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DSM-5: AN UPDATED DEFINITION OF PSYCHOSIS

In the fifth edition of Diagnostic and Statistical Manual of Mental

Disorders (DSM-5), the psychosis phenotype is categorized into a broad

range of clinical diagnoses including schizophrenia, schizoaffective

disorder, other functional psychoses (e.g., delusional disorder, psychosis

due to substance use or general medical condition), as well as schizotypal

personality disorder. The key symptom domains comprising “psychosis”

include delusions, hallucinations, disorganized thought process (formal

thought disorder), and disorganized or abnormal motor behavior

(including catatonia). Despite the absence of unique pathognomonic

psychosis features for each diagnosis, that is, any type of psychotic

symptoms can occur in any diagnosis, DSM-5 emphasizes that some

aspects of psychosis manifestations are characteristic for various psychosis

diagnoses. In schizophrenia spectrum disorders (e.g., schizoaffective

disorder, schizophreniform disorder), psychotic symptoms are typically

comprised of prominent hallucinations and/or delusions as well as formal

thought disorder leading to rather severe behavioral manifestations (e.g.,

disorganized, bizarre, or catatonic behavior). In psychotic disorders due to

general medical conditions as well as in substance-induced psychotic

disorders, psychosis refers to delusions and/or hallucinations temporally

overlapping with the presumably causative event (medical illness,

substance use) which do not occur exclusively during the course of

delirium. In such rare psychotic diagnoses as delusional disorder and

shared psychotic disorder, psychosis is essentially equivalent to isolated

persistent delusions. Importantly, only disorders grouped under the

“Schizophrenia spectrum and other psychotic disorders” section of DSM-5

are conventionally characterized by psychotic symptoms as the key defining

feature comprising the clinical “core” of the diagnosis. Nevertheless,

multiple other psychiatric disorders, such as dementias,

neurodevelopmental disorders, affective disorders, some personality

disorders (besides schizotypal type) may also manifest psychotic symptoms

as associated “secondary” diagnostic features.

In schizophrenia, psychosis presents in its most severe form, frequently

with bizarre delusions and hallucinations leading to dramatic behavioral

manifestations. Although any of five senses may be affected by

hallucinatory experiences, the most common hallucinations in

schizophrenia are auditory, with multiple voices conversing among

themselves, commenting on the patient’s life or behavior, or talking directly

to the patient. Visual hallucinations are rather common, whereas tactile,

olfactory, and gustatory hallucinations are less typical and should alert the

clinician to look for underlying neurological or medical conditions that

mimic psychotic disorder. Delusions in schizophrenia vary broadly in content with most classic examples including paranoid/persecutory,

religious, or somatic forms. Although not entirely specific for

schizophrenia, such delusions as being influenced or controlled by an

outside entity or force (delusions of passivity), phenomena of thought

insertion, withdrawal or thought broadcasting, and delusional

preoccupation with esoteric, symbolic, abstract, or philosophical ideas are

more typical for patients with schizophrenia than for other psychotic

illnesses. Importantly, Schneiderian psychotic features (i.e., presence of

bizarre delusions or hallucinations consisting of a voice that keeps a

running commentary on the person’s behavior or thoughts or multiple

voices conversing with one another) have been de-emphasized in DSM-5

leaving criterion A to a broader range of symptom clusters including (any)

delusions, (any) hallucinations, disorganized speech, grossly disorganized

or catatonic behavior, and negative symptoms.

Although delusions and hallucinations are commonly perceived as core

symptoms of schizophrenic psychosis, they are not an obligate component

of the formal diagnosis of schizophrenia. According to DSM-5, since at least

two Criterion A symptoms are required to fulfill the diagnosis, patients

without either hallucinations or delusions could receive a diagnosis of

schizophrenia; however, in these cases other psychotic symptoms are

required such as thought disorder (e.g., looseness of associations, thought

blocking, derailment, tangentiality, circumstantiality, neologisms,

verbigeration, echolalia, global incoherence), grossly disorganized behavior

or catatonic symptoms. Although the phenomena of a gross impairment in

reality testing and a loss of ego boundaries are not included into formal

psychosis definitions, they are commonly seen in patients with

schizophrenia, especially during acute psychotic states. These clinical

entities describe the lack of a clear sense of where the patient’s own mind

or body end and where those of other people or inanimate objects begin. In

the most severe manifestations, the patients may have experiences that

they mentally or physically disintegrated or fused with an outside object or

with the entire universe. These components of psychosis may be poorly

verbalized by schizophrenia patients due to the complexity of the

experiences; however, they can manifest in peculiar, impulsive, or

dangerous behavior, and therefore, these symptoms should be carefully

evaluated.

Schizophrenic psychosis is usually characterized by a chronic course

with either continuous psychotic symptoms or intermittent periods of

disease exacerbations and remissions. Course types with a single (or few)

episodes followed by a long-term stable remission or clinical recovery are

uncommon. However, in other psychotic disorders the lifetime course of

psychosis can be intermittent or fleeting, with relatively short episodes of

hallucinations and delusions manifesting at the peak of severe depression

or mania, decompensated medical conditions, or induced by substance exposure or medication. In the course of schizophrenia, psychotic

symptoms tend to become less severe with time, whereas a decline in

cognitive functioning and negative symptoms become more apparent. A

further deterioration in the patient’s baseline functioning can follow each

relapse of schizophrenic psychosis. This failure to return to baseline

functioning after each relapse is commonly taken as the major distinction

between schizophrenia and psychotic mood disorders, although recent

studies report that about 20 to 25 percent of patients with affective

disorders show considerable long-term impairment in psycho-social and

basic daily functioning. Without treatment, psychosis in schizophrenia and

related disorders is frequently incapacitating and contributes, along with

negative symptoms and cognitive decline, to an overall poor prognosis of

the illness.

CATEGORICAL AND DIMENSIONAL DIAGNOSTIC APPROACHES IN

SCHIZOPHRENIA

The symptoms comprising DSM-5 criteria for schizophrenia do not define a

diagnosis-specific syndrome and reflect substantial clinical heterogeneity of

the illness. No single clinical sign is pathognomonic for schizophrenia;

every symptom observed in schizophrenia can occur in different psychiatric

disorders. The current categorical concept of schizophrenia (and other

psychiatric diagnoses) is based on having a number of different

combinations of symptoms, such that many variations of the defining and

associated symptoms and symptoms domains are possible. The

phenomenology-driven diagnostic systems, while serving the purpose of

clinical utility, have critical long-term limitations resulting in classifications

that are heterogeneous, lack clear boundaries, and, most importantly,

neither map on emerging experimental biomarker constructs nor reflect

causal biological disease mechanisms. Despite considerable progress in

understanding neurobiological bases of psychiatric disorders, at this point,

it is not possible to propose a biologically based diagnostic system due to a

lack of defining knowledge about the neurophysiologic and molecular

mechanisms of psychiatric disorders. One of the alternative diagnostic

approaches espoused to reduce the clinical heterogeneity of psychiatric

diagnoses is the identification of psychopathological illness dimensions

(such as psychosis) with a research and clinical focus on underlying disease

neurobiology. Such symptom dimensions are comprised of groups of

symptoms that resemble one another, occur together, and are,

hypothetically, based on interrelated pathophysiological and molecular

mechanisms.

Three major symptom dimensions are often described in schizophrenia:

Psychosis, disorganization, and negative symptoms. The psychosis

dimension includes distortions or exaggerations of inferential thinking

(delusions) and perceptual disturbances (hallucinations). The disorganization domain manifests as illogical disorganized thought process and/or grossly disorganized behavior. Although schizophrenic disorganization is commonly perceived as one of the accompanying features of acute psychotic state which tend to resolve as severity of psychosis diminishes, disorganized features are phenomenologically unique, and are specifically associated with poor prognosis, especially in cases of chronic presentation. Therefore, disorganization has been recognized as a distinct clinical domain of schizophrenia, not just a subtype of psychotic symptoms. Negative symptoms dimension includes restrictions in the range and intensity of emotional expression (affective flattening), in the fluency and productivity of thoughts and speech (alogia), and in the initiation of goal-directed behavior (avolition). Recently, a broader dimensional model of schizophrenia has been proposed, including cognitive dysfunction (i.e., deficits in general intelligence level, various aspects of memory, executive function, global processing speed, and

attention) as well as affect dysregulation and mood symptoms (Fig. 12.16–

1). Although neither is yet a part of the current DSM-5 diagnostic

definition, cognitive dysfunction is known to be one of the defining features

of the illness which frequently manifests long before first-break psychosis

and is highly predictive of disease course and overall prognosis.

Comparative studies contrasting dimensional composites with

traditional diagnostic categories have shown that the dimensional

approach may be superior in predicting course, demand for psychiatric

care, treatment outcome, social adaptation, and global prognosis of illness.

Originally, the dimensional models were developed to aid diagnostic

classification. However, more recently these dimensional constructs have

been targeted in various research paradigms, including genetic and disease

biomarker studies, as well as in identifying clinical targets for novel drug

development. Dimensional components within the schizophrenia diagnosis

may be characterized by unique underlying pathogenetic mechanisms and

appear to be, at least partially, pharmacologically independent. To date,

effective treatments are available for only a few of these symptom

dimensions. Psychotic symptoms may be satisfactorily controlled with the

arsenal of first- and second-generation antipsychotic medications, although

treatment-refractory cases are not uncommon. Affective symptoms are

typically alleviated by antidepressants, mood stabilizers, and some

antipsychotic agents. However, no effective treatments exist either for

cognitive deficits or negative symptoms, although treatment development

is very active in these areas. Clinical experience, as well as well-controlled

treatment trials, suggests that psychosis across many diagnostic categories,

including such diagnoses as schizophrenia, bipolar disorder, psychotic

depression, functional and substance-induced psychoses, and various

organic psychoses, show a similar pharmacological treatment response.

One of the current foci in drug development for schizophrenia is treatment for cognitive dysfunction, with hypothetical treatment targets focused on

glutamatergic, cholinergic, and serotoninergic neurotransmitter systems.

PSYCHOSIS SPECTRUM DISORDERS: DOES PSYCHOSIS CUT ACROSS THE FORMAL

DIAGNOSTIC CATEGORIES?

Among the clinical manifestations of psychiatric illnesses, psychosis

represents perhaps the most dramatic and clinically captivating

phenomenon. Historically, in early German and French schools of

psychiatry in the 18th and early 19th centuries, psychosis was described as

a single clinical entity and often was the hallmark of mental illness. Since

1896, when Emil Kraepelin demarcated “dementia praecox” from “manic

depressive insanity,” the nosological (categorical) mode of thinking and

classification has been predominant in psychiatry worldwide. This is

despite the fact that Kraepelin’s concept underwent a complex evolution

that led him to a considerable personal uncertainty about making clear

distinctions among psychosis spectrum disorders, such as dementia

praecox, manic depressive psychosis, intermediate conditions, and

paranoid disorders. In the current psychiatric classification, psychosis is

acknowledged as a clinical phenotype within numerous psychiatric

disorders, including schizophrenia, mood disorders, substance use

disorders, cognitive and neurodevelopmental disorders, and disorders

related to general medical conditions, although it is not an obligate

component of their formal diagnoses (Fig. 12.16–2).

FIGURE 12.16–1. Symptom dimensions of schizophrenia.

Large-scale research studies that utilized multivariate factor analytic

approaches applied to samples spanning various categorical diagnoses

suggest that psychosis represents a distinct clinical domain overlapping abroad spectrum of psychiatric disorders. The strategy of breaking down

phenomena into distinct dimensions has been broadly used in different

medical sciences and is commonly used in psychology. But, at the present

time, there is not a full consensus on how to subclassify various psychosis

spectrum disorders into meaningful, biologically based dimensions. In

recent studies of patients with psychotic disorders (schizophrenia,

schizoaffective disorder, psychotic mood disorders, and other functional

psychosis) and their biological relatives, five distinct symptom domains

spanning these diagnoses were described, including reality distortion

(psychosis), disorganization, mania, depression, and negative symptoms,

commonly referred to as the “pentagonal model” of psychotic disorders.

Different diagnostic categories showed distinct dimensional profiles, with

schizophrenic persons scoring highest in the reality distortion, negative,

and disorganized symptoms; and affective diagnoses scoring highest in

manic and depressive dimensions and lower in the psychosis and negative

symptoms. Interestingly, the mania factor is considered to be the best

discriminator between schizophrenia and mood disorder diagnoses, while

psychosis turned out to be a domain of overlap between these diagnostic

categories. In all dimensional constructs, schizophrenia patients typically

show higher variability compared to patients with mood disorders,

suggesting that bipolar disorder diagnosis may signify a better defined

phenomenological construct than schizophrenia, which appears to be

highly heterogeneous. These studies suggest quantitative variations in

symptom dimensions across diagnostic categories rather than qualitative

differences. However, multiple questions remain, including whether or not

the phenomenological structure of psychosis is the same across diagnoses,

what is the extent of similarities and uniqueness of underlying genetic and

pathophysiological mechanisms of psychosis is, and whether various

psychosis spectrum disorders show the same molecular basis, treatment

response and functional outcomes.

FIGURE 12.16–2. DSM-5 diagnoses overlapping the psychosis dimension. GMC, general

medical conditions.

BIOLOGICAL FACTORS IN PSYCHOSIS: EVIDENCE FROM TRANSLATIONAL

NEUROSCIENCE INVESTIGATIONS

Genetic Studies

Psychotic illnesses are broadly heterogeneous disorders, not caused by a

single etiological factor, but rather due to a complex interplay of different

endogenous and environmental pathogenic influences. There is consistent

evidence that a genetic component contributes to the etiology of psychosis;

however little is known for certain about particular genomic regions or

individual risk genes. Recent findings from large-scale whole genome

studies provide evidence for contribution of numerous genes, each of a very

small effect, to ethiopathogenesis of schizophrenia. Moreover, a substantial

overlap in genetic susceptibility across a broad spectrum of psychiatric

disorders, for example, schizophrenia, bipolar disorder, autism, has been

observed. Some of the identified candidate genes show strong associations

with dimensional constructs, such as psychosis or mood symptoms, that

are not projected directly onto categorical diagnoses. Hypothetically (not

yet well established) genes or sets of genes, interacting with environmental

factors, may predetermine vulnerability to psychosis and other clinical

disease manifestations. Depending on genetic influence and other

endogenous (e.g., neurodevelopmental) and/or environmental interactions,

psychosis may coexist with different clinical phenotypes (e.g., mood

symptoms or cognitive dysfunction), composing epiphenomenal categorical

diagnoses. This conceptualization of psychosis draws preliminary support

from epidemiological and molecular genetic studies.

Family Studies. Family studies of schizophrenia and affective

psychoses have established that psychosis strongly aggregates in families.

Having a relative with schizophrenia or bipolar disorder is a single most

powerful risk factor for developing psychosis. The life-time risk for

developing schizophrenia increases approximately 8 to 12 folds in first-

degree biological relatives of schizophrenic probands. Although the results

of genetic studies in affective psychoses are less consistent, the familial

aggregation of bipolar disorder and major depressive disorder has been

observed. First-degree relatives of individuals with bipolar I disorder have

elevated rates of bipolar I disorder (4 to 24 percent), bipolar II disorder (1

to 5 percent), and major depressive disorder (4 to 24 percent). While it was

originally thought that schizophrenia and affective psychoses are inevitably

segregated, recent reports challenge this. Family studies show that

schizophrenia and affective psychoses can co-occur in the same families,

suggesting shared familial risk. For example, a large epidemiologic study,

using a genetically homogenous population isolate in north-eastern

Finland, reported that 16 percent of siblings of schizophrenic probands

carried a lifetime diagnosis of psychotic disorder, including schizophrenia (0.5 percent), schizoaffective disorder (3.3 percent), bipolar I disorder (1.1

percent), major depressive disorder with psychotic features (2.2 percent),

alcohol-induced (2.2 percent), and other substance-induced (1.1 percent)

psychoses, delusional disorder (1.6 percent) and psychotic disorder, not

otherwise specified (4.4 percent). Over half of the siblings (54 percent) in

this study had a lifetime diagnosis of any mental disorder, with major

depressive disorder (15.3 percent) and anxiety disorders (12 percent)

leading among non-psychotic diagnoses. Numerous reports confirmed that

the increased risk for psychotic illness in relatives of individuals with

schizophrenia does not appear to be confined to schizophrenia alone. On

the other hand, bipolar illness has been associated with increased risk of

schizophrenia in relatives. In one of the recent family studies it was

reported that relatives of women with early onset of bipolar disorder had

the highest morbid risks for both bipolar illness and schizophrenia. The

presence of more than one patient with bipolar disorder in a family

increased the risk for schizophrenia nearly fourfold. In a different study it

was shown that affective disorders were more frequently inherited from the

same parental side of the family as schizophrenia psychosis, suggesting that

the same genetic factors could contribute to susceptibility to both

schizophrenic and affective psychoses. Several studies showed that, in fact,

parents of schizophrenic probands suffer from affective disorders

(especially, major depressive disorder) more often than from

schizophrenia. Schizoaffective disorder occurs at similarly increased rates

both in families of probands with schizophrenia and bipolar disorder.

Likewise, schizophrenia and bipolar disorder have been shown to occur at

increased rates in relatives of probands with schizoaffective disorder.

Further, there is growing evidence that certain clinical phenotypes and

symptom dimensions may predict familial risk of psychosis across

categorical diagnosis. For example, in a large family study from the

Netherlands a syndrome, characterized by bizarre behavior, inappropriate

affect, catatonia and poor rapport, predicted psychosis in biological

relatives of schizophrenic probands. The syndrome characterized by

affective blunting and insidious early onset of illness predicted psychosis in

the first-degree relatives of probands with various types of functional

psychoses. A lifetime history of mania specifically predicted affective

psychosis in the relatives of probands with various psychotic disorders.

Similarly, in a recent study, conducted in a sample of psychotic inpatients

and their 2,987 first-degree relatives in Spain, severe primary negative

symptoms in probands were related to familial liability for schizophrenia,

whereas familial morbid risk of mood disorders was predicted by mania,

depression and catatonia syndromes in probands. Importantly, this familial

association pattern was completely independent of the probands’ diagnosis

of schizophrenia or major mood disorder. These studies provide evidence

that familial liability for psychosis clearly overlaps DSM categories of schizophrenia and mood disorder. From a dimensional perspective,

psychosis may represent a shared phenotype with unique genetic etiologies,

running through family generations.

Twin Studies. Twin studies show that the concordance rate for

schizophrenia is higher in monozygotic twins (47 to 56 percent) than in

dizygotic twins (12 to 16 percent), suggesting a strong heritability

component for the illness. It has been reported that the more severe the

schizophrenia, the more likely it is for the twins to be concordant for the

disorder. Some European studies have reported a concordance rate for

monozygotic twins of over 80 percent in cases of severe schizophrenia with

typical core symptoms. These observations suggest that the schizophrenia

diagnosis includes clinically and etiologically heterogeneous subgroups

with potentially distinct underlying genetic backgrounds. Further, twin

studies suggest that a schizophrenia diagnosis in one twin equally increases

the risk for schizophrenia and affective disorders in the co-twin. A clear

overlap in genetic risk for schizophrenia, schizoaffective, and manic

phenotypes was reported in a sample of 77 monozygotic and 89 same-sex

dizygotic twin pairs, ascertained from the Maudsley Twin Register in

London. In this study, if one member of a monozygotic twin pair had

schizophrenia, there was about an 8 percent chance of schizoaffective

disorder diagnosis in the co-twin and an 8 percent risk of mania. Another

report, based on the Maudsley twin series, showed that the maximum

monozygotic/dizygotic concordance ratio was produced by a combination

of schizophrenia, affective disorder with mood-incongruent psychotic

features, schizotypal personality disorder, and atypical psychosis,

suggesting that these psychosis spectrum disorders share a common

genetic background.

Genetic Linkage Studies. Genetic linkage studies have identified several

chromosomal regions showing linkage to both schizophrenia and affective

psychosis, including 1q32, 10p11-15, 13q32, 18p11.2, and 22q11-13. In one

study significant linkage to psychotic bipolar disorder was obtained on

chromosomes 9q31 and 8p21. Several other chromosomal sites were

supportive of linkage with psychosis in bipolar pedigrees, including 5q, 6q,

8p, 13q, 15q, 17p, and 18q, which are also implicated in schizophrenia. A

recent genome-wide linkage scan in schizoaffective disorder, using British

and Irish pedigrees with at least one member diagnosed with

schizoaffective disorder, bipolar type, confirmed the existence of loci that

influence susceptibility across the functional psychosis spectrum. This

study demonstrated genome-wide significant linkage at chromosome 1q42

and suggestive linkages at 22q11 and 19p13. The evidence for these linkages

was equally contributed by schizophrenia pedigrees (where schizophrenia

was predominant among relatives in addition to schizoaffective disorder) and bipolar disorder pedigrees (with higher proportion of affective

psychosis). Noteworthy, two candidate genes, DISC1 (disrupted in

schizophrenia 1) and COMT (catechol-O-methyltransferase), which have

been consistently implicated in schizophrenia and, more recently, in

bipolar disorder, map to 1q42 and 22q11, respectively.

Studies of Individual Genes and Genome-Wide Association Studies.

Studies of individual genes also support the evidence of overlap between

schizophrenia and different psychotic disorders. In most studies, the

candidate genes were first tested in schizophrenia, but a growing number of

reports suggest that some of these genes may also be involved in etiologies

of affective psychoses and even broader psychopathology, for example,

autism spectrum disorders and epilepsy. In particular, recent genetic

studies have shown increasing evidence for an overlap in genetic

susceptibility across the traditional classification categories, including

association findings at DISC1, COMT, DAOA (G72)/G30), (D-amino acid

oxidase activator (G72)/G30), dysbindin (dystrobrevin-binding protein 1),

BDNF (brain derived neurotrophic factor), NRG1 (neuregulin 1), and RGS4

(regulator of G protein signaling 4). For instance, NRG1 has been

consistently implicated in schizophrenia; more recently, its relationship to

bipolar disorder as a candidate susceptibility gene has also been reported.

A recent study found the association of NRG1 with a clinical phenotype of

bipolar disorder with mood-incongruent psychotic symptoms, as well as

with schizophrenia with lifetime manic episodes, suggesting that NRG1

may confer susceptibility to a specific clinical phenotype with combined

features of psychosis and mania. A number of independent genetic linkage

and association studies in diverse populations support that variation in

DISC1 gene influences susceptibility to disorders of psychosis spectrum,

including schizophrenia, schizoaffective disorder, bipolar disorder, and

major depression. Although this gene has been named “disrupted in

schizophrenia,” in fact, the family in which the DISC1 translocation was

originally observed included cases of both psychosis and mood disorder.

Recently several independent groups have implicated association of DISC1

with bipolar disorder, and in one study the strongest association was

observed with schizoaffective disorder, suggesting that DISC1 influences

susceptibility to a mixed psychosis-mood phenotype that cuts across the

traditional schizophrenia/bipolar divide. Dysbindin is another example of a

candidate gene that was initially implicated in schizophrenia. Nevertheless,

recent reports have also demonstrated an association between a set of

polymorphisms in this gene and a clinical subtype of bipolar disorder with

recurrent psychotic episodes, specifically psychotic mania. Overall, these

findings support variations in NRG1, DISC1, and dysbindin as potential

genetic effects contributing (along with many other genetic and

environmental factors) to susceptibility for psychosis or a mixed phenotype with features of both psychosis and mood symptoms rather than to the

DSM “schizophrenia” phenotype, although these genetic markers were

indeed originally tested as schizophrenia candidate risk genes.

Polymorphisms in G72 (DAOA)/G30 have been broadly linked to both

schizophrenia and bipolar disorder. Furthermore, a recent study from the

United Kingdom, conducted with a large sample of schizophrenia and

bipolar disorder cases, implicated several genetic variations in G72

(DAOA)/G30 as specific risk markers for major mood episodes across the

bipolar and schizophrenia diagnoses. Thus, although this locus was

originally described as a schizophrenia risk gene, this large-scale report

suggests that G72 (DAOA)/G30 appears to be more strongly associated

with the mood symptoms domain, not psychosis, within the schizophrenia-

bipolar diagnostic continuum.

Epidemiological and molecular genetic studies support the hypothesis

that psychosis is a clinical phenotype with multifactorial etiologies, among

which a genetic component is crucial. Family studies of schizophrenia and

affective psychoses have established that psychosis strongly aggregates in

families. Twin studies have suggested high heritability estimates of

psychosis with a complex mode of transmission. Recent whole genome

linkage studies have suggested a number of chromosomal loci that

influence susceptibility to psychosis, independently of diagnostic

categories. Detailed studies of linked genomic regions have identified

several putative candidate genes that appear to be involved in genetic

etiologies of schizophrenia and affective psychoses. Since schizophrenia is a

relatively rare illness with presumably multiple genes of small to very small

effects involved in its etiology, the majority of available to date genetic

studies are still statistically underpowered. Geneticists suggest that tens of

thousands of cases and controls may be needed to find firm associations.

For example, the Schizophrenia Psychiatric Genome-Wide Association

Consortium recently conducted a multi-stage genome-wide association

study (GWAS) including 36,989 schizophrenia cases and 113,075 controls

identified 108 loci associated at genome-wide significance with the

schizophrenia phenotype. Examination of specific candidate genes at these

loci suggested the involvement of dopaminergic regulation (DRD2 gene),

multiple genes involved in glutamatergic neurotransmission and synaptic

plasticity (e.g., GRM3, GRIN2A, SRR, GRIA1), as well as neuronal calcium

signaling (e.g., CACNA1C, CACNB2, CACNA11). Independent of genes

expressed in brain, associations were enriched among genes expressed in

tissue that play important role in immunity (in particular, relevant to B-

lymphocyte lineages involved in acquired immunity), providing support for

the hypothesized link between the immunological effects and

schizophrenia. In addition to polygenic, complex inheritance observed in

schizophrenia and other psychotic disorders, there is also strong indication

that in some patients a deletion or insertion of a larger chromosomal region, so-called copy number variation (CNV), might play a crucial role in

the disease pathogenesis. This could be specifically important in sporadic

cases of schizophrenia, since a higher frequency of de novo mutations has

been associated with these CNVs. Noteworthy, CNV markers linked to

schizophrenia show substantial overlap with neurodevelopmental

disorders, such as intellectual disability and autism spectrum disorders,

providing support for partially overlapping etiologies underlying these

disorders.

Current clinical targets available for genetic studies, for example,

“schizophrenia” or “bipolar disorder,” are highly heterogeneous and do not

clearly map onto molecular or neurophysiologic disease models.

Understanding the biological effect of genetic risk markers is undoubtedly

complex. Although several such candidate markers have been implicated,

the associating variations are likely different in different disease subtypes

and symptom clusters, and it is therefore difficult to determine the specific

biological effect of each risk gene characteristic for specific disease

components. Various epigenetic factors, although poorly explored so far,

add to the complexity of the picture. In addition, environmental factors,

perhaps interacting with risk genes, are likely to contribute and further

complicate endogenous and environmental factors interplay. Although

originally the candidate risk genes were implicated in schizophrenia, recent

findings provide evidence that they show strongest associations with

symptom dimensions, such as psychosis (e.g., NRG1, DISC1, and

dysbindin) or mood symptoms (e.g., G72/G30, BDNF), across the

schizophrenia–mood disorder continuum. Furthermore, recent GWAS

studies support much broader genetic overlaps, from psychotic disorders,

to autism spectrum disorders, to epilepsy and neurodegenerative disorders,

to medical conditions (e.g., autoimmune disorders). Although intriguing,

these observations are still preliminary and should be treated with caution,

given the difficulties in establishing defining evidence for genetic etiologies

in complex, polygenetic disorders. Future genetic studies derived from

large samples, targeting more homogenous disease components (e.g.,

symptom dimensions) and/or biomarker-derived constructs underlying

clinical phenomenology, are needed.

Emerging Candidate Biomarkers for Psychosis

Despite considerable progress in epidemiological and molecular genetics of

psychiatric syndromes made in the past decade, clinical phenotypes, such

as schizophrenia or bipolar disorder, when directly applied in linkage

analyses or studies of individual genes, generally fail to result in consistent

findings. Although multiple genome-wide “hotspots” and associated

candidate genes have been implicated, the causative “psychosis genes” have

not been identified. Even less is known about specific pathways and brain

circuitries through which these genetic effects may contribute to symptom manifestations of psychotic disorders. The inconsistent genetic findings

may be, in part, explained by the presumed complexity of the

pathophysiologic mechanisms of psychiatric disorders, resulting from a

multicomponent interplay of genetic/epigenetic, endogenous and

environmental factors. In addition, the phenomenological heterogeneity of

psychotic disorders as well as lack of biologically based definitions and

clear boundaries in the existing diagnostic categories contribute to the

limited success in identifying causative genetic etiologies. Based on these

kinds of considerations, the focus of genetic and translational studies has

recently shifted toward disease intermediate phenotypes, or biomarkers.

Intermediate phenotypes (often called biomarkers) are specific measurable

alterations in brain function or structure, or abnormalities in peripheral

systems (e.g., hyperactive inflammatory cascades, endocrine effects)

reflecting components of disease pathogenesis which are thought to be

“intermediate” between the aberrant genes and the overt clinical

manifestations of disease. These alterations are frequently referred to as

“disease biomarkers” and can be assessed by objective neurophysiological,

neuroanatomical, or behavioral measurements. An ideal intermediate

phenotype for an illness would be a measure that is associated with the

clinical syndrome, heritable and state-independent. In addition, it co-

segregates in families while being expressed in unaffected family members

and may serve as an informative predictor or risk marker observed long

before full disease manifestations. Intermediate phenotypes are a

promising area of study in the search for genetic factors in psychosis which

may provide more direct clues to the genetic underpinnings than does the

clinical syndrome itself. On the other end, dimensions of disease, such as

psychosis, may be particularly useful in identifying the underlying

intermediate phenotypes, as dimensions clearly provide less heterogeneous

clinical constructs.

Biomarker-focused studies in psychiatry started in the field of

schizophrenia research and up-to-date led to the recognition of several

putative disease biomarkers. These include oculomotor abnormalities

(smooth pursuit eye movement alterations and saccadic eye movement

disinhibition); deficits in sensorimotor gating, measured with

electroencephalography-based event-related potential (ERP) and prepulse

inhibition (PPI) of startle response paradigms; abnormal neurocognitive

performance; as well as structural and functional brain abnormalities

captured with various imaging methodologies. In contrast to the

considerable amount of data in schizophrenia, much less is known about

intermediate phenotypes of other psychotic disorders, although selected

candidate biomarkers have recently begun to be explored in disorders of

neurodevelopmental and affective spectrum. Similar to overlapping clinical

symptom manifestations, the three most common psychotic disorders,

schizophrenia, schizoaffective disorder and bipolar disorder, appear to share common etiologic determinants and biomarker signatures (Fig.

12.16–3). Within the array of neurophysiological, anatomic, and cognitive

measures, there are specific elements that can be targeted as candidate

psychosis biomarkers.

Oculo-Motor Alterations in Psychotic Disorders. Similar abnormalities in

smooth pursuit eye movement (i.e., inability to closely follow a moving

target) and saccadic eye movement disinhibition have been observed in

schizophrenic and psychotic bipolar disorder patients, as well as in their

first-degree relatives and persons with mild psychotic symptoms, such as

those with schizotypal personality disorder. These oculomotor phenotypes

are thought to be mediated by frontal cortex and have been linked to

working visual spatial memory function as well as deficits of prefrontal

inhibitory control. These oculo-motor deficits are stable, trait-like

characteristics, observed in both acute (psychosis, acute mania) and

remission disease phases, and seem to be minimally influenced by

medications. Recent genetic studies of oculomotor biomarkers suggested

linkage of smooth pursuit eye movement alterations to chromosome 6p21

in schizophrenia families. Other studies, using fMRI simultaneously with

eye tracking during the imaging sessions, have reported that schizophrenic

patients tend to activate different brain regions in order to maintain

smooth visual tracking compared to healthy subjects. Patients showed

reduced activation in frontal and, specifically, supplemental eye fields

regions, medial superior temporal and anterior cingulate cortices.

Interestingly, activation in medial occipito-temporal cortex was increased

in patients compare to healthy individuals, perhaps, reflecting recruitment

of different brain regions in order to compensate for a primary prefrontal

deficits underlying smooth pursuit eye movement system dysfunction in

schizophrenia.

Sensory and Sensory-Motor Gating Deficits in Psychotic Disorders.

Sensory/sensory-motor gating is a neurophysiological function of a normal

brain that allows to “filter out” irrelevant and/or excessive environmental

stimuli. It has long been observed that patients with evolving psychosis and

mania display hypersensitivity to environmental stimuli as well as aberrant

stimuli attributions, thought to be mediated by altered sensory and

sensory-motor gating mechanisms. These phenomena are typically

measured by various ERP paradigms using electroencephalography (EEG)

with such probes as P50 (positive EEG wave observed within 50 ms of a

target auditory stimulus) and P300 (positive EEG wave observed within

300 ms of an “odd-ball” auditory stimulus), as well as electromyography

(EMG) reflecting sensory-motor gating function (e.g., blink response in the

prepulse inhibition [PPI] paradigms).

FIGURE 12.16–3. Clinical, biomarker, and genetic components in the schizophrenia–

bipolar disorder continuum. Schizophrenia, schizoaffective disorder, and bipolar disorder

are the three main psychiatric diagnoses overlapping the psychosis dimension. In addition,

other symptom dimensions, such as cognitive dysfunction, disorganization, negative and

affective symptoms, are variably presented in these diagnoses. These symptom

manifestations are thought to result from a complex interplay of environmental and

biological factors, expressed in disease biomarkers such as altered brain anatomy, cognitive

or neurophysiologic abnormalities, captured with electroencephalography, brain imaging

and other objective measurements. Some, though not all, of these biomarkers may be

heritable and subserved by genetic and epigenetic effects.

ELECTROENCEPHALOGRAPHY-BASED BIOMARKERS IN PSYCHOTIC DISORDERS. Auditory

Paired Stimuli ERPs. An overall pattern of gating deficits characteristic

for psychosis is a reduced sensory and sensory-motor gating function

thought to underlay environmental stimuli hypersensitivity phenomena. In

the standard auditory “paired stimuli” paradigm, so called “P50” response

amplitude (i.e., the largest EEG wave within 50 ms after the stimulus

presentation) is measured in response to each of two auditory “clicks.” In

healthy individuals, the P50 wave following the second stimulus is lower

than that to the first stimulus, reflecting normal sensory gating function. In

contrast, both schizophrenia and bipolar patients (specifically, patients

with acute mania) show diminished suppression of P50 ERP associated

with insufficient sensory gating. These sensory gating deficits are thought

to be stable “trait” measures largely independent of active severity of

psychotic or mood symptoms or treatment effects. Some studies report

more prominent P50 abnormalities in patients with disorganized

schizophrenia, although an association between disrupted P50 and

negative symptoms has also been suggested. An intriguing observation,

suggesting that P50 sensory gating deficit may be a unique psychosis

intermediate phenotype, has been recently reported in patients with

bipolar disorder. Persons with bipolar I and lifetime history of psychosis

and those with schizoaffective disorder showed P50 deficits similar to those observed in schizophrenia, whereas bipolar patients with no history of

psychosis exhibited normal P50 suppression. Sensory gating deficits are

thought to be heritable and have been linked to various psychotic disorders

aggregating in families, including schizophrenia. “Schizophrenia-like” P50

suppression deficits are also observed in people with schizotypal

personality disorder as well as in individuals at high risk for developing

psychosis, such as subjects originating from high genetic density families

(i.e., those with several psychotic family members) and individuals with

schizophrenia prodrome, typically preceding frank psychosis

manifestations. Evidence for a linkage between disrupted P50 gating and

chromosome 15q14 has been reported in several studies, specifically to the

promoter region of the α-7 nicotinic cholinergic receptor subunit gene, in

both individuals with schizophrenia and their relatives. Odd Ball Paradigm and P300 ERP. P300 is typically measured in

auditory or visual “odd ball” paradigms where frequently presented stimuli

(“targets”) are interleaved with infrequent and unexpected atypical (“odd

ball”) stimuli and refers to a positive EEG wave occurring within 300ms

following an “odd ball” stimulus. Several large meta-analyses reported

reduced P300 ERP amplitude and delayed P300 latency in probands with

schizophrenia and their biological relatives, as well as in “mild psychosis

phenotypes” such as schizophrenia prodrome and schizotypy. Recently

studies of P300 ERP have been extended to bipolar disorder, and suggested

similar “schizophrenia-like” alterations in P300 amplitude and latency in

individuals with psychotic bipolar disorder and their relatives, albeit less

consistently across different studies. In several studies a frontal

subcomponent of P300 ERP was reported to correlate with severity of

hallucinations in patients with schizophrenia, perhaps due to shifting of

attentional resources from external to internal (psychotic) stimuli.

Similarly, patients with psychotic bipolar disorder showed reductions in

frontal lobe P300 voltage, suggesting a component of overlapping neural

substrate for dysfunction in both schizophrenia and affective psychosis.

Diminished P300 amplitude and increased latency have been also linked to

severity of negative symptoms, illness duration and early age of psychosis

onset, as well as several cognitive dysfunctions, that is, deficits in attention.

Several studies, conducted on healthy twin pairs suggested moderate

heritability estimates for P300 ERP biomarker. Interestingly, the P300

heritability in females appeared to be lower (45 percent compared to 56

percent in males), suggesting that endogenous or environmental factors

may have a stronger modifying influence on the P300 phenotype in

females. Genetic association studies linked P300 alterations to the COMT

genotype (i.e., Met homozygous variant) as well as NRG1 polymorphisms in

patients with schizophrenia.

Sensorimotor Gating Deficits in Psychosis: Prepulse Inhibition.

PPI paradigms measure inhibition of the startle reflex. In healthy individuals, a weaker “prepulse” stimulus leads to an inhibition of a

response magnitude to a startle (“pulse”) stimulus, used as an index of

sensorimotor gating. In individuals with psychotic disorders insufficient

PPI reflecting an exaggerated startle response is commonly observed.

Diminished PPI has been reported in patients with schizophrenia,

schizotypal personality disorder, and both affected and unaffected

biological relatives of schizophrenia probands. Similar findings have been

noted in persons with bipolar disorder, especially during acute manic

phase, although the studies in bipolar are few and less consistent. Several

studies reported associations between PPI deficits and florid psychotic

symptoms, such as disorganized thought process and behavior, greater

distractibility, and bizarre psychotic behavior. However, at least a few

studies in schizophrenia observed disrupted PPI even in remission phases,

supporting this candidate biomarker as a stable “trait” measure. Likewise,

individuals with acute psychotic mania show significantly reduced PPI and

less startle habituation, along with a significant reverse correlation between

PPI sensorimotor gating and severity of psychotic symptoms. In contrast,

euthymic bipolar patients failed to demonstrate abnormalities in PPI.

These observations of similar PPI deficits in schizophrenia and psychotic

mania, abnormal sensorimotor gating may represent one of the putative

biomarkers subserving psychosis as a unique clinical phenotype.

Cognitive Dysfunction as a Candidate Psychosis Biomarker.

Cognitive dysfunction has recently drawn interest as a distinctive

phenotype across psychotic disorders, as well as a treatment target. The

presence of specific cognitive deficits is not yet part of the diagnostic DSM-

5 criteria for schizophrenia; nonetheless it is recognized as a common and

consistent feature of the disorder. Extensive cognition studies have shown

stable, trait-like deficits in the domains of working memory, verbal episodic

memory, attention, processing speed, language comprehension, problem

solving, and executive function in individuals with schizophrenia. Patients

with bipolar disorder manifest deficits in overlapping cognitive domains,

with attention, working memory, and verbal memory difficulties being

among the most prominent, albeit generally less severe that those found in

schizophrenia. A considerable clinical heterogeneity of the bipolar

phenotype correlates with variable presentations of cognitive deficits, with

some patients manifesting profound “schizophrenia-like” abnormalities,

and others showing little or none alterations in cognitive function. It

appears that the greater the burden of illness associated with the disorder,

as manifest in the lifetime history of psychosis, number of past manic

episodes, an overall duration of illness and number of past hospitalizations,

the greater the neurocognitive deficits typically found in bipolar patients.

Moreover, bipolar patients with a lifetime history of psychosis appear to

have a slightly different profile of neurocognitive deficits than those

without a history of psychosis, manifesting more severe impairment on measures of executive function and spatial working memory. More severe

bipolar patients, especially those with psychosis, begin to resemble

schizophrenia patients with regard to the level and profile of

neurocognitive deficits. One of the commonly reported cognitive features

that may help to disambiguate schizophrenia and bipolar disorder is a

general intelligence level, especially, premorbid IQ, with lower scores

typically observed in patients with schizophrenia but normal IQ levels in

bipolar disorder. An extensive research work has been done in attempt to

discover genetic associations for cognitive dysfunction in schizophrenia

and related psychotic disorders, with most consistent findings supporting

links for COMT and executive function, DISC1 and verbal declarative and

working memory deficits in schizophrenia and, less consistently, bipolar

probands, and their biological relatives.

Anatomical Brain Alterations in Psychotic Disorders.

Anatomical brain changes have been examined as candidate psychosis

phenotypes across schizophrenia and related psychotic disorders. Studies

in schizophrenia have consistently reported a modest but measurable

reduction in whole brain volume, particularly in gray matter (averaging 2 to

8 percent for various brain structures, based on meta-analyses), as well as

an increase in ventricular size. Several definite areas of the brain have been

consistently reported to demonstrate volumetric changes, such as

decreased volume in several frontal (e.g., dorso-lateral, orbito-frontal),

temporal (medial temporal lobe [MTL], particularly, the hippocampal

formation; STG), and parietal cortical regions, as well as thalamus. Several

meta-analyses of volume change in schizophrenia reported whole brain,

and, particularly, fronto-temporal gray matter volume reductions in

individuals at the time of their first psychotic break, preceding any

treatments.

The structural findings in psychotic mood disorders are less consistent,

ranging from decreased, to normal, to increased gray and white matter

volumes in various brain regions. Recent large-scale psychosis-focused

studies report regionally overlapping but more focused and lesser in

magnitude gray matter volume reductions in psychotic bipolar disorder

compared to schizophrenia. The most reproducible regional volume

reductions in psychotic bipolar disorder are typically localized to anterior

limbic regions, that is, orbito-frontal, anterior cingulate, insular cortex, as

well as amygdala and anterior temporal cortex. At the same time, volume

increases in amygdala have been reported. Some studies, comparing

individuals across the psychosis dimension, find no abnormalities in gray

matter volume, while volume deficits of white matter were evident

throughout the neocortex and brainstem, with similar regions of white

matter loss found in schizophrenia and bipolar patients.

The question of whether volume loss is progressive during the lifetime

course of psychosis has been explored. Measurable gray matter volume and density changes are typically observed in individuals near psychosis onset,

progress with illness duration, more aggressively during the initial years of

psychosis in some cases, and ultimately result in characteristic gray matter

alterations found in chronic psychosis samples. Data from relatives with

psychosis spectrum disorders (e.g., schizotypal personality disorder)

demonstrate milder but similar gray matter volume reductions suggesting a

heritable link between psychosis manifestations and brain structure

phenotypes. Moreover, recent large-scale reports demonstrate overlapping

gray matter volume reductions in the psychosis probands (including

schizophrenia, schizoaffective disorder, and psychotic bipolar disorder

cases) and their first-degree relatives with psychosis spectrum disorders,

but normal gray matter characteristics in relatives unaffected by lifetime

psychosis, even those with clear non-psychotic diagnoses (e.g., mood

disorders, anxiety disorders). These gray matter alterations may reflect

“psychosis burden,” from extensive reductions in probands where

psychosis is fully manifested, to similarly distributed but milder alterations

in relatives with mild psychosis spectrum phenotypes, to normal gray

matter in relatives without lifetime psychosis. Moreover, associations

between lifetime duration of psychosis and gray matter volume, with more

loss observed as illness progresses, have been reported in schizophrenia

and schizoaffective probands in frontal, temporal cortex, basal ganglia and

thalamus, the regions long implicated in psychosis in both first episode and

chronic samples.

The exact mechanisms underlying these brain structure changes are

unknown, but can be interpreted in the context of available post-mortem

findings of cellular neocortical pathology in psychotic disorders.

Histological examination of schizophrenia cases indicates no neocortical

neuronal loss, yet altered neuronal cell packing, presumably due to reduced

interstitial neuropil, resulting in higher neuronal density and overall

decreased cortical thickness. In contrast, analyses from bipolar cases show

decreased neuronal and glial density but normal overall cortical thickness.

Dendritic spine loss, as well as reduced dendritic length in dorsolateral

prefrontal cortex, has been observed in both schizophrenia and bipolar

post-mortem tissue samples. These post-mortem findings suggest both

overlapping and unique anatomical underpinnings for schizophrenia and

bipolar disorder, providing plausible cellular correlates for the structural

brain changes captured with imaging techniques.

Furthermore, longitudinal studies provide support for a measurable

effect of various psychotropic medications on brain structure. Long-term

treatment with first-generation antipsychotics has been linked to increased

gray matter volume and density in basal ganglia. Both first- and second-

generation antipsychotics are associated with decreased gray and white

matter volume in the fronto-temporal regions. Lithium has been linked to

higher gray matter volume/density in diffuse neocortical regions as well as larger volume of specific subcortical structures, that is, amygdala, in

psychosis and mood disorder samples. Given that the majority of psychotic

and mood disorder patients undergo years of treatment with various

psychotropic agents, it is possible that the gray matter deficits consistently

reported in patients with schizophrenia and schizoaffective disorder are, at

least in part, accounted for by effect of a lifetime antipsychotics use,

whereas a relative gray matter volume preservation in bipolar patients

could be secondary to a medication effect (i.e., chronic treatment with

lithium) and that, even if a “primary” disease-associated loss of neocortical

volume exists in these patients, it could be obscured by a volume-

enhancing effect of chronic lithium use. Disentangling a “primary” disease

and medication effects on brain structure presents considerable difficulty

and requires carefully designed longitudinal research protocols.

Some, though not all studies, have captured associations between brain

anatomy changes and clinical manifestations in schizophrenia and related

disorders. In particular, deficits in the fronto-temporal volume have been

linked to severity of positive symptoms in schizophrenia and schizoaffective

disorder; reductions in various structures within the MTL have been shown

to correlate with the severity of delusions. Additionally, volume reductions

in the MTL have been linked to declarative memory dysfunction in first-

degree relatives of schizophrenic probands. Subsequent data suggest that

the various subgroups within bipolar disorder may have different structural

brain characteristics, depending on whether they have psychosis. The

majority of studies report similar brain structure changes in persons with

schizophrenia and psychotic bipolar disorder, perhaps as one of the

overlapping intermediate phenotypes indicative of psychosis liability.

Intermediate phenotypes represent smaller, homogenous, measurable

units of illness more proximal to pathogenesis of illness and genetic

etiologies than the global diagnosis constructs. Intermediate phenotypes

may be conceptualized somewhat similar to symptom dimensions: While

the dimensions of illness represent more discreet and homogenous clinical

complexes, intermediate phenotypes represent smaller, homogenous

components of illness with strong biologic ties. From this perspective,

intermediate phenotypes may be a promising target in the search for

genetic factors in psychosis, although even this has been difficult to

demonstrate. They may also provide more direct clues for understanding of

psychosis pathogenesis because they are thought to be more intimately

linked to causal biologic pathways of the illness than the clinical

syndromes. At first, the intermediate phenotype/biomarker-focused

approach was used in schizophrenia research and resulted in recognition of

several neurophysiological, neuroanatomical, and cognitive markers. More

recently, these same candidate biomarkers have been used to explore

different psychotic illnesses, specifically psychotic bipolar disorder, in

order to develop valid, objectively defined biological definitions for the psychosis dimension. Among the variety of candidate biomarkers, there are

specific elements that appear to be promising as indicators of psychosis

liability. Future studies focused on intermediate psychosis phenotypes will

explore their genetic linkage, as well as improve overall conceptualization

of clinical and biological boundaries of psychosis spectrum disorders.

PSYCHOSIS AS A CLINICAL CONTINUUM: FROM ATTENUATED PSYCHOSIS

PHENOTYPES TO FRANK PSYCHOTIC DISORDERS

Psychosis manifestations include a broad array of symptom presentations

of various severities which appear to lay on a continuum from mild

subthreshold psychotic phenomena to frank and florid psychosis. Mild

sporadic psychotic symptoms, such as illusions, mild hallucinations (e.g.,

undifferentiated noises or calling a person’s name), ideas of reference,

magical thinking, unusual beliefs and perceptual experiences, and the like

are fairly common in otherwise healthy individuals who don’t carry any

diagnosis of psychiatric illness. Although these symptoms are psychotic by

nature, they are below the threshold for a formal psychosis diagnosis. It

appears that there may be no discrete demarcations between frank

psychosis and minor subclinical psychotic symptoms, other than severity,

breadth and persistence; rather, psychosis represents a clinical continuum

with multiple subtypes and grades of symptom manifestations.

Large longitudinal studies evaluated the frequency of mild psychotic

symptoms in the general population and found that subclinical psychotic

experiences are not uncommon. For example, the large community sample

study using the British National Psychiatric Morbidity Survey data showed

that 4.4 percent of the general population reported incident psychotic

symptoms over an 18-month period. The vast majority of individuals who

reported such psychotic symptoms did not meet full diagnostic criteria for

any psychiatric disorder. These observations may indicate the presence of

latent continuum-like psychopathology in the general population.

Moreover, they are consistent with a multifactorial etiological model of

schizophrenia where many different genes of small effect interact with one

another and with environmental factors to result in the illness. Depending

on a complex interplay of genetic and environmental influences, the

manifestations of psychosis can vary from mild episodic experiences (e.g.,

déjà vu, infrequent thought blocking, or visual illusions), to moderate

psychotic-like symptoms (e.g., magical thinking, ideas of reference, bodily

illusion, or out-of-body experiences), or to severe and persistent frank

psychosis, fulfilling DSM criteria (e.g., delusions or hallucinations). From

the psychosis continuum perspective, subthreshold psychotic symptoms

are considered indicators of proneness to psychosis, with clinical psychosis

emerging when a critical genetic threshold is reached, accompanied by

modifying or triggering epigenetic and environmental factors (Fig. 12.16–

4). Clinically, the continuum nature of psychosis is well illustrated by

premorbid and prodromal symptoms in individuals with schizophrenia and

affective psychosis, psychopathology in biological relatives of psychotic

probands, as well as by certain types of personality disorders, displaying a

wide range of psychotic symptoms, varying from very mild psychotic-like

phenomena to frank psychosis during decompensation phases.

Premorbid and Prodromal Signs and Symptoms in Schizophrenia and Affective

Psychoses

The course of schizophrenia is generally conceptualized as starting with

premorbid (pre-prodromal) signs and symptoms, and then a prodromal

phase of illness, leading to typical clinical manifestations as the illness

evolves. However, it is not always possible to clearly demarcate these

periods due to presence of schizophrenia spectrum personality disorders

and traits characteristic for a proportion of individuals who subsequently

develop schizophrenia, as well as minor psychotic, affective, and behavioral

symptoms that sometimes appear long before the debut of schizophrenia.

In the typical, although not invariable, premorbid history of schizophrenia,

patients have had schizoid or schizotypal personality features and are

characterized as quiet, passive, introverted, emotionally aloof, and

reclusive. Other characteristics, more typical for schizoid personality,

include a low need for emotional bonds: In childhood these individuals

have few friends, by the adolescent period they may show no interest in

dating, and avoid school sports and competitions. Instead, they prefer

solitary activities and seem content by themselves. When schizotypal

features are predominant, thinking, perception, and behavior appear to be

odd or peculiar. Various psychotic-like symptoms, such as magical

thinking, peculiar beliefs, ideas of reference, perceptual illusions, odd

fantasies, or derealization–depersonalization symptoms, are commonly

present. Especially during the adolescent period, peers may exclude them

from the group activities or tease them, as schizotypal individuals have

poor communication skills and distorted social judgment. This often leads

to increased anxiety, feelings of “not fitting in,” and further withdrawal

from the social group. Although different types of personalities (including

paranoid, avoidant, obsessive-compulsive, and, less commonly, borderline)

are also seen in the premorbid period in individuals with schizophrenia,

schizoid, and schizotypal personality traits are believed to be the most

common. Still, the presence of these premorbid and prodromal symptoms

does not inevitably result in conversion to schizophrenia or other psychotic

disorder.

FIGURE 12.16–4. Threshold model of psychosis. In the general population,

considerable evidence indicates the presence of fleeting psychotic symptoms without any

functional impact. When more severe or persistent, psychotic symptoms appear at

subthreshold of formal psychosis diagnosis and manifest in entities like schizophrenia

prodrome and schizophrenia spectrum personality disorders, as well as are frequently seen

in biological relatives of probands with psychotic illnesses. In a proportion of these

individuals psychosis may reach the level of florid clinical manifestations severe enough to

fulfill criteria for DSM diagnosis. Genetic, epigenetic, other biological and environmental

factors can protect against or advance psychosis. Examples of pro-psychotic risk factors

include obstetrical complications, drug abuse, specifically, adolescent cannabis use, and

psychosocial stressors. Less is known about anti-psychotic resilience factors, though high

premorbid functioning, structured environment and cognitive remediation administered

early in the course of evolving psychosis appear to have protective effects. •, candidate

psychosis genes; P-Relatives, psychotic relatives of probands with psychotic disorder; SSPD,

schizophrenia spectrum personality disorders (cluster A: Schizoid, paranoid, schizotypal);

BPD, borderline personality disorders; SZ, schizophrenia; SAD, schizoaffective disorder; BD,

bipolar disorder with psychotic features; MDD, major depressive disorder with psychotic

features; SFD, schizophreniform disorder; SIP, substance-induced psychosis; P-GMC,

psychosis due to general medical conditions; Other Psy, other psychotic disorders.

Although the first hospitalization is often taken to be the beginning of

the illness, in many cases premorbid and prodromal signs and symptoms

may have been present for months or years prior. The majority of

schizophrenia cases are characterized by insidious, gradual onset of

psychosis with no clear date of its first manifestation. The prodromal

symptoms may start with somatic complaints, such as headaches, digestive

problems, autonomic symptoms, or fatigue and generalized weakness.

Family and friends commonly notice that the person has changed, became

withdrawn and isolated, and is no longer functioning well in occupational,

personal, and social settings. Deterioration in personal hygiene and

grooming, decreased appetite, and peculiar eating habits are also common.

During this stage, a patient may begin to develop new, unusual interests in

abstract ideas, philosophy, occult, or religious topics. Gradually, although

acute onset may also occur, subthreshold psychotic symptoms, such as

unusual speech, strange perceptual experiences and bodily illusions, bizarre ideas, and markedly peculiar behavior, build up and subsequently

progress to the level of frank psychosis in the form of hallucinations,

delusions, typical thought and speech disorders, and/or grossly

disorganized behavior.

The validity of the prodromal syndrome is uncertain, since symptoms

are frequently recognized only after the diagnosis of schizophrenia has

been made. During the prodromal phase, patients usually lack insight

regarding their developing symptoms, although some verbalize feeling as if

they have changed. Once schizophrenia is diagnosed, the retrospective

remembrance and the patient’s subjective report of early signs and

symptoms may be affected, therefore obtaining the information about the

early (prodromal) period of illness from the patient’s family may be of

significant help in building a diagnosis. The presence of prodromal

symptoms in affective psychoses is unclear. Although clinical observations

suggests that such symptoms as mood lability, impulsivity, destructibility,

and physical hyperactivity are often present long before the development of

affective psychosis, phenomenology of the bipolar prodrome is not well

characterized. One of the recent studies conducted with early onset bipolar

I disorder individuals showed that there may be unique prodromal

characteristics in patients with and without subsequent bipolar phenotype

that manifests as psychotic mania. In this study, attenuated psychotic

symptoms emerging late in the prodrome and increased energy and goal-

directed activity were more common in individuals with later psychotic

mania. Studies comparing prodromal symptoms in schizophrenia and

affective psychosis revealed considerable overlap; for example, such

symptoms as suspiciousness, sub-threshold hallucinatory experiences,

anxiety, insomnia, impaired school, or work functioning were frequently

present during the prodromal period in both psychoses. On the other hand,

depressed mood, suicidality, mood lability, difficulty thinking/communicating

clearly, tiredness/lack of energy, obsessions/compulsions, and physical agitation were more specific for the bipolar than schizophrenia prodrome.

In research, one of the approaches that is being utilized to characterize

clinical profiles of the prodromal state of psychotic illness and to identify

predictive factors for conversion to fully manifested psychosis is observing

large samples of individuals who are at increased risk for developing

schizophrenia and related psychotic disorders (e.g., offsprings of

schizophrenic parents and individuals who have several schizophrenic

family members). Recent such studies focusing on prodrome and other “at

risk samples” have shown that premorbid and prodromal symptoms,

clinically well accepted as a phase in a course of schizophrenia, are not

necessarily pathognomonic of schizophrenia psychosis. For example, in a

study by the Melbourne group, high-risk individuals with either a family

history of psychotic disorder, schizotypal personality disorder,subthreshold psychotic symptoms, or brief transient psychotic symptoms

were followed for a 12-month period. In that group 40.8 percent of the

high-risk individuals subsequently developed psychosis; however,

diagnoses ranged between schizophrenia, schizoaffective disorder, bipolar

disorder, and major depression with psychosis. Other large-scale studies in

this field suggest that approximately one-third of “at risk” individuals

eventually convert to psychosis, one-third will continue to experience stable

chronic mild psychotic phenomena without full conversion to DSM-level

psychotic illness, and one-third will improve overtime, some to the level of

full recovery. These results indicate that although early signs and

symptoms, including prodromal psychotic-like phenomena, can be

predictive of conversion to a spectrum of psychotic disorder, they do not

indicate the exact type of psychosis, and the long-term outcomes are highly

variable ranging from fully manifested psychotic disorder to full recovery.

Given these research outcomes, in DSM-5, a new diagnostic category,

“Attenuated psychosis syndrome,” has been introduced. It refers to a

broadly defined syndrome characterized by psychotic-like phenomena that

are below a threshold for full psychosis, for example, the symptoms that are

less severe and more transient, and frequently accompanied by a relatively

preserved insight. This diagnostic category is appropriate for some (but not

all) individuals with prodromal or subthreshold symptoms and calls for a

clinician’s judgment on where to draw the line for mild psychotic-like

presentations that do not deserve DSM diagnosis and where it is

appropriate to introduce this diagnosis.

Psychosis Manifestations as a Component of Personality Disorders

The occurrence of brief psychotic symptoms is common in individuals with

personality disorders. Typically, psychotic experiences in these people are

triggered by psychological (e.g., change in employment, loss of a

relationship) or physiological (e.g., medical illness) stressors, or substance

use, when compensatory mechanisms weaken. Certain types of personality

disorders are especially predisposed to psychosis, including cluster A and

borderline personality disorders. In DSM-5, cluster A personality disorders

include paranoid, schizoid, and schizotypal types. These personality

disorders are also called schizophrenia spectrum personality disorders

because their core features resemble symptoms of schizophrenia, albeit in a

milder manifestation. In addition, evidence demonstrates the familial

aggregation of these personality disorders in biological relatives of

probands with schizophrenia and other psychotic disorders.

Schizotypal Personality Disorder. Schizotypal personality disorder is

now described under DSM-5 category of “Schizophrenia Spectrum and

Other Psychotic Disorders” emphasizing long-acknowledged biological link

between this particular Cluster A personality disorder and schizophrenia. Schizotypal personality disorder is characterized by cognitive and

perceptual distortions, eccentric behavior, as well as a persistent pattern of

social and interpersonal deficits. Mild psychotic symptoms, such as magical

thinking, perceptual alterations, bizarre rituals, ideas of reference,

paranoid ideation, derealization/depersonalization, idiosyncratic speech,

odd or eccentric behavior, are core features of schizotypal personality

disorder. In response to stress, schizotypal individuals may decompensate

and display frank psychotic symptoms (e.g., hallucinations, delusions,

disorganization of thought process, and behavior); however, these episodes

are generally brief and fragmentary. Usually, these psychotic symptoms are

transitory and insufficient in duration and severity to draw an additional

diagnosis of a psychotic disorder. Nevertheless, in some cases clinically

significant psychotic symptoms may develop that ultimately meet criteria

for brief psychotic disorder, schizophreniform disorder, delusional

disorder, or even schizophrenia. In these cases schizotypal personality

disorder may be indicated in the diagnosis as a premorbid personality

disorder, in parallel with a diagnosis of psychotic illness.

Sufficient research evidence has shown that among cluster A

personality disorders schizotypy is most intimately related to schizophrenia

and other psychoses. There is a higher density of schizotypal personality

disorder cases in the biological relatives of schizophrenia probands than in

controls. Although schizotypal personality disorder occurs in 0.3 to 3

percent of the general population, studies have reported rates of 0.8 to 4.7

percent in the biological relatives of psychotic patients. Recent linkage

studies from genome-wide scans in schizophrenia and schizotypal

personality disorder, conducted with the large sample of high-density

schizophrenia families, have suggested that at least a subset of candidate

schizophrenia susceptibility genes is also involved in etiology of schizotypy

in nonpsychotic relatives of schizophrenic probands.

In the large epidemiologic study called the Roscommon Family Study,

which collected 534 probands with psychotic and affective illnesses and

2,043 of their biological relatives, schizotypal personality disorder showed

a strong familial relationship not only with schizophrenia, but also with the

other major psychotic disorders. Further factor analysis from this research

sample showed that schizotypy is a complex, multidimensional clinical

construct, whose various dimensions differ widely in the specificity with

which they reflect the familial liability to psychosis. In this study seven

schizotypal dimensions were described, among which sub-psychotic

thought disorder, negative schizotypal signs, such as poor rapport and odd

behavior,

deficient

occupational

functioning,

and

social

isolation/avoidance best disambiguated relatives of schizophrenic

probands from relatives of matched controls. Different studies reported

that the disorganization dimension of schizotypy was common to relatives

of both schizophrenia and psychotic bipolar disorders, but not in therelatives of nonpsychotic bipolar probands. Interestingly, schizotypal

disorganization symptoms were suggested as a unique phenotype

associated with an increased familial risk for both schizophrenia and

affective psychosis. From this perspective, schizotypy represents a

subthreshold psychosis phenotype that cuts across the categorical diagnosis

of schizophrenia and bipolar disorder.

Paranoid Personality Disorder. The essential feature of paranoid

personality disorder is a pattern of long-standing suspiciousness and

mistrust of people in general such that their motives are interpreted as

malevolent. Subthreshold psychotic symptoms are not uncommon in

persons with paranoid personality disorder, of which ideas of reference and

associated verbal and visual illusions are seen most often. Under stressful

conditions, specifically in a situation naturally provoking paranoid feelings

(e.g., when these patients are being criticized or disagreed with, relocating,

facing new professional environment), they may decompensate and

experience brief psychotic episodes, lasting minutes to hours. Among frank

psychotic symptoms, paranoid and persecutory delusions are the most

common, although brief visual and auditory hallucinations may also occur.

There is evidence of a genetic association between paranoid personality

disorder and psychosis spectrum illnesses. For example, in some instances,

paranoid personality disorder may appear as the premorbid antecedent of

schizophrenia or delusional disorder. An increased incidence of major

depressive disorder with psychotic features has been also reported in

patients with paranoid personality disorder. There have been few

controlled studies of familial risk of paranoid personality disorder based on

direct interviews of relatives, blind to proband’s diagnosis. However, there

is substantial evidence for a familial relationship between paranoid

personality disorder and psychotic disorders with reports of higher

prevalence of paranoid personality disorder among first-degree relatives of

schizophrenic, schizoaffective and psychotic bipolar probands ranging from

1.7 to 8.6 percent in different studies compared to 0.5 to 2.5 percent in the

general population. In contrast to schizotypal personality disorder,

paranoid personality disorder is less common in relatives of probands with

affective psychosis, although one study reported increased familial risk of

paranoid personality disorder for unipolar depression (2.9 percent), which

was higher than for relatives of schizophrenia patients (1.7 percent).

Schizoid Personality Disorder. Individuals with schizoid personality

disorder are characterized by a pervasive pattern of detachment from social

relationships and a restricted range of emotional expressions. This

behavioral pattern begins in childhood and is usually clinically obvious by

early adulthood, appearing in a variety of contexts. Although subclinical

psychotic symptoms are not uncommon in persons with different Cluster Apersonality disorders, individuals with schizoid personality disorder do not

show many unusual perceptual experiences, distorted thinking processes,

or bizarre behavioral patterns. Although, they appear self-absorbed,

detached, and emotionally aloof, they have a normal capacity to recognize

reality. On rare occasions, particularly in response to social or

interpersonal stressful circumstances, individuals with this disorder may

experience very brief psychotic episodes (lasting minutes to hours). The

content of psychotic symptoms may vary but is usually limited to delusions

of reference, paranoid or persecutory delusions, and brief visual and

auditory hallucinations relevant to the social or interpersonal stressors.

Although a genetic association between schizoid personality disorder

and functional psychoses has been suggested, the data to support this are

contradictory. Some studies (e.g., the Roscommon Family Study, Bipolar-

Schizophrenia Network on Intermediate Phenotypes) have reported that

schizoid personality disorder has significantly increased prevalence in the

relatives of individuals with schizophrenia (1.2 to 3.4 percent), although

this association is modest compared to schizotypal personality disorder. In

contrast, several studies showed that the rate of schizoid personality

disorder among biological relatives of schizophrenic probands is not any

higher than in the general population (reports vary between 0.3 to 0.7

percent). Similarly, reports of schizoid personality disorder co-segregated

in families with affective psychoses are uncommon. One of the difficulties is

that people with isolated schizoid personality disorder are not commonly

seen in clinical settings, and the prevalence of this personality disorder in

the general population is not clearly established. Schizoid personality

disorder may appear as the premorbid precursor of schizophrenia;

however, the proportion of patients who eventually convert to

schizophrenia is unknown. Schizoid personality disorder most often co-

occurs with schizotypal and paranoid personality disorders, as well as with

avoidant personality disorders, which has been also reported to be

associated with schizophrenia.

Borderline Personality Disorder. The crucial feature of borderline

personality disorder is a pervasive pattern of instability of self-image,

interpersonal relationships, and affective reactions, as well as marked

impulsivity and self-damaging behavior. Borderline personality disorder is

clinically perceived as a condition “on the border” of psychotic functioning;

therefore, historically, in psychoanalytic literature it has been called

“ambulatory schizophrenia” (a term introduced by Helene Deutsch) and

“psychotic character disorder” (described by John Frosch). Individuals with

borderline personality disorder are prone to transient psychotic episodes

that occur most frequently during periods of stress, specifically in response

to a real or imagined abandonment. In fact, psychotic-like symptoms are

included as diagnostic criteria for borderline personality disorder (criterion9: Transient, stress-related paranoid ideation or severe dissociative

symptoms). Other broadly defined psychotic symptoms are also often

reported, including ideas of reference, hypnagogic phenomena, and body-

image distortions. More severe psychotic symptoms, including frank

hallucinations and delusions, occur less frequently. Typically, the

symptoms tend to be transient, lasting minutes to hours. However, one

study by a Cornell group reported that 27 percent of the patients with

borderline personality disorder had psychotic episodes, lasting for weeks,

which were not attributed to comorbid affective or substance abuse

disorders.

It is noteworthy that in some cases psychotic symptoms in persons with

borderline personality disorder may be of a factitious nature (e.g.,

Canadian studies report up to 13 percent of factitious psychotic symptoms

in inpatients with borderline personality disorder), thus a thorough

psychiatric history, observation of patient’s behavior, and objective

information obtained from the family members are crucial. In some cases,

the psychotic symptoms in borderline personality disorder respond well to

external structuring and situational changes (e.g., the real or perceived

return of subjectively valuable person or caregiver may result in remission

of the transient psychosis). However, in more severe cases antipsychotic

medications are warranted.

Borderline personality disorder shows a strong familial pattern. For

example, the risk to acquire borderline personality disorder for first-degree

biological relatives of those with the disorder is about five times greater

than in the general population. There is also an increased familial

association of borderline personality disorder with mood disorders,

antisocial personality disorder, substance-related disorders, and eating

disorders. Although considerable co-occurrence of borderline personality

disorder with schizotypal personality disorder has been reported, as well as

occurrence of premorbid borderline personality features in persons with

schizophrenia, the majority of studies do not support a familial link

between borderline personality disorder and schizophrenia. The large-scale

epidemiologic studies of schizophrenia-related personality disorders in

relatives (e.g., the Roscommon Family Study) reported that borderline

personality disorder was rare among first-degree relatives of schizophrenic

probands, but showed a modest clustering of cases in relatives of patients

with psychotic and nonpsychotic affective disorders. Recent findings from a

large multisite consortium in biomarkers of psychosis, Bipolar-

Schizophrenia Network on Intermediate Phenotypes, demonstrated that 1.3

percent of first-degree relatives of schizophrenia patients met rigorous

DSM-IV-TR criteria for borderline personality disorder, whereas 4.1 and

3.2 percent of relatives of patients with schizoaffective disorder and

psychotic bipolar I disorder, respectably, met such criteria. Family studies

of borderline personality disorder have also indicated increased rates of mood disorders in the relatives of borderline probands compared with

healthy controls. Recent studies have suggested that borderline personality

disorder and bipolar disorder may exist on a spectrum and, perhaps, share

partially overlapping pathogenesis and may be rooted in the same genetic

etiology, similar to cluster A personality disorders and schizophrenia.

However, the question of whether a borderline personality disorder is

related specifically to psychotic bipolar disorder and to psychosis in general

remains open. Pilot studies suggest that persons who have borderline

personality disorder with a history of psychotic-like symptoms show

distinct eye tracking abnormalities, similar to those in patients with

schizophrenia. This may suggest that borderline personality disorder with

psychotic symptoms may fall into the psychosis spectrum disorders

continuum and share some endophenotypic and genetic markers,

underlying psychosis. Psychotic-like symptoms and narrowly defined

psychosis appear to be a promising target dimension for future research in

borderline personality disorder and mood disorders.

Clinical and research evidence suggest that psychosis is best conceived

of as a clinical continuum with multiple subtypes and grades of symptoms,

similar to hypertension or congestive heart failure. In fact, there appear to

be no clear demarcation between frank, clinically significant, psychosis and

mild psychotic-like symptoms, other than severity and duration. Large

epidemiologic studies suggest that fleeting psychotic symptoms are

common in the general population. The majority of individuals who have

these psychotic experiences show no functional impairment and are

considered to be free of any formal psychiatric diagnosis. These

observations suggest that psychosis can manifest in mild forms long before

its manifestation to a clinically significant level. Moreover, many of the

individuals with such subthreshold symptoms will remain stable for years,

without further progression into a full psychosis phenotype. Only a modest

proportion of them will convert to a psychotic illness in the future. These

“at risk” individuals, while rarely evaluated in psychiatrists’ offices, may be

a valuable source for studying proneness to psychosis, as well as for

exploring pro-psychotic risk factors and individual resilience against

psychosis.

In more severe and persistent presentations, psychotic symptoms

appear at the border of formal psychosis diagnosis and manifest in entities

like schizophrenia prodrome and cluster A personality disorders,

frequently seen in biological relatives of probands with psychotic illnesses.

Although cluster A personality disorders (in particular, schizotypy) are

generally thought to be biologically related to schizophrenia, recent family

and whole genome linkage studies have shown that schizotypal personality

disorder may present a unique phenotype associated with an increased

familial risk for psychosis in general, independent of the categorical

diagnosis. Similarly, prodromal symptoms, which are classicallyconceptualized as a phase in a course of schizophrenia, appear to be not

unique to schizophrenia psychosis. Instead, they signify risk for a spectrum

of functional psychoses but not the exact diagnosis that will develop.

From the disease continuum perspective, the final diagnosis of a

psychotic disorder is the end point of a longitudinal pathway from

asymptomatic, to subthreshold psychotic experiences, to frank but

infrequent psychotic symptoms, to development of persistent psychosis. It

is possible that this pathway is based on a dynamic matrix of genetic, gene

expression and epigenetic influences which are in a complex interplay with

environmental factors, with frank psychosis emerging when a critical

genetic effects threshold is reached, accompanied by modifying or

triggering epigenetic, individual biological and/or environmental factors.

Although subthreshold manifestations of psychosis are considered

indicators of proneness to schizophrenia and other functional psychoses,

they do not signify an inevitable conversion to psychosis. Whether or not

an individual at risk will traverse this pathway may depend on interaction

between pro-psychotic factors (e.g., individual biological vulnerability,

obstetrical

complications,

maternal/in-utero

immune

stimulation,

adolescent cannabis use, childhood trauma) and protective resilience

factors (e.g., high premorbid functioning, high IQ, stable social

environment).

ACKNOWLEDGMENTS

We would like to thank Four Seasons Decorations, Dallas, TX, for their help

with graphic design and illustrations for this chapter.

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Psychosis as a Defining Dimension in Schizophrenia

DSM-5: AN UPDATED DEFINITION OF PSYCHOSIS

In the fifth edition of Diagnostic and Statistical Manual of Mental

Disorders (DSM-5), the psychosis phenotype is categorized into a broad

range of clinical diagnoses including schizophrenia, schizoaffective

disorder, other functional psychoses (e.g., delusional disorder, psychosis

due to substance use or general medical condition), as well as schizotypal

personality disorder. The key symptom domains comprising “psychosis”

include delusions, hallucinations, disorganized thought process (formal

thought disorder), and disorganized or abnormal motor behavior

(including catatonia). Despite the absence of unique pathognomonic

psychosis features for each diagnosis, that is, any type of psychotic

symptoms can occur in any diagnosis, DSM-5 emphasizes that some

aspects of psychosis manifestations are characteristic for various psychosis

diagnoses. In schizophrenia spectrum disorders (e.g., schizoaffective

disorder, schizophreniform disorder), psychotic symptoms are typically

comprised of prominent hallucinations and/or delusions as well as formal

thought disorder leading to rather severe behavioral manifestations (e.g.,

disorganized, bizarre, or catatonic behavior). In psychotic disorders due to

general medical conditions as well as in substance-induced psychotic

disorders, psychosis refers to delusions and/or hallucinations temporally

overlapping with the presumably causative event (medical illness,

substance use) which do not occur exclusively during the course of

delirium. In such rare psychotic diagnoses as delusional disorder and

shared psychotic disorder, psychosis is essentially equivalent to isolated

persistent delusions. Importantly, only disorders grouped under the

“Schizophrenia spectrum and other psychotic disorders” section of DSM-5

are conventionally characterized by psychotic symptoms as the key defining

feature comprising the clinical “core” of the diagnosis. Nevertheless,

multiple other psychiatric disorders, such as dementias,

neurodevelopmental disorders, affective disorders, some personality

disorders (besides schizotypal type) may also manifest psychotic symptoms

as associated “secondary” diagnostic features.

In schizophrenia, psychosis presents in its most severe form, frequently

with bizarre delusions and hallucinations leading to dramatic behavioral

manifestations. Although any of five senses may be affected by

hallucinatory experiences, the most common hallucinations in

schizophrenia are auditory, with multiple voices conversing among

themselves, commenting on the patient’s life or behavior, or talking directly

to the patient. Visual hallucinations are rather common, whereas tactile,

olfactory, and gustatory hallucinations are less typical and should alert the

clinician to look for underlying neurological or medical conditions that

mimic psychotic disorder. Delusions in schizophrenia vary broadly in content with most classic examples including paranoid/persecutory,

religious, or somatic forms. Although not entirely specific for

schizophrenia, such delusions as being influenced or controlled by an

outside entity or force (delusions of passivity), phenomena of thought

insertion, withdrawal or thought broadcasting, and delusional

preoccupation with esoteric, symbolic, abstract, or philosophical ideas are

more typical for patients with schizophrenia than for other psychotic

illnesses. Importantly, Schneiderian psychotic features (i.e., presence of

bizarre delusions or hallucinations consisting of a voice that keeps a

running commentary on the person’s behavior or thoughts or multiple

voices conversing with one another) have been de-emphasized in DSM-5

leaving criterion A to a broader range of symptom clusters including (any)

delusions, (any) hallucinations, disorganized speech, grossly disorganized

or catatonic behavior, and negative symptoms.

Although delusions and hallucinations are commonly perceived as core

symptoms of schizophrenic psychosis, they are not an obligate component

of the formal diagnosis of schizophrenia. According to DSM-5, since at least

two Criterion A symptoms are required to fulfill the diagnosis, patients

without either hallucinations or delusions could receive a diagnosis of

schizophrenia; however, in these cases other psychotic symptoms are

required such as thought disorder (e.g., looseness of associations, thought

blocking, derailment, tangentiality, circumstantiality, neologisms,

verbigeration, echolalia, global incoherence), grossly disorganized behavior

or catatonic symptoms. Although the phenomena of a gross impairment in

reality testing and a loss of ego boundaries are not included into formal

psychosis definitions, they are commonly seen in patients with

schizophrenia, especially during acute psychotic states. These clinical

entities describe the lack of a clear sense of where the patient’s own mind

or body end and where those of other people or inanimate objects begin. In

the most severe manifestations, the patients may have experiences that

they mentally or physically disintegrated or fused with an outside object or

with the entire universe. These components of psychosis may be poorly

verbalized by schizophrenia patients due to the complexity of the

experiences; however, they can manifest in peculiar, impulsive, or

dangerous behavior, and therefore, these symptoms should be carefully

evaluated.

Schizophrenic psychosis is usually characterized by a chronic course

with either continuous psychotic symptoms or intermittent periods of

disease exacerbations and remissions. Course types with a single (or few)

episodes followed by a long-term stable remission or clinical recovery are

uncommon. However, in other psychotic disorders the lifetime course of

psychosis can be intermittent or fleeting, with relatively short episodes of

hallucinations and delusions manifesting at the peak of severe depression

or mania, decompensated medical conditions, or induced by substance exposure or medication. In the course of schizophrenia, psychotic

symptoms tend to become less severe with time, whereas a decline in

cognitive functioning and negative symptoms become more apparent. A

further deterioration in the patient’s baseline functioning can follow each

relapse of schizophrenic psychosis. This failure to return to baseline

functioning after each relapse is commonly taken as the major distinction

between schizophrenia and psychotic mood disorders, although recent

studies report that about 20 to 25 percent of patients with affective

disorders show considerable long-term impairment in psycho-social and

basic daily functioning. Without treatment, psychosis in schizophrenia and

related disorders is frequently incapacitating and contributes, along with

negative symptoms and cognitive decline, to an overall poor prognosis of

the illness.

CATEGORICAL AND DIMENSIONAL DIAGNOSTIC APPROACHES IN

SCHIZOPHRENIA

The symptoms comprising DSM-5 criteria for schizophrenia do not define a

diagnosis-specific syndrome and reflect substantial clinical heterogeneity of

the illness. No single clinical sign is pathognomonic for schizophrenia;

every symptom observed in schizophrenia can occur in different psychiatric

disorders. The current categorical concept of schizophrenia (and other

psychiatric diagnoses) is based on having a number of different

combinations of symptoms, such that many variations of the defining and

associated symptoms and symptoms domains are possible. The

phenomenology-driven diagnostic systems, while serving the purpose of

clinical utility, have critical long-term limitations resulting in classifications

that are heterogeneous, lack clear boundaries, and, most importantly,

neither map on emerging experimental biomarker constructs nor reflect

causal biological disease mechanisms. Despite considerable progress in

understanding neurobiological bases of psychiatric disorders, at this point,

it is not possible to propose a biologically based diagnostic system due to a

lack of defining knowledge about the neurophysiologic and molecular

mechanisms of psychiatric disorders. One of the alternative diagnostic

approaches espoused to reduce the clinical heterogeneity of psychiatric

diagnoses is the identification of psychopathological illness dimensions

(such as psychosis) with a research and clinical focus on underlying disease

neurobiology. Such symptom dimensions are comprised of groups of

symptoms that resemble one another, occur together, and are,

hypothetically, based on interrelated pathophysiological and molecular

mechanisms.

Three major symptom dimensions are often described in schizophrenia:

Psychosis, disorganization, and negative symptoms. The psychosis

dimension includes distortions or exaggerations of inferential thinking

(delusions) and perceptual disturbances (hallucinations). The disorganization domain manifests as illogical disorganized thought process and/or grossly disorganized behavior. Although schizophrenic disorganization is commonly perceived as one of the accompanying features of acute psychotic state which tend to resolve as severity of psychosis diminishes, disorganized features are phenomenologically unique, and are specifically associated with poor prognosis, especially in cases of chronic presentation. Therefore, disorganization has been recognized as a distinct clinical domain of schizophrenia, not just a subtype of psychotic symptoms. Negative symptoms dimension includes restrictions in the range and intensity of emotional expression (affective flattening), in the fluency and productivity of thoughts and speech (alogia), and in the initiation of goal-directed behavior (avolition). Recently, a broader dimensional model of schizophrenia has been proposed, including cognitive dysfunction (i.e., deficits in general intelligence level, various aspects of memory, executive function, global processing speed, and

attention) as well as affect dysregulation and mood symptoms (Fig. 12.16–

1). Although neither is yet a part of the current DSM-5 diagnostic

definition, cognitive dysfunction is known to be one of the defining features

of the illness which frequently manifests long before first-break psychosis

and is highly predictive of disease course and overall prognosis.

Comparative studies contrasting dimensional composites with

traditional diagnostic categories have shown that the dimensional

approach may be superior in predicting course, demand for psychiatric

care, treatment outcome, social adaptation, and global prognosis of illness.

Originally, the dimensional models were developed to aid diagnostic

classification. However, more recently these dimensional constructs have

been targeted in various research paradigms, including genetic and disease

biomarker studies, as well as in identifying clinical targets for novel drug

development. Dimensional components within the schizophrenia diagnosis

may be characterized by unique underlying pathogenetic mechanisms and

appear to be, at least partially, pharmacologically independent. To date,

effective treatments are available for only a few of these symptom

dimensions. Psychotic symptoms may be satisfactorily controlled with the

arsenal of first- and second-generation antipsychotic medications, although

treatment-refractory cases are not uncommon. Affective symptoms are

typically alleviated by antidepressants, mood stabilizers, and some

antipsychotic agents. However, no effective treatments exist either for

cognitive deficits or negative symptoms, although treatment development

is very active in these areas. Clinical experience, as well as well-controlled

treatment trials, suggests that psychosis across many diagnostic categories,

including such diagnoses as schizophrenia, bipolar disorder, psychotic

depression, functional and substance-induced psychoses, and various

organic psychoses, show a similar pharmacological treatment response.

One of the current foci in drug development for schizophrenia is treatment for cognitive dysfunction, with hypothetical treatment targets focused on

glutamatergic, cholinergic, and serotoninergic neurotransmitter systems.

PSYCHOSIS SPECTRUM DISORDERS: DOES PSYCHOSIS CUT ACROSS THE FORMAL

DIAGNOSTIC CATEGORIES?

Among the clinical manifestations of psychiatric illnesses, psychosis

represents perhaps the most dramatic and clinically captivating

phenomenon. Historically, in early German and French schools of

psychiatry in the 18th and early 19th centuries, psychosis was described as

a single clinical entity and often was the hallmark of mental illness. Since

1896, when Emil Kraepelin demarcated “dementia praecox” from “manic

depressive insanity,” the nosological (categorical) mode of thinking and

classification has been predominant in psychiatry worldwide. This is

despite the fact that Kraepelin’s concept underwent a complex evolution

that led him to a considerable personal uncertainty about making clear

distinctions among psychosis spectrum disorders, such as dementia

praecox, manic depressive psychosis, intermediate conditions, and

paranoid disorders. In the current psychiatric classification, psychosis is

acknowledged as a clinical phenotype within numerous psychiatric

disorders, including schizophrenia, mood disorders, substance use

disorders, cognitive and neurodevelopmental disorders, and disorders

related to general medical conditions, although it is not an obligate

component of their formal diagnoses (Fig. 12.16–2).

FIGURE 12.16–1. Symptom dimensions of schizophrenia.

Large-scale research studies that utilized multivariate factor analytic

approaches applied to samples spanning various categorical diagnoses

suggest that psychosis represents a distinct clinical domain overlapping abroad spectrum of psychiatric disorders. The strategy of breaking down

phenomena into distinct dimensions has been broadly used in different

medical sciences and is commonly used in psychology. But, at the present

time, there is not a full consensus on how to subclassify various psychosis

spectrum disorders into meaningful, biologically based dimensions. In

recent studies of patients with psychotic disorders (schizophrenia,

schizoaffective disorder, psychotic mood disorders, and other functional

psychosis) and their biological relatives, five distinct symptom domains

spanning these diagnoses were described, including reality distortion

(psychosis), disorganization, mania, depression, and negative symptoms,

commonly referred to as the “pentagonal model” of psychotic disorders.

Different diagnostic categories showed distinct dimensional profiles, with

schizophrenic persons scoring highest in the reality distortion, negative,

and disorganized symptoms; and affective diagnoses scoring highest in

manic and depressive dimensions and lower in the psychosis and negative

symptoms. Interestingly, the mania factor is considered to be the best

discriminator between schizophrenia and mood disorder diagnoses, while

psychosis turned out to be a domain of overlap between these diagnostic

categories. In all dimensional constructs, schizophrenia patients typically

show higher variability compared to patients with mood disorders,

suggesting that bipolar disorder diagnosis may signify a better defined

phenomenological construct than schizophrenia, which appears to be

highly heterogeneous. These studies suggest quantitative variations in

symptom dimensions across diagnostic categories rather than qualitative

differences. However, multiple questions remain, including whether or not

the phenomenological structure of psychosis is the same across diagnoses,

what is the extent of similarities and uniqueness of underlying genetic and

pathophysiological mechanisms of psychosis is, and whether various

psychosis spectrum disorders show the same molecular basis, treatment

response and functional outcomes.

FIGURE 12.16–2. DSM-5 diagnoses overlapping the psychosis dimension. GMC, general

medical conditions.

BIOLOGICAL FACTORS IN PSYCHOSIS: EVIDENCE FROM TRANSLATIONAL

NEUROSCIENCE INVESTIGATIONS

Genetic Studies

Psychotic illnesses are broadly heterogeneous disorders, not caused by a

single etiological factor, but rather due to a complex interplay of different

endogenous and environmental pathogenic influences. There is consistent

evidence that a genetic component contributes to the etiology of psychosis;

however little is known for certain about particular genomic regions or

individual risk genes. Recent findings from large-scale whole genome

studies provide evidence for contribution of numerous genes, each of a very

small effect, to ethiopathogenesis of schizophrenia. Moreover, a substantial

overlap in genetic susceptibility across a broad spectrum of psychiatric

disorders, for example, schizophrenia, bipolar disorder, autism, has been

observed. Some of the identified candidate genes show strong associations

with dimensional constructs, such as psychosis or mood symptoms, that

are not projected directly onto categorical diagnoses. Hypothetically (not

yet well established) genes or sets of genes, interacting with environmental

factors, may predetermine vulnerability to psychosis and other clinical

disease manifestations. Depending on genetic influence and other

endogenous (e.g., neurodevelopmental) and/or environmental interactions,

psychosis may coexist with different clinical phenotypes (e.g., mood

symptoms or cognitive dysfunction), composing epiphenomenal categorical

diagnoses. This conceptualization of psychosis draws preliminary support

from epidemiological and molecular genetic studies.

Family Studies. Family studies of schizophrenia and affective

psychoses have established that psychosis strongly aggregates in families.

Having a relative with schizophrenia or bipolar disorder is a single most

powerful risk factor for developing psychosis. The life-time risk for

developing schizophrenia increases approximately 8 to 12 folds in first-

degree biological relatives of schizophrenic probands. Although the results

of genetic studies in affective psychoses are less consistent, the familial

aggregation of bipolar disorder and major depressive disorder has been

observed. First-degree relatives of individuals with bipolar I disorder have

elevated rates of bipolar I disorder (4 to 24 percent), bipolar II disorder (1

to 5 percent), and major depressive disorder (4 to 24 percent). While it was

originally thought that schizophrenia and affective psychoses are inevitably

segregated, recent reports challenge this. Family studies show that

schizophrenia and affective psychoses can co-occur in the same families,

suggesting shared familial risk. For example, a large epidemiologic study,

using a genetically homogenous population isolate in north-eastern

Finland, reported that 16 percent of siblings of schizophrenic probands

carried a lifetime diagnosis of psychotic disorder, including schizophrenia (0.5 percent), schizoaffective disorder (3.3 percent), bipolar I disorder (1.1

percent), major depressive disorder with psychotic features (2.2 percent),

alcohol-induced (2.2 percent), and other substance-induced (1.1 percent)

psychoses, delusional disorder (1.6 percent) and psychotic disorder, not

otherwise specified (4.4 percent). Over half of the siblings (54 percent) in

this study had a lifetime diagnosis of any mental disorder, with major

depressive disorder (15.3 percent) and anxiety disorders (12 percent)

leading among non-psychotic diagnoses. Numerous reports confirmed that

the increased risk for psychotic illness in relatives of individuals with

schizophrenia does not appear to be confined to schizophrenia alone. On

the other hand, bipolar illness has been associated with increased risk of

schizophrenia in relatives. In one of the recent family studies it was

reported that relatives of women with early onset of bipolar disorder had

the highest morbid risks for both bipolar illness and schizophrenia. The

presence of more than one patient with bipolar disorder in a family

increased the risk for schizophrenia nearly fourfold. In a different study it

was shown that affective disorders were more frequently inherited from the

same parental side of the family as schizophrenia psychosis, suggesting that

the same genetic factors could contribute to susceptibility to both

schizophrenic and affective psychoses. Several studies showed that, in fact,

parents of schizophrenic probands suffer from affective disorders

(especially, major depressive disorder) more often than from

schizophrenia. Schizoaffective disorder occurs at similarly increased rates

both in families of probands with schizophrenia and bipolar disorder.

Likewise, schizophrenia and bipolar disorder have been shown to occur at

increased rates in relatives of probands with schizoaffective disorder.

Further, there is growing evidence that certain clinical phenotypes and

symptom dimensions may predict familial risk of psychosis across

categorical diagnosis. For example, in a large family study from the

Netherlands a syndrome, characterized by bizarre behavior, inappropriate

affect, catatonia and poor rapport, predicted psychosis in biological

relatives of schizophrenic probands. The syndrome characterized by

affective blunting and insidious early onset of illness predicted psychosis in

the first-degree relatives of probands with various types of functional

psychoses. A lifetime history of mania specifically predicted affective

psychosis in the relatives of probands with various psychotic disorders.

Similarly, in a recent study, conducted in a sample of psychotic inpatients

and their 2,987 first-degree relatives in Spain, severe primary negative

symptoms in probands were related to familial liability for schizophrenia,

whereas familial morbid risk of mood disorders was predicted by mania,

depression and catatonia syndromes in probands. Importantly, this familial

association pattern was completely independent of the probands’ diagnosis

of schizophrenia or major mood disorder. These studies provide evidence

that familial liability for psychosis clearly overlaps DSM categories of schizophrenia and mood disorder. From a dimensional perspective,

psychosis may represent a shared phenotype with unique genetic etiologies,

running through family generations.

Twin Studies. Twin studies show that the concordance rate for

schizophrenia is higher in monozygotic twins (47 to 56 percent) than in

dizygotic twins (12 to 16 percent), suggesting a strong heritability

component for the illness. It has been reported that the more severe the

schizophrenia, the more likely it is for the twins to be concordant for the

disorder. Some European studies have reported a concordance rate for

monozygotic twins of over 80 percent in cases of severe schizophrenia with

typical core symptoms. These observations suggest that the schizophrenia

diagnosis includes clinically and etiologically heterogeneous subgroups

with potentially distinct underlying genetic backgrounds. Further, twin

studies suggest that a schizophrenia diagnosis in one twin equally increases

the risk for schizophrenia and affective disorders in the co-twin. A clear

overlap in genetic risk for schizophrenia, schizoaffective, and manic

phenotypes was reported in a sample of 77 monozygotic and 89 same-sex

dizygotic twin pairs, ascertained from the Maudsley Twin Register in

London. In this study, if one member of a monozygotic twin pair had

schizophrenia, there was about an 8 percent chance of schizoaffective

disorder diagnosis in the co-twin and an 8 percent risk of mania. Another

report, based on the Maudsley twin series, showed that the maximum

monozygotic/dizygotic concordance ratio was produced by a combination

of schizophrenia, affective disorder with mood-incongruent psychotic

features, schizotypal personality disorder, and atypical psychosis,

suggesting that these psychosis spectrum disorders share a common

genetic background.

Genetic Linkage Studies. Genetic linkage studies have identified several

chromosomal regions showing linkage to both schizophrenia and affective

psychosis, including 1q32, 10p11-15, 13q32, 18p11.2, and 22q11-13. In one

study significant linkage to psychotic bipolar disorder was obtained on

chromosomes 9q31 and 8p21. Several other chromosomal sites were

supportive of linkage with psychosis in bipolar pedigrees, including 5q, 6q,

8p, 13q, 15q, 17p, and 18q, which are also implicated in schizophrenia. A

recent genome-wide linkage scan in schizoaffective disorder, using British

and Irish pedigrees with at least one member diagnosed with

schizoaffective disorder, bipolar type, confirmed the existence of loci that

influence susceptibility across the functional psychosis spectrum. This

study demonstrated genome-wide significant linkage at chromosome 1q42

and suggestive linkages at 22q11 and 19p13. The evidence for these linkages

was equally contributed by schizophrenia pedigrees (where schizophrenia

was predominant among relatives in addition to schizoaffective disorder) and bipolar disorder pedigrees (with higher proportion of affective

psychosis). Noteworthy, two candidate genes, DISC1 (disrupted in

schizophrenia 1) and COMT (catechol-O-methyltransferase), which have

been consistently implicated in schizophrenia and, more recently, in

bipolar disorder, map to 1q42 and 22q11, respectively.

Studies of Individual Genes and Genome-Wide Association Studies.

Studies of individual genes also support the evidence of overlap between

schizophrenia and different psychotic disorders. In most studies, the

candidate genes were first tested in schizophrenia, but a growing number of

reports suggest that some of these genes may also be involved in etiologies

of affective psychoses and even broader psychopathology, for example,

autism spectrum disorders and epilepsy. In particular, recent genetic

studies have shown increasing evidence for an overlap in genetic

susceptibility across the traditional classification categories, including

association findings at DISC1, COMT, DAOA (G72)/G30), (D-amino acid

oxidase activator (G72)/G30), dysbindin (dystrobrevin-binding protein 1),

BDNF (brain derived neurotrophic factor), NRG1 (neuregulin 1), and RGS4

(regulator of G protein signaling 4). For instance, NRG1 has been

consistently implicated in schizophrenia; more recently, its relationship to

bipolar disorder as a candidate susceptibility gene has also been reported.

A recent study found the association of NRG1 with a clinical phenotype of

bipolar disorder with mood-incongruent psychotic symptoms, as well as

with schizophrenia with lifetime manic episodes, suggesting that NRG1

may confer susceptibility to a specific clinical phenotype with combined

features of psychosis and mania. A number of independent genetic linkage

and association studies in diverse populations support that variation in

DISC1 gene influences susceptibility to disorders of psychosis spectrum,

including schizophrenia, schizoaffective disorder, bipolar disorder, and

major depression. Although this gene has been named “disrupted in

schizophrenia,” in fact, the family in which the DISC1 translocation was

originally observed included cases of both psychosis and mood disorder.

Recently several independent groups have implicated association of DISC1

with bipolar disorder, and in one study the strongest association was

observed with schizoaffective disorder, suggesting that DISC1 influences

susceptibility to a mixed psychosis-mood phenotype that cuts across the

traditional schizophrenia/bipolar divide. Dysbindin is another example of a

candidate gene that was initially implicated in schizophrenia. Nevertheless,

recent reports have also demonstrated an association between a set of

polymorphisms in this gene and a clinical subtype of bipolar disorder with

recurrent psychotic episodes, specifically psychotic mania. Overall, these

findings support variations in NRG1, DISC1, and dysbindin as potential

genetic effects contributing (along with many other genetic and

environmental factors) to susceptibility for psychosis or a mixed phenotype with features of both psychosis and mood symptoms rather than to the

DSM “schizophrenia” phenotype, although these genetic markers were

indeed originally tested as schizophrenia candidate risk genes.

Polymorphisms in G72 (DAOA)/G30 have been broadly linked to both

schizophrenia and bipolar disorder. Furthermore, a recent study from the

United Kingdom, conducted with a large sample of schizophrenia and

bipolar disorder cases, implicated several genetic variations in G72

(DAOA)/G30 as specific risk markers for major mood episodes across the

bipolar and schizophrenia diagnoses. Thus, although this locus was

originally described as a schizophrenia risk gene, this large-scale report

suggests that G72 (DAOA)/G30 appears to be more strongly associated

with the mood symptoms domain, not psychosis, within the schizophrenia-

bipolar diagnostic continuum.

Epidemiological and molecular genetic studies support the hypothesis

that psychosis is a clinical phenotype with multifactorial etiologies, among

which a genetic component is crucial. Family studies of schizophrenia and

affective psychoses have established that psychosis strongly aggregates in

families. Twin studies have suggested high heritability estimates of

psychosis with a complex mode of transmission. Recent whole genome

linkage studies have suggested a number of chromosomal loci that

influence susceptibility to psychosis, independently of diagnostic

categories. Detailed studies of linked genomic regions have identified

several putative candidate genes that appear to be involved in genetic

etiologies of schizophrenia and affective psychoses. Since schizophrenia is a

relatively rare illness with presumably multiple genes of small to very small

effects involved in its etiology, the majority of available to date genetic

studies are still statistically underpowered. Geneticists suggest that tens of

thousands of cases and controls may be needed to find firm associations.

For example, the Schizophrenia Psychiatric Genome-Wide Association

Consortium recently conducted a multi-stage genome-wide association

study (GWAS) including 36,989 schizophrenia cases and 113,075 controls

identified 108 loci associated at genome-wide significance with the

schizophrenia phenotype. Examination of specific candidate genes at these

loci suggested the involvement of dopaminergic regulation (DRD2 gene),

multiple genes involved in glutamatergic neurotransmission and synaptic

plasticity (e.g., GRM3, GRIN2A, SRR, GRIA1), as well as neuronal calcium

signaling (e.g., CACNA1C, CACNB2, CACNA11). Independent of genes

expressed in brain, associations were enriched among genes expressed in

tissue that play important role in immunity (in particular, relevant to B-

lymphocyte lineages involved in acquired immunity), providing support for

the hypothesized link between the immunological effects and

schizophrenia. In addition to polygenic, complex inheritance observed in

schizophrenia and other psychotic disorders, there is also strong indication

that in some patients a deletion or insertion of a larger chromosomal region, so-called copy number variation (CNV), might play a crucial role in

the disease pathogenesis. This could be specifically important in sporadic

cases of schizophrenia, since a higher frequency of de novo mutations has

been associated with these CNVs. Noteworthy, CNV markers linked to

schizophrenia show substantial overlap with neurodevelopmental

disorders, such as intellectual disability and autism spectrum disorders,

providing support for partially overlapping etiologies underlying these

disorders.

Current clinical targets available for genetic studies, for example,

“schizophrenia” or “bipolar disorder,” are highly heterogeneous and do not

clearly map onto molecular or neurophysiologic disease models.

Understanding the biological effect of genetic risk markers is undoubtedly

complex. Although several such candidate markers have been implicated,

the associating variations are likely different in different disease subtypes

and symptom clusters, and it is therefore difficult to determine the specific

biological effect of each risk gene characteristic for specific disease

components. Various epigenetic factors, although poorly explored so far,

add to the complexity of the picture. In addition, environmental factors,

perhaps interacting with risk genes, are likely to contribute and further

complicate endogenous and environmental factors interplay. Although

originally the candidate risk genes were implicated in schizophrenia, recent

findings provide evidence that they show strongest associations with

symptom dimensions, such as psychosis (e.g., NRG1, DISC1, and

dysbindin) or mood symptoms (e.g., G72/G30, BDNF), across the

schizophrenia–mood disorder continuum. Furthermore, recent GWAS

studies support much broader genetic overlaps, from psychotic disorders,

to autism spectrum disorders, to epilepsy and neurodegenerative disorders,

to medical conditions (e.g., autoimmune disorders). Although intriguing,

these observations are still preliminary and should be treated with caution,

given the difficulties in establishing defining evidence for genetic etiologies

in complex, polygenetic disorders. Future genetic studies derived from

large samples, targeting more homogenous disease components (e.g.,

symptom dimensions) and/or biomarker-derived constructs underlying

clinical phenomenology, are needed.

Emerging Candidate Biomarkers for Psychosis

Despite considerable progress in epidemiological and molecular genetics of

psychiatric syndromes made in the past decade, clinical phenotypes, such

as schizophrenia or bipolar disorder, when directly applied in linkage

analyses or studies of individual genes, generally fail to result in consistent

findings. Although multiple genome-wide “hotspots” and associated

candidate genes have been implicated, the causative “psychosis genes” have

not been identified. Even less is known about specific pathways and brain

circuitries through which these genetic effects may contribute to symptom manifestations of psychotic disorders. The inconsistent genetic findings

may be, in part, explained by the presumed complexity of the

pathophysiologic mechanisms of psychiatric disorders, resulting from a

multicomponent interplay of genetic/epigenetic, endogenous and

environmental factors. In addition, the phenomenological heterogeneity of

psychotic disorders as well as lack of biologically based definitions and

clear boundaries in the existing diagnostic categories contribute to the

limited success in identifying causative genetic etiologies. Based on these

kinds of considerations, the focus of genetic and translational studies has

recently shifted toward disease intermediate phenotypes, or biomarkers.

Intermediate phenotypes (often called biomarkers) are specific measurable

alterations in brain function or structure, or abnormalities in peripheral

systems (e.g., hyperactive inflammatory cascades, endocrine effects)

reflecting components of disease pathogenesis which are thought to be

“intermediate” between the aberrant genes and the overt clinical

manifestations of disease. These alterations are frequently referred to as

“disease biomarkers” and can be assessed by objective neurophysiological,

neuroanatomical, or behavioral measurements. An ideal intermediate

phenotype for an illness would be a measure that is associated with the

clinical syndrome, heritable and state-independent. In addition, it co-

segregates in families while being expressed in unaffected family members

and may serve as an informative predictor or risk marker observed long

before full disease manifestations. Intermediate phenotypes are a

promising area of study in the search for genetic factors in psychosis which

may provide more direct clues to the genetic underpinnings than does the

clinical syndrome itself. On the other end, dimensions of disease, such as

psychosis, may be particularly useful in identifying the underlying

intermediate phenotypes, as dimensions clearly provide less heterogeneous

clinical constructs.

Biomarker-focused studies in psychiatry started in the field of

schizophrenia research and up-to-date led to the recognition of several

putative disease biomarkers. These include oculomotor abnormalities

(smooth pursuit eye movement alterations and saccadic eye movement

disinhibition); deficits in sensorimotor gating, measured with

electroencephalography-based event-related potential (ERP) and prepulse

inhibition (PPI) of startle response paradigms; abnormal neurocognitive

performance; as well as structural and functional brain abnormalities

captured with various imaging methodologies. In contrast to the

considerable amount of data in schizophrenia, much less is known about

intermediate phenotypes of other psychotic disorders, although selected

candidate biomarkers have recently begun to be explored in disorders of

neurodevelopmental and affective spectrum. Similar to overlapping clinical

symptom manifestations, the three most common psychotic disorders,

schizophrenia, schizoaffective disorder and bipolar disorder, appear to share common etiologic determinants and biomarker signatures (Fig.

12.16–3). Within the array of neurophysiological, anatomic, and cognitive

measures, there are specific elements that can be targeted as candidate

psychosis biomarkers.

Oculo-Motor Alterations in Psychotic Disorders. Similar abnormalities in

smooth pursuit eye movement (i.e., inability to closely follow a moving

target) and saccadic eye movement disinhibition have been observed in

schizophrenic and psychotic bipolar disorder patients, as well as in their

first-degree relatives and persons with mild psychotic symptoms, such as

those with schizotypal personality disorder. These oculomotor phenotypes

are thought to be mediated by frontal cortex and have been linked to

working visual spatial memory function as well as deficits of prefrontal

inhibitory control. These oculo-motor deficits are stable, trait-like

characteristics, observed in both acute (psychosis, acute mania) and

remission disease phases, and seem to be minimally influenced by

medications. Recent genetic studies of oculomotor biomarkers suggested

linkage of smooth pursuit eye movement alterations to chromosome 6p21

in schizophrenia families. Other studies, using fMRI simultaneously with

eye tracking during the imaging sessions, have reported that schizophrenic

patients tend to activate different brain regions in order to maintain

smooth visual tracking compared to healthy subjects. Patients showed

reduced activation in frontal and, specifically, supplemental eye fields

regions, medial superior temporal and anterior cingulate cortices.

Interestingly, activation in medial occipito-temporal cortex was increased

in patients compare to healthy individuals, perhaps, reflecting recruitment

of different brain regions in order to compensate for a primary prefrontal

deficits underlying smooth pursuit eye movement system dysfunction in

schizophrenia.

Sensory and Sensory-Motor Gating Deficits in Psychotic Disorders.

Sensory/sensory-motor gating is a neurophysiological function of a normal

brain that allows to “filter out” irrelevant and/or excessive environmental

stimuli. It has long been observed that patients with evolving psychosis and

mania display hypersensitivity to environmental stimuli as well as aberrant

stimuli attributions, thought to be mediated by altered sensory and

sensory-motor gating mechanisms. These phenomena are typically

measured by various ERP paradigms using electroencephalography (EEG)

with such probes as P50 (positive EEG wave observed within 50 ms of a

target auditory stimulus) and P300 (positive EEG wave observed within

300 ms of an “odd-ball” auditory stimulus), as well as electromyography

(EMG) reflecting sensory-motor gating function (e.g., blink response in the

prepulse inhibition [PPI] paradigms).

FIGURE 12.16–3. Clinical, biomarker, and genetic components in the schizophrenia–

bipolar disorder continuum. Schizophrenia, schizoaffective disorder, and bipolar disorder

are the three main psychiatric diagnoses overlapping the psychosis dimension. In addition,

other symptom dimensions, such as cognitive dysfunction, disorganization, negative and

affective symptoms, are variably presented in these diagnoses. These symptom

manifestations are thought to result from a complex interplay of environmental and

biological factors, expressed in disease biomarkers such as altered brain anatomy, cognitive

or neurophysiologic abnormalities, captured with electroencephalography, brain imaging

and other objective measurements. Some, though not all, of these biomarkers may be

heritable and subserved by genetic and epigenetic effects.

ELECTROENCEPHALOGRAPHY-BASED BIOMARKERS IN PSYCHOTIC DISORDERS. Auditory

Paired Stimuli ERPs. An overall pattern of gating deficits characteristic

for psychosis is a reduced sensory and sensory-motor gating function

thought to underlay environmental stimuli hypersensitivity phenomena. In

the standard auditory “paired stimuli” paradigm, so called “P50” response

amplitude (i.e., the largest EEG wave within 50 ms after the stimulus

presentation) is measured in response to each of two auditory “clicks.” In

healthy individuals, the P50 wave following the second stimulus is lower

than that to the first stimulus, reflecting normal sensory gating function. In

contrast, both schizophrenia and bipolar patients (specifically, patients

with acute mania) show diminished suppression of P50 ERP associated

with insufficient sensory gating. These sensory gating deficits are thought

to be stable “trait” measures largely independent of active severity of

psychotic or mood symptoms or treatment effects. Some studies report

more prominent P50 abnormalities in patients with disorganized

schizophrenia, although an association between disrupted P50 and

negative symptoms has also been suggested. An intriguing observation,

suggesting that P50 sensory gating deficit may be a unique psychosis

intermediate phenotype, has been recently reported in patients with

bipolar disorder. Persons with bipolar I and lifetime history of psychosis

and those with schizoaffective disorder showed P50 deficits similar to those observed in schizophrenia, whereas bipolar patients with no history of

psychosis exhibited normal P50 suppression. Sensory gating deficits are

thought to be heritable and have been linked to various psychotic disorders

aggregating in families, including schizophrenia. “Schizophrenia-like” P50

suppression deficits are also observed in people with schizotypal

personality disorder as well as in individuals at high risk for developing

psychosis, such as subjects originating from high genetic density families

(i.e., those with several psychotic family members) and individuals with

schizophrenia prodrome, typically preceding frank psychosis

manifestations. Evidence for a linkage between disrupted P50 gating and

chromosome 15q14 has been reported in several studies, specifically to the

promoter region of the α-7 nicotinic cholinergic receptor subunit gene, in

both individuals with schizophrenia and their relatives. Odd Ball Paradigm and P300 ERP. P300 is typically measured in

auditory or visual “odd ball” paradigms where frequently presented stimuli

(“targets”) are interleaved with infrequent and unexpected atypical (“odd

ball”) stimuli and refers to a positive EEG wave occurring within 300ms

following an “odd ball” stimulus. Several large meta-analyses reported

reduced P300 ERP amplitude and delayed P300 latency in probands with

schizophrenia and their biological relatives, as well as in “mild psychosis

phenotypes” such as schizophrenia prodrome and schizotypy. Recently

studies of P300 ERP have been extended to bipolar disorder, and suggested

similar “schizophrenia-like” alterations in P300 amplitude and latency in

individuals with psychotic bipolar disorder and their relatives, albeit less

consistently across different studies. In several studies a frontal

subcomponent of P300 ERP was reported to correlate with severity of

hallucinations in patients with schizophrenia, perhaps due to shifting of

attentional resources from external to internal (psychotic) stimuli.

Similarly, patients with psychotic bipolar disorder showed reductions in

frontal lobe P300 voltage, suggesting a component of overlapping neural

substrate for dysfunction in both schizophrenia and affective psychosis.

Diminished P300 amplitude and increased latency have been also linked to

severity of negative symptoms, illness duration and early age of psychosis

onset, as well as several cognitive dysfunctions, that is, deficits in attention.

Several studies, conducted on healthy twin pairs suggested moderate

heritability estimates for P300 ERP biomarker. Interestingly, the P300

heritability in females appeared to be lower (45 percent compared to 56

percent in males), suggesting that endogenous or environmental factors

may have a stronger modifying influence on the P300 phenotype in

females. Genetic association studies linked P300 alterations to the COMT

genotype (i.e., Met homozygous variant) as well as NRG1 polymorphisms in

patients with schizophrenia.

Sensorimotor Gating Deficits in Psychosis: Prepulse Inhibition.

PPI paradigms measure inhibition of the startle reflex. In healthy individuals, a weaker “prepulse” stimulus leads to an inhibition of a

response magnitude to a startle (“pulse”) stimulus, used as an index of

sensorimotor gating. In individuals with psychotic disorders insufficient

PPI reflecting an exaggerated startle response is commonly observed.

Diminished PPI has been reported in patients with schizophrenia,

schizotypal personality disorder, and both affected and unaffected

biological relatives of schizophrenia probands. Similar findings have been

noted in persons with bipolar disorder, especially during acute manic

phase, although the studies in bipolar are few and less consistent. Several

studies reported associations between PPI deficits and florid psychotic

symptoms, such as disorganized thought process and behavior, greater

distractibility, and bizarre psychotic behavior. However, at least a few

studies in schizophrenia observed disrupted PPI even in remission phases,

supporting this candidate biomarker as a stable “trait” measure. Likewise,

individuals with acute psychotic mania show significantly reduced PPI and

less startle habituation, along with a significant reverse correlation between

PPI sensorimotor gating and severity of psychotic symptoms. In contrast,

euthymic bipolar patients failed to demonstrate abnormalities in PPI.

These observations of similar PPI deficits in schizophrenia and psychotic

mania, abnormal sensorimotor gating may represent one of the putative

biomarkers subserving psychosis as a unique clinical phenotype.

Cognitive Dysfunction as a Candidate Psychosis Biomarker.

Cognitive dysfunction has recently drawn interest as a distinctive

phenotype across psychotic disorders, as well as a treatment target. The

presence of specific cognitive deficits is not yet part of the diagnostic DSM-

5 criteria for schizophrenia; nonetheless it is recognized as a common and

consistent feature of the disorder. Extensive cognition studies have shown

stable, trait-like deficits in the domains of working memory, verbal episodic

memory, attention, processing speed, language comprehension, problem

solving, and executive function in individuals with schizophrenia. Patients

with bipolar disorder manifest deficits in overlapping cognitive domains,

with attention, working memory, and verbal memory difficulties being

among the most prominent, albeit generally less severe that those found in

schizophrenia. A considerable clinical heterogeneity of the bipolar

phenotype correlates with variable presentations of cognitive deficits, with

some patients manifesting profound “schizophrenia-like” abnormalities,

and others showing little or none alterations in cognitive function. It

appears that the greater the burden of illness associated with the disorder,

as manifest in the lifetime history of psychosis, number of past manic

episodes, an overall duration of illness and number of past hospitalizations,

the greater the neurocognitive deficits typically found in bipolar patients.

Moreover, bipolar patients with a lifetime history of psychosis appear to

have a slightly different profile of neurocognitive deficits than those

without a history of psychosis, manifesting more severe impairment on measures of executive function and spatial working memory. More severe

bipolar patients, especially those with psychosis, begin to resemble

schizophrenia patients with regard to the level and profile of

neurocognitive deficits. One of the commonly reported cognitive features

that may help to disambiguate schizophrenia and bipolar disorder is a

general intelligence level, especially, premorbid IQ, with lower scores

typically observed in patients with schizophrenia but normal IQ levels in

bipolar disorder. An extensive research work has been done in attempt to

discover genetic associations for cognitive dysfunction in schizophrenia

and related psychotic disorders, with most consistent findings supporting

links for COMT and executive function, DISC1 and verbal declarative and

working memory deficits in schizophrenia and, less consistently, bipolar

probands, and their biological relatives.

Anatomical Brain Alterations in Psychotic Disorders.

Anatomical brain changes have been examined as candidate psychosis

phenotypes across schizophrenia and related psychotic disorders. Studies

in schizophrenia have consistently reported a modest but measurable

reduction in whole brain volume, particularly in gray matter (averaging 2 to

8 percent for various brain structures, based on meta-analyses), as well as

an increase in ventricular size. Several definite areas of the brain have been

consistently reported to demonstrate volumetric changes, such as

decreased volume in several frontal (e.g., dorso-lateral, orbito-frontal),

temporal (medial temporal lobe [MTL], particularly, the hippocampal

formation; STG), and parietal cortical regions, as well as thalamus. Several

meta-analyses of volume change in schizophrenia reported whole brain,

and, particularly, fronto-temporal gray matter volume reductions in

individuals at the time of their first psychotic break, preceding any

treatments.

The structural findings in psychotic mood disorders are less consistent,

ranging from decreased, to normal, to increased gray and white matter

volumes in various brain regions. Recent large-scale psychosis-focused

studies report regionally overlapping but more focused and lesser in

magnitude gray matter volume reductions in psychotic bipolar disorder

compared to schizophrenia. The most reproducible regional volume

reductions in psychotic bipolar disorder are typically localized to anterior

limbic regions, that is, orbito-frontal, anterior cingulate, insular cortex, as

well as amygdala and anterior temporal cortex. At the same time, volume

increases in amygdala have been reported. Some studies, comparing

individuals across the psychosis dimension, find no abnormalities in gray

matter volume, while volume deficits of white matter were evident

throughout the neocortex and brainstem, with similar regions of white

matter loss found in schizophrenia and bipolar patients.

The question of whether volume loss is progressive during the lifetime

course of psychosis has been explored. Measurable gray matter volume and density changes are typically observed in individuals near psychosis onset,

progress with illness duration, more aggressively during the initial years of

psychosis in some cases, and ultimately result in characteristic gray matter

alterations found in chronic psychosis samples. Data from relatives with

psychosis spectrum disorders (e.g., schizotypal personality disorder)

demonstrate milder but similar gray matter volume reductions suggesting a

heritable link between psychosis manifestations and brain structure

phenotypes. Moreover, recent large-scale reports demonstrate overlapping

gray matter volume reductions in the psychosis probands (including

schizophrenia, schizoaffective disorder, and psychotic bipolar disorder

cases) and their first-degree relatives with psychosis spectrum disorders,

but normal gray matter characteristics in relatives unaffected by lifetime

psychosis, even those with clear non-psychotic diagnoses (e.g., mood

disorders, anxiety disorders). These gray matter alterations may reflect

“psychosis burden,” from extensive reductions in probands where

psychosis is fully manifested, to similarly distributed but milder alterations

in relatives with mild psychosis spectrum phenotypes, to normal gray

matter in relatives without lifetime psychosis. Moreover, associations

between lifetime duration of psychosis and gray matter volume, with more

loss observed as illness progresses, have been reported in schizophrenia

and schizoaffective probands in frontal, temporal cortex, basal ganglia and

thalamus, the regions long implicated in psychosis in both first episode and

chronic samples.

The exact mechanisms underlying these brain structure changes are

unknown, but can be interpreted in the context of available post-mortem

findings of cellular neocortical pathology in psychotic disorders.

Histological examination of schizophrenia cases indicates no neocortical

neuronal loss, yet altered neuronal cell packing, presumably due to reduced

interstitial neuropil, resulting in higher neuronal density and overall

decreased cortical thickness. In contrast, analyses from bipolar cases show

decreased neuronal and glial density but normal overall cortical thickness.

Dendritic spine loss, as well as reduced dendritic length in dorsolateral

prefrontal cortex, has been observed in both schizophrenia and bipolar

post-mortem tissue samples. These post-mortem findings suggest both

overlapping and unique anatomical underpinnings for schizophrenia and

bipolar disorder, providing plausible cellular correlates for the structural

brain changes captured with imaging techniques.

Furthermore, longitudinal studies provide support for a measurable

effect of various psychotropic medications on brain structure. Long-term

treatment with first-generation antipsychotics has been linked to increased

gray matter volume and density in basal ganglia. Both first- and second-

generation antipsychotics are associated with decreased gray and white

matter volume in the fronto-temporal regions. Lithium has been linked to

higher gray matter volume/density in diffuse neocortical regions as well as larger volume of specific subcortical structures, that is, amygdala, in

psychosis and mood disorder samples. Given that the majority of psychotic

and mood disorder patients undergo years of treatment with various

psychotropic agents, it is possible that the gray matter deficits consistently

reported in patients with schizophrenia and schizoaffective disorder are, at

least in part, accounted for by effect of a lifetime antipsychotics use,

whereas a relative gray matter volume preservation in bipolar patients

could be secondary to a medication effect (i.e., chronic treatment with

lithium) and that, even if a “primary” disease-associated loss of neocortical

volume exists in these patients, it could be obscured by a volume-

enhancing effect of chronic lithium use. Disentangling a “primary” disease

and medication effects on brain structure presents considerable difficulty

and requires carefully designed longitudinal research protocols.

Some, though not all studies, have captured associations between brain

anatomy changes and clinical manifestations in schizophrenia and related

disorders. In particular, deficits in the fronto-temporal volume have been

linked to severity of positive symptoms in schizophrenia and schizoaffective

disorder; reductions in various structures within the MTL have been shown

to correlate with the severity of delusions. Additionally, volume reductions

in the MTL have been linked to declarative memory dysfunction in first-

degree relatives of schizophrenic probands. Subsequent data suggest that

the various subgroups within bipolar disorder may have different structural

brain characteristics, depending on whether they have psychosis. The

majority of studies report similar brain structure changes in persons with

schizophrenia and psychotic bipolar disorder, perhaps as one of the

overlapping intermediate phenotypes indicative of psychosis liability.

Intermediate phenotypes represent smaller, homogenous, measurable

units of illness more proximal to pathogenesis of illness and genetic

etiologies than the global diagnosis constructs. Intermediate phenotypes

may be conceptualized somewhat similar to symptom dimensions: While

the dimensions of illness represent more discreet and homogenous clinical

complexes, intermediate phenotypes represent smaller, homogenous

components of illness with strong biologic ties. From this perspective,

intermediate phenotypes may be a promising target in the search for

genetic factors in psychosis, although even this has been difficult to

demonstrate. They may also provide more direct clues for understanding of

psychosis pathogenesis because they are thought to be more intimately

linked to causal biologic pathways of the illness than the clinical

syndromes. At first, the intermediate phenotype/biomarker-focused

approach was used in schizophrenia research and resulted in recognition of

several neurophysiological, neuroanatomical, and cognitive markers. More

recently, these same candidate biomarkers have been used to explore

different psychotic illnesses, specifically psychotic bipolar disorder, in

order to develop valid, objectively defined biological definitions for the psychosis dimension. Among the variety of candidate biomarkers, there are

specific elements that appear to be promising as indicators of psychosis

liability. Future studies focused on intermediate psychosis phenotypes will

explore their genetic linkage, as well as improve overall conceptualization

of clinical and biological boundaries of psychosis spectrum disorders.

PSYCHOSIS AS A CLINICAL CONTINUUM: FROM ATTENUATED PSYCHOSIS

PHENOTYPES TO FRANK PSYCHOTIC DISORDERS

Psychosis manifestations include a broad array of symptom presentations

of various severities which appear to lay on a continuum from mild

subthreshold psychotic phenomena to frank and florid psychosis. Mild

sporadic psychotic symptoms, such as illusions, mild hallucinations (e.g.,

undifferentiated noises or calling a person’s name), ideas of reference,

magical thinking, unusual beliefs and perceptual experiences, and the like

are fairly common in otherwise healthy individuals who don’t carry any

diagnosis of psychiatric illness. Although these symptoms are psychotic by

nature, they are below the threshold for a formal psychosis diagnosis. It

appears that there may be no discrete demarcations between frank

psychosis and minor subclinical psychotic symptoms, other than severity,

breadth and persistence; rather, psychosis represents a clinical continuum

with multiple subtypes and grades of symptom manifestations.

Large longitudinal studies evaluated the frequency of mild psychotic

symptoms in the general population and found that subclinical psychotic

experiences are not uncommon. For example, the large community sample

study using the British National Psychiatric Morbidity Survey data showed

that 4.4 percent of the general population reported incident psychotic

symptoms over an 18-month period. The vast majority of individuals who

reported such psychotic symptoms did not meet full diagnostic criteria for

any psychiatric disorder. These observations may indicate the presence of

latent continuum-like psychopathology in the general population.

Moreover, they are consistent with a multifactorial etiological model of

schizophrenia where many different genes of small effect interact with one

another and with environmental factors to result in the illness. Depending

on a complex interplay of genetic and environmental influences, the

manifestations of psychosis can vary from mild episodic experiences (e.g.,

déjà vu, infrequent thought blocking, or visual illusions), to moderate

psychotic-like symptoms (e.g., magical thinking, ideas of reference, bodily

illusion, or out-of-body experiences), or to severe and persistent frank

psychosis, fulfilling DSM criteria (e.g., delusions or hallucinations). From

the psychosis continuum perspective, subthreshold psychotic symptoms

are considered indicators of proneness to psychosis, with clinical psychosis

emerging when a critical genetic threshold is reached, accompanied by

modifying or triggering epigenetic and environmental factors (Fig. 12.16–

4). Clinically, the continuum nature of psychosis is well illustrated by

premorbid and prodromal symptoms in individuals with schizophrenia and

affective psychosis, psychopathology in biological relatives of psychotic

probands, as well as by certain types of personality disorders, displaying a

wide range of psychotic symptoms, varying from very mild psychotic-like

phenomena to frank psychosis during decompensation phases.

Premorbid and Prodromal Signs and Symptoms in Schizophrenia and Affective

Psychoses

The course of schizophrenia is generally conceptualized as starting with

premorbid (pre-prodromal) signs and symptoms, and then a prodromal

phase of illness, leading to typical clinical manifestations as the illness

evolves. However, it is not always possible to clearly demarcate these

periods due to presence of schizophrenia spectrum personality disorders

and traits characteristic for a proportion of individuals who subsequently

develop schizophrenia, as well as minor psychotic, affective, and behavioral

symptoms that sometimes appear long before the debut of schizophrenia.

In the typical, although not invariable, premorbid history of schizophrenia,

patients have had schizoid or schizotypal personality features and are

characterized as quiet, passive, introverted, emotionally aloof, and

reclusive. Other characteristics, more typical for schizoid personality,

include a low need for emotional bonds: In childhood these individuals

have few friends, by the adolescent period they may show no interest in

dating, and avoid school sports and competitions. Instead, they prefer

solitary activities and seem content by themselves. When schizotypal

features are predominant, thinking, perception, and behavior appear to be

odd or peculiar. Various psychotic-like symptoms, such as magical

thinking, peculiar beliefs, ideas of reference, perceptual illusions, odd

fantasies, or derealization–depersonalization symptoms, are commonly

present. Especially during the adolescent period, peers may exclude them

from the group activities or tease them, as schizotypal individuals have

poor communication skills and distorted social judgment. This often leads

to increased anxiety, feelings of “not fitting in,” and further withdrawal

from the social group. Although different types of personalities (including

paranoid, avoidant, obsessive-compulsive, and, less commonly, borderline)

are also seen in the premorbid period in individuals with schizophrenia,

schizoid, and schizotypal personality traits are believed to be the most

common. Still, the presence of these premorbid and prodromal symptoms

does not inevitably result in conversion to schizophrenia or other psychotic

disorder.

FIGURE 12.16–4. Threshold model of psychosis. In the general population,

considerable evidence indicates the presence of fleeting psychotic symptoms without any

functional impact. When more severe or persistent, psychotic symptoms appear at

subthreshold of formal psychosis diagnosis and manifest in entities like schizophrenia

prodrome and schizophrenia spectrum personality disorders, as well as are frequently seen

in biological relatives of probands with psychotic illnesses. In a proportion of these

individuals psychosis may reach the level of florid clinical manifestations severe enough to

fulfill criteria for DSM diagnosis. Genetic, epigenetic, other biological and environmental

factors can protect against or advance psychosis. Examples of pro-psychotic risk factors

include obstetrical complications, drug abuse, specifically, adolescent cannabis use, and

psychosocial stressors. Less is known about anti-psychotic resilience factors, though high

premorbid functioning, structured environment and cognitive remediation administered

early in the course of evolving psychosis appear to have protective effects. •, candidate

psychosis genes; P-Relatives, psychotic relatives of probands with psychotic disorder; SSPD,

schizophrenia spectrum personality disorders (cluster A: Schizoid, paranoid, schizotypal);

BPD, borderline personality disorders; SZ, schizophrenia; SAD, schizoaffective disorder; BD,

bipolar disorder with psychotic features; MDD, major depressive disorder with psychotic

features; SFD, schizophreniform disorder; SIP, substance-induced psychosis; P-GMC,

psychosis due to general medical conditions; Other Psy, other psychotic disorders.

Although the first hospitalization is often taken to be the beginning of

the illness, in many cases premorbid and prodromal signs and symptoms

may have been present for months or years prior. The majority of

schizophrenia cases are characterized by insidious, gradual onset of

psychosis with no clear date of its first manifestation. The prodromal

symptoms may start with somatic complaints, such as headaches, digestive

problems, autonomic symptoms, or fatigue and generalized weakness.

Family and friends commonly notice that the person has changed, became

withdrawn and isolated, and is no longer functioning well in occupational,

personal, and social settings. Deterioration in personal hygiene and

grooming, decreased appetite, and peculiar eating habits are also common.

During this stage, a patient may begin to develop new, unusual interests in

abstract ideas, philosophy, occult, or religious topics. Gradually, although

acute onset may also occur, subthreshold psychotic symptoms, such as

unusual speech, strange perceptual experiences and bodily illusions, bizarre ideas, and markedly peculiar behavior, build up and subsequently

progress to the level of frank psychosis in the form of hallucinations,

delusions, typical thought and speech disorders, and/or grossly

disorganized behavior.

The validity of the prodromal syndrome is uncertain, since symptoms

are frequently recognized only after the diagnosis of schizophrenia has

been made. During the prodromal phase, patients usually lack insight

regarding their developing symptoms, although some verbalize feeling as if

they have changed. Once schizophrenia is diagnosed, the retrospective

remembrance and the patient’s subjective report of early signs and

symptoms may be affected, therefore obtaining the information about the

early (prodromal) period of illness from the patient’s family may be of

significant help in building a diagnosis. The presence of prodromal

symptoms in affective psychoses is unclear. Although clinical observations

suggests that such symptoms as mood lability, impulsivity, destructibility,

and physical hyperactivity are often present long before the development of

affective psychosis, phenomenology of the bipolar prodrome is not well

characterized. One of the recent studies conducted with early onset bipolar

I disorder individuals showed that there may be unique prodromal

characteristics in patients with and without subsequent bipolar phenotype

that manifests as psychotic mania. In this study, attenuated psychotic

symptoms emerging late in the prodrome and increased energy and goal-

directed activity were more common in individuals with later psychotic

mania. Studies comparing prodromal symptoms in schizophrenia and

affective psychosis revealed considerable overlap; for example, such

symptoms as suspiciousness, sub-threshold hallucinatory experiences,

anxiety, insomnia, impaired school, or work functioning were frequently

present during the prodromal period in both psychoses. On the other hand,

depressed mood, suicidality, mood lability, difficulty thinking/communicating

clearly, tiredness/lack of energy, obsessions/compulsions, and physical agitation were more specific for the bipolar than schizophrenia prodrome.

In research, one of the approaches that is being utilized to characterize

clinical profiles of the prodromal state of psychotic illness and to identify

predictive factors for conversion to fully manifested psychosis is observing

large samples of individuals who are at increased risk for developing

schizophrenia and related psychotic disorders (e.g., offsprings of

schizophrenic parents and individuals who have several schizophrenic

family members). Recent such studies focusing on prodrome and other “at

risk samples” have shown that premorbid and prodromal symptoms,

clinically well accepted as a phase in a course of schizophrenia, are not

necessarily pathognomonic of schizophrenia psychosis. For example, in a

study by the Melbourne group, high-risk individuals with either a family

history of psychotic disorder, schizotypal personality disorder,subthreshold psychotic symptoms, or brief transient psychotic symptoms

were followed for a 12-month period. In that group 40.8 percent of the

high-risk individuals subsequently developed psychosis; however,

diagnoses ranged between schizophrenia, schizoaffective disorder, bipolar

disorder, and major depression with psychosis. Other large-scale studies in

this field suggest that approximately one-third of “at risk” individuals

eventually convert to psychosis, one-third will continue to experience stable

chronic mild psychotic phenomena without full conversion to DSM-level

psychotic illness, and one-third will improve overtime, some to the level of

full recovery. These results indicate that although early signs and

symptoms, including prodromal psychotic-like phenomena, can be

predictive of conversion to a spectrum of psychotic disorder, they do not

indicate the exact type of psychosis, and the long-term outcomes are highly

variable ranging from fully manifested psychotic disorder to full recovery.

Given these research outcomes, in DSM-5, a new diagnostic category,

“Attenuated psychosis syndrome,” has been introduced. It refers to a

broadly defined syndrome characterized by psychotic-like phenomena that

are below a threshold for full psychosis, for example, the symptoms that are

less severe and more transient, and frequently accompanied by a relatively

preserved insight. This diagnostic category is appropriate for some (but not

all) individuals with prodromal or subthreshold symptoms and calls for a

clinician’s judgment on where to draw the line for mild psychotic-like

presentations that do not deserve DSM diagnosis and where it is

appropriate to introduce this diagnosis.

Psychosis Manifestations as a Component of Personality Disorders

The occurrence of brief psychotic symptoms is common in individuals with

personality disorders. Typically, psychotic experiences in these people are

triggered by psychological (e.g., change in employment, loss of a

relationship) or physiological (e.g., medical illness) stressors, or substance

use, when compensatory mechanisms weaken. Certain types of personality

disorders are especially predisposed to psychosis, including cluster A and

borderline personality disorders. In DSM-5, cluster A personality disorders

include paranoid, schizoid, and schizotypal types. These personality

disorders are also called schizophrenia spectrum personality disorders

because their core features resemble symptoms of schizophrenia, albeit in a

milder manifestation. In addition, evidence demonstrates the familial

aggregation of these personality disorders in biological relatives of

probands with schizophrenia and other psychotic disorders.

Schizotypal Personality Disorder. Schizotypal personality disorder is

now described under DSM-5 category of “Schizophrenia Spectrum and

Other Psychotic Disorders” emphasizing long-acknowledged biological link

between this particular Cluster A personality disorder and schizophrenia. Schizotypal personality disorder is characterized by cognitive and

perceptual distortions, eccentric behavior, as well as a persistent pattern of

social and interpersonal deficits. Mild psychotic symptoms, such as magical

thinking, perceptual alterations, bizarre rituals, ideas of reference,

paranoid ideation, derealization/depersonalization, idiosyncratic speech,

odd or eccentric behavior, are core features of schizotypal personality

disorder. In response to stress, schizotypal individuals may decompensate

and display frank psychotic symptoms (e.g., hallucinations, delusions,

disorganization of thought process, and behavior); however, these episodes

are generally brief and fragmentary. Usually, these psychotic symptoms are

transitory and insufficient in duration and severity to draw an additional

diagnosis of a psychotic disorder. Nevertheless, in some cases clinically

significant psychotic symptoms may develop that ultimately meet criteria

for brief psychotic disorder, schizophreniform disorder, delusional

disorder, or even schizophrenia. In these cases schizotypal personality

disorder may be indicated in the diagnosis as a premorbid personality

disorder, in parallel with a diagnosis of psychotic illness.

Sufficient research evidence has shown that among cluster A

personality disorders schizotypy is most intimately related to schizophrenia

and other psychoses. There is a higher density of schizotypal personality

disorder cases in the biological relatives of schizophrenia probands than in

controls. Although schizotypal personality disorder occurs in 0.3 to 3

percent of the general population, studies have reported rates of 0.8 to 4.7

percent in the biological relatives of psychotic patients. Recent linkage

studies from genome-wide scans in schizophrenia and schizotypal

personality disorder, conducted with the large sample of high-density

schizophrenia families, have suggested that at least a subset of candidate

schizophrenia susceptibility genes is also involved in etiology of schizotypy

in nonpsychotic relatives of schizophrenic probands.

In the large epidemiologic study called the Roscommon Family Study,

which collected 534 probands with psychotic and affective illnesses and

2,043 of their biological relatives, schizotypal personality disorder showed

a strong familial relationship not only with schizophrenia, but also with the

other major psychotic disorders. Further factor analysis from this research

sample showed that schizotypy is a complex, multidimensional clinical

construct, whose various dimensions differ widely in the specificity with

which they reflect the familial liability to psychosis. In this study seven

schizotypal dimensions were described, among which sub-psychotic

thought disorder, negative schizotypal signs, such as poor rapport and odd

behavior,

deficient

occupational

functioning,

and

social

isolation/avoidance best disambiguated relatives of schizophrenic

probands from relatives of matched controls. Different studies reported

that the disorganization dimension of schizotypy was common to relatives

of both schizophrenia and psychotic bipolar disorders, but not in therelatives of nonpsychotic bipolar probands. Interestingly, schizotypal

disorganization symptoms were suggested as a unique phenotype

associated with an increased familial risk for both schizophrenia and

affective psychosis. From this perspective, schizotypy represents a

subthreshold psychosis phenotype that cuts across the categorical diagnosis

of schizophrenia and bipolar disorder.

Paranoid Personality Disorder. The essential feature of paranoid

personality disorder is a pattern of long-standing suspiciousness and

mistrust of people in general such that their motives are interpreted as

malevolent. Subthreshold psychotic symptoms are not uncommon in

persons with paranoid personality disorder, of which ideas of reference and

associated verbal and visual illusions are seen most often. Under stressful

conditions, specifically in a situation naturally provoking paranoid feelings

(e.g., when these patients are being criticized or disagreed with, relocating,

facing new professional environment), they may decompensate and

experience brief psychotic episodes, lasting minutes to hours. Among frank

psychotic symptoms, paranoid and persecutory delusions are the most

common, although brief visual and auditory hallucinations may also occur.

There is evidence of a genetic association between paranoid personality

disorder and psychosis spectrum illnesses. For example, in some instances,

paranoid personality disorder may appear as the premorbid antecedent of

schizophrenia or delusional disorder. An increased incidence of major

depressive disorder with psychotic features has been also reported in

patients with paranoid personality disorder. There have been few

controlled studies of familial risk of paranoid personality disorder based on

direct interviews of relatives, blind to proband’s diagnosis. However, there

is substantial evidence for a familial relationship between paranoid

personality disorder and psychotic disorders with reports of higher

prevalence of paranoid personality disorder among first-degree relatives of

schizophrenic, schizoaffective and psychotic bipolar probands ranging from

1.7 to 8.6 percent in different studies compared to 0.5 to 2.5 percent in the

general population. In contrast to schizotypal personality disorder,

paranoid personality disorder is less common in relatives of probands with

affective psychosis, although one study reported increased familial risk of

paranoid personality disorder for unipolar depression (2.9 percent), which

was higher than for relatives of schizophrenia patients (1.7 percent).

Schizoid Personality Disorder. Individuals with schizoid personality

disorder are characterized by a pervasive pattern of detachment from social

relationships and a restricted range of emotional expressions. This

behavioral pattern begins in childhood and is usually clinically obvious by

early adulthood, appearing in a variety of contexts. Although subclinical

psychotic symptoms are not uncommon in persons with different Cluster Apersonality disorders, individuals with schizoid personality disorder do not

show many unusual perceptual experiences, distorted thinking processes,

or bizarre behavioral patterns. Although, they appear self-absorbed,

detached, and emotionally aloof, they have a normal capacity to recognize

reality. On rare occasions, particularly in response to social or

interpersonal stressful circumstances, individuals with this disorder may

experience very brief psychotic episodes (lasting minutes to hours). The

content of psychotic symptoms may vary but is usually limited to delusions

of reference, paranoid or persecutory delusions, and brief visual and

auditory hallucinations relevant to the social or interpersonal stressors.

Although a genetic association between schizoid personality disorder

and functional psychoses has been suggested, the data to support this are

contradictory. Some studies (e.g., the Roscommon Family Study, Bipolar-

Schizophrenia Network on Intermediate Phenotypes) have reported that

schizoid personality disorder has significantly increased prevalence in the

relatives of individuals with schizophrenia (1.2 to 3.4 percent), although

this association is modest compared to schizotypal personality disorder. In

contrast, several studies showed that the rate of schizoid personality

disorder among biological relatives of schizophrenic probands is not any

higher than in the general population (reports vary between 0.3 to 0.7

percent). Similarly, reports of schizoid personality disorder co-segregated

in families with affective psychoses are uncommon. One of the difficulties is

that people with isolated schizoid personality disorder are not commonly

seen in clinical settings, and the prevalence of this personality disorder in

the general population is not clearly established. Schizoid personality

disorder may appear as the premorbid precursor of schizophrenia;

however, the proportion of patients who eventually convert to

schizophrenia is unknown. Schizoid personality disorder most often co-

occurs with schizotypal and paranoid personality disorders, as well as with

avoidant personality disorders, which has been also reported to be

associated with schizophrenia.

Borderline Personality Disorder. The crucial feature of borderline

personality disorder is a pervasive pattern of instability of self-image,

interpersonal relationships, and affective reactions, as well as marked

impulsivity and self-damaging behavior. Borderline personality disorder is

clinically perceived as a condition “on the border” of psychotic functioning;

therefore, historically, in psychoanalytic literature it has been called

“ambulatory schizophrenia” (a term introduced by Helene Deutsch) and

“psychotic character disorder” (described by John Frosch). Individuals with

borderline personality disorder are prone to transient psychotic episodes

that occur most frequently during periods of stress, specifically in response

to a real or imagined abandonment. In fact, psychotic-like symptoms are

included as diagnostic criteria for borderline personality disorder (criterion9: Transient, stress-related paranoid ideation or severe dissociative

symptoms). Other broadly defined psychotic symptoms are also often

reported, including ideas of reference, hypnagogic phenomena, and body-

image distortions. More severe psychotic symptoms, including frank

hallucinations and delusions, occur less frequently. Typically, the

symptoms tend to be transient, lasting minutes to hours. However, one

study by a Cornell group reported that 27 percent of the patients with

borderline personality disorder had psychotic episodes, lasting for weeks,

which were not attributed to comorbid affective or substance abuse

disorders.

It is noteworthy that in some cases psychotic symptoms in persons with

borderline personality disorder may be of a factitious nature (e.g.,

Canadian studies report up to 13 percent of factitious psychotic symptoms

in inpatients with borderline personality disorder), thus a thorough

psychiatric history, observation of patient’s behavior, and objective

information obtained from the family members are crucial. In some cases,

the psychotic symptoms in borderline personality disorder respond well to

external structuring and situational changes (e.g., the real or perceived

return of subjectively valuable person or caregiver may result in remission

of the transient psychosis). However, in more severe cases antipsychotic

medications are warranted.

Borderline personality disorder shows a strong familial pattern. For

example, the risk to acquire borderline personality disorder for first-degree

biological relatives of those with the disorder is about five times greater

than in the general population. There is also an increased familial

association of borderline personality disorder with mood disorders,

antisocial personality disorder, substance-related disorders, and eating

disorders. Although considerable co-occurrence of borderline personality

disorder with schizotypal personality disorder has been reported, as well as

occurrence of premorbid borderline personality features in persons with

schizophrenia, the majority of studies do not support a familial link

between borderline personality disorder and schizophrenia. The large-scale

epidemiologic studies of schizophrenia-related personality disorders in

relatives (e.g., the Roscommon Family Study) reported that borderline

personality disorder was rare among first-degree relatives of schizophrenic

probands, but showed a modest clustering of cases in relatives of patients

with psychotic and nonpsychotic affective disorders. Recent findings from a

large multisite consortium in biomarkers of psychosis, Bipolar-

Schizophrenia Network on Intermediate Phenotypes, demonstrated that 1.3

percent of first-degree relatives of schizophrenia patients met rigorous

DSM-IV-TR criteria for borderline personality disorder, whereas 4.1 and

3.2 percent of relatives of patients with schizoaffective disorder and

psychotic bipolar I disorder, respectably, met such criteria. Family studies

of borderline personality disorder have also indicated increased rates of mood disorders in the relatives of borderline probands compared with

healthy controls. Recent studies have suggested that borderline personality

disorder and bipolar disorder may exist on a spectrum and, perhaps, share

partially overlapping pathogenesis and may be rooted in the same genetic

etiology, similar to cluster A personality disorders and schizophrenia.

However, the question of whether a borderline personality disorder is

related specifically to psychotic bipolar disorder and to psychosis in general

remains open. Pilot studies suggest that persons who have borderline

personality disorder with a history of psychotic-like symptoms show

distinct eye tracking abnormalities, similar to those in patients with

schizophrenia. This may suggest that borderline personality disorder with

psychotic symptoms may fall into the psychosis spectrum disorders

continuum and share some endophenotypic and genetic markers,

underlying psychosis. Psychotic-like symptoms and narrowly defined

psychosis appear to be a promising target dimension for future research in

borderline personality disorder and mood disorders.

Clinical and research evidence suggest that psychosis is best conceived

of as a clinical continuum with multiple subtypes and grades of symptoms,

similar to hypertension or congestive heart failure. In fact, there appear to

be no clear demarcation between frank, clinically significant, psychosis and

mild psychotic-like symptoms, other than severity and duration. Large

epidemiologic studies suggest that fleeting psychotic symptoms are

common in the general population. The majority of individuals who have

these psychotic experiences show no functional impairment and are

considered to be free of any formal psychiatric diagnosis. These

observations suggest that psychosis can manifest in mild forms long before

its manifestation to a clinically significant level. Moreover, many of the

individuals with such subthreshold symptoms will remain stable for years,

without further progression into a full psychosis phenotype. Only a modest

proportion of them will convert to a psychotic illness in the future. These

“at risk” individuals, while rarely evaluated in psychiatrists’ offices, may be

a valuable source for studying proneness to psychosis, as well as for

exploring pro-psychotic risk factors and individual resilience against

psychosis.

In more severe and persistent presentations, psychotic symptoms

appear at the border of formal psychosis diagnosis and manifest in entities

like schizophrenia prodrome and cluster A personality disorders,

frequently seen in biological relatives of probands with psychotic illnesses.

Although cluster A personality disorders (in particular, schizotypy) are

generally thought to be biologically related to schizophrenia, recent family

and whole genome linkage studies have shown that schizotypal personality

disorder may present a unique phenotype associated with an increased

familial risk for psychosis in general, independent of the categorical

diagnosis. Similarly, prodromal symptoms, which are classicallyconceptualized as a phase in a course of schizophrenia, appear to be not

unique to schizophrenia psychosis. Instead, they signify risk for a spectrum

of functional psychoses but not the exact diagnosis that will develop.

From the disease continuum perspective, the final diagnosis of a

psychotic disorder is the end point of a longitudinal pathway from

asymptomatic, to subthreshold psychotic experiences, to frank but

infrequent psychotic symptoms, to development of persistent psychosis. It

is possible that this pathway is based on a dynamic matrix of genetic, gene

expression and epigenetic influences which are in a complex interplay with

environmental factors, with frank psychosis emerging when a critical

genetic effects threshold is reached, accompanied by modifying or

triggering epigenetic, individual biological and/or environmental factors.

Although subthreshold manifestations of psychosis are considered

indicators of proneness to schizophrenia and other functional psychoses,

they do not signify an inevitable conversion to psychosis. Whether or not

an individual at risk will traverse this pathway may depend on interaction

between pro-psychotic factors (e.g., individual biological vulnerability,

obstetrical

complications,

maternal/in-utero

immune

stimulation,

adolescent cannabis use, childhood trauma) and protective resilience

factors (e.g., high premorbid functioning, high IQ, stable social

environment).

ACKNOWLEDGMENTS

We would like to thank Four Seasons Decorations, Dallas, TX, for their help

with graphic design and illustrations for this chapter.

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PENGARUH MEDIA PEMBELAJARAN IINTERAKTIFTTERHADAP MOTIVASIXBELAJARLDANHHASILFBELAJARBSISWA8KELAS XI MATA PELAJARAN BAHASA INDONESIA SEMESTER GENAP GENAPPTAHUN PELAJARAN=2018-2019 DI MA ASHRI JEMBER

Devi=Eka Kumalasari, NIM 20171861030019

devijember60@gmail.com

ABSTRAKK

Penelitian ini merupakan penelitian kuantitatif kausal.Tujuan penelitian: (1) MengujiiadakahpPengaruh penggunaan media interaktif terhadap motivasibbelajar siswa, (2) MengujiiadakahhPengaruh penggunaan media interaktif terhadap hasil belajar siswa, (3) MengujiiadakahhPengaruh penggunaannmedia interaktif terhadappmotivasi Belajar  dan  hasilbbelajar siswassecara bersama- sama. Responden penelitian ini adalah siswi MA Ashri Jember kelas XI-A dan XI-B sejumlah 57 siswa padaasemesterggenapttahun pelajaran 2018-2019, daerah penelitian menggunakan purposive sampling area. Alat pengumpulan data menggunakan  angket,  tes dan  metode bantu dokumentasi danwwawancara.=Derajad0valid\dan reliabel=alat=dengan8uji validitassdanrreliabilitas. Uji12analisis56instrumen67dengan menggunakanKL: 1)uuji deskriptif, 2)uuji normalitas, 3)uuji9homogenitas.UUji hipotesis iniddengan: 1)uuji chi square  2)uuji F.Hasil penelitian menunjukkan bahwa: 1)dengan hasil  F 1,056 pada T hitung taraf signifikansi 0,063. Karena hasil uji sig. t ≥ 0.05 maka H0 ditolak artinya hipotesis nihil ditolak sehingga berlaku hipotesis kerja (Ha) yakni “ada12Pengaruh5Penggunaan7Media5Pembelajaran2Interaktif TerhadapEMotivasiOBelajar siswa, 2) dengan hasil  F 1,056 pada T hitung taraf signifikansi 0,057. Karena hasil uji sig. t ≥ 0.05 maka H0 ditolak artinya hipotesis nihil ditolak sehingga berlaku hipotesis kerja (Ha) yakni “Ada PengaruhZpenggunaanVmedia interaktif terhadap=hasil+belajar*siswa, 3) dengan hasil  F 1,056 pada T hitung taraf signifikansi 0,072. Karena hasil uji sig. t ≥ 0.05 maka H0 ditolak artinya hipotesis nihil ditolak sehingga berlakuhhipotesis kerja (Ha) yakni “Ada1Pengaruh2penggunaan3media4interaktif5terhadap6motivasi7Belajar8dan 9hasil9belajar0siswa8secara7bersama- sama.

 Kata=Kunci: multimedia interaktif, motivasi belajar,*hasil belajar

PENGARUH MODEL CONTEXTUAL TEACHING AND LEARNING  DAN MODEL STUDENT TEAM ACHIEVEMENT DIVISIONS  TERHADAP HASIL BELAJAR BAHASA INDONESIA

Savitaria

savitaria83@gmail.com

ABSTRAK

Penelitian ini adalah jenis penelitian kuantitatif kausal yang bertujuan untuk mengetahui Pengaruh Model Contextual Teaching And Learning  Dan Model Student Team Achievement Divisions  Terhadap Hasil Belajar Bahasa Indonesia Siswa Kelas VIII di MTs Syirkah Salafiyah Jenggawah Semester Ganjil  Tahun Pelajaran 2019/2020.

Permasalahan yang dikaji dalam penelitian ini adalah: 1) adakah pengaruh model Contextual Teaching and Learning (CTL) terhadap hasil belajar materi Bahasa Indonesia?, 2) adakah pengaruh model Student Team Achievement Divisions (STAD) terhadap hasil belajar materi Bahasa Indonesia, dan  3) adakah pengaruh model Contextual Teaching and Learning (CTL) dan Student Team Achievement Divisions (STAD) secara bersamaan terhadap hasil belajar materi Bahasa Indonesia? Tujuan: 1) untuk mengetahui ada tidaknya pengaruh model Contextual Teaching and Learning (CTL) terhadap hasil belajar materi Bahasa Indonesia, 2) untuk mengetahui ada tidaknya pengaruh model Student Team Achievement Divisions (STAD) terhadap hasil belajar materi Bahasa Indonesia, 3) untuk mengetahui ada tidaknya pengaruh model Contextual Teaching and Learning (CTL) dan Student Team Achievement Divisions (STAD) secara bersamaan terhadap hasil belajar materi Bahasa Indonesia.

Responden penelitian ini adalah siswa kelas VIII di MTs Syirkah Salafiyah Jenggawah Semester Ganjil Tahun Pelajaran 2019/2020 dengan jumlah 44 anak, daerah penelitian ditentukan dengan metode purposive sampling. Penelitian ini merupakan penelitian kuantitatif dengan desain kausal. Alat pengumpul data menggunakan  angket,  tes serta  metode bantu dokumentasi dan wawancara. Derajad valid dan reliabel alat dengan uji validitas dan reliabilitas. Uji analisis instrumen menggunakan: 1) uji deskriptif, 2) uji normalitas, 3) uji homogenitas. Uji hipotesis dengan: 1) uji t dan  2) uji F.

Hasil penelitian menunjukkan bahwa: 1) nilai sig. dari variabel model Contextual Teaching and Learning (CTL) terhadap hasil belajar materi Bahasa Indonesia 0.000, kesimpulan sig. > 0,05, berarti terdapat pengaruh model Contextual Teaching and Learning (CTL) terhadap hasil belajar materi Bahasa Indonesia, 2) nilai sig. dari variabel pengaruh pengaruh model Student Team Achievement Divisions (STAD) terhadap hasil belajar materi Bahasa Indonesia adalah 0.000, kesimpulan sig. > 0,05, ini berarti terdapat pengaruh pengaruh model Student Team Achievement Divisions (STAD) terhadap hasil belajar materi Bahasa Indonesia, 3) hasil output analisis regresi diperoleh  Fhitung 31.654 dengan sig. 0,000, karena >0,05 maka terdapat pengaruh model Contextual Teaching and Learning (CTL) dan Student Team Achievement Divisions (STAD) secara bersamaan terhadap hasil belajar materi Bahasa Indonesia.

Saran dari penelitian ini adalah agar guru dapat menerapkan model pembelajaran utamanya CTL dan STAD agar dapat meningkatkan hasil belajar.  

 Kata Kunci: Contextual Teaching and Learning (CTL), Student Team Achievement Divisions (STAD), Hasil Belajar

PENGARUH MODEL PEMBELAJARAN KOOPERATIF JIGSAW DAN MOTIVASI BELAJAR TERHADAP HASIL BELAJAR SISWA KELAS VII PADA MATA PELAJARAN PPKN DI MTS SYIRKAH SALAFIYAH JENGGAWAH

Hafidz1, M. Rudy Sumiharsono2, Waris3

IKIP PGRI Jember

boyhafidz49@gmail.com

ABSTRAK

 Penelitian ini adalah penelitian kuantitatif kausal bermaksud untuk mengetahui pengaruh model pembelajaran kooperatif Jigsaw dan motivasi belajar terhadap hasil belajar siswa kelas VII pada mata pelajaran PPKn di MTs Syirkah Salafiyah Jenggawah.

Permasalahan yang dikaji dalam penelitian ini adalah: 1) adakah pengaruh model pembelajaran kooperatif Jigsaw terhadap hasil belajar? 2)adakah pengaruh motivasi belajar terhadap hasil belajar, dan 3) adakah pengaruh model pembelajaran kooperatif Jigsaw dan motivasi belajar terhadap hasil belajar secara bersama-sama? Tujuan: 1) menguji adakah pengaruh model pembelajaran kooperatif Jigsaw terhadap hasil belajar, 2) menguji adakah pengaruh motivasi belajar terhadap hasil belajar, 3) menguji adakah pengaruhmodel pembelajaran kooperatif Jigsaw dan motivasi belajar terhadap hasil belajar secara bersama-sama.

Responden penelitian ini adalah siswa kelas VII pada mata pelajaran PPKn semester genap tahun pelajaran 2018-2019 di MTs Syirkah Salafiyah Jenggawah dengan jumlah 42 anak, daerah penelitian ditentukan dengan metode purposive sampling. Penelitian ini merupakan penelitian kuantitatif dengan desain kausal. Alat pengumpul data menggunakan angket, tes serta metode bantu dokumentasi dan wawancara. Derajad valid dan reliabel alat dengan uji validitas dan reliabilitas. Uji analisis instrumen menggunakan: 1) uji deskriptif, 2) uji normalitas, 3) uji homogenitas 4) uji multikulinearitas. Uji hipotesis dengan: 1) regresi linear berganda dan 2) uji F.

Hasil penelitian menunjukkan bahwa: 1) nilai sig. dari variabel model pembelajaran kooperatif Jigsaw terhadap hasil belajar.011a, kesimpulan sig. < 0,05, berarti terdapat pengaruh model pembelajaran kooperatif Jigsaw terhadap hasil belajar, 2)nilai sig. dari variabel pengaruh pengaruh motivasi belajar terhadap hasil belajar adalah .000a, kesimpulan sig. < 0,05, ini berarti terdapat pengaruh motivasi belajar terhadap hasil belajar, 3)hasil output analisis regresi diperoleh  Fhitung 15.247dengan sig. .000a, karena <0,05 maka terdapat pengaruh model pembelajaran kooperatif Jigsaw dan motivasi belajar terhadap hasil belajar secara bersama-sama.

Kata Kunci: Model Pembelajaran Jigsaw, Motivasi Belajar, Hasil Belajar

PERBEDAAN MEDIA POWERPOINT BERBASIS HYPERLINK VS MEDIA POWERPOINT TEMPLETE DAN MOTIFASI BELAJAR TERHADAP HASIL BELAJAR KOGNITIF MATA PELAJARAN PRODUKTIF DI SMKN 1 SEMPOL.

ASYIK SULAIMAN

asyik_sulaiman@yahoo.co.id

SMK NEGERI 1 SEMPOL, Kabupaten Bondowoso, asyik_sulaiman@yahoo.co.id

Abstrak: Cara untuk  mengetahui pengaruh yang signifikan penggunaan media powerpoint berbasis hyperlink terhadap motivasi belajar, hasil belajar siswa, dengan pendekatan penelitian deskriptif kuantitatif akan diketahui korelasi antara variable yang nantinya akan memunculkan asumsi yang terkait dengan judul yang telah di tulis dalam penelitian ini, Media Media Power Point Hyperlink VS Power Point Templete berpengaruh 4.8% namun tidak signifikan pengaruhnya terhadap hasil belajar, motivasi belajar ini berpengaruh sebesar 3.4% terhadap hasil belajar siswa dengan nilai signifikan (0,753 , 0.0500. Artinya ada pengaruh sebesar 3.4% namun penggaruhnya tidak signifikan.

      Kata kunci: Media Powerpoint Berbasis Hyperlink, Mata Pelajaran Produktif

PENGARUH METODE LEMPAR BOLA PERTANYAAN DAN MOTIVASI BELAJAR SISWA TERHADAP HASIL BELAJAR PPKN KELAS VII DI SMPN 13 JEMBER TAHUN PELAJARAN 2018/2019

Tesis. Program Studi Teknologi Pembelajaran, Program Pascasarjana, IKIP PGRI Jember. RATNA WAHYUNI. NIM 20171861030002; Pembimbing: I. Prof. Dr. HM.Rudy Sumiharsono., MM., II. Dr. Muljono, M.Pd

ABSTRAK

Penelitian ini adalah penelitian kuantitatif kausal yang ingin mengetahui pengaruh metode pembelajaran lempar bola pertanyaan dan motivasi belajar terhadap hasil belajar PPKn kelas VII SMPN 13 Jember Semester Ganjil tahun pelajaran 2018/2019.

Permasalahan yang dikaji dalam penelitian ini adalah: 1) adakah pengaruh metode pembelajaran lempar bola pertanyaan terhadap hasil belajar?, 2) adakah pengaruh motivasi belajar terhadap hasil belajar, dan  3) adakah pengaruh metode pembelajaran lempar bola pertanyaan dan motivasi belajar terhadap hasil belajar secara bersama-sama? Tujuan: 1) menguji adakah pengaruh metode pembelajaran lempar bola pertanyaan terhadap hasil belajar, 2) menguji adakah pengaruh motivasi belajar terhadap hasil belajar, 3)menguji adakah pengaruh metode pembelajaran lempar bola pertanyaan dan motivasi belajar terhadap hasil belajar secara bersama-sama.

Responden penelitian ini adalah kelas VII SMPN 13 Jember Semester Ganjil tahun pelajaran 2018/2019 dengan jumlah 80 anak, daerah penelitian ditentukan dengan metode purposive sampling area. Penelitian ini merupakan penelitian kuantitatif dengan desain kausal. Alat pengumpul data menggunakan  angket,  tes serta  metode bantu dokumentasi dan wawancara. Derajad valid dan reliabel alat dengan uji validitas dan reliabilitas. Uji analisis instrumen menggunakan: 1) uji deskriptif, 2) uji normalitas, 3) uji homogenitas. Uji hipotesis dengan: 1) uji t dan  2) uji F.

Hasil penelitian menunjukkan bahwa: 1) nilai sig. dari variabel metode pembelajaran lempar bola pertanyaan terhadap hasil belajar 0.000, kesimpulan sig. > 0,05, berarti terdapat pengaruh metode pembelajaran lempar bola pertanyaan terhadap hasil belajar, 2) nilai sig. dari variabel pengaruh motivasi belajar terhadap hasil belajar adalah 0.000, kesimpulan sig. > 0,05, ini berarti terdapat pengaruh motivasi belajar terhadap hasil belajar, 3) hasil output analisis regresi diperoleh  Fhitung 31.654 dengan sig. 0,000, karena >0,05 maka terdapat pengaruh metode pembelajaran lempar bola pertanyaan dan motivasi belajar terhadap hasil belajar secara bersama-sama.

Saran yang diajukan agar para guru dapat menerapakan metode pembelajaran lempar bola pertanyaan dan motivasi belajar sehingga dapat meningkatkan hasil belajar.

Kata Kunci: Metode Lempar Bola Pertanyaan, Motivasi Belajar, Hasil Belajar

PENGARUH MODEL TGT TERHADAP MOTIVASI BELAJAR DAN PERKEMBANGAN SOSIAL EMOSIONAL  ANAK DI PAUD AL-MAHRUS II JEMBER SEMESTER GENAP TAHUN AJARAN 2018-2019

Sitti Shafiyyah1. M. Rudy Sumiharsono2,. Kustiyowati3.

IKIP PGRI Jember

sittishafiyyah@gmail.com

 ABSTRAK

Penelitian ini adalah penelitian kuantitatif kausal yang ingin mengetahui penggunaan model pembelajaran Team Game Tournament (TGT) pengaruhnya terhadap motivasi belajar dan perkembangan sosial emosional anak PAUD Al-Mahrus II Jember Semester Genap Tahun Pembelajaran 2018-2019.

Permasalahan yang dikaji dalam penelitian ini adalah: 1) adakah pengaruh model pembelajaran Team Game Tournament (TGT) terhadap motivasi belajar?; 2) adakah pengaruh model pembelajaran Team Game Tournament (TGT) pengaruhnya terhadap perkembangan sosial emosional; dan  3) adakah pengaruh model pembelajaran Team Game Tournament (TGT) terhadap motivasi belajar dan perkembangan sosial emosional secara bersama-sama? Tujuan: 1) menguji adakah pengaruh model pembelajaran Team Game Tournament (TGT) pengaruhnya terhadap motivasi belajar; 2) menguji adakah pengaruh model pembelajaran Team Game Tournament (TGT) terhadap perkembangan sosial emosional; 3) menguji adakah pengaruh model pembelajaran Team Game Tournament (TGT) terhadap motivasi belajar dan perkembangan sosial emosional secara bersama-sama?

Responden penelitian ini adalah anak PAUD Al-Mahrus II Jember Semester Genap Tahun Pembelajaran 2018-2019 dengan jumlah 30 anak, daerah penelitian ditentukan dengan metode purposive sampling. Penelitian ini merupakan penelitian kuantitatif dengan desain kausal. Alat pengumpul data menggunakan  angket,  dokumentasi, dan wawancara. Derajad valid dan reliabel alat dengan uji validitas dan reliabilitas. Uji analisis instrumen menggunakan:     1) uji deskriptif; 2) uji normalitas; dan 3) uji homogenitas. Uji hipotesis dengan: 1) regresi linier berganda; dan  2) uji F.

Hasil penelitian menunjukkan bahwa: 1) nilai sig. dari variabel model pembelajaran Team Game Tournament (TGT) pengaruhnya terhadap motivasi belajar 0.000, kesimpulan sig. > 0,05, berarti terdapat pengaruh model pembelajaran Team Game Tournament (TGT) pengaruhnya terhadap motivasi belajar, 2) nilai sig. dari variabel pengaruh model pembelajaran Team Game Tournament (TGT) pengaruhnya terhadap perkembangan sosial emosional adalah 0.000, kesimpulan sig. > 0,05, ini berarti terdapat pengaruh model pembelajaran Team Game Tournament (TGT) terhadap perkembangan sosial emosional, 3) hasil output analisis regresi diperoleh  Fhitung 31.654 dengan sig. 0,000, karena >0,05 maka terdapat pengaruh model pembelajaran Team Game Tournament (TGT) terhadap motivasi belajar dan perkembangan sosial emosional secara bersama-sama.

Saran supaya pendidik PAUD dapat menerapkan model pembelajaran Team Game Tournament (TGT), memperhatikan motivasi belajar anak dan perkembangan sosial emosional.

 Kata Kunci: Model Pembelajaran TGT, Motivasi Belajar, Perkembangan Sosial Emosional

Prosiding rena fix

Model Pemangsa dan Mangsa Lotka-Voltera Proposional Terhadap Model Logistik Termodifikasi

PITALOCA 2