Psychosis Prodrome and In-School Adolescents in Ile-Ife, Osun State

Contents

Overview of Psychotic Disorder
Classification of Psychosis

Pathophysiology (and Hypothesis) of Psychotic Disorders

Epidemiology:

Etiology of Psychosis

Diagnosis

Prodromal Psychosis

Models for investigating Psychosis Prodromes
Education and Psychosis Prodromes
Ile-Ife, Osun state: A case study

Bibliography

Introduction

In recent years, there has been growing concerns over the alarming global prevalence of mental disorders such as depression, anxiety, sleep disorders, psychosis amongst other neurological disorders. Interestingly, while genome-wide association studies have linked these disorders to genomic and epigenetic interactions within the cellular organisation; other studies have made allusions to non-biological variables like socio–demographic differences amongst individuals. In this review, the author discusses the previous researches focused on the prevention of the diverse shades of psychosis via evaluatiing the myriad of prodromal signs during the adolescent phase of human development.

Overview of Psychotic Disorder

The early 1900s witnessed the commencement of research on the clinical syndrome of psychotic disorders (Kraepelin et al., 1919; Bleuler, 1950; Larsson et al., 2010).

Psychosis has since been described in several ways by researchers (McGee et al., 2000; Dhossche et al., 2002; Escher et al, 2002; Scott et al., 2006; Askenazy et al., 2007). Typically, it is a syndrome that markedly interferes with an individual’s functioning, characterized by conditions like the mood disorders (e.g., anxiety, depression) among others but typically hallucination (false sensory perceptions in the absence of external stimuli) and delusion (strongly held beliefs, not shared by other members of the community, arising from an incorrect interpretation of external reality, incompatible with a person’s social or religious background) (Starling et al., 2012; Larsson et al., 2010).

Fundamentally, since the early 1900s, the classical symptoms of psychotic disorders have been analyzed based on a set of symptoms (Hughlings-Jackson, 1931; Strauss and Carpenter, 1974). In a series of studies, researchers examined the relevance of symptom distinctions in consecutively admitted in-patients diagnosed with schizophrenia, one of many psychotic disorders (Andreasen and Olsen, 1982; Andreasen and Grove, 1986). The symptoms were divided into positive and negative dimension. The positive symptoms were said to represent an excess or distortion of normal functions (such as hallucinations or delusions) while negative symptoms referred to a reduction or loss of normal functioning (for example; loss of normal emotional reactivity, social withdrawal, impaired cognitive functioning) (Larsson et al., 2010; Starling et al., 2012).

According to the fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), psychotic disorders have characterized by five hallmarks including hallucinations, delusions, disorganized thought/speech, negative symptoms, and disorganized/abnormal motor behavior (APA, 2013; Heckers et al., 2013).

In addition, there are researches that suggest that asides a greater risk of progression to clinical psychosis, there may be an association between the presence of prodromal psychotic symptomatology and the risk of a wide range of non-psychotic disorders (Bartels-Velthuis et al., 2011; Kelleher et al., 2012b).

Summarily, following the contribution of authors; several associated factors have been found to correlate with the various psychotic disorders as illustrated below.

Table 1: Frequently reported correlates of schizophrenia (Cederlöf, 2016).

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In the same vein; similar to schizophrenia and most other psychiatric disorders, co-occurrence with other psychiatric disorder is also applies to bipolar disorder. Some of the most commonly described psychiatric and somatic correlates are listed in the table below.

Table 2: Frequently reported correlates of bipolar disorder (Cederlöf, 2016).

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Classification of Psychosis

Psychoses could be classified based on the etiology of the disease (functional, organic and psychogenic psychoses) (Tengan and Maia, 2004). Similarly, psychosis may be categorized as acute or chronic, based on the onset and duration of its symptoms (Krynski and Assumpção, 1987; Tengan and Maia, 2004). According to onset and duration of its symptoms therefore; the acute psychoses include brief psychotic disorder (reactive or psychogenic psychoses), acute and recurrent psychoses (cycloid psychosis), substance-induced psychotic disorder and acute organic psychoses. On the other hand, the chronic psychoses include schizophrenia, schizoaffective disorder, schizophreniform disorder, persistent delusional disorder.

Alternatively, psychosis have been differentiated into non-affective and affective psychoses based on whether the mood, or affective symptoms (Larsson et al., 2010).

Accordingly, the non-affective psychotic disorders involve psychotic episodes that typically occur with the exception of mood episode, and are typically considered to include schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to medical condition, substance- induced psychotic disorder and psychotic disorder not otherwise specified. On the other hand, affective psychotic disorders differ in that the psychotic episodes co-occur with severe mood disorders. They include bipolar disorder with psychotic features and depression with psychotic features (Angst and Sellaro, 2000; WHO, 2002; Goodwin and Jamison, 2007; Merikangas et al., 2011; Philips and Kupfer, 2013).

Pathophysiology (and Hypothesis) of Psychotic Disorders

Extensive research into the pathogenesis of psychotic disorders has traced the disorder to the interaction between genes and the environment (Tsuchiya et al., 2003; Bienvenu, Davydow and Kendler, 2011; Song et al., 2014).

Specifically, in the field of neuroscience, there has been appreciable work in schizophrenia research using in research methodologies in molecular genetics. One of the most notable has been the genome-wide association study (GWAS) from the Schizophrenia Working Group of the Psychiatric Genomic consortium has provided important clues into etiological processes of the disorder. In this study, 108 (about 130 after subsequent studies) biologically plausible locations in the genome (i.e., loci) were identified, out of which 83 had not been reported previously. Several identified risk loci included genes involved in glutamatergic transmission and synaptic plasticity, which is consistent with one of the leading pathophysiological theories of schizophrenia (Javitt, 2012).

Another important hypothesis is the ‘neurochemical hypothesis’ which postulates that psychotic disorder may be associated with hyperactivity in the dopaminergic neuronal pathway (Meltzer & Stahl, 1976). One study also reported on possible relationship between the dopamine D2 receptor gene and schizophrenia (O’Donovan, 2015).

Furthermore, epidemiological findings have suggested that schizophrenia may be as a result of the dysregulation in the immune system (Benros et al., 2012). This hypothesis is also known as the immunological hypothesis of schizophrenia.

Finally, there has also been certain hypothesis that delineates the role of brain development with mental disorders. To this effect, the pathogenesis of psychotic disorders has been described under the theories of neurodevelopmental or neurodegenerative.

On a neurodevelopmental basis, the disorder is illustrated on the notion that vulnerability to psychosis may indeed originate a defective fetal brain development process (Murray and Lewis, 2005). There are scholars that have supported the theory that psychosis stem from early development, but are generally manifested in late adolescence as a result of the developmental trajectory of the brain. In other words, the human brain continues to develop at least the second decade of life; and therefore it has been hypothesized that it is at this point in the brain development that the underlying neural structures reflect functional deficits (such as early intellectual and neuromotor abnormalities) to the extent that they lead to behavioral manifestations of psychosis (Davidson et al., 1999; Munro et al., 2002; Schenkel and Silverstein, 2004; Walker, 1994; Walker et al., 1999). Furthermore, following the neurodevelopmental theory; Zipursky et al., reported that by the first episode of psychosis, there was evidence that sufferers may develop slightly larger lateral ventricle and slightly less cerebral gray matter volume than healthy controls (Zipursky et al., 2004).

Additionally, there has been a plethora of studies that have suggested an association between neurodevelopmental problems and deviations in children. These children were reported to develop schizophrenia in their later life, compared with children who will develop other non-psychotic psychiatric disorders or no psychiatric disorder at all (Welham et al., 2010; MacCabe et al., 2013).

More so, considering obstetric complications, it has been found that complications especially during pregnancy (such as diabetes), problems with fetal growth and status at delivery (e.g. low birth weight or small head circumference), and delivery complications (e.g. caesarian section or lack of oxygen) are related to an elevated risk of schizophrenia (Fish, 1992; Cannon et al., 2002; Rapoport et al., 2005).

Furthermore, in influential studies; childhood problems with motor behavior (Walker et al., 1994; Erlenmeyer-Kimling et al., 2000) and receptive language (Cannon et al., 2002) have been associated with adult psychotic disorder. In the same vein, two cohort studies have reported that delays in speech and/or motor development predict later psychosis (Done et al., 1994; Jones et al., 1994; Welham et al., 2010).

One study reported that relative decline in verbal ability and other cognitive abilities during adolescence were associated with increased risk of adult psychosis in males (MacCabe et al., 2013). This finding partly suggested that disturbance also in late neurodevelopmental phase may be part of the trajectory to psychosis for some individuals, and may aptly correspond with the brain changes reported in adolescents who will later develop schizophrenia (Pantelis et al., 2003; Rapoport et al., 2005).

On the other hand, a second theory has been developed termed the neurodegeneration model. In the early 1990s, researchers like Kraepelin observed that a chronic period of illness, now characterized as the duration of untreated psychosis (DUP), was associated with persistent symptoms and functional disabilities (Kraepelin et al., 1919).

Various studies have demonstrated that a longer DUP may be directly associated with worse functional outcomes in addition to greater symptoms, poorer quality of life and a poorer response to antipsychotic medications (Harrington et al., 2003; Addington et al., 2004; Marshall et al., 2005; Perkins et al., 2005; Barnes et al., 2008).

Notably in contrast to schizophrenia, one research on neurodevelopmental aberrations in bipolar disorder indicated that adolescents with excellent school grades were more likely at risk of later bipolar disorder, after adjusting for the potential effects of socioeconomic status and parental education (Maccabe et al., 2010).

Epidemiology:

The understanding of mental disorders is amongst other factors; driven by knowledge of the rate and frequency with which they occur in different societies and cultures. With regards to mental disorders; over a period of time, changes in the incidence and prevalence of particular disorders have predictably occurred. Yet in reality, researchers are still faced with the challenge of obtaining highly reliable evidence that such changes have actually occurred (Jablensky et al., 1992).

With psychotic disorders, there has always been the challenge of under-diagnosis due to the fact that symptoms often lack specificity in relation to other psychiatric diseases. Children are still developing, however, symptoms become more diagnostic in adulthood (McClellan, 2000; Hollis, 2003; Lee, 1996).

Broadly, schizophrenia has been reported to affect approximately 1% of the population, with age at onset between 15 and 30 years (McClellan, 2000). This is also corroborated by the fact that early-onset schizophrenia have been noted to begin before the age of 17- 18 years, whereas childhood schizophrenia has been reported occurs before the age of 13 years which are also a quite rare phenomenon (McKenna et al., 1994; Weery and Taylor, 1992; Lord and Rutter, 1994; McClellan, 2000; Hollis, 2000). Tengan and Co. also reiterated that psychotic disorders may especially become more expressive at around the age of 11 (Tengan and Maia, 2004).

Schizophrenia crosses all socioeconomic, cultural, and racial boundaries. The lifetime risk of developing the illness has been estimated at about 8 per 1,000. Schizophrenia is the single largest cause of admissions to mental hospitals and accounts for an even larger proportion of the permanent populations of such institutions. The illness usually first manifests itself in the teen years or in early adult life, and its subsequent course is extremely variable. About one-third of all schizophrenic patients make a complete and permanent recovery, one-third have recurring episodes of the illness, and one-third deteriorate into chronic schizophrenia with severe disability (León, 1989; Thara et al., 1996).

Several large-scale epidemiological studies have highlighted certain associated factors with the predominant pattern of mental disorders. For instance; strong epidemiological association have been reported between socioeconomic class and the occurrence of certain types of mental disorders. One study found that the lower the socioeconomic class, the greater the prevalence of psychotic disorders. Also schizophrenia was found to be 11 times more frequent among the unskilled manual workers than among the highest class (professionals) (King et al., 1994; Selten and Sijben, 1994).

Furthermore, there have also been reports of gender differences in the incidence of certain types of mental disorders. For instance, males have been reported to be more likely to exhibit early onset of psychosis with peak incidence in the early twenties in contrast with the late twenties or early thirties found in females (Jablensky et al., 1992).

Furthermore, the manifestation of particular psychiatric symptoms has been closely linked with specific periods in life. Accordingly, certain mental illnesses have been found to be prevalent in childhood and adolescence (including anorexia nervosa, schizophrenia, bipolar disorder, drug abuse). The middle age group was more likely to suffer from alcohol dependence and its consequences, paranoid schizophrenia, and repeated attacks of depression while senile and arteriosclerotic dementias are characteristic of the elderly.

It is also to take into consideration the living environment of patients. For instance; in a WHO 10-country-two-year follow-up study, the percentage of cases with full remission after a single episode ranged between 3% in the USA and 54% in India, while the cases with continuous psychotic illness varied between 2% in Nigeria and 33% in Japan (Jablensky et al., 1992). In this study, environment was attributed to play a crucial role as an outcome determinant in schizophrenia. (León, 1989; Thara et al., 1996). Furthermore, certain variables have been associated with higher improvement rates in developing countries including better tolerance of the sick role, availability of suitable jobs, supportive family attitudes and extended family networks have been suggested as explanations (Leff et al., 1987; Leff et al., 1992; El-Islam, 1982).

Risk factors:

As outlined earlier, schizophrenia – one of several psychotic disorder has been defined by five hallmarks (hallucinations, delusions, blunted emotions, disordered thought, and a withdrawal from reality).

Essentially, till date no single cause has been exclusively hinged to the psychotic disorders; however, there is strong evidence that a combination of genetic and environmental factors plays an important role in the development of the disease. Consequently, various theories of the origin of the psychoses have highlighted anatomical, biochemical, psychological, social, genetic, and environmental etiologies.

Fundamentally, most psychotic disorders have been broadly classified into three main categories including socio-demographic characteristics; predisposing factors; precipitating factors based on their a number of correlates (Cooper, 1978; Nandi et al., 1980; Eaton et al., 1988).

Within the first category i.e. socio-demographic factors, the association between lower social class and schizophrenia in urban settlements of developed countries has been attributed to the selection-drift hypothesis that posits that individuals at risk of psychotic disorders or with insidious onset of the disorder are either prevented from attaining higher class status or move progressively downward (Eaton et al., 1988). On the other hand, there is a counterargument that confounds this hypothesis. For instance; the environmental conditions in lower class neighbourhoods, including occupational hazards, poor maternal and obstetric care or high psychosocial stressors, may play a role in some subgroups of people with living diagnosed with psychosis. Moreover, this counterargument has been corroborated by studies in non-western countries such as India where prevalence of psychosis is greater in individuals in the higher social class (Nandi et al., 1980; Eaton et al., 1988).

Another addition to the socio-demographic factors is marital status. The risk ratio for unmarried individuals compared with the married is approximately 4 (Eaton et al., 1988). Looking critically, this may not be unconnected to the social class factor, there are some suggestions that marriage, as well as any close interpersonal relationship, could act as a protective factor.

Among the predisposing factors, genetic ones are most important. Also in the category of predisposing factor is the possible role played by pregnancy and birth complications. It has hypothesized that individuals who later develop schizophrenia will have experienced a greater number of such problems (McNeil, 1995), although the strength of the association was not impressive.

Furthermore, it has been reported that the preponderance of psychosis in males seem to be one of the major difference between childhood-onset schizophrenia and adult-onset schizophrenia (McKenna et al., 1994; Werry and Taylor, 1994). Also, while the proportion of men and women is approximately the same in the adult population, boys are affected twice as much as girls in the pediatric population (Tengan and Maia, 2004). In addition, research has revealed that differences as regard the course of the disease between genders. These reports reveal that psychosis often develops earlier in men than in women, with a more intense cognitive involvement, and a worse outcome, in addition to a poor response to neuroleptics (Werry and Taylor, 1994; Cancro and Lehmann, 2000).

Lastly, amongst the myriad of interpersonal, social and cultural variables termed as precipitating factors; the familial environment ranks among the best documented. For example; in a large body of research; it was found that family interaction patterns characterized by lack of clarity or fragmented communication, negative affective style, criticism, hostility and over involvement were strong predictors of relapse into schizophrenia (Tienari et al., 1989; Miklowitz, 1994).

Researchers have found that rare inherited gene mutations appear to occur three to four times more frequently in people with schizophrenia compared with healthy people. These mutations typically occur in genes involved in neurodevelopment, of which there are hundreds. In addition, thousands of small-effect genetic variants have been identified on chromosome 6 in persons with schizophrenia. It is believed that the interaction of these variants—many of which occur in a region of the chromosome that contains the major histocompatibility complex, a group of genes associated with regulating responses of the immune system—contributes to some 30 percent of cases of the illness (Kendler and Diehl, 1993; Gottesman, 1991).

Similarly, a polygenic pattern, in which many minor genetic variants interact to give rise to disease, has also been found in persons with bipolar disorder. This knowledge sheds light on the enormous complexity of mental disorders associated with genetic factors (Kendler and Diehl, 1993; Gottesman, 1991).

Furthermore; it is important to note that the investigation into the genetic causes of mental disorders require both the laboratory analysis of the human genome and the statistical analysis of the frequency of a particular disorder's occurrence among individuals who share related genes—i.e., family members and particularly twins. Briefly, family risk studies compare the observed frequency of occurrence of a mental illness in close relatives of the patient with its frequency in the general population. First-degree relatives (parents, siblings, and children) share 50 percent of their genetic material with the patient, and higher rates of the illness in these relatives than expected indicate a possible genetic factor. In twin studies the frequency of occurrence of the illness in both members of pairs of identical (monozygous) twins is compared with its frequency in both members of a pair of fraternal (dizygous) twins. A higher concordance for disease among the identical than the fraternal twins suggests a genetic component. Further information on the relative importance of genetic and environmental factors accrues from comparing identical twins reared together with those reared apart. Adoption studies comparing adopted children whose biological parents had the illness with those whose parents did not can also be useful in separating biological from environmental influences.

Such studies have demonstrated a clear role for genetic factors in the causation of schizophrenia. When one parent is found to have the disorder, the probability of that person's children developing schizophrenia is at least 10 times higher (about a 12 percent risk probability) than it is for children in the general population (about a 1 percent risk probability). If both parents have schizophrenia, the probability of their children developing the disorder is anywhere from 35 to 65 percent. If one member of a pair of fraternal twins develops schizophrenia, there is about a 12 percent chance that the other twin will too. If one member of a pair of identical twins has schizophrenia, the other identical twin has at least a 40 to 50 percent chance of developing the disorder. Although genetic factors seem to play a less significant role in the causation of other psychotic and personality disorders, studies have demonstrated a probable role for genetic factors in the causation of many mood disorders and some anxiety disorders.

The role of gene as a predisposing factor in psychosis has been well established and is estimated around 60% (Kendler and Diehl, 1993). Available data leave considerable room for environmental influences, as shown by concordance rates of less than 50% in monozygotic twins and lifetime risk of about 45% in children of two schizophrenic parents. However, only 10% of people with schizophrenia have an affected parent (Kendler and Diehl, 1993; Gottesman, 1991). Given the heterogeneous nature of schizophrenic disorders, it is also possible that both epigenetic factors play an important role in the disorder.

The risk factors for schizophrenia in adolescents and young adults are well described (Owens and Johnstone, 2006; Yung et al, 2004).

Accordingly; evaluating the interaction between age and psychoses, early-onset schizophrenia, where children’s symptoms meet criteria for diagnosis of schizophrenia and where symptoms has been found to start before the age of 13 have been reported to have prevalence of less than 1/10,000 according to a Childhood-onset Schizophrenia Study at the NIMH (Rapoport and Inoff-Germain, 2000; Asarnow et al, 2004). These studies drew from a wide geographical area and had strict exclusion criteria. Information from these cohorts suggests that childhood onset schizophrenia is a severe form of the late adolescent/early adult onset disorder. Findings from these cohorts studies include more pre-morbid adjustment than seen in those with later onset, with an increased prevalence of cytogenetic (Addington & Rapoport, 2009) and developmental abnormalities including pervasive developmental disorders and mental retardation (Rapoport et al, 2009).

Pre-morbid social difficulties, motor abnormalities and a family history of schizophrenia were more common than in controls. The onset of the illness was often insidious with cognitive deterioration (Bedwell et al., 1999) and neuroanatomical changes (Arango et al., 2008) occurring early in the illness. Unfortunately, only a few children with psychotic symptoms fulfill diagnostic criteria for childhood onset schizophrenia and by the time diagnostic criteria are met they are chronically ill, with significant disability.

Among adolescents, psychotic disorders of all types have been found to be highly prevalence one in 500 among 18 year olds. From retrospective studies, about one third of adults with psychotic disorders reported that their illness started before the age of 20 while some adolescents with psychosis have been found to come from such high risk groups of early-onset schizophrenia (Kendler et al, 1996).

In this group the typical illness course starts with a prodrome, with non-specific symptoms including low mood, anxiety, cognitive and functional deterioration. Combinations of these symptoms have been described as the “ultra high risk” mental state. The likelihood of transition to psychosis with these risk factors has been found to be high (Owens and Johnstone, 2006; Yung et al, 2004). Yet it should also be mentioned that such risk has been found reduce significantly following early intervention (Yung et al, 2008).

Consequences:

The implication of living with psychosis has been reported to lead to a myriad of dire consequences. Some of the consequences are discussed below.

- Mortality: Although schizophrenia is not in itself a fatal disease, mortality rates of individuals diagnosed with psychotic disorder are at least twice as high as those in the general population. The higher rate have been attributed in socio-economic factors like possible poor conditions and cost of long term institutional care, leading to high occurrence of tuberculosis and other communicable diseases as in the case of asylum-like institutions (Allebeck, 1989).

Similarly, there are studies that suggest an association between schizophrenia and suicide (and other diseases like cardiovascular disorders) as leading causes of death in both developing and developed countries (Allebeck, 1989; Caldwell and Gottesman, 1990; Jablensky et al., 1992). Specifically, there appears to be a positive correlation between mortality from cardiovascular disorders and the side-effects of antipsychotic drugs (Allebeck, 1989)

- Social disability: In concordance with 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.”

With psychotic disorders, disability can hinder social functioning in various broad areas (Janca et al., 1996), namely:

a. self-care, which refers to personal hygiene, dressing and feeding;
b. occupational performance, which refers to expected functioning in paid activities, studying, homemaking;
c. roles in relation to family, referring to expected interactions with spouses, parents, children or other relatives;
d. role in a broader social context.

Findings from European and North American studies have revealed a consistent pattern of disability of moderate or severe degree in about 40% of males suffering from schizophrenia, compared 25% of females (Shepherd et al., 1989; Leff et al., 1992).

- Social stigma: The consequence of societal stigmatization often leads to a damaged sense of one’s self worth and social isolation (Goffman, 1963). Stigma is largely pervasive within the cultural setting of the many societies whether urban or rural settlements (Warner, 1985; Fabrega jr., 1991). It is therefore, commonplace for sufferers of mental illnesses to be stigmatized. In fact, in most cases, stigmatization often lead to many forms of discrimination such as loss of employment, restricted access to social services, fewer chances for marriage, increased maltreatment and institutionalization (Leete, 1982; Deegan, 1990; Carling, 1995; Desjarlais et al., 1995).

- Impact on caregivers: There is undoubtedly a huge burden that is often placed on families or others living in close contact with a mentally ill person (Fadden et al., 1987). Studies have shown 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). In many societies, family involvement and distress may not necessarily reduce in a case where the sufferer lives away from home (Winefield and Harvey, 1993). There is a widely held belief that distress is more often related to patients’ apathy, inactivity or failure to comply with social duties, than with more evident positive psychotic symptoms or behavioural disturbances (Leff and Vaughn, 1985). Some of the ways that diseases can impact caregivers (although varied across diverse cultural setting) include (Westermeyer, 1984; Advisory Mental Health Council, 1993; Davies and Drummond, 1994; Salleh, 1994; Flyckt et al., 2011):

i. the financial burden needed to support the patient and the loss of productivity of the family unit;
ii. emotional burden to the patient’s illness, such as guilt, a feeling of loss and fear about the future;
iii. the stress of coping with the patient’s disturbed behaviour;
iv. disruption of household routine;
v. problems of coping with social withdrawal or awkward interpersonal behaviour;
vi. constraints on social activities.

In addition, there has been efforts towards assessing the global social burden of all illnesses and injuries, considering not only mortality but the degree of disability and allowing comparisons across various categories of diseases. The measure of disability-adjusted life years (DALYs) lost has widely adopted as a highly significant health status indicator (Murray and Lopez, 1996). The relevance of these indicators invariably help policy makers to put the burden associated with schizophrenia within a comprehensive public health framework.

Consequently, for psychotic disorders; the loss in DALYs was estimated at the end of the 20th century to be slightly below 13 million, which accounted for about 1% of the total burden of diseases around the world. Schizophrenia was 26th in the list of the diseases, ranked according to their contribution to the overall burden. However, if one takes into account the predicted modifications in social structure in most developing countries and the increase of populations at risk over the coming decades, psychotic disorders has been projected to be in 20th position by the year 2020, with more than 17 millions of DALYs lost, accounting for 1.25% of the overall burden (National Advisory Mental Health Council, 1993; Murray and Lopez, 1996).

Etiology of Psychosis

Quite often the pathophysiological basis of many mental disorders is idiopathic or at best multifactorial in nature as in the case of the psychotic disorders. From centuries of research, in the absence of a singular genetic or environmental pathogenic agent; scientists have turned to their focus to various disease models involving multiple factors. With mental disorders, the same type of disorder may have different causes in different persons. Arguably, the fact that quite different therapeutic approaches can produce equal improvements in different patients with the same type of disorder reflexes the complex and ambiguous nature of the causes of mental illness.

Summarily, the etiology of psychotic disorders has been studied under an integration of various models including genetic, biochemical, neuropathological variables.

One early attempt at understanding the etiology was the ‘two-hit hypothesis’ which suggests that a prenatal genetic or environmental ‘first hit’ disrupts some aspect of brain development, thereby establishing increased vulnerability to a ‘second hit’ that may occur later in life. It is important to note that neither insult by itself is sufficient to induce disorder. In this way, a two-hit model for psychosis therefore suggests that perturbations in the development of the central nervous system may predispose one to the disorder; yet that the onset of symptoms in a vulnerable brain would be triggered by environmental factors (Bayer et al., 1999).

The two-hit model was later modified to the ‘three hit model’ to include neurodegenerative factors, which were thought to be induced or accelerated by the disease onset itself (i.e. developmental risk factors, precipitating factors, and neurodegenerative factors) (Keshavan, 1999).

Lastly, ‘Multiple Hit’ model which underscores the importance of additive effects of environmental risk factors against a background of genetic predisposition has also been suggested (Ritsner, 2011). The Multi‐Hits Vulnerability Model (MHV Model) is based on interaction between four main hits and it’s illustrated in the figure below.

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Figure 1: A Multi-Hits Vulnerability Model of functional psychoses (Ritsner, 2011).

a) Genetic load hit (or genetic vulnerability): From GWAS and follow-up studies, there are evidences of an association between psychotic disorders and genetic aberrations. It has also been revealed that some cases of psychosis might be due to rare genetic structural variations in addition to cumulative effects of common variations in multiple genes, which in combination with environmental stressors may lead to the development of psychotic disorders (Schwab and Wildenauer, 2009; Walsh et al., 2008). Familial factors, and especially genetic factors, have been strongly implicated; twin studies indicate a heritability of around 80% (Sullivan et al., 2003) and the recurrence risk, i.e., the risk of schizophrenia in first- degree relatives to individuals with the disorder, is increased by a factor of ten (Lichtenstein et al., 2006).
b) Neurodevelopmental hit (‘neuronal vulnerability’): The etiology of psychosis may involve pathologic processes, caused by both genetic and environmental factors, before the brain approaches its adult anatomical state in adolescence (Rapoport et al, 2005). So, it has been hypothesized that some event will disrupt the normal development of brain structure and function at a stage prior (pre- and perinatal period) to the brain having reached a stage of full maturity and will lie silent until after puberty, when maturational events lead to the emergence of the symptoms of psychosis (Weinberger, 1987). Two models have been proposed to explain this latent period:

- early neurodevelopmental model: this is based on the view that a fixed lesion from early life interacts with normal neurodevelopment occurring later, lying dormant until the brain matures sufficiently to call into operation the damaged systems (Murray and Lewis, 1987).
- late neurodevelopmental model: based on data that indicate substantial changes in brain biology during adolescence, this model proposed that psychosis may result from an abnormality in peri-adolescent synaptic pruning (Feinberg, 1983). Genetic predisposition may produce an inappropriately high ‘synapse use threshold’ and lead to excessive pruning (Pogue-Geile, 1997). Thereby, these neurodevelopmental abnormalities have been suggested to lead to the activation of pathologic neural circuits during adolescence or young adulthood, which leads to the emergence of psychotic symptoms (Fatemi, 2005). Furthermore, it has been postulated that the genes involved in the regulation of pruning are under some element of hormonal control and this may have an influence on the gender difference in age of onset of symptoms (Corroon, 2005).

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