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Etiology/ RISK FACTORS/CAUSES OF SCHIZOPHRENIA:
Recently, the etiology of schizophrenia is not known. There are various theories regarding its cause. These include:
• a genetic hypothesis,
• cortical disconnection syndrome,
• neurotransmitter dysfunction,
• failure to establish cerebral asymmetry, and
• A neuro-developmental syndrome. It is noted that these possible causes has been linked, and are not considered mutually exclusive. The current thesis focuses on Miller’s (1996, 2008) hypothesis.
1. Miller’s Hypothesis:
There is a strong theme of altered lateralization in the literature on schizophrenia. Miller (1996, 2008) has provided a comprehensive theory that proposes that the underlying enduring abnormal psychological traits observed in people with schizophrenia, as opposed to episodes of active psychosis, can be viewed as the result of an alteration in normal cerebral lateralization. Miller proposes that the functional specialization seen within each hemisphere, namely the location of language in the left hemisphere and visuospatial processing in the right hemisphere (in the right-handed, neurologically normal population) is due to a greater ratio of fast-conducting myelinated and large calibre axons to slow conducting unmyelinated
and small calibre axons in the right hemisphere when compared to the left
hemisphere. This greater ratio of fast conducting axons in the right hemisphere allows for fast parallel processing of visuospatial information. While the greater number of unmyelinated and small calibre axons in the left hemisphere affords the greater temporal resolution needed for speech and language functions located in that hemisphere. Furthermore, Miller proposes that this asymmetry of axonal myelination and calibre type is global within each hemisphere, as opposed to being present only within regions involved in language and visual processing (Miller, 1996). Miller also suggests that callosal projections are made up of axons projecting from one hemisphere to the other. This results in the common finding of faster right-to-left, relative to left-to-right, interhemispheric transfer times (IHTT) in the right-handed normal population (Barnett & Corballis, 2005; Brown, Larson, & Jeeves, 1994; Iwabuchi & Kirk, 2009; Marzi, Bisiacchi, & Nicoletti, 1991; Moes, Brown, & Minnema, 2007; Norwicka, Grabowska, & Fersten, 1996)

2. Genetic Hypothesis:

Schizophrenia tends to run in families, but no single gene is thought to be responsible.

It’s more likely that different combinations of genes make people more vulnerable to the condition. However, having these genes doesn’t necessarily mean you’ll develop schizophrenia.

Evidence that the disorder is partly inherited comes from studies of twins. Identical
twins share the same genes.

In identical twins, if one twin develops schizophrenia, the other twin has a one in two chance of developing it, too. This is true even if they’re raised separately.

In non-identical twins, who have different genetic make-ups, when one twin develops schizophrenia, the other only has a one in seven chance of developing the condition.

While this is higher than in the general population, where the chance is about 1 in
100, it suggests genes aren’t the only factor influencing the development of
schizophrenia.
3. Specific genes:-
According to, Meta-analysis of genetic linkage studies strong evidence of susceptibility for schizophrenia has found on loci 13q, 22q11-12 and 8p21-22. According to evidence for susceptibility many other loci is also there (Badner ; Gershon, 2002; DeLisi, Crow, et al., 2002; Levinson, Lewis, ; Wise, 2002; Lewis et al., 2003; Tandon, Keshavan, ; Nasrallah, 2008).

In some individuals in the development of schizophrenia some rare specific genetic aberrations have been implicated. These are microdeletions of part of chromosome 22q11.2, which leads to a 20-fold increase in risk for schizophrenia (Bassett et al., 2005), and deletions in 1q21.1, 15q11.2, and 15q13.3 (Stefansson et al., 2008). These microdeletions accounts for up to 2% of schizophrenia (Bassett, et al., 2005).

In rare causes of schizophrenia other genes implicated include Val66Met (Gratacòs et al., 2007), GAD1 (Straub et al., 2007), and DISC1 (disrupted in schizophrenia 1) (Hennah, Thompson, Peltonen, ; Porteous, 2006). Furthermore, Neuroregulin 1 (NRG1), COMPT (catechol-O-methyl-transferase), ALC6A3, DRD3, DTNBP1 (dysbindin) and SLC184 are implicated in schizophrenia (Duan et al., 2007; Nicodemus et al., 2007; Riley et al., 2009; Tan et al., 2007).

4. Neurotransmitter Dysfunction Hypotheses:
A. Dopamine:

Dopamine is a neurotransmitter which is important in the pathology of schizophrenia. Drugs that block dopamine receptors, specifically D2 receptors (Carlsson, Carlsson, ; Milsson, 2004), have an ameliorating effect on symptoms of schizophrenia (Creese, Burt, ; Snyder, 1996), and those that increase the action of dopamine exacerbate symptoms (Snyder, 1972).

B. Serotonin, glutamate and ?-aminobutyric acid:

Cerebral serotonin imbalances have been implicated in schizophrenia. Second
generation antipsychotics are, amongst other actions, serotonin antagonists (Meltzer, Matsubara, ; Lee, 1989), and are more effective for treatment resistant schizophrenia than typical antipsychotics (Bondolfi et al., 1998). Serotonin antagonists have also proved effective in the treatment of negative symptoms (Duinkerke et al., 1993). However, the exact mechanism via which serotonin plays a role in schizophrenia is not fully understood (Duncan, Zorn, ; Lieberman, 1999).

Another neurotransmitter that has been implicated in schizophrenia is glutamate. This hypothesis was drawn from the ability of glutamate agonists, such as Ketamine, to produce quasi psychotic symptoms in the normal population and in people with schizophrenia (Malhotra et al., 1996, 1997).

The inhibitory neurotransmitter ?-aminobutyric acid (GABA) has also been
proposed to play a role in schizophrenia. Post-mortem studies of the brains of people with schizophrenia have found abnormalities in the GABA neurotransmitter system in the frontal lobes (Benes, Vincent, Marie, ; Khan, 1996; Sherman, Davidson, Baruah, Hegwood, ; Waziri, 1991). GABA plays an important function in working memory, and it has been proposed that these GABA reductions may be linked to deficits in working memory found in schizophrenia (Lewis, Hashimoto, ; Volk, 2005; Lewis, Volk, ; Hashimoto, 2004; Volk ; Lewis, 2002).

5. Neurodevelopmental Hypothesis:

Some gestational and perinatal factors have been found to significantly
increase the risk of developing schizophrenia in later life. These include prenatal famine; high levels of maternal distress in the first trimester; low birth weight; and shorter gestation (Jones, Rantakallio, Hartikainen, Isohanni, ; Sipila, 1998; Khashan et al., 2008; St Clair et al., 2005; Susser et al., 1996).

Obstetric complications have also been linked to the later development of schizophrenia. These include preeclampsia (which is linked to foetal malnutrition); caesarean section due to foetal distress, manual extraction of the baby; haemorrhage during delivery; and premature delivery (Byrne, Agerbo, Bennedsen, Eaton, ; Mortensen, 2007; Dalman, Allebeck, Cullberg, Grunewald, ; Köster, 1999).

It has been proposed that these events confer some form of brain damage, such as hypoxia to the foetus, which is linked to the later development of the disorder (Geddes et al., 1999; Marenco ; Weinberger, 2000).

Winter and spring birth and older paternal age at conception are also linked to the development of schizophrenia (Davies, Welham, Chant, Torrey, ; McGrath, 2003; Wohl ; Gorwood, 2007; Wu, Liu, Zhao, Ma, ; Li, 2011).

Foetal exposure to a virus during the first two trimesters has also been linked
to the development of schizophrenia.

Anatomical abnormalities present in schizophrenia, such as increased
ventricular size and decreased brain volume, lend further support to the
neurodevelopmental hypothesis (McCarley et al., 1999).

6. Cortical Dysconnection Syndrome Hypothesis:

The dysconnection hypothesis states that schizophrenia is caused by
disturbance (decrease or increase) in the connections between brain regions due to reduced synaptic plasticity and structural aberrations in the brain (Stephen, Baldeweg, ; Friston, 2006). This results in a lack of functional integration between brain regions and a reduction in the ability of synapses to modulate plasticity in memory systems, emotions, and learning, which results in a lack of reinforcement of adaptive behaviorv(Friston, 1998, 1999).

In people with schizophrenia there appears to be a disruption in the anterior
cingulate cortex’s (ACC) modulation of the temporal and the prefrontal areas
(Fletcher, McKenna, Friston, Frith, & Dolan, 1999).

Fletcher et al. (1999) propose that the lack of integration between these two areas by the ACC may result in the deficits in attention (Bench, Grasby, & Friston, 1993), performance monitoring (Carter et al., 1998), and willed action (Frith, Friston, Liddle, & Frackowiak, 1991) found in people with schizophrenia.

(2005) showed people with schizophrenia had altered functional networks between the ACC, and the cerebellum and the pre- and post-central gyrus.

Positron emission tomography has demonstrated aberrant cortical connections between semantic processing areas in the cerebellum, and temporal and occipital lobes (Kim et al., 2005), and between the prefrontal and parietal lobes during a working memory task performed by people with schizophrenia (Kim et al., 2003).

Deficits in parieto-motor area interactions have also been found in a study of
medicated and non-medicated people with schizophrenia using a trascranial magnetic stimulation (Koch et al., 2008).

There is evidence that there may be alterations in the connections and communication between the hemispheres in people with schizophrenia (Barnett, Corballis, & Kirk, 2005; Endrass, Mohr, & Rockstroh, 2002). These findings appear to consistently point towards an altered association or connectivity between several brain regions in people with schizophrenia.

7. Brain Anatomical Differences in Schizophrenia:

Structural differences between the brains of people with schizophrenia and
people without schizophrenia show that there is no one reliable deviation in brain structure observed in every person with schizophrenia. However, commonly found structural abnormalities include a decrease in cerebral volume and increase in ventricle size (Fannon et al., 2000; McCarley, et al., 1999; Shenton, Dickey, Frumin, & McCarley, 2001; Steen, Mull, McClure, Hamer, & Lieberman, 2006; Wright et al., 2000). Meta-analysis has found abnormalities in the medial-temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus), corpus callosum, and frontal
lobes, as well as reduced volume in the occipital, and parietal lobes (McCarley, et al., 1999; Shenton, et al., 2001). One meta-analysis also reported that 20% of the studies they reviewed found an increase in the size of the fourth ventricle (Shenton, et al., 2001). Another meta-analysis, however, found no enlargement of the fourth ventricle in people with schizophrenia (McCarley, et al., 1999).

a. Corpus Callosum

The corpus callosum (CC) is the largest of the commissures in the brain
(Keshavan et al., 2002). Its primary role is to facilitate the rapid transfer of
information between homologous regions, and beyond, in the left and right
hemispheres of the brain (Aboitiz, Scheibel, Fisher, & Zaidel, 1992; Jarbo, Verstynen, & Schinder, 2012).

The size of the CC increases into adult years (Pujol, Vendrell, Junqué, Martí-Vilalta, & Capdevila, 1993). Meta-analysis has found that people with
schizophrenia have reductions in the size of the corpus callosum (Woodruff,
McManus, & David, 1995).

Moreover, a meta-analysis of MRI studies found 67% of the studies reviewed reported people with schizophrenia had differences in the CC when compared to the normal population (Shenton, et al., 2001).

Specifically, reductions in the width and volume of the splenium, genu, isthmus, and area of the anterior midbody of the CC have been reported in people with schizophrenia (Bersani, Quartini, Iannitelli, Paolemili, & Ratti, 2010; Knöchel et al., 2012; Walterfang et al., 2009; Walterfang et al., 2008).

Investigations into the integrity of the white matter of the CC in people with
schizophrenia using FA have found decreased white matter FA bilaterally in the CC (Mitelman, et al., 2007), with specific decreases found in the genu, isthmus and splenium (Knöchel, et al., 2012; Price et al., 2007).

b. Altered Cerebral Asymmetries

• Reduced Physical Asymmetry in the Brain:
Cerebral physical asymmetry can be observed in several parts of the brain. In
the normal population the brain displays asymmetry with larger right hemisphere prefrontal and frontal regions, and larger left hemisphere occipitoparietal, occipital, and sensorimotor regions (Falkai, Schneider, Greve, Klieser, & Bogerts, 1995; Sharma et al., 1999). These asymmetries have been found to be reduced or absent in people with schizophrenia and their first degree family members (Bilder et al., 1994; Falkai, et al., 1995; Sharma, et al., 1999; Sommer, André, Ramsey, Bouma, & Kahn, 2001; Turetsky et al., 1995).

The role of the temporal lobe in schizophrenia has been of interest in the study of schizophrenia as direct stimulation has been demonstrated to invoke auditory hallucinations (Penfield & Perot, 1963).

• Functional Asymmetry in the Brain:

Further cerebral asymmetry can be observed in the functional specialisation of each hemisphere. This is demonstrated in the lateralisation of language to the left hemisphere in more than 90% of right-handers (Springer et al., 1999), 85% of ambidextrous people, and 73% of left-handers in the normal population (Knecht et al., 2000). People with schizophrenia have been found to have decreased cerebral lateralisation of language.

• Schizophrenia as a By-Product of Cerebral Lateralisation and Language:
It has been proposed that schizophrenia should have been selected against
during human evolution as it is inherently non-adaptive due to people with
schizophrenia having reduced fecundity compared with people without schizophrenia (Crow, 2000; Haverkamp, Propping, & Hilger, 1982; Nanko & Moridaira, 1993; Svensson, Lichtenstein, Sandin, & Hultman, 2007). However, due to the continued stable incidence of schizophrenia it has been postulated that schizophrenia is linked to genes that are fundamentally involved in the speciation event that led to the evolution of Homosapiens (Crow, 2000).

• Handedness and Cerebral Functional Asymmetry

More evidence for altered asymmetries in the schizophrenia population comes from studies in human handedness. Approximately 90% of the normal population is right-handed (Dragovic & Hammond, 2008; Hardyck & Petrinovich, 1977), which is linked with the functional lateralisation in the cerebral cortex (Corballis, 1991; Springer, et al., 1999).

Left-handed people with schizophrenia have higher levels of thought disorder
and higher rates of disorganised type schizophrenia, when compared with righthanded people with schizophrenia (Dollfus, Buijsrogge, Benali, Delamilleure, & Brazo, 2002; Manoach, Maher, & Manschreck, 1988).

c. Left Hemisphere Dysfunction:

Left hemisphere dysfunction in people with schizophrenia is evidenced in physiological and behavioural differences. Functional magnetic resonance imaging (fMRI) has shown people with schizophrenia with prominent negative symptoms have anatomical abnormalities in the left neocortical and limbic regions, and related white matter tracts (Sigmundsson et al., 2001). People with schizophrenia have also been shown to exhibit reduced left hemisphere advantage during a dichotic fused words task, and this was correlated with higher levels of positive symptoms (Bruder et al., 1995). Studies using fMRI found decreased activity in Wernicke’s area, an area linked to formal thought disorder, in people with schizophrenia (Kircher et al., 2001).

d. Right Hemisphere Dysfunction

Researchers looking at the right hemisphere in people with schizophrenia have also found evidence of differences between the schizophrenia population and the normal population. The right hemisphere is thought to be involved in speech prosody, recognition of facial affect, and the interpretation of metaphors (Brownell, Potter, ; Michelow, 1984; Kucharska-Pietura ; Klimkowski, 2002; Ross ; Monnot, 2008), skills that are often disturbed in people with schizophrenia (Addington, Penn, Woods, Addington, ; Perkins, 2008; Kucharska-Pietura ; Klimkowski, 2002; Murphy ; Cutting, 1990).

In addition, people with right hemisphere damage can experience
delusional misidentification (Capgras Syndrome) (F?rstl, Almeida, Owen, Burns, ; Howard, 1991), break-down of self/other boundaries (Bogousslavsky ; Regli, 1988), and loss of will (Coslett ; Heilman, 1989), all of which are symptoms of schizophrenia (Cutting, 1994).

Moreover, right hemisphere lesions can result in the loss of the ability to use
prosody and emotional gesticulation when speaking (Ross ; Marek-Marsel, 1979). Right hemisphere damage is also linked to deficits in the ability to express and perceive emotion (Borod, 1992; Borod, Koff, Perlman, ; Nicholas, 1986), and removal of the right hemisphere can result in deficits in perceiving negative emotional expressions, lies, and sarcasm (Fournier, Calverly, Wagner, Poock, ; Crossley, 2008).

8. Electroencephalography and Schizophrenia:

A. EEG:
EEG creates an attenuated view of the synchronous excitatory and inhibitory
neuronal post-synaptic potentials in the cerebral cortex (Barlow, 1993; Olejniczak, 2006). Experimentally its basic function is to observe the physiological output, or change in neural activity in the cortex, as a function of different stimuli or behaviour, thus allowing for the inference of the role of different cortical areas to various sensory or behavioural functions (Lopes da Silva, 2005). The recorded activity is the summation of the electrical activity primarily from groups of pyramidal neurons, which creates a picture of temporal brain activity (Barlow, 1993; Olejniczak, 2006).

C. Medication Effect on EEG:

Comparison between studies of people with schizophrenia is confounded by
some studies using medicated individuals and others using non-medicated individuals. Furthermore, there exists a range of possible antipsychotic medications available, further confounding comparisons between studies, as participants in different studies may be medicated differently. There appears to be a lack of recent literature addressing this issue from which to draw upon.

The effect of medication on EEG is a complex issue. As such the influence
that it has on EEG signals should be reviewed on a case by case basis.

D. Source Localization of the EEG:

One technique for source localisation is ‘Low Resolution Electromagnetic
Tomography’ (LORETA). This creates a three dimensional image of the electricalnactivity within the cortex from the 2-dimensional scalp recordings (Pascual-Marqui, et al., 1994). This technique creates a topographic map of the EEG oscillations byncalculating the smoothest “3-dimensional current distributions” between thenoscillations based on the data (Pascual-Marqui, et al., 1994, p. 49). Subsequently, we will reconstruct the current density dynamics from each estimated source. The peak energy at each source (within a particular time window) can then be used as a potentially more accurate estimate of the latency differences between activation of particular areas of the brain.

9. Event Related Potentials (ERPs)

ERPs are the summation of synchronous activation of pyramidal neurons that
consist of negative and positive wave forms (Epstein, 2003). They are considered to be the neurobiological response or transient change of regularly occurring wave forms as a function of sensory stimulation or internal event processing (Celesia ; Peachey, 2005), and are considered to be indicative of cortical information processing (Pfurtscheller ; Lopes da Silva, 2005).

10.Exposure to early biological risks

There is now a growing evidence indicating that certain environmental factors to
which a baby may be exposed in the mother’s womb or at birth are related to
vulnerability in developing schizophrenia. (Mueser & Gingerich, 1994). Perhaps
exposure to early biological risks explains how a person who does not have the
inherited tendency becomes the first person in his family to have schizophrenia.
Exposure to early biological risks can be via two ways: viral infection or birth
complications.
(a) Viral infection:
Several studies have shown that schizophrenia may be associated with prenatal
exposure to influenza. For example, Sarnoff Mednick and his colleagues (1991)
followed a large number of people after a severe influenza epidemic in Helsinki,
Finland and found that those whose mothers were exposed to influenza during their
pregnancy were much more likely to have schizophrenia than others. This observation has been confirmed by some researchers (eg. O’Callaghan et al., 1991; Venables, 1996). However, there are also researchers who did not agree to this observation (Torrey, Rawlings, ; Waldman, 1988). (Cited in Barlow ; Durand, 2002)
(b) Pregnancy and Birth complications:
More convincingly are the evidence of birth complications in identical twins. Carson ; Sanislow (1993) found that birth complications such as the loss of oxygen (anoxia) could affect only one of the identical twins. McNeil (1987) found that obstetrical complications appear often among twins with schizophrenia in discordant identical pairs, and among the more severely affected if both twins have schizophrenia. (Cited in Barlow ; Durand, 2002.) Other examples of birth complications reported are forceps delivery and fetal distress. Some scientists suggested that exposure to these types of environmental “insult” may cause small amounts of brain damage which only become apparent later in the person’s development. (Mueser & Gingerich, 1994.)
©Stress:
If a person has a biological vulnerability/predisposition to schizophrenia, excessive
stress can trigger the symptoms of schizophrenia according to the Stress-Vulnerability Model. Excessive stress can be in the form of traumatic life events such as the death of a loved one, marital or boy-girl relationship break up, or loss of job. Living in an environment in which there is a great deal of conflict, hostility, criticism or negativity between the patient and others (either family members or professional staff) can be stressful to patients and increase their risk of relapse. (Mueser & Gingerich; Brown, 1959; Brown et al., 1962). Also, an environment that places heavy demands on the patient can be stressful. (Mueser & Gingerich, 1994).
(d)Coping Skills:
Coping skills refers to a patient’s ability to handle stress effectively and thereby
reduce the negative effects of stress. Some evidences of poor coping skills are a lack of social skills and the inability to relax. Having had a biological vulnerability to schizophrenia, the excessive stress a person experiences and is unable to cope with will trigger an onset of schizophrenia or a relapse. (Mueser ; Gingerich, 1994.)
(e) Drug abuse:
Drugs don’t directly cause schizophrenia, but studies have shown drug misuse
increases the risk of developing schizophrenia or a similar illness.
Certain drugs, particularly cannabis, cocaine, LSD or amphetamines, may trigger
symptoms of schizophrenia in people who are susceptible.
Using amphetamines or cocaine can lead to psychosis, and can cause a relapse in
people recovering from an earlier episode.
Three major studies have shown teenagers under 15 who use cannabis regularly,
especially “skunk” and other more potent forms of the drug, are up to four times
more likely to develop schizophrenia by the age of 26.

Consequences of schizophrenia
1. Mortality:
Although schizophrenia is not in itself a fatal disease, death rates of people
with schizophrenia are at least twice as high as those in the general population. The excess mortality has been related in the past to poor conditions of prolonged institutional care, leading to high occurrence of tuberculosis and other communicable diseases (Allebeck, 1989). This may still be an important problem wherever large numbers of patients spend a long time in crowded asylum-like institutions. However, recent studies of people with schizophrenia living in the community showed suicide and other accidents as leading causes of death in both developing
and developed countries (Jablensky et al., 1992).

2. Social disability:
According to the International classification of impairments, disability and
Handicaps (WHO, 1980) impairment represents any loss or abnormality of
psychological, physiological or anatomical structure or function, while disability
is any restriction or lack (resulting from an impairment) of ability to perform
an activity in the manner or within the range considered normal for an
individual in his or her socio-cultural setting.
In mental disorders, such as schizophrenia, disability can affect social functioning
in various broad areas (Janca et al., 1996), namely:
• self-care, which refers to personal hygiene, dressing and feeding;
• occupational performance, which refers to expected functioning in paid
activities, studying, homemaking;
• functioning in relation to family and household members, which refers to
expected interactions with spouses, parents, children or other relatives;
• functioning in a broader social context, which refers to socially appropriate
interaction with community members, and participation in leisure and other
social activities.

Data from European and North American studies show persisting disability of
moderate or severe degree in about 40% of males with schizophrenia, in
contrast with 25% of females (Shepherd et al., 1989). Substantially lower
figures have been found in India, Africa and Latin America (Leff et al., 1992).
Global assessment of disability, however, hides wide variations across life
domains, which can be affected in different ways.

There is good evidence that for most patients nature and extent of social
disability are more relevant as outcome indicators than clinical symptoms.

3. Social stigma:
Social stigma refers to a set of deeply discrediting attributes, related to negative attitudes and beliefs towards a group of people, likely to affect a person’s identity and thus leading to a damaged sense of self through social rejection, discrimination and social isolation (Goffman, 1963). Stigma is strongly linked with the label of mentally ill and is, to a certain extent, unrelated to the actual characteristics or behaviours of those stigmatized. (Desjarlais et al., 1995).

4. Impact on caregivers:
The available data show that the proportion of persons with schizophrenia living with their relatives ranges between 40% in United States to more than 90% in China ( Torrey and Wolfe, 1986; Xiong et al., 1994).

Various aspects of impact on caregivers should be considered, including:

• The economic burden related to the need to support the patient and the loss of productivity of the family unit;
• Emotional reactions to the patient’s illness, such as guilt, a feeling of loss and fear about the future;
• The stress of coping with disturbed behaviour;
• Disruption of household routine;
• Problems of coping with social withdrawal or awkward interpersonal behaviour;
• Curtailment of social activities.

5. Social costs:
In recent years a major effort has been made towards the quantification of the
global social burden of all illnesses and injuries, taking into account not only
mortality but the extent of disability and allowing comparisons between
different categories of illness. The measure of disability-adjusted life years
(DALYs) lost has been used as a health status indicator (Murray and Lopez,
1996). Although this approach may not be completely suitable for most
mental disorders, including schizophrenia, because of their variable course and the fluctuating nature of the related disability, it enables social scientists and policy-makers to put the burden associated with schizophrenia within a comprehensive public health framework.

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