Aetiology of Schizophrenia

1. Biological Factors

i) Genetic Factors

 Schizophrenia is strongly influenced by genetics. Numerous studies

demonstrate higher rates of schizophrenia among biological relatives of affected
individuals, with first-degree relatives having about a 10% risk of developing the
disorder. Studies such as those involving twins and adoption have confirmed the
significant genetic component. Monozygotic (identical) twins have about a 50%
concordance rate (50 out of 100 pairs of twins) for schizophrenia, which is 4-5
times higher than in dizygotic (fraternal) twins or other first-degree relatives.
 The modes of genetic transmission in schizophrenia are unknown, but several
genes appear to make a contribution to schizophrenia vulnerability (polygenic).
Linkage and association genetic studies have provided strong evidence for nine
linkage sites: 1q, 5q, 6p, 6q, 8p, 10p, 13q, 15q, and 22q.

*Concordance rate: A statistical measurement that shows the percentage of pairs of

people who share a particular trait or attribute.

*In genetics, linkage refers to the closeness of genes or other DNA sequences on a
chromosome. Genes that are closer together on a chromosome are more likely to be
inherited together than genes that are farther apart.

Research Example:
Research on the heritability of schizophrenia shows that certain genes may contribute
to this predisposition, but no single gene has been identified as the definitive cause.
Many genes are likely involved, each contributing a small effect. The rare and
common genetic variants both play roles, with environmental interactions also
influencing the onset.

ii) Prenatal Factors

Non-genetic prenatal risk factors such as exposure to viral infections (e.g., influenza),
obstetric complications, maternal stress, and nutritional deficiencies are linked to a
higher likelihood of developing schizophrenia later in life. A mother’s experience of
extreme stress or infections during pregnancy may also increase the risk.

iii) Neurodevelopmental Hypothesis

Schizophrenia may arise from disturbances in early brain development. Events such
as maternal infection, birth complications, or genetic factors might disrupt normal
brain development, increasing the likelihood of schizophrenia onset in adolescence or
early adulthood.

2. Neurochemical Factors
  Dopamine Hypothesis
The dopamine hypothesis suggests that schizophrenia involves excess
dopamine activity in certain brain pathways, particularly those governing
salience. This dysregulation may lead to aberrant attributions of importance to
irrelevant stimuli, thus contributing to delusions and hallucinations.
 Glutamate Hypothesis
In addition to dopamine, glutamate dysfunction is implicated in schizophrenia.
The symptoms and cognitive impairment are due to hypofunction of NMDARs
and excessive glutamate release, especially in brain areas including prefrontal
cortex and hippocampus. Research has shown that drugs like PCP
(Phencyclidine/ angel dust), which block glutamate receptors, produce
schizophrenia-like symptoms (extracellular excess). This suggests that impaired
glutamate transmission may also contribute to the development of the disorder.
 GABA. The inhibitory amino acid neurotransmitter γ-aminobutyric acid (GABA)
has been implicated in the pathophysiology of schizophrenia based on the
finding that some patients with schizophrenia have a loss of GABAergic neurons
in the hippocampus. GABA has a regulatory effect on dopamine activity,
and the loss of inhibitory GABAergic neurons could lead to the
hyperactivity of dopaminergic neurons.

*Glutamate is the most abundant excitatory neurotransmitter in the brain and central
nervous system. Learning and memory. Too much leads to neural toxicity and
neuronal death. Linked to Alzheimer’s (excess of glutamate).

*PCP: A dissociative anesthetic mainly used recreationally for its significant mind-
altering effects. PCP may cause hallucinations, distorted perceptions of sounds, and
violent behavior

3. Brain Abnormalities

 Individuals with schizophrenia often show structural brain abnormalities,

including enlarged lateral and third ventricles and reduced gray matter in the
prefrontal cortex, hippocampus, and amygdala. MRI studies have found these
abnormalities are often present before the full onset of symptoms, suggesting a
developmental origin.
 Reduced Symmetry: There is reduced brain symmetry in areas such as the
temporal, frontal, and occipital lobes, likely due to disruption in brain
lateralization during fetal development.
 Limbic System: The limbic system, involved in emotion regulation, shows
abnormalities, including smaller size in areas such as the amygdala,
hippocampus, and parahippocampal gyrus. The hippocampus is both
structurally smaller and functionally abnormal (e.g., disturbances in glutamate
transmission and neuronal disorganization).
 Prefrontal Cortex: Anatomical abnormalities in the prefrontal cortex are
supported by postmortem studies. Functional deficits are also seen in brain
imaging, with symptoms resembling those found in patients with frontal lobe
syndromes.
  Thalamus: Studies show volume shrinkage or neuronal loss in the thalamus,
particularly in the medial dorsal nucleus, which has connections with the
prefrontal cortex. Neuronal and glial cell reduction (30-45%) is not attributable
to antipsychotic medication, as it occurs in both medicated and medication-
naive patients.
 Basal Ganglia and Cerebellum: Schizophrenia patients often display odd
movements (awkward gait, facial grimacing), possibly linked to dysfunction in
the basal ganglia and cerebellum. Diseases affecting the basal ganglia (e.g.,
Huntington's, Parkinson's) are associated with psychosis. Findings on cell loss or
volume reduction in the basal ganglia are inconclusive, but an increase in D2
receptors has been observed in certain areas (caudate, putamen, nucleus
accumbens), though this may be due to antipsychotic treatment.

4. Psychosocial Factors

 Double Bind. The double-bind concept was formulated by Gregory Bateson

and Donald Jackson to describe a hypothetical family in which children receive
conflicting parental messages about their behavior, attitudes, and feelings. In
Bateson’s hypothesis, children withdraw into a psychotic state to escape the
unsolvable confusion of the double bind. Unfortunately, the family studies that
were conducted to validate the theory were seriously flawed methodologically.
The theory has value only as a descriptive pattern, not as a causal explanation
of schizophrenia. An example of a double bind is a parent who tells a child to
provide cookies for his or her friends and then chastises the child for giving
away too many cookies to playmates.

 Schisms and Skewed Families. Theodore Lidz described two abnormal

patterns of family behavior. In one family type, with a prominent schism
between the parents, one parent is overly close to a child of the opposite
gender. In the other family type, a skewed relationship between a child and one
parent involves a power struggle between the parents and the resulting
dominance of one parent. These dynamics stress the tenuous adaptive capacity
of the person with schizophrenia.

Marital schism: A term coined by Theodore Lidz and his colleagues to describe
a family environment where parents don't support each other and undermine
role reciprocity. In a marital schism, parents may:
 Threaten to separate
 Demand that the other parent conform to their expectations
 Engage in recriminations instead of supporting each other

Skewed family: A family with characteristics such as:

 A parent forming a special bond with a child
 A parent-child relationship that remains eroticized
 Blurred generation lines
 An irrational, paranoid atmosphere

 Family and Expressed Emotion (EE: Pseudomutual and Pseudohostile

Families)
Earlier theories blamed family dynamics for schizophrenia, but modern research
highlights that family communication patterns, such as high expressed emotion
(EE), can influence the course of the illness rather than cause it. High EE,
 characterized by critical, hostile, or over-involved behaviors, increases the
likelihood of relapse.

 Urban Living and Immigration

People living in urban environments and immigrants are at higher risk for
schizophrenia. The stress associated with urban living or migration, including
factors such as social isolation, discrimination, and economic difficulties, might
contribute to the development of the disorder.
 Cannabis Use
Cannabis use, especially during adolescence, has been associated with an
increased risk of developing schizophrenia. Studies indicate that individuals who
use cannabis show greater loss of gray matter over time, exacerbating the
progression of schizophrenia.

5. Immune System and Inflammation

Recent studies suggest that schizophrenia may be linked to immune system

dysregulation. Genes involved in immune function, particularly on chromosome 6, are
implicated in the disorder. Maternal inflammation, as indicated by elevated levels of
C-reactive protein during pregnancy, can increase the risk of schizophrenia in
offspring.

Autoimmune Disorders
There is a strong association between schizophrenia and autoimmune disorders such
as psoriasis and Crohn’s disease. This connection suggests that immune dysregulation
might contribute to the development of schizophrenia.

6. The Diathesis-Stress Model

Schizophrenia is best understood through the diathesis-stress model, where genetic

vulnerability interacts with environmental stressors to trigger the disorder.
Environmental factors like prenatal infections, cannabis use, and urban living may act
as stressors that activate genetic predispositions.

Interesting Facts:

 Delayed Development in Childhood: Children who later develop

schizophrenia often show delayed speech and motor development. Studies of
home movies have found that "preschizophrenic" children display more motor
abnormalities and less positive facial expressions than their healthy siblings.

 Immigrant Risk: Immigrants, especially those with darker skin, are at higher
risk of developing schizophrenia due to potential social stressors like
discrimination.
 Relationship
Mood
to
Disorder Key Characteristics Duration Symptom
Schizophreni
s
a
The psychotic
- Severe psychotic symptoms must
symptoms (delusions, persist for at
hallucinations, least 6 months, Core disorder;
May occur
disorganized thinking, with active characterized
Schizophrenia but are not
and negative symptoms) symptoms for by chronic
prominent
- Social and at least 1 psychosis
occupational month
dysfunction
≥ 6 months
- Same psychotic
Milder, shorter
symptoms as
duration than
schizophrenia At least 1 month
Schizophrenifo May be schizophrenia;
- Less social or of Sx but less
rm Disorder present may develop
occupational than 6 months
into
dysfunction compared to
schizophrenia
schizophrenia
Schizoaffectiv - Symptoms of Psychotic Prominent Hybrid of
e Disorder schizophrenia combined symptoms are mood mood disorder
with a major mood continuous, but episodes and
episode (depression or the mood (depressiv schizophrenia;
mania) episode e or features
(depression or manic) psychosis and
- Psychotic symptoms mania) must be mood
persist without mood present for the disturbance
symptoms for at least majority of the
2 weeks illness duration

Psychosis: ≥ 2
weeks without
mood symptoms

There must be a
period of at least
2 weeks during
which only
psychotic
symptoms are
present without
mood
symptoms to
differentiate
schizoaffective
disorder from a
mood disorder
with psychotic
features. In
contrast, in
depressive or
bipolar
 Relationship
Mood
to
Disorder Key Characteristics Duration Symptom
Schizophreni
s
a
disorder with
psychotic
features, the
psychotic
features only
occur during the
mood
episode(s).
- Pervasive pattern of Absent
detachment from social
relationships
- Restricted range of
emotional expression
- Little interest in social
interactions or
relationships
-Lack a desire for Related
intimacy through
Long-term,
Schizoid -choose solitary shared social
enduring
Personality activities withdrawal,
personality
Disorder -Choose but lacks
pattern
mechanical/abstract psychotic
tasks such as features
computer/mathematical
games
-No close
friends/confidants
-Indifferent to
approval/criticism
-Superficial/socially
inept/self-absorbed
Schizotypal -Pervasive Long-term, Absent Similar to
Personality pattern of social and enduring schizophrenia
Disorder interpersonal deficits personality but without
marked by acute pattern full-blown
discomfort with, and psychosis;
reduced capacity for, involves
close relationships eccentric
behavior and
-Odd beliefs or beliefs
magical thinking
(magical control over
others/special powers to
sense events or read
others’ thoughts

-Unusual perceptual
experiences

- Suspiciousness or
 Relationship
Mood
to
Disorder Key Characteristics Duration Symptom
Schizophreni
s
a
paranoid ideation

-Ideas of reference

- Social anxiety (Their

social anxiety does not
easily abate, even when
they spend more time in
the setting or become
more familiar with the
other people, because
their anxiety tends to be
associated with
suspiciousness
regarding
others’ motivations. For
example, when
attending a dinner
party, the
individual with
schizotypal personality
disorder will not become
more relaxed as time
goes on, but rather may
become increasingly
tense and suspicious.)