Schizophrenia: A Concise Overview of Etiology, Epidemiology Diagnosis and Management: Review of literatures

Abstract

Schizophrenia is arguably the most severe of the psychiatric disorders. It is among the most disabling and economically catastrophic medical disorders, ranked by the World Health Organization as one of the top ten illnesses contributing to the global burden of disease.

The lifetime prevalence of schizophrenia has generally been estimated to be approximately 1% worldwide. The prevalence of schizophrenia is about the same in men and women.

The onset of schizophrenia usually occurs between the late teens and the mid 30s. The onset of schizophrenia is later in women than in men, and the clinical manifestations are less severe. For males, the peak age of onset for the first psychotic episode is in the early to middle 20s; for females, it is in the late 20s. This may be because of the antidopaminergic influence of estrogen.

Schizophrenia is a disease caused by biopsychosocial influences, including genetic, perinatal, neuroanatomic, neurochemical and other biologic abnormalities. In addition psychological and socioenvironmental factors may increase the risk of schizophrenia in international migrants or urban populations of ethnic minorities. Increased paternal age is associated with a greater risk of schizophrenia.

Diagnosis of Schizophrenia must be made after differentiating other psychiatric and medical illnesses, as well as from disorders such as heavy metal toxicity, adverse effects of drugs, and vitamin deficiencies which may manifest with psychosis.

Schizophrenia treatment requires an integration of medical, psychological, and psychosocial inputs. The bulk of care occurs in an outpatient setting and is best carried out by a multidisciplinary team. Psychosocial rehabilitation is an essential part of treatment

Keywords: Schizophrenia; Antipsychotics; Psychotherapy; Neurotransmitters; Epidemiology

Background

Schizophrenia is a clinical syndrome of variable, but profoundly disruptive, psychopathology that involves cognition, emotion, perception, and other aspects of behavior. The hallmark symptom of schizophrenia is psychosis, such as experiencing auditory hallucinations (voices) and delusions (fixed false beliefs) [1]. It is arguably the most severe of the psychiatric disorders. Schizophrenia is among the most disabling and economically catastrophic medical disorders, ranked by the World Health Organization as one of the top ten illnesses contributing to the global burden of disease [2].

It carries a lifetime risk of around 0.5-1%, and its early onset and tendency to chronicity mean that its prevalence is relatively high. Disability results, particularly from negative symptoms and cognitive deficits, features that can have a greater impact on long-term functioning than the more dramatic delusions and hallucinations which often characterize relapses. The social and economic impact of the illness is enormous, and its impact on sufferers and their families can be devastating [1].

Schizophrenia is a clinical diagnosis. It must be differentiated from other psychiatric and medical illnesses, as well as from disorders such as heavy metal toxicity, adverse effects of drugs, and vitamin deficiencies [3].

Treatment of schizophrenia requires an integration of medical, psychological, and psychosocial inputs. The bulk of care occurs in an outpatient setting and is best carried out by a multidisciplinary team. Psychosocial rehabilitation is an essential part of treatment [3].

Etiology of Schizophrenia

Research has identified several factors that contribute to the risk of developing schizophrenia. It is a disease caused by biopsychosocial influences including genetic, perinatal, neuroanatomic, neurochemical and other biologic abnormalities. In addition, psychological and socio-environmental factors may increase the risk of schizophrenia in international migrants or urban populations of ethnic minorities. Increased paternal age is associated with a greater risk of schizophrenia [4,5,6].

Genetic factors

Studies indicate that schizophrenia runs in families. The risk of schizophrenia is elevated in biologic relatives of persons with schizophrenia but not in adopted relatives [7]. The risk of schizophrenia in first-degree relatives of persons with schizophrenia is 10%. If both parents have schizophrenia, the risk of schizophrenia in their child is 40%. Concordance for schizophrenia is about 10% for dizygotic twins and 40-50% for monozygotic twins.

The modes of genetic transmission in schizophrenia are unknown, but several genes appear to make a contribution to schizophrenia vulnerability. Linkage and association genetic studies have provided strong evidence for nine linkage sites: 1q, 5q, 6p, 6q, 8p, 10p, 13q, 15q, and 22q. Further analyses of these chromosomal sites have led to the identification of specific candidate genes, and the best current candidates are alpha-7 nicotinic receptor, DISC 1, GRM 3, COMT, NRG 1, RGS 4, and G 72. Recently, mutations of the genes dystrobrevin (DTNBP1) and neureglin 1 have been found to be associated with negative features of schizophrenia [8,9,10,11,12].

In a recent study, researchers identified new genetic loci not previously known to be associated with schizophrenia. Of the 108 genetic loci linked to schizophrenia that were identified in the study, 83 had not previously been found. The investigators also determined that among 128 independent associations related to the 108 loci, enriched associations existed not only among genes expressed in the brain, but also among those expressed in tissues related to immunity, giving support to the theory linking the immune system to schizophrenia. Some loci of particular interest include the following: Catechol-O-Methyltransferase (COMT) gene, RELN gene , Nitric Oxide Synthase 1 Adaptor Protein ( NOS1AP) gene, nMetabotropic Glutamate Receptor 3 ( GRM3) gene [8-13].Other genetic changes involve the structure of the gene. For example, copy number variants are deletions and duplications of segments of DNA; they can involve genes or regulatory regions. These variants are usually inherited, but can arise spontaneously. Copy number variants such as the deletions found at 1q21.1, 15q13.3, and 22q11.2 increase the risk of developing schizophrenia [14,15,16]. At most, however, these findings probably account for only a small part of the heritability of schizophrenia.

In a study of 39,000 people referred to a diagnostic laboratory, about 1000 had a copy number variant at 1 of the following loci: 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11, and 22q11.2. Clinically, these people had various neurologic or psychiatric disorders, including developmental delay, intellectual disability, and autismrelated disorders. Subjects also had congenital anomalies [17].

Many studies have also looked for abnormalities in neurodevelopmental genes. Disruptions in the DISC1, NRG1, DTNBP1, KCNH2, AKT1, and RGS4 genes have been associated with schizophrenia, albeit with significant variability between studies [18-30].These findings also lend support to the hypothesis that schizophrenia is a disease in which multiple rare genetic variants lead to a common clinical outcome.

As can be seen, working out the details of these genetic factors is difficult. Interactions with the rest of the genome and with the environment will doubtless prove to be important. Nonetheless, a meta-analysis of twin studies estimated that genetic factors account for about four fifths of liability to schizophrenia [31].

Neurotransmitters (Biochemical factors)

Multiple biochemical pathways likely contribute to schizophrenia, which is why detecting one particular abnormality is difficult. A number of neurotransmitters have been linked to this disorder, largely based on patients’ responses to psychoactive agents. Dopamine, serotonin, norepinephrine, GABA and glutamate are among the common neurotransmitters involved in pathogenesis of schizophrenia [32-36].

The role of dopamine in schizophrenia is based on the dopamine Hypothesis, which evolved from two observations. First, drug group which blocks dopamine function, known as the phenothiazines, could reduce psychotic symptoms. Second, amphetamines, which increase dopamine release, can induce a paranoid psychosis and exacerbate schizophrenia and that disulfiram inhibits dopamine hydroxylase and exacerbates schizophrenia [32-34].

The role of glutamate in schizoprenia is largely based on Glutamate hypothesis, reduced function of the NMDA glutamate receptor is implicated in the pathophysiology of schizophrenia. This has largely been suggested by abnormally low levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and ingestion of phencyclidine and ketamine a glutamate antagonist, produces an acute syndrome similar to schizophrenia and mimic cognitive problems associated with schizophrenia [32,35,36].

Serotonin hypothesis is another evidence of schizophrenia indicating, serotonin excess as a cause of both positive and negative symptoms in schizophrenia. The serotonin antagonist activity of clozapine and other second-generation antipsychotics, coupled with the effectiveness of clozapine to decrease positive symptoms in chronic patients has contributed to the validity of this proposition [32].

Norepinephrine neurotransmitters implicated in the pathophysiology of schizophrenia where selective neuronal degeneration within the norepinephrine reward neural system could account for anhedonia in schizophrenic patients [32,34].

Pregnancy and birth complications (perinatal factors)

Studied suggests pregnancy and birth complications can have a small effect on the risk of later development of schizophrenia. Women who are malnourished or who have certain viral illnesses during their pregnancy may be at greater risk of giving birth to children who later develop schizophrenia [37]. For example, children born to Dutch mothers who were malnourished during World War II have a high rate of schizophrenia.

After the 1957 influenza A2 epidemics in Japan, England, and Scandinavia, rates of schizophrenia were higher among offspring of women who contracted influenza during their second trimester. Women in California who were pregnant between 1959 and 1966 were more likely to have a child who developed schizophrenia if they had influenza in the first trimester of their pregnancy [38].

Obstetric complications may be associated with a higher incidence of schizophrenia [39]. A study of Finnish women supported an interaction between genetic and environmental influences on causation of schizophrenia [40].In this study, a review of 9596 women in Helsinki who received hospital treatment during pregnancy for an upper urinary tract infection between 1947 and 1990 found no overall significant increase in the risk of schizophrenia among their offspring but a 5-fold higher risk among the offspring of women who also had a family history of psychosis. The authors estimated that among offspring of women with both prenatal pyelonephritis and a positive family history of psychotic disorders, 38-46% of schizophrenia cases resulted from the synergistic action of the 2 risk factors [40].

Season of birth

Children born in the winter months may be at greater risk for developing schizophrenia.. Winter birth in people who later develop schizophrenia is a robust epidemiological finding, at least in the northern hemisphere. It is likely to be a proxy indicator for some seasonally fluctuating environmental factor. The most popular hypotheses relate to seasonal variation in exposure to intrauterine viral infections around the time of birth, or variation in light, temperature/weather, or external toxins [39].

Cannabis use

Different studies suggest that heavy marijuana use in teenagers aged 15-17 years may hasten the onset of psychosis in those at high risk for developing a psychotic disorder. In an analysis of 247 hospitalized patients who had experienced first-episode psychosis, the Allied Cohort on the Early course of Schizophrenia (ACES)-II project found that the onset of psychosis in those who used cannabis from age 15 to 17 years occurred at a mean age of 21.07 years, compared with a mean age of 23.86 years in patients who did not use cannabis during those same teenage years. However, the researchers could not say whether marijuana use may actually cause psychosis to develop early or whether people who have a predilection for earlier onset of psychosis also may be more likely, owing to various factors, to use marijuana [41].

Epidemiology

The lifetime prevalence of schizophrenia has generally been estimated to be approximately 1% worldwide [42]. However, a systematic review by Saha et al of 188 studies drawn from 46 countries found a lifetime risk of 4.0 per 1000 population; prevalence estimates from countries considered least developed were significantly lower than those from countries classed as emerging or developed [43]. Immigrants to developed countries show increased rates of schizophrenia, with the risk extending to the second generation [44- 46].

Socio demographic factors

The onset of schizophrenia usually occurs between the late teens and the mid 30s [3]. For males, the peak age of onset for the first psychotic episode is in the early to middle 20s; for females, it is in the late 20s. The first 5-10 years of the illness can be stormy, but this initial period is usually followed by decades of relative stability (though a return to baseline is unusual). Positive symptoms are more likely to remit than are cognitive and negative symptoms [3].

Although some variation by race or ethnicity has been reported, no racial differences in the prevalence of schizophrenia have been positively identified. Some research indicates that schizophrenia is diagnosed more frequently in black people than in white people; this finding has been attributed to the cultural bias of practitioners.

The prevalence of schizophrenia is about the same in men and women. The onset of schizophrenia is later in women than in men, and the clinical manifestations are less severe. This may be because of the antidopaminergic influence of estrogen.

Suicide and aggression in schizophrenia

Patients with schizophrenia also have high rates of suicide. Even though schizophrenia has a relatively low prevalence (1%), a recent review estimated that up to 50 percent of schizophrenic patients attempt suicide and up to 13 percent of all deaths due to suicide are attributable to schizophrenia [48]. People with schizophrenia are more likely to use serious and violent methods in response to hallucinatory voices and delusions compared to patients with other disorders [49]. Compared to the general population (suicide prevalence about 1 percent), people with schizophrenia have a more than eight-fold increased risk of suicide. They also have an increased risk of death from natural causes such as cardiovascular and respiratory diseases [44].

In the mind of the general public, schizophrenia is sometimes synonymous with unreasoned violence. For those with schizophrenia, and for their families and advocates for those with mental illness, the real problem is that people with schizophrenia are far more likely to be the victims of violence than the general populations, which increased stigmatization and poorer treatment outcomes. Probably the most important causes are the presence of comorbid substance abuse, dependence, and intoxication. In addition, the disease process itself may produce hallucinations and delusions, which may provoke violence. Often, poor impulse control related to neuropsychiatric deficits may facilitate the discharge of aggressive tendencies. Moreover, failure to treat schizophrenic patients adequately is a major risk factor for aggression. The finding suggests that people with schizophrenia are four times as likely as people without schizophrenia to be engaged in violent acts [3,46].

Diagnosing Schizophrenia (Current Diagnostic Criteria- DSM-5)

Diagnosing schizophrenia is difficult because there is no single symptom which is unique to schizophrenia and there are no definitive blood tests or scans for the disorder. Making a diagnosis currently requires recognizing a constellation of symptoms for at least 6 months. Seeing a deterioration in the level of functioning of the person with the symptoms, as well as ‘ruling out’ other possible explanations for the observed disturbance.

According to DSM -5- Six criteria’s are required for the diagnoses of schizophrenia [3]

The DSM-V Symptomatic criterion (Criterion A): The DSM-V symptomatic criterion (Criterion A) requires the presence of a characteristic symptom or symptoms for at least 1-month duration or for less time if there is successful treatment. At least two Criterions A symptoms must be present for a significant portion of time during a 1-month period or longer. At least one of these symptoms must be the clear presence of delusions (Criterion Al), hallucinations (Criterion A2), or disorganized speech (Criterion A3). Grossly disorganized or catatonic behavior (Criterion A4) and negative symptoms (Criterion A5) may also be present (Table 1).

  

    
DSM-V    Diagnostic Criteria for Schizophrenia 
  
  

    
A.  Two (or more) of the following, each    present for a significant portion of time during a
      
1    -month period (or less if successfully treated). At least one of these must    be (1 ), (2), or (3):
      
1.  Delusions.
      
2.  Hallucinations.
      
3.  Disorganized speech (e.g., frequent    derailment or incoherence).
      
4.  Grossly disorganized or catatonic behavior.
      
5.  Negative symptoms (i.e., diminished    emotional expression or avolition).
      
B.  For a significant portion of the time since    the onset of the disturbance, level of function­ing in one or more major    areas, such as work, interpersonal relations, or self-care, is markedly below    the level achieved prior to the onset (or when the onset is in childhood or    adolescence, there is failure to achieve expected level of interpersonal,    academic, or occupational functioning).
      
C.  Continuous signs of the disturbance persist    for at least 6 months. This 6-month period must include at least 1 month of    symptoms (or less if successfully treated) that meet Criterion A (i.e.,    active-phase symptoms) and may include periods of prodromal or residual    symptoms. During these prodromal or residual periods, the signs of the    disturbance may be manifested by only negative symptoms or by two or more    symptoms listed in Criterion A present in an attenuated form (e.g., odd    beliefs, unusual perceptual experiences).
      
D.  Schizoaffective disorder and depressive or    bipolar disorder with psychotic features have been ruled out because either    1) no major depressive or manic episodes have occurred concurrently with the    active-phase symptoms, or 2) If mood episodes have occurred during    active-phase symptoms, they have been present for a minority of the total    duration of the active and residual periods of the illness.
      
E.  The disturbance is not attributable to the    physiological effects of a substance (e.g., a drug of abuse, a medication) or    another medical condition.
      
F.  If there is a history of autism spectrum    disorder or a communication disorder of child­ hood onset, the additional    diagnosis of schizophrenia is made only if prominent delusions or    hallucinations, in addition to the other required symptoms of schizophrenia,    are also present for at least 1 month (or less if successfully treated).
      
Specify    if: 
      
The    following course specifies are only to be used after a 1-year duration of the    disorder and if they are not in contradiction to the diagnostic course    criteria.
      
First    episode, currently in acute episode:     First manifestation of the disorder meeting the defining diagnostic    symptom and time criteria. Acute episodes a time period in which the symptom    criteria are fulfilled.
      
First    episode, currently in partial remission:     Partial remission is a period of time during which an improvement    after a previous episode is maintained and in which the defining criteria of    the disorder are only partially fulfilled.
      
First    episode, currently in full remission:     Full remission is a period of time after a previous episode during    which no disorder-specific symptoms are present.
      
Multiple  episodes,     currently  in  acute     episode:  Multiple  episodes     may  be  deter­ mined after a minimum of two    episodes (i.e.,  after a first episode,    a remission and a minimum of one relapse).
      
Multiple    episodes, currently in partial remission 
      
Multiple    episodes, currently in full remission 
      
Continuous:  Symptoms fulfilling the diagnostic symptom    criteria of the disorder are remaining for the majority of the illness    course, with sub threshold symptom periods being very brief relative to the    overall course. 
      
Unspecified 
      
The presence or absence of catatonia is specified.    Individuals meeting the criteria for catatonia receive an additional    diagnosis of catatonia associated with schizophrenia to indicate the presence    of the comorbidity.
      
Finally, the current severity of the disorder is    specified by evaluating the primary symptoms of psychosis and rating their    severity on a 5-point scale ranging from 0 (not present) to 4 (present and    severe).
      
 
  

Table 1:  DSM- V diagnostic criteria for schizophrenia.