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4
2 Epidemiology, Etiology, and Pathophysiology
genetic factors. For example, 11–19% of adopted children whose birth par-
ents have been diagnosed with schizophrenia also develop the disorder, whereas
adopted children with non-affected parents develop schizophrenia in only 0–11%
of cases in later life. In general, however, it is assumed that genetic factors merely
coin a vulnerability to the development of the disorder. In the sense of a diathe-
sis-stress model, it is assumed that additional factors (second hit) are necessary to
promote the onset of schizophrenia later in life. These can be, for example, noxae,
i.e. damaging factors, which cause a disturbance in pre- or perinatal brain matura-
tion. In this context, reference has been made, among other things, to the role of
maternal viral infections in the second trimester of pregnancy, a critical period of
central nervous system development. Similarly, seasonal effects of the incidence
rate of schizophrenic disorders are explained. Thus, there is an increased risk of
developing schizophrenia if the mother was pregnant in her second trimester dur-
ing the winter months. Birth complications, such as hypoxia during delivery, also
appear to play a role. However, cases of childhood schizophrenia are very rare.
Thus, the consequences of impaired brain development seem to manifest them-
selves fully only when the maturation of frontal brain areas is completed in late
adolescence.
2.1 Comorbidities
Affective and substance use disorders represent the most common comorbid dis-
orders in patients with schizophrenia. In particular, the frequent co-occurrence of
psychotic and substance use disorders is striking and will be discussed in more
detail here, as several studies (e.g. Manning et al., 2007; Thoma et al., 2007;
Thoma & Daum, 2008) provide interesting findings regarding cognitive abnor-
malities of these dual diagnosis groups and their contribution to the frequent
occurrence of this comorbidity.
Approximately 50% of all patients with schizophrenia simultaneously meet
the criteria for substance abuse or dependence. Patients with this dual diagnosis
are more likely to be male and younger at illness onset than patients who only
meet diagnostic criteria for schizophrenia. Dual diagnosis patients also show
more pronounced depressive and fewer negative symptoms, lower treatment com-
pliance, and generally decreased quality of life. They are also more significantly
affected by unemployment and homelessness and show higher rates of violent
behavior. The most commonly abused substances include nicotine, caffeine, alco-
hol, cannabis, and cocaine. Up to 80% of all patients with schizophrenia smoke,
59–70% drink coffee, and 9.4% abuse alcohol use to the point of dependence.
5
All drugs ultimately influence the neurotransmitters dopamine, glutamate, and
GABA, which play a central role in the pathophysiology of schizophrenia (see the
review article by Thoma & Daum, 2013).
Different approaches exist to explain the high rates of comorbidity between the
two groups of disorders. Among the most important ones are diathesis-stress mod-
els, the cumulative risk factors hypothesis, the self-medication hypothesis, and
the affect regulation model. Diathesis-stress models (Fowles, 1992) assume that
substance abuse, in the sense of an environmental stressor, can lead to premature
onset of schizophrenia in individuals with a genetic propensity to develop schizo-
phrenia. This is supported by data according to which patients with an additional
substance dependence diagnosis develop schizophrenia earlier than non-abus-
ing patients. In contrast, proponents of the “cumulative risk factors” hypothesis
(Mueser et al., 1998) make the opposite assumption: they postulate that patients
with schizophrenia are at higher risk of developing schizophrenia due to their
lower socioeconomic status and reduced cognitive capacities compared to the
general population. However, convincing evidence for this has been lacking to
date. The prominent self-medication hypothesis (Khantzian, 1997) states that
patients with schizophrenia use drugs to ameliorate, in particular, negative symp-
toms and their cognitive impairments and to counteract the side effects of antip-
sychotic medication. Evidence exists that symptom reduction through substance
abuse is indeed successful in the short term. However, the model cannot explain
why substance use may precede psychosis in some cases. In contrast, the affect
regulation model (Blanchard et al., 2000) assumes that stable personality traits,
such as increased impulsivity and neuroticism, rather than transient symptoms,
condition an individual’s tendency to resort to maladaptive emotion regulation
strategies, such as substance use. According to related approaches, patients with
schizophrenia specifically seek to regulate dysfunction of the dopamine system
through substance use. Here, it is assumed that a pathologically altered dopamine
transmission in the so-called reward system (reward system) leads to an over-
valuation of the positive consequences of substance abuse and a devaluation of
the negative consequences. Furthermore, some authors suggest, based on animal
studies, that certain abnormalities in temporo-limbic circuits (Chambers et al.,
2001) favor both the susceptibility to the development of a dependence disease
and the development of psychosis. Overall, empirical evidence exists for all of
the above theories. Difficulties arise especially for approaches that presuppose a
specific temporal sequence of psychosis and dependence, as this cannot always
be clearly delineated in practice and may also vary from individual to individ-
ual. This, together with the fact that the neurocognitive performance of some of
the patients with the dual diagnosis of schizophrenia/substance dependence is
2.1 Comorbidities
6
2 Epidemiology, Etiology, and Pathophysiology
sometimes even superior to that of non-dependent schizophrenic patients (e.g.,
Thoma & Daum, 2008), raises the question of whether they might not rather rep-
resent fundamentally different diagnostic entities. However, imaging findings for
the dual diagnosis of schizophrenia/dependence, in particular, are so sparse that
further research is urgently needed. The possibly better preserved cognitive func-
tions in some of the patients with the dual diagnosis of schizophrenia/depend-
ence, on the other hand, should be further strengthened and used therapeutically
in a targeted manner.
u Reward System Decisively involved in the mediation of positive emotions,
such as pleasure, and the positively reinforcing effect of drugs. Dopamine is the
central neurotransmitter in the reward circuit, which includes structures such as
the nucleus accumbens, the ventral tegmental area, the orbitofrontal cortex, the
gyrus cinguli, and the amygdala.
Interim Summary
Schizophrenia is a developmental neurobiological disorder. A genetic vulnera-
bility can lead to the onset of the disease, usually not before adolescence, in a
complex interaction with other damaging factors occurring before birth, /per-
inatally and in the further course of development. Most frequently, comorbid
affective disorders and addictive disorders occur.
7
Neurocognitive Changes
Since cognitive changes are an essential feature of schizophrena, it has been
debated for some time to what extent it would make sense to include cognitive
dysfunctions as a diagnostic criterion in the major diagnostic manuals.
3.1 Importance of Cognitive Impairment
Since cognitive changes are an important feature of schizophrena, it has been
debated for some time whether it would be useful to include cognitive dys-
function as a diagnostic criterion in the major diagnostic manuals (e.g., Chong,
2008). Among other things, this would have the advantage of making practition-
ers more aware of the importance of cognitive impairment in their patients with
schizophrenia. Such an effect would ideally lead to a greater focus on cognitive
problems both in diagnosis and treatment. Another hope associated with the con-
sideration of cognitive abnormalities as a diagnostic criterion is that differential
diagnosis might be facilitated, e.g. with regard to the better differentiation of the
disorder from affective disorders with psychotic features. At this point, however,
there is a need for further research. Even if, at the group level, many findings
indicate that, for example, the global severity of cognitive impairment is high-
est in patients with schizophrenia, second highest in patients with bipolar affec-
tive disorders, and lowest in patients with unipolar depression (Harvey, 2011),
it remains difficult to make a sufficiently valid diagnostic classification into the
aforementioned disorder categories based on the cognitive findings in individual
cases. Overall, it has not yet been possible to identify clear and specific neuro-
cognitive impairment profiles in patients with schizophrenia or syndromally
defined subgroups (e.g., those with predominant negative symptoms) of patients
3
© Springer Fachmedien Wiesbaden GmbH, part of Springer Nature 2022
P. Thoma, Neuropsychology of Schizophrenia, Springer essentials,
https://doi.org/10.1007/978-3-658-36400-7_3
8
3 Neurocognitive Changes
with schizophrenia. About one-third of the patients show no cognitive abnormal-
ities at all compared to norm samples of healthy individuals, although it remains
unclear to what extent at least in some patients undetected deterioration compared
to a significantly higher premorbid level of functioning could play a role in this
regard. In another third of the patients, cognitive problems remit in symptom-free
phases, while in a further subgroup of patients cognitive functioning deteriorates.
Considering cognitive progression markers as a diagnostic criterion would there-
fore not necessarily reduce the heterogeneity of the disease at this stage. In any
case, the presence of cognitive impairment represents a major limitation in the
overall level of functioning of patients with schizophrenia. Cognitive deficits pre-
dict the continuation of everyday activities, general life satisfaction, and the abil-
ity to continue educational or occupational careers after illness onset (Rajji et al.,
2014).
3.2 Progression and Severity of Cognitive
Impairment
The cognitive abnormalities that occur in the context of schizophreniform psy-
choses presumably represent vulnerability markers for schizophrenia since they
can also be observed—in milder manifestations—in prodromal phases of schiz-
ophrenia, i.e. in part long before the onset of psychotic symptoms, and also in
individuals who have an increased risk of developing schizophrenia. Biological
relatives of patients with schizophrenia, who may be genetically more suscepti-
ble to the development of psychotic symptoms, represent one of the rather heter-
ogeneous groups at an increased risk for developing schizophrenia. Others also
include individuals who are classified as clinically vulnerable to the development
of full-blown schizophrenia due to intermittent positive symptoms (such as hear-
ing voices). There is not yet sufficient evidence to differentiate these groups in
terms of their cognitive functioning. In any case, these individuals, as well as
individuals with manifest schizophrenia, appear to show similar developmen-
tal neuropsychological abnormalities and are characterized by increased rates
of comorbidity with Axis I disorders. Early-onset of negative and disorganiza-
tion symptoms, as well as neurocognitive deficits in general and impairments in
social cognition in particular, represent predictors of poor functional outcome in
this setting (see the review article by Cotter et al., 2014). The identification of
neurocognitive vulnerability markers is of great importance potentially facil-
itating identification of individuals at risk at an early stage and prevention of
the full manifestation of the disease through timely intervention strategies, usu-
9
ally through the use of low-dose antipsychotics and psychosocial therapeutic
approaches. However, the success of these treatment strategies is not yet clear. It
is recommended that cognitive remediation approaches (see following sections),
which have been shown to be helpful in the treatment of patients with full-blown
schizophrenia, are given greater consideration in the therapeutic management of
cognitively impaired high-risk individuals (Cotter et al., 2014).
In high-risk individuals, the cognitive deficits are usually milder than in indi-
viduals who are actually ill, or they are not even detectable at the behavioural
level. In contrast, functional and structural abnormalities in the brain can often
be observed in these individuals and also in the prodromal stage of psychotic
illness. The more individuals in the family are affected by abnormalities, the
more pronounced these abnormalities become. Those individuals with the great-
est abnormalities generally carry the highest risk of actually developing the dis-
order. Although there are findings suggesting that cognitive dysfunction may also
occur iatrogenically as a result of long-term illness and associated medication, it
has also been shown that cognitive impairment occurs independently even in nev-
er-medicated, first-episode patients with schizophrenia. In addition, impairments
of theory of mind have been shown to be less pronounced in at-risk subjects than
in manifestly ill patients (Bora & Pantelis, 2013).
The pattern of cognitive abnormalities observed in the different phases of
schizophrenic psychosis is not consistent across existing studies. The most con-
sistently reported deficits are in verbal memory. The first episode of schizophre-
nia is also usually accompanied by deterioration in general cognitive functioning.
During florid phases, cognitive deficits are most pronounced in verbal memory,
visual memory, and information processing speed (Rajji et al., 2014). It is still
unclear whether the cognitive deficits observed in patients with schizophrenia are
best viewed as being domain-specific, as has been done in this section, or rather
in terms of a single construct (Dickinson et al., 2008).
Most authors agree that the cognitive deficits in patients with schizophre-
nia remain relatively stable over the lifespan and tend not to take a progressive
course. This contradicts earlier assumptions of a progressive decline in cognitive
functions in terms of “dementia praecox”. However, recent reviews show that
there may be two critical points in development at which the patient's cognitive
performance deteriorates quite decisively: firstly, before the first psychotic epi-
sode and secondly, after the age of 65 (Harvey, 2014). A good review of recent
findings on the course of cognitive impairment across the different phases of
illness concerning the underlying neural correlates is provided by Kelly and col-
leagues (2018).
3.2 Progression and Severity of Cognitive Impairment
10
3 Neurocognitive Changes
Interim Summary
Neurocognitive deficits often occur temporally before the onset of a psychotic
episode and before the initiation of medication, remain relatively stable over
the lifespan with marked deteriorations before the onset of illness and after
age 65, and predict the development of manifest schizophrenia in at-risk popu-
lations. They are associated with limitations in overall functioning and require
early intervention.
11
Neurocognitive Models of Negative
symptoms
Negative symptoms of schizophrenia include flattening of affect, anhedonia,
impoverishment of verbal and non-verbal expressivity, and social withdrawal.
Negative symptoms of schizophrenia include flattening of affect, anhedonia,
impoverishment of linguistic and non-verbal expressivity, and social withdrawal.
Often, as in Mrs. L.’s case, negative symptoms precede the onset of florid psy-
chotic illness and persist long beyond the acute phase. Some of the patients
almost consistently show predominant negative symptoms; a phenomenon for
which the term “deficit syndrome” has been coined. Negative symptoms do not
occur specifically in the context of schizophrenia but also in several other mental
(e.g., depression) and neurological (e.g., Parkinson’s disease) disorders. However,
recent research suggests that despite a number of overlaps in the neural correlates
of negative symptoms in these disorders, some changes may also be specific to
schizophrenia (Millan et al., 2014).
4.1 Cognitive Contributions
At the cognitive level, negative symptoms were primarily associated with
impaired social cognition, which is not surprising given the psychopathological
characteristics. Social cognition is a heterogeneous construct that refers to func-
tions that facilitate social interactions. It includes more basic abilities, such as
emotion recognition, as well as more complex functions, such as empathy, men-
tal perspective taking, and social problem-solving. Problems, e.g. with regard to
the ability to empathize with others, can be a consequence of negative symptoms
(e.g. social withdrawal) or an expression of them (e.g. in the form of reduced
emotional expressivity). Impairments in social cognition also intensify positive
4
© Springer Fachmedien Wiesbaden GmbH, part of Springer Nature 2022
P. Thoma, Neuropsychology of Schizophrenia, Springer essentials,
https://doi.org/10.1007/978-3-658-36400-7_4
12
4 Neurocognitive Models of Negative symptoms
symptoms, such as paranoia, as the actions of others are often misinterpreted as
a result. In addition, negative symptoms are mainly associated with disorders of
attention, memory, and executive functions, which seems plausible in view of the
neuronal changes in the corresponding brain areas described below.
4.2 Neuronal Changes
Reviews (Millan et al., 2014) conclude that at the neuronal level, primarily struc-
tural and functional abnormalities in the prefrontal cortex and temporal lobe seem
to underlie the negative symptoms. In addition, the interaction between these
regions as well as between frontal and corticostriatal parts of the brain is dis-
turbed. In the frontal brain, reductions in grey matter in the inferior frontal gyrus
and the anterior cingulate cortex were observed in connection with the negative
symptoms—regions that are particularly related to sociocognitive functions, such
as empathy. This could explain patients’ difficulties regarding emotion processing
and related deficits in social interaction. Similarly, the orbitofrontal cortex, which
has been particularly associated with reward processing, is also affected. Here,
patients with marked negative symptoms also appear to have poorer communica-
tion with subcortical structures involved in reward processing than healthy indi-
viduals. This may explain core aspects of negative symptoms, namely apathy and
anhedonia, understood as a lack of ability to motivate oneself to engage in poten-
tially rewarding activities. In particular, the anticipatory rather than the consum-
matory aspect of reward processing appears to be impaired: This may indicate
that although patients have difficulty motivating themselves to engage in self-
initiated activities, they do not necessarily experience them as less rewarding
when they do them.
In the temporal lobe, reductions in the grey matter of temporal gyri, such as
the fusiform gyrus and the superior temporal gyrus are prominent in connection
with negative symptoms. These brain areas have been associated with face pro-
cessing, theory of mind, and language functions, again suggesting the observed
impairments in social cognition and social interaction in the context of negative
symptoms.
Very consistently, reductions in white matter have also been observed in the
pathways that connect individual prefrontal regions, prefrontal brain areas and
other cortical regions (especially the temporal lobe), as well as prefrontal and
subcortical regions, such as the striatum, in association with negative symptoms.
13
On a functional level, corresponding reduced activations of the regions for
which the above-mentioned structural changes have been described are usually
evident. In particular, a connection between a dysfunctional activation of the
default mode network (default mode network), involving the ventromedial pre-
frontal cortex, and the negative symptoms has been reported. This is a network of
brain regions that are activated particularly under resting conditions, i.e., when no
specific task processing is to be performed by the brain. A faulty activation of the
“rest mode” in the brain could thus partly explain the listlessness of patients with
negative symptoms.
u Default Mode Network Also known as the “resting network”. Refers to a
network of brain regions (including the prefrontal cortex, gyrus cinguli, precu-
neus, and hippocampus) that are active when the brain is not engaged in a specific
cognitive task. During task processing, this network is deactivated.
Biochemically, patients with predominantly negative symptoms primarily show
dopaminergic hypoactivity in frontostriatal circuits. In contrast, there is dopamin-
ergic hyperactivity of the mesolimbic dopamine system associated with positive
symptoms (Chap. 5). The two systems are subject to reciprocal inhibition. This
means that reduced activity in the frontostriatal dopamine system causes disinhi-
bition of the mesolimbic dopamine system.
Interim Summary
Negative symptoms have been predominantly associated with structural and
functional changes of frontotemporal and frontosubcortical networks. In par-
ticular, dysfunctions of brain regions that have been associated with executive
action control, anticipatory processing of rewarding experiences, and social
cognition have been observed.
4.2 Neuronal Changes