Secondary Schizophrenia (5 page)

tively
[68].

NAA reductions may also be present prior to
Although limited by small sample sizes and other
the illness onset. An early study
[56]
detected a
methodological constraints, most DTI studies in
trend toward NAA/choline ratio reductions in the
schizophrenia document reduced structural integrity
anterior cingulate region in adolescent offspring at
of white matter tracts, as measured by fractional
genetic risk for schizophrenia. Furthermore, reduced
anisotropy (FA) in a number of areas, such as the
NAA/choline in anterior cingulate predicted conver-corpus callosum, the arcuate, and the unicinate fas-sion to psychosis in those with prodromal symptoms
ciculi
[69].
Similarly, one study of childhood-onset
of schizophrenia
[79].

schizophrenia found lesser FA in frontal WM bilaterA relatively smaller number of studies have
ally, as well as in right occipital WM
[70].

employed in vivo 31P spectroscopy in schizophrenia. In an early study
[80],
decreased phosphomo-What is the neurochemical nature of the
noesters (PME) in the prefrontal region of first-episode, antipsychotic-naive schizophrenia subjects
brain abnormalities in schizophrenia?

was observed, suggesting a reduction in synthe-Neurochemical brain imaging using PET and single
sis of membrane phospholipids (MPLs). The results
photon emission computed tomography (SPECT) can
seemed to support Feinberg’s hypothesis of abnor-inform us about receptors and neurotransmitters such
mal neurodevelopment in schizophrenia because of
7

as dopamine (DA) that are critical for understanding
an exaggerated preadolescent synaptic pruning in the

Introduction – Section 1

Odds Ratio

Figure 1.2
Environmental factors in the
pathogenesis (abbreviations: CNS, central
0

1

2

3

4

5

6

7

8

9

10

nervous system; depr, depression; Rh, Rhesus)
Winter

Place/time of birth

[91].

Urban

Influenza

Respiratory

Infection

Rubella

Poliovirus

CNS

Famine

Bereavement

Prenatal

Flood

Unwantedness

Maternal depr

Rh incompatibility

Hypoxia

Obstetric

CNS damage

Low birth weight

Pre-eclampsia

Family history

prefrontal region
[80, 81].
Subsequent studies of first-vulnerable individuals develop features of schizophre-episode schizophrenia patients largely confirmed these
nia spectrum psychopathology (e.g., schizotypy) but
alterations
[82, 83, 84, 85, 86, 87].
Nevertheless, collec-only a small proportion (
∼
10%) go on to develop
tively, there is compelling evidence of diminished mass
the full-blown manifestations of schizophrenia. Later
or content of MPL at the early stage of schizophre-environmental risk factors such as psychosocial stress,
nia (i.e., neurophil), which is consistent with the find-hormonal factors, and drug abuse may interact to
ings of postmortem studies
[88].
Work by our group
result in the pathophysiologic substrate underlying the
shows reduced prefrontal PME in adolescent offspring
vulnerability to schizophrenia and increase risk.

at genetic risk for schizophrenia, suggesting that these
alterations may precede symptomatic manifestations
When does the illness develop?

[89].

Schizophrenia as a progressive

What factors cause brain dysfunction?

neurodevelopmental disorder

Schizophrenia is being increasingly viewed as a disor-Genetic and environmental influences
der of brain development. Circa 2007, it was well estab-Although the pathophysiology of schizophrenia is
lished that brain development starts in intrauterine life
progressively being better understood, thanks to the
and continues into early adulthood. Multiple lines of
advent of neuroimaging and neuropathological stud-research have detected evidence of neurogenesis and
ies, our knowledge of the etiology of this illness is still
neuronal migration during pre-and perinatal periods.

limited. What is well known, however, is the strong
Synaptic proliferation that follows these changes seems
genetic contribution to schizophrenia supported by
to continue into childhood. Subsequent development
family, adoption, and twin studies. Several genes have
during late childhood and adolescence is character-recently been identified that may hold the key to finally
ized by programmed elimination or pruning of redun-understanding the causes of schizophrenia
[90].
How-dant synapses and myelination that continues into
ever, the fact that the concordance for schizophre-adulthood.

nia in monozygotic twins is about 50% suggests an
Derailments in these developmental and degener-important role for environmental factors. Many envi-ative processes have been proposed as possible mecha-ronmental factors, all of relatively small effects, have
nisms underlying schizophrenia. Evidence from mul-been reported to influence risk for schizophrenia
tiple lines of research has resulted in more than one
(Figure 1.2).

model for the pathogenesis of schizophrenia. For
Even the presence of genetic and early environ-example, findings of increased rates of birth complica-mental risk factors does not always predict who is at
tions, minor physical abnormalities, neurological soft
a later risk for schizophrenia. Among those at genetic
signs, and subtle behavioral abnormalities in those
8

risk, such as offspring of parents with this illness, many
who later develop schizophrenia has led to the early
Chapter 1 – Neurobiology and etiology of primary schizophrenia: current status

developmental (or “doomed from the womb”) model,
the presence of the general medical condition. The
which proposes that abnormalities in brain devel-next step, establishing the cause–effect relationship
opment around or before birth cause the failure of
between medical condition and psychosis, is often dif-brain functions in early adulthood. Defective neuronal
ficult, but can be helped by considering the following
migration during the second trimester of pregnancy
factors:

has been proposed as one of such mechanisms
[92].

1. The temporal relationship between the psychosis
One argument against this model is the low positive
and the medical condition:

predictive value, that only a small proportion of people who exhibit these risk factors eventually develop
The psychosis begins following the onset of the
schizophrenia.

medical condition, varies in severity with the severity
The typical delay in the onset of salient symptoms
of the medical condition, and resolves when the med-of schizophrenia until adolescence or early adulthood
ical condition gets better. This rule has many excep-is often cited as evidence of derailed late development in
tions, however. For example, psychosis may sometimes
schizophrenia. According to this model, excessive pro-be an early indicator of a medical illness that becomes
grammed neuronal pruning and pronounced loss of
evident later. Conversely, a medical illness may simply
synapses have a role in the emergence of the illness.

trigger a protracted schizophrenia illness without nec-This model is supported by the evidence of reductions
essarily causing it.

in dendrite density in cortical brain regions in post-2. Atypicality of presentation:
mortem studies of schizophrenia
[93].

Deterioration in the first few years of the illness in
A medical cause for psychosis should be especially
many patients has been attributed to a post-illness onset
considered if the presentation is atypical. A later age of
degenerative process
[94].
The three pathophysiologi-onset, severe disorientation and/or confusion, and the
cal models mentioned above are not necessarily con-presence of multimodality hallucinations (e.g. visual
sidered mutually exclusive; a sequential combination
and tactile) increase the possibility of an organic cause.

of these processes has also been proposed. The effect of
Specific aspects of psychotic symptoms may some-environmental factors, such as illicit drug use and psy-times provide clues to regional alterations in brain
chosocial stressors as potential triggers, has also been
function and trigger suspicion of neurological disease.

recognized.

For example, denial of blindness that may appear delu-sional should trigger suspicion of Anton’s Syndrome
Investigating primary versus

(cortical blindness, due to visual cortex lesions) and
denial of paralysis should lead to a consideration of
secondary schizophrenia

anosognosia (due to lesions in nondominant parietal
Virtually any substance, prescribed drugs, or medi-cortex). Likewise, an isolated delusion of misidentifi-cal condition affecting nervous system function can
cation (Capgras Syndrome), as well as olfactory hallu-present with psychiatric symptoms. This can be said
cinations, should point to a temporal lobe disease.

with some confidence to be true for psychosis as well
3. The psychosis is not better explained by a primary
(Table 1.2).
Establishing a cause–effect relationship
psychotic disorder or another mental disorder:
between substance use/medical illness and psychosis,
however, is not easy. Suspecting an underlying med-For example, even if a concomitant medical illness
ical illness is a logical initial step when encountering
may raise suspicion of a secondary psychosis, the pres-psychosis in general medical settings. Comorbid med-ence of a strong family history of schizophrenia and a
ical illnesses are also quite common in patients pre-premorbid schizoid personality should raise the suspi-senting with psychotic symptoms, especially among
cion of a primary schizophrenic illness.

the elderly. However, suspecting and identifying an
In every case, a detailed history and complete
underlying medical illness in younger, newly present-physical, including a neurological examination
ing patients with psychosis in mental health settings
and laboratory evaluation is an essential first step
(in which the base rate of medical illnesses is low) is
(Table 1.3).
In light of emerging knowledge about
more challenging.

secondary causes of schizophrenia, one needs to con-In making the distinction between primary and
duct additional investigations such as neurocognitive
9

secondary psychosis, it is important to first establish
examinations, brain imaging, and electrophysiological
Introduction – Section 1

Table 1.2
Possible causes of secondary schizophrenia: well known disorders that may present with psychosis and approaches
∗
to
investigate them
Category

Example of well known causes

Investigations that may help diagnosis

Trauma

Penetrating or closed head injury

CT/MRI

Autoimmune

Systemic lupus erythematosus

Autoantibody titres (e.g. antinuclear antibodies for
lupus)

Congenital/cytogenetic

Agenesis of corpus callosum

MRI/CT

Velocardiofacial syndrome

Karyotyping

Toxic

Drug intoxication: cocaine, 3–4

Urine drug screen

methylenedioxymethamphetamine (MDMA),
Urine heavy metal screen

amphetamines, phencyclidine (PCP), alcohol, lead
poisoning

Iatrogenic