Duration Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include
at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase
symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or
residual periods, the signs of the disturbance may be manifested by only negative symptoms or by
two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual
perceptual experiences).
D Schizoaffective Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been ruled out
and mood disorder because either (1) no major depressive or manic episodes have occurred concurrently with the active
exclusion phase symptoms; or (2) if mood episodes have occurred during active-phase symptoms, they have
been present for a minority of the total duration of the active and residual periods of the illness.
E Substance/general The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a
medical condition medication) or another medical condition.
exclusion
F Relationship to Global If there is a history of autism spectrum disorder or a communication disorder of childhood onset, the
Developmental Delay additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition
or Autism Spectrum to the other required symptoms of schizophrenia, are also present for at least 1 month (or less if
Disorder successfully treated).
Course specifiers 1. First episode, currently in acute episode
2. First episode, currently in partial remission
3. First episode, currently in full remission
4. Multiple episodes, currently in acute episode
5. Multiple episodes, currently in partial remission
6. Multiple episodes, currently in full remission
7. Continuous
8. Unspecified
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each other) (Tandon et al., 2013). The reason for the change relates to a general consensus in the field that there was poor empirical
evidence to support the prior stipulation.
Criterion B emphasizes that, in addition to the presence of characteristic symptoms, there must be significant social/occupational
dysfunction. Schizophrenia can be diagnosed with DSM-5 when these signs and symptoms of the disorder are present for six months
(including prodromal and residual phases – the phases preceding and following the psychotic disorder) (Criterion C). Further,
significant mood disorders, such as depression or mania, along with schizoaffective disorder must be ruled out to ensure that the
symptoms present are not better accounted for by one of these diagnoses (Criterion D). Also, general medical conditions or sub-
stance use that might lead to psychotic symptoms must be ruled out (Criterion E). Finally, Criterion F stipulates that if a pervasive
developmental disorder (PDD) or autistic disorder or other communication disorder of childhood onset is present, schizophrenia
could only be diagnosed if prominent delusions or hallucinations were present for at least one month or less if successfully treated
(Dyck, Piek, & Patrick, 2011; Tandon et al., 2013).
A dimensional rating of severity of core symptoms is included in Section III, a section of the manual that includes tools to
enhance diagnosis. The schizophrenia workgroup had strongly recommended including this dimensional approach in the primary
text section but this decision was overturned at the last minute because the American Psychiatric Association (APA) was concerned
that this would hamper communication between providers and insurance companies (Barch et al., 2013). Despite this, the inclusion
of this new dimensional approach in DSM-5 highlights the heterogeneous presentation of schizophrenia and, in theory, negates the
necessity of subtypes while providing the possibility for increased diagnostic description for more effective communication between
providers (Pagsberg, 2013).
There are eight course specifiers for schizophrenia in DSM-5 that define the acute and longitudinal nature of the illness. These
specifiers indicate whether the episode being assessed is the first episode or one of multiple episodes, along with coding whether
the episode is active (currently in acute episode) or in full or partial remission. Finally, there are two course specifiers that allow for
some ambiguity through labeling the episodes as continuous (i.e., the episodes are too continuous to determine a specific course
of symptoms) and unspecified (i.e., the information needed to clarify course of symptoms is lacking). The main purpose of these
changes was to reduce comorbidity and the incidence of the “not otherwise specified” diagnoses as well as to improve diagnostic
communication between healthcare providers. It remains to be seen whether comorbidity and diagnostic ambiguity will lessen and
communication improve through these changes; however, the specifiers do appear to add some specificity to course of illness
description that was absent in previous diagnostic manuals (Tandon et al., 2013).
In Section III of DSM-5, “Emerging Measures and Models,” attenuated psychosis syndrome (APS) has been included, which was not
included in previous editions. This category identifies individuals who do not meet full criteria for schizophrenia, but who
exhibit attenuated (less intense or severe) characteristic symptoms and intact reality testing. These individuals are at heightened
risk of developing a psychosis spectrum disorder. The decision to include the new diagnosis accompanied a fierce debate in the
period leading up to publication. Although expert consensus for the diagnosis is still evolving, the impetus for including APS in
DSM-5 arose from accumulating evidence that high-risk patients are currently ill and at elevated risk for more serious mental
illness (Cannon et al., 2008), the criteria for a risk state can be made with reliability and validity (in a research setting), and no
DSM-IV diagnosis accurately captured the current illness/future risk (Addington et al., 2007; Yung et al., 2007). The proponents
argued that providing a DSM-5 diagnosis could minimize potential harm to patients and families and could improve general
provider education (Woods et al., 2010). Those who argued against the new label suggested that inclusion was premature
because of a lack of information from community-based trials and significant concern about stigma (Shrivastava et al., 2011).
Opponents also questioned the clinical validity of the syndrome because APS is predictive of a number of disorders outside
schizophrenia (e.g., affective psychoses) and therefore, the label is in a non-specific initial stage. These critics also noted that
because a primary focus relates to risk for future illness, a high rate of false positives (i.e., those who do not transition to psy-
chosis) is ethically problematic as it exposes a disproportionate number of youth to unnecessary medications and stigma (Cor-
coran, First, & Cornblatt, 2010). The ultimate decision to place APS in the research section of DSM-5 speaks to the valid points
on both sides of this debate, and to the complex and delicate issues accompanying the diagnosis. A recent study exploring the
stigma of using terms such as APS and Clinical High Risk for Psychosis (CHR) found that patients at risk of psychosis may expe-
rience less stigma related to labels than expected by professionals, and those more likely to experience stigma were those who
have had previous stigmatizing experiences such as a family history of psychosis and those who had transitioned to psychosis
(Kim et al., 2017). However, there is still ongoing debate as to the use of this label with previous proponents van Os and Gulok-
suz arguing that in using such terms we may be applying “misleadingly simple, unnecessary and inefficient binary concepts of
‘risk’ ” (van Os & Guloksuz, 2017).
Several other diagnoses under the ‘schizophrenia spectrum and other psychotic disorders’ group are worth noting. The first is
schizotypal personality disorder (SPD), which now falls both under this grouping, as well as under personality disorders. The diagnostic
criteria for SPD includes social anxiety or withdrawal, affective abnormalities, eccentric behavior, unusual ideas (e.g., persistent
belief in extrasensory perception/phenomena, aliens), and unusual sensory experiences (e.g., repeated experiences with confusing
noises with peoples’ voices, or seeing objects move). Although the individual’s unusual ideas and perceptions are not severe or
persistent enough to meet criteria for delusions or hallucinations, they are recurring and atypical of the person’s cultural context.
An extensive body of research demonstrates genetic and developmental links between schizophrenia and SPD. The genetic link
between SPD and schizophrenia has been documented in twin and family history studies (Barrantes-Vidal Grant & Kwapil, 2015;
254 | MATILDA AZIS E T AL.

Ettinger et al., 2014; Kendler, Neale, & Walsh, 1995; Raine & Mednick, 1995). The developmental transition from schizotypal signs
to schizophrenia in young adulthood has been followed in several more recent longitudinal studies, with researchers reporting that
20–40% of schizotypal youth eventually develop a schizophrenia spectrum disorder (Cannon et al., 2008; Miller et al., 2002; Yung
et al., 1998). The inclusion of schizotypal personality disorder in this grouping again illustrates the shift towards conceptualization
of psychosis on a dimensional continuum.
An additional category, schizophreniform disorder, is for individuals whose symptoms do not meet the six-month criterion. This
diagnosis is frequently made as a prelude to the diagnosis of schizophrenia when the patient presents for treatment early in the
course of the disorder. Some individuals who fall into this category, however, will recover completely and not suffer further episodes
of psychosis.
It is important to emphasize that, despite advances in diagnosis, the diagnostic boundaries of schizophrenia are still quite
unclear (Wolff, 1991). Moreover, the boundaries between schizophrenia and mood disorders are sometimes obscure. Many indi-
viduals who meet criteria for schizophrenia show marked signs of depression or manic tendencies. These symptoms are sometimes
present before the onset of schizophrenia, and frequently occur in combination with marked psychotic symptoms. As a result, the
DSM-5 includes a diagnostic category called schizoaffective disorder. This disorder can be conceived of as a hybrid between the mood
disorders (bipolar disorder or major depression with psychotic features) and schizophrenia. The two subtypes of schizoaffective
disorder are the depressive subtype (i.e., if the mood disturbance includes only depressive episodes) and the bipolar subtype (i.e., where
the symptoms of the disorder have included either a manic or a mixed episode). The prognosis for patients with schizoaffective
disorder is, on average, somewhere between that of schizophrenia and the mood disorders.

International Statistical Classification of Diseases and Related Health Problems (ICD)

The ICD, currently undergoing revision for its 11th edition (released in 2019) is a second diagnostic system used alongside DSM.
The ICD classification system is focused on clinical use and is therefore designed to be practical, clear, and concise for clinical
decision-making. In order to ensure the simple practical implementation of the system, two phases of field-testing were used for
ICD-11, firstly in case-controlled field studies, mental health professionals were presented with cases for diagnosis (Keeley et al.,
2016) to determine reliability; and secondly in a naturalistic setting to determine usability (Keeley & Gaebel, 2018).
Previously (in ICD-10, World Health Organization [WHO], 1992) individuals with schizophrenia were categorized into one of
a set of discrete subtypes. The subtypes each represented a prototypic combination of schizophrenia symptoms, however critics have
argued that these subtypes are not of diagnostic value. The list is not exhaustive and some individuals may not fit in to a specific
subtype, while individuals’ symptomatic presentation may change over time therefore changing the subtype for which they meet
criteria, and furthermore the subtypes have not been found to have distinct course and prognosis (Braff, Ryan, Rissling, & Carpenter,
2013).
Similarly to DSM-5, ICD-11 has moved away from a categorical approach to a more dimensional approach, describing the pres-
ence or absence of clinical symptoms and the relative severity of specific symptoms (Gaebel, 2012; Gaebel, Zielasek, & Cleveland,
2012). The scale includes six domains: Positive Symptoms, Negative Symptoms, Depressive Symptoms, Manic Symptoms, Psycho-
motor Symptoms, and Cognitive Symptoms. A course specifier, similar to DSM-5, is also included. Again, similarly to DSM, APS will
not be included in the main diagnostic categories, but in the “Mental Health States Requiring Further Study” section.
The organizers behind DSM and ICD (APA and WHO, respectively) have worked together to create harmonious systems in more
recent editions; however, there are differences between the two publications. Whereas the ICD is aimed at practical implementation
by a wide range of professionals, DSM is mainly targeted at mental health specialists, and includes more detailed descriptions, rec-
ommendations, and assessments. This is evident in schizoaffective disorder: there is no longitudinal criteria in ICD-11 so as to
simplify the diagnostic process, whereas DSM-5 maintains the longitudinal approach, making a time-consuming history taking
necessary (Biedermann & Fleischhacker, 2016).

Dimensional Approaches
A dimensional approach argues that a categorical approach such as that used in the DSM and ICD, where diagnosis is determined on
the basis of symptoms and characteristics typical of a disorder into discrete and distinct disorders, does not accurately represent
clinical presentation. Such a categorical approach does not take into account that significant overlap may exist between different
diagnostic categories, while imposing categories on dimensional phenomena may lead to a simplistic picture, missing valuable
clinical information due to the need to achieve diagnostic reliability (Brown & Barlow, 2009). Several dimensional approaches have
been proposed:

1. Research Domain Criteria (RDoC): In 2009, the NIMH (one of the primary funding sources for research on schizophrenia)
created a working group to set in motion efforts to develop new ways of classifying psychopathology based on dimensions
of observable behavior and neurobiological measures. This allows for a new approach to research aimed at cutting across
diagnostic labels to create improved classification of mental disorders through understanding underlying dimensions of
functioning. This approach, views schizophrenia not as a specific disease, but rather as a syndrome that is composed of
several symptom dimensions and represents one segment of a broad spectrum of serious mental illness (Morris,
 SCHIZOPHRENIA SPEC TRUM AND OTHER PSYCHOTIC DISORDERS | 255

Vaidyanathan, & Cuthbert, 2016). Further, a focus of this initiative is to integrate multiple levels of analysis including genes,
behavior, and neurobiology with the hope of translating basic research into improved understanding of psychopathology
and better targeted treatment (Insel et al., 2010).
2. The Hierarchical Taxonomy Of Psychopathology (HiTOP): This is another empirically driven classification system based on
advances in quantitative research on the organization of psychopathology. Mental health is defined as a spectrum from normal-
ity to pathology with no arbitrary cut off for diagnosis. In accordance with recent empirical evidence, HiTOP also does not
categorize risk factors for diagnosis, but rather identifies risk profiles for certain symptomatic presentations. HiTOP posits that
psychopathology is hierarchically structured: level 1 – symptoms/signs; nested within level 2 – syndromes/traits; nested
within level 3 – factors; nested within level 4 – broad spectra (Kotov et al., 2017). While RDoC is aimed at examining genetic
and neurobiological factors contributing to symptomatology, HiTOP focuses on the structure of the symptoms themselves, to
provide an empirical organization of psychopathology (Hengartner & Lehmann, 2017). Similarly to RDoC, this allows us to
think of schizophrenia as several symptom dimensions graded on a continuum.
3. Systems Neuroscience of Psychosis (SyNoPsis): This is a conceptual framework specifically for schizophrenia and defining it as
a disorder of interindividual communication. This is done in order to disentangle the clinical manifestations of schizophrenia
into behavioral domains and the underlying neurobiological systems. It includes an operational clinical rating scale and defines
psychotic symptoms according to three dimensions: language, affectivity, and motor behavior (Strik, 2017). It includes an
assessment scale strongly rooted in theory (the Bern Psychopathology Scale) and aims to guide theoretically informed research
while directly informing intervention development (Mittal, 2017).

While DSM-5 and ICD-10 are purely diagnostic tools, the dimensional approaches described above provide an alternate framework
for research and have the potential to redefine mental disorders in future versions of the DSM and ICD. This approach is already being
adopted, as has been evidenced by the shift towards incorporating a dimensional approach in both DSM-5 and ICD-11.

The Origins of Schizophrenia

Kraepelin, Bleuler, and other early writers on schizophrenia did not offer specific theories about the origins of schizophrenia. They
did suggest, however, that there might be a biological basis for at least some cases of the illness. Likewise, contemporary ideas about
the origins of schizophrenia focus on biological vulnerabilities that are assumed to be present in early development. Researchers
have identified two sources of constitutional vulnerability: genetic factors and environmental factors (e.g., prenatal or obstetric
complications, traumatic brain injury). Both appear to have implications for prenatal and postnatal brain development, which is a
focus of our understanding of the development of schizophrenia.

The Genetics of Schizophrenia

One of the most well-established findings in schizophrenia research is that a vulnerability to the illness can be inherited (Gottesman,
1991). Behavior genetic studies utilizing twin, adoption, and family history methods have all yielded evidence that the risk for
schizophrenia is elevated in individuals who have a biological relative with the disorder; the closer the level of genetic relatedness,
the greater the likelihood the relative will also suffer from schizophrenia (Hilker et al., 2018).
In a review of family, twin, and adoption studies conducted from 1916 to 1989, Irving Gottesman (1991) outlined the com-
pelling evidence for the role of genetic factors in schizophrenia. Monozygotic twins, who essentially share 100% of their genes,
have the highest concordance rate for schizophrenia. Among monozygotic co-twins of patients with schizophrenia, 25–50% will
develop the illness. Dizygotic twins and other siblings share, on average, only about half of their genes. About 10–15% of the dizy-
gotic co-twins of patients are also diagnosed with the illness (Sullivan, Kendler, & Neale, 2003). Further, as genetic relatedness of
the relative to the patient becomes more distant, such as from first-degree (parents and siblings) to second-degree relatives (grand-
parents, half siblings, aunts, and uncles), the relative’s lifetime risk for schizophrenia is reduced. However, the presence of schizo-
phrenia in a first degree relative does not only increase the risk of schizophrenia, but also many other psychiatric disorders (Cheng
et al., 2017; Shah et al., 2017)
Adoption studies have provided evidence that the tendency for schizophrenia to run in families is primarily due to genetic
factors, rather than the environmental stressors related to growing up in close proximity to a mentally ill family member. In a seminal
adoption study, Heston (1966) examined the rates of schizophrenia in adoptees with and without a biological parent who was
diagnosed with the illness. He found higher rates of schizophrenia, and other mental illnesses, in the biological offspring of parents
with schizophrenia, when compared with adoptees with no mental illness in biological parents. Similarly, in a Danish sample, Kety
(1988) examined the rates of mental illness in the relatives of adoptees with and without schizophrenia. He found that the biolog-
ical relatives of adoptees who suffered from schizophrenia had a significantly higher rate of the disorder than the adoptive relatives
who reared them. Also, the rate of schizophrenia in the biological relatives of adoptees with schizophrenia was higher than in the
relatives (biological or adoptive) of healthy adoptees. These adoption studies provide ample evidence for a significant genetic com-
ponent in the etiology of schizophrenia.
256 | MATILDA AZIS E T AL.

Findings from an adoption study in Finland indicate that genetic influences often act in concert with environmental factors.
Tienari, Wynne, Moring, and Lahti (1994) found that the rate of psychosis and other severe disorders was significantly higher
in adoptees who had biological mothers with schizophrenia than in the matched control adoptees who had no history of having
a first-degree relative with psychosis. However, the difference between the groups was only detected in adoptive families that
were rated as dysfunctional. The genetic vulnerability was mainly expressed in association with a disruptive adoptive environ-
ment and was not detected in adoptees reared in a healthy, possibly protective, family environment. A meta-analysis of twin
studies found a high heritability along with significant environmental effects (Sullivan et al., 2003). These findings, which
highlight a genetic vulnerability interacting with environmental events, are consistent with the prevailing diathesis stress models
of etiology.
Taken together, the findings from behavioral genetic studies of schizophrenia lead to the conclusion that the disorder involves
multiple genes, rather than a single gene (Gottesman, 1991; Van Winkel et al., 2010; Wimberley et al., 2017). Consistent with this
assumption, attempts to identify a genetic locus that accounts for a significant proportion of cases of schizophrenia have not met
with success. Instead, researchers using molecular genetic techniques have identified numerous genes that may account for a small
proportion of cases. In the past decade, linkage studies using genome-wide association scans have evaluated over 1,000 genes for
schizophrenia (Gejman, Sanders, & Kendler, 2011, Ruderfer et al., 2018). Association studies compare variations in specific gene
sequences between individuals with and without schizophrenia. Variants found with significantly different frequency among those
with schizophrenia are considered to confer susceptibility to the disease. Results from association studies generally have very small
effect sizes, owing to the large number of gene variants that can potentially be evaluated; thus, while replication is critical, efforts
to do so have met with limited success (Gejman et al., 2011). However, through combining data from multiple studies, results have
uncovered a number of notable common polymorphisms (variations in DNA sequence, such as single nucleotide polymorphisms
involving the alteration in a single nucleotide of the DNA sequence) and copy number variants (variations in DNA structure involv-
ing the number of copies of a section of DNA within an individual’s genotype; Gejman et al., 2011; Insel, 2010; Van Winkel et al.,
2010). Over 100 loci have been shown to be associated with schizophrenia risk as identified by single nucleotide polymorphisms
(SNPs) in genome-wide association studies (Harrison, 2015), however the cumulative effect of common variants found cannot
explain the high heritability of schizophrenia.
More recently, Compliment Component 4 (C4), a small protein found in the blood as part of the immune system, has been the
first specific gene to shown to be associated with schizophrenia risk (Sekar et al., 2016). Although finding only a small effect on
schizophrenia, this was the first study to link genetic variants to biologically meaningful changes in function. A study of copy num-
ber variants (sections of the genome that are repeated) previously found to be associated with schizophrenia demonstrated that
although they had a substantial effect on risk of schizophrenia they were in fact more likely to result in other phenotypes, such as
developmental disorder, autism spectrum disorder, and congenital malformations (Coelewij & Curtis, 2018; Kirov et al., 2014).
Findings from genome-wide association studies (a study of the whole sequence of DNA or genome, to find variations across indi-
viduals) have allowed for the discovery of many risk variants, which has led to the formulation of the Polygenic Risk Score (PRS),
a score based on variation in multiple genetic loci and their associated impact on (Wray et al., 2014), which has been shown to be
associated with increased risk of psychotic disorder (Agerbo et al., 2015) as well as several different psychopathologies within
schizophrenia (Mistry, Harrison, Smith, Escott-Price, & Zammit, 2017).
Despite the large number of genetic variants involved, research postulates that approximately 32% of the underlying contribu-
tion to schizophrenia may be explained by such common polymorphisms (a discontinuous genetic variation dividing individuals
into distinct groups; Purcell et al., 2009; Ripke et al., 2013). However, the genetic basis of schizophrenia has proven to be highly
complex, heterogeneous, and polygenic. Despite advances in molecular genetics, our knowledge of the etiology of schizophrenia
and our understanding of the gene-environment interaction remain limited (Henriksen, Nordgaard, & Jansson, 2017).
Using quantitative genetic techniques with large twin samples, researchers have shown that there is significant overlap in the
genes that contribute to schizophrenia, schizoaffective disorder, bipolar disorder, and other neurodevelopmental disorders such as
autism (Cardno, Rijsdijk, Sham, Murray, & McGuffin, 2002; Fanous & Kendler, 2005; van Winkel et al., 2010). Based on these and
other findings, many experts have concluded that genetic vulnerability does not conform to the diagnostic boundaries listed in DSM
and other taxonomies (Boks, Leask, Vermunt, & Kahn, 2007; Pelletier & Mittal, 2012). Rather, it appears that there is a genetic vul-
nerability to psychosis in general, and that the expression of this vulnerability can take the form of schizophrenia or an affective
psychosis, depending on other genetic and acquired risk factors. Clearly, more research is needed to understand the specificity for
genetic liability for schizophrenia and mood disorders.
As already mentioned, we now know that the environment begins to have an impact before birth; prenatal events are linked
with risk for schizophrenia, and some of these events are discussed below. Thus, in order to index environmental events that con-
tribute to non-genetic constitutional vulnerability, we must include both the prenatal and postnatal periods. There has been inves-
tigation in to epigenetic (heritable changes in gene function that do not involve changes in the DNA sequence) changes that can be
passed on to future generations, suggesting that environmental factors encountered by the parents can possibly affect the child’s
genetic code (Roth et al., 2009). At this point, however, researchers are not in a position to estimate the relative magnitude of the
inherited and environmental contributors to the etiology of schizophrenia. Moreover, we do not yet know whether genetic vulner-
ability is present in all cases of schizophrenia or if some cases of the illness may be solely attributable to environmental risk
factors.
 SCHIZOPHRENIA SPEC TRUM AND OTHER PSYCHOTIC DISORDERS | 257

Neurotransmitter Alterations
The idea that schizophrenia involves an abnormality in the brain first began with a focus on neurotransmission. Initial neurotrans-
mitter theories focused on epinephrine and norepinephrine. Subsequent approaches have hypothesized that serotonin, glutamate,
and/or gamma-aminobutyric acid (GABA) abnormalities are involved in schizophrenia. But, compared with other neurotransmit-
ters, dopamine (DA) has played a more enduring role in theorizing about the biochemical basis of schizophrenia. In this section,
we review the major neurotransmitter theories of schizophrenia, with an emphasis on dopamine.
In the early 1950s, investigators began to suspect that dopamine might be playing a central role in schizophrenia. Dopamine
is widely distributed in the brain and is one of the neurotransmitters that enables communication in the circuits that link subcortical
with cortical brain regions (Jentsch, Roth, & Taylor, 2000). Since the 1950s, support for this idea has waxed and waned. In the past
decade, however, there has been a resurgence of interest in dopamine, largely because research findings have offered a new
perspective.
The initial support for the role of dopamine in schizophrenia was based on two indirect pieces of evidence (Carlsson, 1988):

1. Drugs that reduce dopamine activity also serve to diminish psychotic symptoms.
2. Drugs that heighten dopamine activity exacerbate or trigger psychotic episodes.

It was eventually shown that standard antipsychotic drugs had their effect by blocking dopamine receptors, especially the “D2”
subtype that is prevalent in subcortical regions of the brain. The newer antipsychotic drugs, or “atypical” antipsychotics, have the
advantage of causing fewer motor side effects. Nonetheless, they also act on the dopamine system by blocking various subtypes of
dopamine receptors.
The relationship between dopamine activity and psychotic symptoms can be demonstrated by studies examining compounds,
such as levodopa, that are used to treat Parkinson’s disease by increasing dopamine transmission. For example, motor abnormalities
associated with Parkinson’s disease (i.e., hypokinesias – loss of muscle movement, slow jerking movements, and rigidity) are related
to low levels of dopamine characteristic of the disease. However, patients with Parkinson’s disease, who are being treated with
dopamine agonists (compounds that activate dopamine receptors) show drug-induced dyskinesias (i.e., involuntary bodily move-
ments such as writhing or jerking; Hoff, Plas, Wagemans, & van Hilten, 2001), and in extreme cases, psychotic symptoms (Hinkle
et al., 2018, Papapetropoulos & Mash, 2005). In a similar vein, other amphetamines such as cocaine increase dopamine activity and
can cause both hyperkinesias and psychotic symptoms (Weiner, Rabinstein, Levin, Weiner, & Shulman, 2001). The interplay between
dopamine activity and movement can also be seen in research examining genetics and drug responsivity in schizophrenia. For
example, schizophrenia patients with genes that related to poor metabolization of neuroleptic drugs show a heightened rate of
dyskinesias (abnormal, uncontrolled, involuntary movement; Ellingrod, Schultz, & Arndt, 2002; Ravyn, Ravyn, Lowney, & Nasrallah,
2013).
Early studies of dopamine in schizophrenia sought to determine whether there was evidence of excess neurotransmitter in
patients with schizophrenia. But concentrations of dopamine and its metabolites were generally found not to be elevated in body
fluids from patients with schizophrenia. When investigators examined dopamine receptors, however, there was some evidence of
increased densities. Both postmortem and functional magnetic resonance imaging studies of patients’ brains yielded evidence that
the number of dopamine D2 receptors tends to be greater in patients than normal controls (Kestler, Walker, & Vega, 2001). Contro-
versy has surrounded this literature, because antipsychotic drugs can change dopamine receptor density. Nonetheless, even studies
of never-medicated patients with schizophrenia have shown elevations in dopamine receptors (Kestler et al., 2001). Thus, the first
version of the dopamine hypothesis focused on hyperdopaminergic (increased levels of dopamine) activity in the brain based on
noted increased transmission of dopamine and the blocking of receptors to treat psychosis; this hypothesis was further refined in
the 1990s to highlight hyperdopaminergic activity in the subcortical regions of the brain and hypoactivation (reduced activity) in
the prefrontal cortex (Howes & Kapur, 2009; Klippel et al., 2017).
The role of dopamine in schizophrenia has been further clarified following research showing additional abnormalities in
dopamine transmission (Grace, 2016). For example, dopamine synthesis and release may be more pronounced in the brains of
people with schizophrenia than among unaffected individuals (Lindström et al., 1999). When patients with schizophrenia and
normal controls are given amphetamine, a drug that enhances dopamine release, the patients show more augmented dopamine
release (Abi-Dargham et al., 1998; Soeares & Innis, 1999). Further, there are a number of replicated studies showing elevated pre-
synaptic dopamine (higher levels of in patients with psychosis; Howes & Kapur, 2009). In concordance with these results, more
recent evidence suggests that the primary dopamine activity abnormalities for schizophrenia exists in the three areas involving
presynapse, synapse, and release of dopamine, rather than in the dopamine receptors themselves (Howes et al., 2012). The dopa-
mine hypothesis has thus evolved to posit that environmental stress, substance abuse, and their interaction with genetic susceptibil-
ity lead to dopamine dysregulation, which in turn increases in striatal presynaptic dopamine concentration (dopamine in the nerve
cells before release to the synapses) and thus may cause psychosis through aberrant salience to external stimuli: the attribution of
significance to stimuli that would normally be considered irrelevant. Although a recent study found that the capacity for dopamine
synthesis is associated with the severity of psychotic symptoms, irrespective of diagnostic class (Jauhar et al., 2017), there are still
questions surrounding this hypothesis, the role of medication, and the methodological limitations of previous studies
258 | MATILDA AZIS E T AL.

(Hengartner & Moncrieff, 2018). At present, antipsychotic medications do not target these areas, and some suggest that treatment
should emphasize presynaptic synthesis and release (Howes et al., 2012).
Glutamate, an excitatory neurotransmitter (one that increases the probability of an action potential or nerve impulse in the cell,
as opposed to an inhibitory neurotransmitter, which would decrease the probability of an action potential), may also play an impor-
tant role in the neurochemistry of schizophrenia. Glutamatergic neurons are part of the pathways that connect the hippocampus,
prefrontal cortex, and thalamus, all regions that have been implicated in schizophrenia. There is evidence of diminished activity at
glutamatergic receptors in these brain regions among patients with schizophrenia (Carlsson, Hansson, Waters, & Carlsson, 1999;
Coyle, 2006; Ghose, Gleason, Potts, Lewis-Amezcua, & Tamminga, 2009; Marsman et al., 2013). One of the chief receptors for
glutamate in the brain is the N-methyl-D-aspartic acid (NMDA) subtype of receptor. Blocking NMDA receptors produces psychotic
symptoms in normal subjects, including negative symptoms and cognitive impairments. For example, administration of NMDA
receptor antagonists, such as phencyclidine and ketamine, induces a broad range of schizophrenic-like symptomatology in humans,
and these findings have contributed to a hypoglutamatergic (decreased levels of glutamate in the brain) hypothesis of schizophrenia
(Coyle, 2006; Marsman et al., 2013). Conversely, drugs that indirectly enhance NMDA receptor function can reduce negative symp-
toms and improve cognitive functioning in schizophrenia patients. It is important to note that the idea of dysfunction of glutama-
tergic transmission is not inconsistent with the dopamine hypothesis of schizophrenia, because there are reciprocal connections
between forebrain dopamine projections and systems that use glutamate (Grace, 2010; Howes, McCutcheon, & Stone, 2015). Thus,
dysregulation of one system will likely alter neurotransmission in the other (Stone, Morrison, & Pilowsky, 2007). Furthermore, the
progressive deterioration of brain tissue seen in schizophrenia may be tied to the dysfunction of the NMDA receptors and the glu-
tamatergic system (Marsman et al., 2013).
There also is evidence of abnormalities in GABA neurotransmission in the dorsolateral prefrontal cortex (Egerton, Modinos,
Ferrera, & McGuire, 2017; Lewis & Hashimoto, 2007; Lewis et al., 2012; Taylor & Tso, 2015). Although the implications of GABA
alterations remain unclear (Taylor, Demeter, Luan Phan, Tso, & Welsh, 2013), disruptions in GABA, an inhibitory neurotransmitter,
may underlie the reduced capacity for working memory in schizophrenia. Current theories assume that GABA is important because
cortical processes require an optimal balance between GABA inhibition and glutamatergic excitation (Costa et al., 2004). In addition
to work highlighting the connection between GABA and cognition, recent research has identified potential clinical relevance of
GABA. For example, the blockage of GABA receptor activity can create psychotic symptoms in individuals with schizophrenia who
are not actively psychotic (Ahn, Gil, Seibyl, Sewell, & D’Souza, 2011). Furthermore, current evidence suggests that GABA receptors
are linked with negative affect in schizophrenia (Taylor et al., 2013; Wierońska et al., 2015).
The true picture of the neurochemical abnormalities in schizophrenia may be more complex than we would like to assume.
All neurotransmitter systems interact in intricate ways at multiple levels in the brain’s circuitry (Carlsson et al., 2001; Gill & Grace,
2016). Consequently, an alteration in the synthesis, reuptake or receptor density, and/or affinity for any one of the neurotransmitter
systems will likely have implications for one or more of the other neurotransmitter systems. Further, because neural circuits involve
multiple segments that rely on different transmitters, an abnormality in even one specific subgroup of receptors could result in the
dysfunction of all the brain regions linked by a particular brain circuit.

Abnormalities in Brain Structure

The first reports of abnormal brain structure in individuals with schizophrenia were based on computerized axial tomography
(CAT) and showed that affected individuals had enlarged brain ventricles (cavities filled with fluid in the brain), especially increased
volume of the lateral ventricles (Dennert & Andreasen, 1983). However, these signs were viewed as non-specific because enlarged
ventricles could reflect widespread brain matter abnormalities (i.e., smaller volume is reflected in larger ventricles). As new tech-
niques for brain scanning were developed, these findings were replicated and additional abnormalities were detected (Henn &
Braus, 1999). Magnetic resonance imaging, a technique capable of providing significantly greater detail, revealed decreased frontal,
temporal and whole brain volume among people with schizophrenia (Lawrie & Abukmeil, 1998; Tanskanen et al., 2010). More
fine-grained analyses demonstrated reductions in the size of the anterior cingulate, amygdala, thalamus, insula, and hippocampus
(Shepard et al., 2012). Diffusion tensor imaging (DTI) has allowed investigators to examine neuronal connections and white matter
tracts in the brain and has shown widespread pathology in multiple tracts. White matter integrity refers to the ability of water mol-
ecules to diffuse along the axon in one direction and thus indicates increased fiber integrity and level of myelination. Deficient white
matter integrity may be particularly present in the front-temporal areas of the brain (Ellison-Wright & Bullmore, 2009). Further-
more, recent evidence suggests that white matter integrity may be related to negative symptoms of schizophrenia (Bijanki, Hodis,
Magnotta, Zeien, & Andreasen, 2015; Nakamura et al., 2012).
Current neurodevelopmental theory of schizophrenia postulates that there may be deficient myelination (the process of form-
ing a myelin sheath around a nerve to speed the transmission of electrical impulses) and interneuron activity in the brain along
with excessive pruning of excitatory synapses (i.e., overstepping the normal maturational process of removing synapses no longer
in use) and that the aggregate impact of these abnormalities may account for the progressive decrease in gray matter volume seen
in schizophrenia (Insel, 2010; Palaniyappan et al., 2018). Furthermore, the deficient myelination may be related to abnormal con-
nectivity within the brain, emphasizing the need to further study brain circuitry using methods such as DTI.
 SCHIZOPHRENIA SPEC TRUM AND OTHER PSYCHOTIC DISORDERS | 259

There is also a wealth of evidence to suggest that irregularities in neural development during the adolescent period (immedi-
ately before the mean age of onset) contribute to the abnormalities of structural and connective tissue observed in adults with
schizophrenia. Although few longitudinal studies of high-risk individuals (prospective designs) have been conducted, results sug-
gest a developmental pattern of declining gray matter structures in left inferior fontal, medial temporal, cerebral, and cingulate
regions (Job, Whalley, Johnstone, & Lawrie, 2005; Mechelli et al., 2011; Pantelis et al., 2007). A meta-analysis in 2012 of gray matter
in high-risk patients who were not taking antipsychotics revealed decreased gray matter in the temporal and limbic prefrontal cortex
along with reductions in temporal, anterior cingulate, cerebellar, and insular regions being associated with psychosis onset in first-
episode patients (Fusar-Poli, Radua, McGuire, & Borgwardt, 2012). A more recent meta-analysis (Bartholomeusz et al., 2017)
focusing on longitudinal neuroimaging across the psychosis spectrum found declines in grey matter in frontal, temporal, insular,
and parietal regions during first episode of psychosis.
It may be that disrupted neural connectivity causes impaired communication between brain regions leading to symptoms and
cognitive changes present in schizophrenia (Van Den Heuvel, Mandl, Kahn, & Hulshoff Pol, 2009). White matter is the basis of
structural connections between brain regions, and there has been extensive exploration in patients with schizophrenia. Burns, Job,
Bastin, & Whalley (2003) found evidence for frontotemporal and frontoparietal structural disconnectivity in schizophrenia, a find-
ing which has been replicated in first episode (Federspiel et al., 2006) indicating that this alteration may reflect the beginning of a
deleterious disease process in schizophrenia.
Research in Clinical High Risk for Psychosis (CHR) individuals has found heterogeneous results, noting numerous tracts and
various lobes exhibiting white matter abnormalities. Researchers have observed DTI evidence that patients failed to show a normal
pattern of increasing white matter integrity with age (Carletti et al., 2012; Karlsgodt et al., 2009), and findings indicate declining
white matter integrity coinciding with progression to psychosis (Krakauer et al., 2018; von Hohenberg et al., 2013). Specifically,
multiple studies have highlighted reduced white matter integrity in the superior longitudinal fasciculus (a fibrous tract connecting
the frontal, occipital, parietal, and temporal lobes), together with connections involving the frontal, fronto-temporal, and fronto-
limbic regions (Bernard et al., 2014; Bloemen et al., 2010; Carletti et al., 2012; Dean et al., 2013; Karlsgodt et al., 2009; Mittal et al.,
2013; Samartzis, Dima, Fusar-Poli, & Kyriakopoulos, 2013; von Hohenberg et al., 2013). While a recent review noted changes in
white matter integrity in chronic psychosis, first-episode psychosis and patients at ultra-high risk for psychosis, which correlated
with specific cognitive deficits and clinical symptoms (Parnanzone et al., 2017). Taken together, this accumulating evidence points
to a prominent role of abnormal adolescent neurodevelopment and conductivity in the pathogenesis of schizophrenia and suggests
that many of the noted structural and connective deficits may have been present prior to the formal onset of illness.
With recent developments in Magnetic Resonance Imaging (MRI), it is also now possible to non-invasively assess functional
connectivity. Arterial spin labeling (ASL), an MRI technique that allows for quantitative measurement of cerebral blood flow (CBF) by
using magnetically labeled arterial blood water as an endogenous tracer has been used (Detre, Leigh, Williams, & Koretsky, 1992).
The non-invasive nature of ASL, conducted using an MRI scanner, allows for repeated measurements with limited discomfort to
participants. (Chen, Wieckowska, Meyer, & Pike, 2008; Gevers, Majoie, Van den Tweel, Lavini, & Nederveen, 2009; Wang et al.,
2011). By measuring CBF, it is possible to provide a direct and quantitative measure of perfusion (blood flow) and therefore an
indirect measure of neural function telling us which areas of the brain are active.
Recent studies using ASL have found an overall pattern of prefrontal hypoperfusion (decreased blood flow) and subcortical/
temporal hyperperfusion (increased blood flow): Pinkham et al., (2011) found patients showed increased CBF in left putamen and
right middle temporal gyrus, as well as distinct patterns of perfusion according to symptom presentation. Zhu et al., (2015) found
increased CBF in the bilateral inferior temporal gyri, thalami, and putamen and decreased CBF in the left insula and middle frontal
gyrus and the bilateral anterior cingulate cortices and middle occipital gyri. Similarly in CHR a pattern of increased perfusion in the
basal ganglia and hippocampus has been found and replicated across samples (Allen et al., 2017; Allen et al., 2016). These findings
are consistent with animal models that propose that psychotic symptoms may be generated when hippocampal hyperactivity drives
hyperactivity in regions involved in dopamine signaling.
Despite the plethora of research findings indicating the presence of abnormalities in the brains of patients with schizophrenia,
no specific abnormality has yet been shown to be definitely specifically characteristic. In other words, there is no evidence that a
specific abnormality is unique to schizophrenia or characterizes all schizophrenia patients. The structural brain abnormalities
observed in schizophrenia are, therefore, gross manifestations of the occurrence of a deviation in neurodevelopment that has impli-
cations for the functioning of neurocircuitry.

Onset, Course, and Prognosis

In the early part of the 20th century, psychosocial theories of schizophrenia dominated the literature. For example, Sigmund Freud,
the father of psychoanalysis, believed that psychological processes resulted in the development of psychotic symptoms (Howells,
1991). In 1948, Frieda Fromm-Reichmann proposed a theory of schizophrenia which postulated that the disorder arose in response
to rearing by a “schizophrenogenic mother” (Fromm-Reichmann, 1948). Although this hypothesis has fallen into disfavor because
of a lack of support from empirical research, it caused considerable suffering for families. Subsequently, family interaction models
260 | MATILDA AZIS E T AL.

of the etiology of schizophrenia were offered by various theorists (Howells, 1991). Although these early psychosocial theories
contributed relatively little to our understanding of the etiology of schizophrenia, they did highlight the importance of considering
the role of the family in relapse prevention and recovery for the patient. There has also been considerable focus on other types of
environmental stressors involving prenatal and perinatal factors.

Prenatal and Perinatal Factors

There is extensive evidence that obstetric complications have an adverse impact on the developing fetal brain and may contribute
to vulnerability for schizophrenia. Birth cohort studies have shown that patients with schizophrenia are more likely to have a history
of exposure to obstetric complications (Brown & Derkits, 2010; Forsyth et al., 2013; Takagai et al., 2006). Included among these
are prenatal conditions, such as preeclampsia – the abrupt increase in maternal blood pressure and protein releases into urine, both
of which can have a detrimental impact on the mother and the fetus, and labor and delivery complications. A meta-analysis of the
literature on obstetric complications concluded that, among the different types of obstetric complication, complications of preg-
nancy (bleeding, preeclampsia, diabetes, and rhesus factor incompatibility) were the most strongly linked with later schizophrenia,
followed by abnormal fetal growth and development and complications of delivery (Cannon, Jones, & Murray, 2002) In the National
Collaborative Perinatal Project, which involved over 9,000 children followed from birth through adulthood, the odds of developing
adult onset schizophrenia increased linearly with an increasing number of hypoxia-related complications (resulting from lack of
oxygen at birth) (Cannon, 1998; Zornberg, Buka, & Tsuang, 2000). Recent studies found that individuals identified as at high risk
for developing schizophrenia have higher conversion rates if they have experienced obstetric complications (Kotlicka-Antczak et al.,
2017), and that the earlier age of onset is associated with complications such as preeclampsia, low birth weight, and need for an
incubator (Rubio-Abdal et al., 2015).
Another prenatal event that has been linked with increased risk for schizophrenia is maternal viral infection. A recent study
found that prenatal maternal exposure to a wide range of infections was associated with a 1.16 fold increase in schizophrenia risk
(Nielsen, Meyer, & Mortensen, 2016). The risk rate for schizophrenia is elevated for individuals born shortly after an influenza
epidemic (Barr, Mednick, & Munk-Jorgensen, 1990; Brown et al., 2004; Limosin, Rouillon, Payen, Cohen, & Strub, 2003; Murray,
Jones, O’Callaghan, & Takei, 1992), or after being prenatally exposed to rubella (Brown, Cohen, Harkavy-Friedman, & Babulas,
2001). For example, research suggests that there may be a threefold increase in risk for schizophrenia if a fetus is exposed to influ-
enza in the first half of gestation and sevenfold increase if exposed in the first trimester (Brown & Derkits, 2010). Furthermore, the
prenatal maternal infection may have a synergetic effect with other risk factors. One study found that females prenatally exposed to
infections had an increased risk for schizophrenia, and that the risk significantly increased for both males and females if they have
also experienced psychological trauma in childhood (Debost et al., 2017).
Studies of rodents and non-human primates have shown that prenatal maternal stress can interfere with fetal brain development
and is associated with elevated glucocorticoid release and hippocampal abnormalities in the offspring (Charil, Laplante, Vaillan-
court, & King, 2010; Coe et al., 2003). Along the same lines, in humans, there is evidence that stressful events during pregnancy
are associated with greater risk for schizophrenia and other psychiatric disorders in adult offspring. Researchers have linked the
incidence of schizophrenia to various maternal stressors during pregnancy, including bereavement (Huttunen, 1989), famine
(Susser & Lin, 1992; St Clair et al., 2005), military invasion (van Os & Selten, 1998), war (Malaspina et al., 2008), exposure to
terror attacks (Weinstein et al., 2018), flood (Selten, Graaf, van Duursen, Gispen-de Wied, & Kahn, 1999), earthquake (Watson,
Mednick, Huttunen, & Wang, 1999), and even daily life stressors (Fineberg et al., 2016). It is likely that prenatal stress triggers the
release of maternal stress hormones, which have been found to disturb fetal neurodevelopment and subsequent functioning of the
hypothalamic–pituitary–adrenal (HPA) axis, which, in turn influences behavior and cognition (Seckl & Holmes, 2007). In addition,
maternal stress may affect maternal proinflammatory cytokines (proteins that are secreted by specific cells of the immune system),
which have been associated with increased risk of offspring with schizophrenia (Brown & Derkits, 2010).
One of the chief questions confronting researchers is whether obstetric complications act independently to increase risk for
schizophrenia or have their effect in conjunction with a genetic vulnerability (Mittal, Ellman, & Cannon, 2008). One possibility is
that the genetic vulnerability for schizophrenia involves an increased sensitivity to prenatal factors that interfere with fetal neurode-
velopment (Cannon, 1998; Preti, 2005; Walshe et al., 2005). It is also plausible that obstetric events act independently of genetic
vulnerabilities, although such effects would likely entail complex interactions among factors (Susser, Brown, & Gorman, 1999). For
example, to produce the neurodevelopmental abnormalities that confer risk for schizophrenia, it may be necessary for a specific
obstetric complication to occur during a critical period of tissue formation during embryonic development and/or in conjunction
with other factors such as maternal fever or immune response. Research shows evidence that the presence of serious obstetric com-
plications may interact with certain genes, those that are regulated by hypoxia or involved in neurovascular function, to increase
risk for schizophrenia (Nicodemus et al., 2008). More recently, there is some evidence to suggest that the former hypothesis is
true – that the exposure to obstetric complications influences the overall genetic risk for schizophrenia. More specifically, the pla-
centa may have a mediating role in the interaction between obstetric complications and schizophrenia risk genes as the placental
levels of these genes are more highly expressed during complicated pregnancies. This interaction is more striking in males than
females which could explain the higher prevalence rates of the illness in males (Ursini et al., 2018).
 SCHIZOPHRENIA SPEC TRUM AND OTHER PSYCHOTIC DISORDERS | 261

Premorbid Development
Assuming that genetic and obstetrical factors confer vulnerability for schizophrenia, the diathesis must be present at birth. Yet,
schizophrenia is typically diagnosed in late adolescence or early adulthood, with the average age of diagnosis in males about
four years earlier than for females (Riecher-Rossler & Hafner, 2000). This raises intriguing questions about the developmental
course prior to the clinical onset. Most of these signs are subtle and do not reach the severity of clinical disorder. Nonetheless, when
compared with children with healthy adult outcomes, children who later develop schizophrenia manifest deficits in multiple
domains. In some of these domains, the deficits are apparent as early as infancy.
In the area of cognitive functioning, children who later develop schizophrenia tend to perform below their healthy siblings
and classmates. These cognitive deficits are reflected in lower scores on measures of achievement, poorer grades in school, and a
lower childhood IQ compared with peers who do not go on to develop schizophrenia (Aylward, Walker, & Bettes, 1984; Dickinson,
2014; Dickson et al., 2018; Jones, Rodgers, Murray, & Marmot, 1994). However, results are mixed, and a recent meta-analysis
showed no significant difference in performance on general academic achievement tests or mathematic achievement tests between
those who go on to develop schizophrenia and those who do not (Dickson et al., 2012). Specifically, research suggests early impair-
ment in verbal knowledge, visual knowledge, simple reasoning skills, and a worsening trajectory of speeded performance, working
memory, and complex problem solving (Dickinson, 2014; Reichenberg et al., 2010). Children who later are diagnosed with schiz-
ophrenia also show abnormalities in social behavior. They are less responsive in social situations, show less positive emotion
(Walker & Lewine, 1990; Walker, Grimes, Davis, & Smith, 1993), and have poorer social adjustment than children with healthy adult
outcomes (Done, Crow, Johnstone, & Sacker, 1994; Cannon et al., 2002b). Children with genetic predisposition for schizophrenia
show higher rates of behavioral difficulties and deficits in social and communication skills as early as preschool age (Jansen et al.,
2018; Riglin et al., 2017). Studies of the childhood home movies of patients with schizophrenia found that the children who
develop schizophrenia later in life showed more negative facial expression of emotion than did their siblings as early as the first year
of life, indicating that the vulnerability for schizophrenia is subtly manifested in the earliest interpersonal interactions (Walker,
Grimes, Davis, & Smith, 1993; Cannon et al., 2002).
Vulnerability to schizophrenia is also apparent in motor functions. When compared with their siblings with healthy adult
outcomes, children who develop schizophrenia show more delays and abnormalities in motor development, including deficits in
the acquisition of early motor milestones, such as bimanual manipulation and walking (Walker, Savoie, & Davis, 1994). A recent
cohort study found that delays in standing up and walking without support, holding the head up, and grabbing an object are asso-
ciated with the increased risk for schizophrenia. In individuals with a history of parental psychosis, the mean age for reaching these
milestones was even higher (Keskinen et al., 2015). Deficits in motor function extend throughout the premorbid period (Walker,
Lewis, Loewy, & Palyo, 1999), and persist after the onset of the clinical illness (McNeil, Cantor-Graae, & Weinberger, 2000). Fur-
thermore, abnormal gesture behavior has been observed in both premorbid (Mittal et al., 2006; Mittal et al., 2010) and unmedi-
cated individuals with schizophrenia (Troisi, Spalletta, & Pasini, 1998).These data imply that the movement abnormalities recognized
in schizophrenia are likely to have complex interactions with language and motor planning centers.
It is important to note that neuromotor abnormalities are not pathognomonic for schizophrenia, in that they are observed in
children at risk for a variety of disorders, including learning disabilities, and conduct and mood disorders. But they are one of several
important clues pointing to the involvement of brain dysfunction in schizophrenia. Further, although medication-induced move-
ment abnormalities, such as tardive dyskinesia, involve characteristic motor signs, these are not to be confused with involuntary
movements which have been demonstrated to be present in drug-free groups such as at-risk infants (Fish, 1987), at-risk adolescents
(Walker et al., 1999), and never medically treated schizophrenia patients (Khot & Wyatt, 1991).
Despite the subtle signs of abnormality that have been identified in children at risk for schizophrenia, most of these children
do not manifest diagnosable mental disorders in childhood. Thus, while their parents may recall some irregularities in their devel-
opment, most children who eventually develop schizophrenia were not viewed as clinically disturbed in childhood. But the picture
often changes in adolescence. Many adolescents who go on to develop schizophrenia show a pattern of escalating adjustment prob-
lems (Walker & Baum, 1998), including a gradual increase in feelings of depression, social withdrawal, irritability, and noncompli-
ance. This developmental pattern is not unique to schizophrenia; adolescence is also the critical period for the expression of the first
signs of mood disorders, substance abuse, and other mental disorders. As a result, researchers view adolescence as a critical period
for the emergence of various kinds of behavioral dysfunction (Corcoran et al., 2003; Walker, 2002).
Among the behavioral risk indicators sometimes observed in “pre-schizophrenic” adolescents are “subclinical” signs of psy-
chotic symptoms. These signs comprise the risk state that is now referred to as “clinical high-risk” (CHR) or attenuated psychosis
syndrome (APS) in the DSM-5 research section (APA, 2013; described in the section on “Classification,” p. 253) and is considered
to represent the putative prodromal stage of psychosis. Specifically, these symptoms are termed attenuated positive symptoms and
in research clinics, typically fall under one of the following five subgroups: unusual thought content; suspiciousness/paranoia;
grandiosity; perceptual abnormalities; or disorganized communication (Gee & Cannon, 2011). For APS criteria, the individual must
experience the presence of symptoms at least once per week in the last month and the onset of the symptoms must be in the last
12 months or symptoms must have worsened in the last 12 months (Tsuang et al., 2013). These individuals tend to exhibit declin-
ing social and role functioning along with the sub-threshold psychotic symptoms. Furthermore, research suggests that the neuro-
cognitive and social cognitive performance of youth with APS is somewhat between that of healthy controls and patients with
262 | MATILDA AZIS E T AL.

schizophrenia. Although this risk period requires further study, the most recent meta-analysis suggests that approximately 18% of
those identified as APS will convert to a psychotic disorder within the first six months and 36% after three years (Fusar-Poli et al.,
2012). A more recent study showed that the probability of conversion to a psychotic disorder after two years is 16% (Cannon et al.,
2016). Research indicates that with each year, there is a reduction in this risk of conversion to a psychotic disorder, but it remains
unclear whether early intervention is responsible for this decrease in psychosis transition or whether a certain portion of these
individuals identified as at-risk would never have converted (i.e., false positives; Yung et al., 2007).
Current research presents a broader debate regarding the efficacy of prevailing efforts for identifying CHR state and the feasi-
bility for predicting schizophrenia and altering its course. Some research is quite polarizing with authors on one end arguing for
completely discarding CHR criteria, and on the other end for maintaining the status quo; however, the majority of the current
research focuses on incorporating and assessing critiques of the current CHR state and modifying its existing features to improve
its diagnostic and prognostic power (Fusar-Poli, 2018). The most prominent critiques of the current CHR designation are its lack
of transdiagnostic power (or the ability to detect at-risk states for psychosis across nonpsychotic disorders), its lack of applicability
to non-help-seeking individuals, and overly simplistic and binary risk and transition concepts which do not account for factors such
as false positives and multidimensional nature of psychopathology (Fusar-Poli, 2018; van Os & Guloksuz, 2017).
Improving diagnostic and prognostic accuracy of diagnostic measures for CHR is crucial, and a recent study found that the APS
designation as outlined in the DSM-5 can be clinically relevant and with improvements can have better prognostic power (Fusar-Poli
et al., 2018). Further, there is a call to focus on transdiagnostic risk state and move beyond identifying CHR for psychosis only (Lee
et al., 2018). One study retrospectively examined transition rates to formal psychosis and found that approximately two-thirds of
first episode psychosis individuals would have met CHR criteria prior to their first episode (Shah et al., 2017). Although that number
is striking, the last third may be accounted for by looking at indicators of psychosis risk transdiagnostically, and another study found
that psychotic disorders may emerge from risk states for nonpsychotic disorders (Lee et al., 2018).
Similar to transdiagnostic approach, the potential diagnostic pluripotentiality of CHR criteria (or their ability to identify risk
for other psychiatric disorders) is favorably regarded in current research. Because the rates of incidence, persistence, and recurrence
of nonpsychotic disorders at follow-up assessments in the CHR group are high and related functional decline is common, pluripo-
tentiality can be useful in that it can facilitate easier access to treatment (Lin et al., 2015; Rutigliano et al., 2016). However, evidence
shows that CHR criteria are predictive of emergence of psychotic disorders only, and that the incidence and persistence of other
disorders is similar in individuals not meeting CHR criteria (Fusar-Poli, 2018; Woods, 2018). Supplementing the existing CHR
assessments with novel instruments such as risk calculators including additional criteria could be useful in predicting and preventing
nonpsychotic disorders in CHR individuals (Fusar-Poli, 2018). Lastly, early intervention treatments could be improved by including
services that are more accessible and relevant to the community and focused on multidimensional psychopathology in youth and
on reducing stigma related to being identified as at risk for a serious mental illness (Fusar-Poli, 2018; van Os & Guloksuz, 2017).
Although progress has been made over the last two decades in this area, the current debates and mixed findings yield the need for
identifying more accurate predictive factors contributing to onset of schizophrenia and persistence or emergence of nonpsychotic
disorders and for a more comprehensive approach to detecting clinical high-risk and intervening at this illness stage.

Illness Onset
The picture that has emerged to describe illness onset is best described in the framework of the diathesis-stress model that has
dominated the field for several decades (Walker & Diforio, 1997; Walker, Mittal, & Tessner, 2008). As empirical research rapidly
grows in the schizophrenia field, an extended model informed by most current findings has been proposed. This model is designed
to accommodate further empirical advances (Pruessner, Cullen, Aas, & Walker, 2017).
Figure 12.1 illustrates a contemporary version of the diathesis-stress model. This particular model postulates that constitutional
vulnerability (i.e., the diathesis) emanates from both inherited and acquired constitutional factors. The inherited factors are genet-
ically determined characteristics of the brain that influence its structure and function. Acquired vulnerabilities arise mainly from
prenatal events that compromise fetal neurodevelopment.
Whether the constitutional vulnerability is a consequence of genetic factors or environmental factors, or a combination of both,
the model assumes that vulnerability is, in most cases, congenital. But the assumption that vulnerability is present at birth does not
imply that it will be clinically expressed at any point in the life span. Rather, the model posits that two sets of factors determine the
postnatal course of the vulnerable individual. First, external stressors will influence the expression of the vulnerability. Although this
is a long-standing assumption among theorists, it is important to clarify it. Empirical research has provided evidence that episodes
of schizophrenia follow periods of increased life stress (Horan et al., 2005; Ventura, Nuechterlein, Hardesty, & Gitlin, 1992). None-
theless, there is no evidence that individuals affected by schizophrenia experience more stressful events, perhaps with the exception
of childhood trauma, than individuals without schizophrenia, but rather that they are more sensitive to stress when it occurs (Holtz-
man et al., 2013). This assumption is the essence of the model; the interaction between vulnerability and stress is critical.
Diathesis-stress models have incorporated mechanisms to account for the adverse impact of stress on brain function (Walker &
Diforio, 1997; Walker, Mittal, & Tessner, 2008). The HPA axis, which is responsible for the release of cortisol and other stress hor-
mones, has been examined as one of the primary neural systems triggered by stress exposure, leading to the expression of vulner-
ability for schizophrenia (Walder, Walker, & Lewine, 2000). Results from this research indicate that psychotic disorders are associated
Figure 12.1 A diathesis-stress model of the etiology of schizophrenia.
264 | MATILDA AZIS E T AL.

with elevated baseline and challenge-induced HPA activity, that antipsychotic medications reduce HPA activation, and that agents
that augment stress hormone release exacerbate psychotic symptoms (Walker et al., 2008).
In addition, the model assumes that neuromaturation is a key element. In particular, adolescence/early adulthood appears to
be a critical period for the expression of the vulnerability for schizophrenia. Thus, some aspects of brain maturational processes
during the post-pubertal period are likely playing an important role in triggering the clinical expression of latent liabilities (Corco-
ran et al., 2003; Insel, 2010; Walker, Kestler, Bollini, & Hochman, 2004).
Exposure to stress can exacerbate schizophrenia symptoms. Researchers have found an increase in the number of stressful events
in the months immediately preceding a schizophrenia relapse (Horan et al., 2005; Ventura et al., 1992). Finally, a rapidly accumu-
lating body of research indicates that heavy, consistent cannabis use is associated with a threefold increase in risk of schizophrenia,
earlier onset of disorder in vulnerable individuals, and exacerbation of psychotic symptoms (Helle et al., 2016; Manrique-Garcia
et al., 2012; Rey, Martin, & Krabman, 2004). Some evidence shows that patients with schizophrenia who started using cannabis
early and chronically in life had better neurocognitive performance than patients who used later on, showing that this early cannabis
use group may have a specific, less-impaired neurocognitive profile (Yücel et al., 2012). Psychosocial features of urban environ-
ments such as low social cohesion, disorder in neighborhoods, and crime victimization increase risk for schizophrenia (Bhavsar
et al., 2014; Veling et al., 2015), with psychotic symptoms related to these factors occurring as early as age 12 (Newbury et al.,
2016).
The onset of the first episode of schizophrenia may be sudden or gradual. Longer untreated psychotic episodes may be harmful
for patients with schizophrenia and may result in a worse course of illness (Birnbaum, Wan, Broussard, & Compton, 2017; David-
son & McGlashan, 1997; Harris et al., 2005; Perkins et al., 2004). However, this conclusion is controversial, and some researchers
suggest that the relation between longer duration of untreated psychosis and worse prognosis may be a product of poorer premor-
bid functioning and an insidious onset (Larsen et al., 2001). Nonetheless, early intervention is important, regardless of the specific
causal factors, as recent evidence suggests that duration of untreated psychosis is indeed a significant predictor of outcome and that
the relationship between duration and functioning may be mediated by the presence of negative symptoms (Hill et al., 2012).

Prognosis
People with schizophrenia vary in their course of illness and prognosis. Being male, having a gradual onset, an early age of onset,
poor premorbid functioning, and a family history of schizophrenia are all associated with poorer prognosis (Gottesman, 1991). In
addition, some environmental factors contribute to a worse outcome. For example, patients with schizophrenia who live in homes
where family members express more negative emotion are more likely than those with supportive families to have more frequent
relapses (Butzlaff & Hooley, 1998; Rosenfarb, Bellack, & Aziz, 2006).
For many schizophrenia patients, the prognosis is poor. Around 20% of individuals with schizophrenia may become homeless
within the first year of diagnosis (Folsom et al., 2005). Within the first five years, 13.7% are able to achieve full remission of symp-
toms along with adequate social/role functioning, and within 25 years, around 30% are able to achieve a favorable long-term
outcome (Harrison, 2001; Robinson, Woerner, McMeniman, Mendelowitz, & Bilder, 2004). Further, patients with schizophrenia
often suffer from other comorbid (i.e., co-occurring) conditions. For example, the rate of substance abuse among patients with
schizophrenia is very high, with as many as 50% of all patients with schizophrenia and 90% in prison settings meeting lifetime
DSM-IV criteria for substance abuse or dependence (Regier et al., 1990; Thoma & Daum, 2013).
Suicide is the leading cause of death among people with schizophrenia. It has been estimated that 50% of patients with schiz-
ophrenia attempt suicide and 4–5% successfully commit suicide (Donker et al., 2013). Risk factors associated with suicide in this
population include previous attempts, more severe depressive symptoms, being male, having an earlier onset, suffering recent
traumatic events, and recent hospitalization (Donker et al., 2013; Gallego et al., 2015; Schwartz & Cohen, 2001). Further, the risk
of suicide for individuals with schizophrenia is increased in the earlier stages of illness, and particularly within the first year of
diagnosis (Donker et al., 2013).

Evidence-Based Interventions
Researchers have not yet identified any biological or psychological cures for schizophrenia. However, significant progress has been
made in treatments that greatly improve the prognosis of the illness. As a result of this research progress, the quality of life for indi-
viduals with schizophrenia is dramatically better than it was at the turn of the 20th century. Indeed, a recent meta-analysis shows
that higher illness remission rates have been observed in studies in more recent years (Lally, Ajnakina, Stubbs, & Cullinane, 2018).
The first issue to be addressed in the evaluation and treatment of schizophrenia is safety. The risk of self-harm and potential for
violence must be assessed (McGirr et al., 2006; Siris, 2001). A medical examination is typically conducted to rule out other illnesses
that can cause or exacerbate psychotic symptoms. This examination includes a review of the medical history, a physical examination,
and laboratory tests. Many patients with schizophrenia have untreated or undertreated medical conditions such as nutritional defi-
ciencies and infections that are a result of their psychological and/or socio-economic limitations (Goff, Heckers, & Freudenreich,
2001).
 SCHIZOPHRENIA SPEC TRUM AND OTHER PSYCHOTIC DISORDERS | 265

If a patient is not at acute risk to self or others, the next consideration becomes the type of treatment that would be most ben-
eficial. There are several factors to consider. These include the person’s living situation (many patients with schizophrenia are home-
less), level of insight, willingness to accept treatment, past treatment history, financial resources (including health insurance), and
family and other available social support. To increase chances of success, the patient with schizophrenia should be encouraged to
talk openly about their treatment preferences, beliefs about medication, and concerns about side effects or changes.
The treatment of schizophrenia can be divided into three phases: the acute, stabilization, and maintenance phases (Sadock &
Sadock, 2000). In the acute phase, the goal of treatment is to reduce the severity of symptoms. This phase is usually four to eight
weeks in duration. In the stabilization phase, the goal is to consolidate treatment gains. This usually takes about six months. Finally,
during the maintenance phase, the symptoms are in remission (partial or complete). At this point, the goal of treatment is to prevent
relapse and improve functioning. One of the major challenges during the maintenance phase is preventing treatment discontinua-
tion, and studies show that stopping treatment is significantly related to increased risk for relapse and poor clinical outcomes (Hui
et al., 2018; Mayoral-van Son et al., 2016) as well as high hostility rates (Volavka et al., 2016). A study comparing clinical outcomes
of patients who discontinued pharmacological treatment and those who maintained it found that relapse rates are greater in the
former group – 67.4% of patients in discontinuation group relapsed opposed to 31.8% in maintenance group. Furthermore, in both
groups, those who relapsed endorsed more severe symptoms and poorer overall functioning (Mayoral-van Son et al., 2016).

Biological/Pharmacological Interventions
The mainstay of the biological treatment of schizophrenia are antipsychotic medications. First developed in the 1950s, these med-
ications had an enormous impact on the lives of people afflicted with schizophrenia. Their psychotic symptoms improved and many
were able to leave psychiatric hospitals (deinstitutionalization). The first effective biological treatment for schizophrenia, chlor-
promazine (Thorazine®), was the first in a line of medications now referred to as the “typical” antipsychotics or “neuroleptics.” All
of these medications act by blocking activity in the dopamine systems. The typical antipsychotic medications are classified as high,
medium, and low potency, and differ from each other in adverse-effect profiles (Table 12.2). High-potency neuroleptics tend to
carry a higher risk of extrapyramidal effects (e.g., motor abnormalities), and are prescribed in low dosages. Some examples of high-
potency agents are: fluphenazine (Prolixin®), trifluoperazine (Stelazine®), and haloperidol (Haldol®). Low-potency neuroleptics
are prescribed in higher milligram doses and have lower risk of motor effects, but a higher risk of inducing seizures, antihistaminic
effects (including sedation and weight gain), anticholinergic effects (including cognitive dulling, dry mouth, blurry vision, urinary
hesitancy, and constipation), and antiadrenergic effects (including postural hypotension and sexual dysfunction). Examples of low-
potency neuroleptics include chlorpromazine and thioridazine (Mellaril®). Medium-potency agents tend to have adverse effects
intermediate between the low- and high-potency drugs. Examples of these include: perphenazine (Trilafon®) and loxapine
(Loxitane®).
In the 1990s, a new generation of anti-psychotic medications became available for therapeutic use in Europe and North Amer-
ica. The new class of medication is commonly referred to as “atypical” or “second generation” antipsychotics. Medications in this
class share a lower risk of both the early occurring and the late emerging (or tardive) movement disorders, although recent evidence
suggests there is some variation within the atypical antipsychotics as to their ability to cause these extrapyramidal effects (Rummel-
Kulge et al., 2012). The atypical antipsychotics include: risperidone (Risperdal®), olanzapine (Zyprexa®), olanzapine/fluoxetine
(Symbyax®), quetiapine (Seroquel®), ziprasidone (Geodon®), aripiprazole (Abilify®), paliperidone (Invega®), asenapine

Table 12.2 Selected Anti-psychotic Drugs (from Sadock & Sadock, 2000, p. 1204)

Drug Route of Usual daily oral Sedation Autonomic Extrapyramidal

administration dose (mg) adverse effects

Chlorpromazine Oral, IM 200–600 +++ +++ ++

Fluphenazine Oral, IM, depot 2–20 + + +++
Trifluoperazine Oral, IM 5–30 ++ + +++
Perphenazine Oral, IM 8–64 ++ + +++
Haloperidol Oral, IM, depot 5–20 + + +++
Loxapine Oral, IM 20–100 ++ + ++
Olanzapine Oral 7.5–25 + ++ 0?
Quetiapine Oral 150–750 ++ ++ 0?
Risperidone Oral 2–16 + ++ +
Clozapine Oral 150–900 +++ +++ 0?

IM = intramuscular
266 | MATILDA AZIS E T AL.

(Saphris®), iloperidone (Fanapt®), lurasidone (Latuda®), and clozapine (Clozaril®). The individual medications differ signifi-
cantly from one another in the neurotransmitter receptors that they occupy. Although all block dopamine neurotransmission to
some extent, they vary in the extent to which they affect serotonin, glutamate, and other neurotransmitters. These atypical antipsy-
chotics have become the first line of treatment for schizophrenia. The efficacy of the atypical antipsychotics for the treatment of
positive symptoms is at least equivalent to that of the typical antipsychotics. Some studies suggest that they are more effective for
negative symptoms and the cognitive impairments associated with the disorder, although findings are mixed and inconclusive
(Forster, Buckley, & Phelps, 1999; Kane & Correll, 2010; Sadock & Sadock, 2000). Of practical clinical significance, however, is the
substantial risk of developing a “metabolic syndrome” related to the use of this class of medicines. A recent meta-analysis has
revealed that the atypical antipsychotics carry an elevated risk of substantial weight gain, hyperlipidemia, glucose intolerance, and
cardiovascular problems (Chong et al., 2016).
Antipsychotic medications are usually administered orally. For patients who are not compliant with oral medication, injectable,
long-lasting (depot) antipsychotic medication may be administered (usually every two to four weeks). Six depot neuroleptics are
commercially available in the United States. Two are first generation or “typical” antipsychotics and four are second generation or
“atypical” antipsychotics. Benefits of depot neuroleptics include the ease of use for the patient, and the fact that compliance is easily
monitored by the clinician. The risks are similar to the risks of all of the “typical” antipsychotics. The only additional risk is that of
localized pain or swelling at the injection site.
Drug-induced movement disorders can be divided into acute and late onset syndromes. Acute, or early emerging motor symp-
toms include pseudo-Parkinsonism, bradykinesias (decreased movement), rigidity, and dystonic reactions (sudden onset of sus-
tained intense, uncontrollable muscle contraction commonly occurring in the facial and neck muscles). Tardive dyskinesia is a late
emerging syndrome that includes irregular choreiform (twisting, or worm-like) movements that usually involve the facial muscles
but can involve any voluntary muscle group. The rate of tardive dyskinesia has declined since the introduction of atypical neurolep-
tics. These drug-induced movement abnormalities are a distinct and separate entity from the spontaneous movement abnormalities
noted earlier, which occur as a natural correlate of schizophrenia.
Mention should also be made of the neuroleptic malignant syndrome (NMS). This is a rare, idiopathic, life-threatening com-
plication of neuroleptic medication. It is characterized by mental status changes (delirium), immobility, rigidity, tremulousness,
staring, fever, sweating, and autonomic instability (labile blood pressure and tachycardia). Laboratory investigations often reveal an
elevated white blood cell count (in the absence of infection), and an elevated creatine phosphokinase level. Treatment involves dis-
continuation of neuroleptic medication, supportive medical treatment, a peripheral muscle relaxant, and bromocriptine (a D2
receptor agonist; Rosebush & Mazurek, 2001; Pileggi & Cook, 2016).

Psychosocial Treatments of Schizophrenia

Although antipsychotic medication is the crucial first step in the treatment of schizophrenia, psychosocial interventions can also be
beneficial for both the patient and the family, although such treatments are not always available because of limited mental health
resources. Nonetheless, it is generally agreed that the optimal treatment approach is one that integrates pharmacologic and psycho-
social interventions.
Research supports the use of family therapy, which includes psychoeducational and behavioral components, in treatment pro-
grams for schizophrenia (Bustillo, Lauriello, Horan, & Keith, 2001; Caqueo-Urízar et al., 2015). Family therapy has been shown to
reduce the risk of relapse, reduce family burden, and improve family members’ knowledge of and coping with schizophrenia.
Briefly, treatment includes psychoeducation about symptoms, diagnosis, and prognosis, along with therapeutic modules focusing
on communication and problem-solving skills.
Comprehensive programs for supporting the patient’s transition back into the community have been effective in enhancing
recovery and reducing relapse. One such program, called assertive community treatment (ACT), was originally developed in the 1970s by
researchers in Madison, Wisconsin (Bustillo et al., 2001; Saddock & Sadock, 2000; Udechuku et al., 2005). ACT is a comprehensive
treatment approach for the seriously mentally ill living in the community. Patients are assigned to a multidisciplinary team (nurse,
case manager, general physician, and psychiatrist) that has a fixed caseload and a high staff/patient ratio (1:12). The team delivers
all services to the patient when and where he or she needs it and is available to the patient at all times. Services include home delivery
of medication, monitoring of physical and mental health status, in vivo social skills training, and frequent contact with family mem-
bers. Studies suggest that ACT can reduce time spent in hospital, improve housing stability, and increase patient and family satisfac-
tion. Research shows that ACT treatment can aid in the stable living in a community but has little impact in other areas such as social
functioning and employment (Mueser, Deavers, Penn, & Cassisi, 2013). However, a more recent clinical trial examining an integra-
tive care treatment including ACT, intensive outpatient therapy, and regular family members involvement, found that over 48 months
in the trial, patients’ illness severity, quality of life, and functioning improved. Illness severity continued improving over the course
of four years, and the other aspects remained stable after the first two years. Notably, rates of involuntary hospitalization dropped
from 34.8% in the two years before care to 7.8% in the two years while receiving care (Schöttle et al., 2018).
A recent study on a different integrative treatment model examined the long-term effects of coping-oriented therapy in an
inpatient setting that included psychoeducation about the illness and risk and protective factors, treatment options, coping and
relapse prevention training, identifying stressors and warning signs, stress management and relaxation training, and problem
 SCHIZOPHRENIA SPEC TRUM AND OTHER PSYCHOTIC DISORDERS | 267

solving. At a two-year follow-up, rehospitalization rates were relatively low and that, compared to supportive therapy, patients main-
tained improvements in overall symptomatology, particularly anxiety and depression. The results show promising effects of such
integrative program on long-term well-being after discharge (Schaub et al., 2016).
Social skills training seeks to improve the overall functioning of patients by teaching the skills necessary to improve perfor-
mance of activities of daily living, employment related skills, and interaction with others. Research indicates that social skills training
can improve social competence in the laboratory and in the clinic, along with impacts in social/daily living skills, community
functioning, and negative symptoms (Bustillo et al., 2001; Kurtz & Mueser, 2008; Penn & Mueser, 1996; Turner et al., 2018). Some
evidence suggests that combining social skills training with attention training can enhance outcomes (Silverstein et al., 2009).
The rate of competitive employment for the severely mentally ill has been estimated at less than 20% (Lehman, 1995; Marwaha &
Johnson, 2004); thus, vocational rehabilitation has been a major focus of many treatment programs. Some evidence suggests that “sup-
ported employment programs” produce better results than traditional vocational rehabilitation programs as measured by patients’ ability
to obtain competitive, independent employment and increased wages earned (Bond, Drake, & Becker, 2012; Mueser et al., 2013).
Cognitive behavior therapy for schizophrenia draws on the tenets of cognitive therapy that were originally developed by Beck
and Ellis (Beck, 1976; Ellis, 1986). The theory is that normal psychological processes can help maintain or reduce specific psychotic
symptoms. Cognitive-behavioral therapy (CBT) for psychosis challenges the notion of a discontinuity between psychotic and nor-
mal thinking. The normal cognitive mechanisms that are already being used in the non-psychotic aspects of the patient’s thinking
can be used to help the psychotic individuals deal directly with their symptoms (Kingdon & Turkington, 2005). The choice of target
symptoms is based on the patient’s preference and/or severity of the problems created by the psychotic symptom in question.
Psychotic beliefs are never directly confronted, although specific psychotic symptoms such as hallucinations, delusions, and related
problems are targeted for intervention by means of education and cognitive restructuring skills around the symptoms, their onset,
along with providing insight into how the behavioral framework of antecedents, beliefs, and consequences functions in psychosis
(ABC model; Dickerson, 2000). There have been somewhere near 40 randomized controlled trials evaluating the efficacy of CBT for
psychosis. A recent review (Mueser et al., 2013) noted that CBT was linked to decreases in psychotic symptoms, negative symptoms,
and mood problems, as well as better social functioning. However, findings comparing CBT with other active treatments are mixed
and currently somewhat inconclusive, as most studies of the efficacy of CBT where compared to treatment as usual (Mueser et al.,
2013). Further, one meta-analysis suggests that CBT only has a small therapeutic effect for psychosis, which is made even smaller
when acknowledging biases in research methodology (Jauhar et al., 2014). When integrated with social skills training, CBT has
more promising results in improving negative symptoms and overall functioning (Granholm, Holden, & Worley, 2016).
Within this cognitive behavioral framework, another therapeutic modality entitled acceptance and commitment therapy (ACT)
has shown some promise in treating psychosis. ACT works within the context of CBT and emphasizes increased awareness and
openness, psychological flexibility, living in-line with one’s values, and finding actions that are workable. The original studies found
that receiving ACT was associated with lower rates of hospitalization and decreases in psychotic symptoms (Bach & Hayes, 2002;
Gaudiano & Herbert, 2006). More recent findings indicate long-term decreases in hospitalization and negative symptoms following
a trial of ACT, although findings using this approach are still new, limited, and warrant future attention (Bach, Hayes, & Gallop,
2011; Tonarelli et al., 2016).

Treatment for Psychosis-Risk Populations

Several reports indicate that antipsychotics may be effective in reducing the progression of prodromal syndromes into psychotic
disorders. A review of several recently completed randomized clinical trials with antipsychotic medication reports that following the
end of treatment, antipsychotic medication as a pre-psychotic intervention may delay the onset of psychosis or ameliorate pre-
psychotic symptoms (de Koning et al., 2009). However, most studies find no significant differences at the end of follow up one to
four years later. Although the onset may be delayed, there is no indication that psychosis is prevented.
The potential risks of antipsychotic medications should be considered when they are used as a preventative intervention (Cor-
coran et al., 2010). The adverse effects of second-generation antipsychotics include extrapyramidal symptoms, weight gain, and
metabolic complications. With no proven long-term effects, the benefit/risk ratio of using antipsychotics as a pre-psychotic inter-
vention must be weighed carefully. We also do not yet know the effects of these medications on prodromal adolescents. As our
knowledge of the effects of psychotropic medication on adolescent growth and development increases, we will be in a better posi-
tion to weigh any adverse effects against potential benefits, both short term and long term (Jensen et al., 1999).
There are considerably fewer randomized controlled trials evaluating psychosocial treatments for the prodromal population
compared with patients with schizophrenia. The limited research base has primarily evaluated CBT, supportive therapy, integrative
therapy, and cognitive remediation. The findings from these treatment studies suggest that while short-term benefits may be found,
lasting effects past 12 months were not apparent in most studies. The exception was from one study evaluating integrated therapy
(combining CBT, skills training, cognitive remediation, and family education), where benefits lasted up to 24 months, and another
study where trending effects were noted at 18 months for CBT (Addington et al., 2011; Bechdolf et al., 2012; Morrison, 2009; van
der Gaag et al., 2012). There is also a recent emphasis on highlighting the family as a means of intervention in the prodromal phase.
Research is currently underway to examine whether family focused treatment (Miklowitz, George, Richards, Simoneau, & Suddath,
2003) may help to delay or prevent the onset of psychosis (Schlosser et al., 2012).
268 | MATILDA AZIS E T AL.

Although the efficacy of available treatments for prodromal populations is unclear, unfavorable outcomes even for those indi-
viduals who do not transition to a formal psychotic disorder emphasize the importance of early detection and treatment options.
Recent findings show that only 7% of those identified as at risk for schizophrenia did not experience any psychiatric difficulties over
the next two to 14 years, while 28% continued experiencing attenuated psychotic symptoms, and 68% endorsed nonpsychotic
disorders (Lin et al., 2015).
A group of researchers is examining a proposed treatment course for the CHR population based on the clinical staging model (Nel-
son et al., 2018). Clinical staging is widely used in clinical medicine and could be applied to psychiatric illnesses to improve treat-
ment benefits and reduce associated risks. The purpose of clinical staging is to define the progression of an illness from early stages
to chronicity to identify the most appropriate treatment course for different illness stages. The model assumes that patients in earlier
illness stages respond more favorably to treatments, have better prognosis and that treatment options in early stages should have
limited to no side effects, and be the most effective (McGorry et al., 2006). Translated to an early intervention for CHR populations,
clinical staging would involve the following sequential strategy: support and problem solving low-level intervention with no formal
psychotherapy; CBT strategies embedded in case management; and medications. The researchers are examining the effects of this
stepwise, sequential treatment on improving functional outcomes in the CHR sample. The goal is to develop a treatment approach
with the safest modes at the earliest stages of CHR and more intensive modes with potential adverse effects at later stages for those
who do not respond favorably to earlier interventions. Additionally, pinpointing the most accurate timing for administering different
treatment levels is crucial (Nelson et al., 2018).

Cognitive Remediation and Other Promising New Interventions

Cognitive remediation therapy has also received attention with over 40 randomized controlled trials published evaluating its use in treating
psychosis. Cognitive remediation generally takes the form of computerized tasks aimed at enhancing specific cognitive skills such
as attention, working memory, or planning. The origins of cognitive remediation for schizophrenia are research showing the brain
to be plastic (i.e., able to be changed by behavior and experience). Results find that cognitive remediation significantly improves
cognition, with mixed findings on whether functioning is affected (Mueser et al., 2013; Revell et al., 2015). Some evidence suggests
that cognitive remediation may allow for the acquisition of new skills and improved functioning and symptoms by combining it
with other empirically supported interventions (Mueser et al., 2013). There has been a focus on usage of omega-3 fatty acids to
prevent transition to psychosis, following a randomized controlled trial showing significantly less conversion to psychosis in indi-
viduals who received omega-3 treatment (Amminger et al., 2010). Finally, exercise is also being investigated as an intervention in
prodromal populations and individuals diagnosed with schizophrenia, owing to research linking aerobic activity with the reversal
of brain abnormalities commonly seen in schizophrenia (i.e., increases in hippocampal gray matter following exercise) (Mittal,
Gupta et al., 2013; Pajonk et al., 2010). Recent research shows that aerobic exercise improves positive, negative, and general symp-
toms and overall quality of life (Dauwan et al., 2015; Wang et al., 2018) as well as cognitive function (Firth et al., 2017) in indi-
viduals with schizophrenia. Similar improvements can be observed in the CHR population (Dean et al., 2017).

Summary
This chapter has reviewed a broad range of scientific research on the nature and origins of schizophrenia. Spanning over a century,
the efforts of investigators have yielded, piece by piece, a clearer view of the illness. The puzzle is not solved, but we can certainly
claim progress toward a solution.
This chapter reviews the changing concept of what schizophrenia is, from its initial identification in the early 20th century to
our current understanding of the facets of the disease and the classification systems currently used for diagnosis. Although there still
has not been one specific cause identified, the second section of this chapter goes on to highlight some of the underlying genetic,
neurodevelopmental, and neurobiological abnormalities associated with a high risk for developing schizophrenia. The onset, course,
and prognosis of the disease is then considered, with particular focus on the potential mechanisms at work during onset, the typical
course, and the importance of early intervention. Finally, the current intervention and treatment options are reviewed, accompanied
with examination of their efficacy and an exploration of potential new treatment options.
Although we have not found all the pieces of the puzzle, we have made significant progress in moving toward a comprehensive
account of the etiology of schizophrenia. Among the mental disorders, schizophrenia remains a clear illustration of the complex
interactions taking place between the individual and the environment. In the coming years, we can expect research to yield impor-
tant information about the precise nature of the brain vulnerabilities associated with schizophrenia, and the mechanisms involved
in the interaction of congenital vulnerability with subsequent life stress and neuromaturation. Genetic data and research into gene
expression will provide insight into etiology, as well as further our understanding of the role neurotransmitter abnormalities in
schizophrenia. Longitudinal studies conducted during the prodromal period hold strong promise of elucidating the complicated
interactions between development (e.g., hormones, neural maturation), and latent constitutional vulnerabilities. Furthermore,
research during this period holds strong potential to inform the next generation of psychosocial and pharmacological preventive
interventions.
 SCHIZOPHRENIA SPEC TRUM AND OTHER PSYCHOTIC DISORDERS | 269

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