SCHIZOPHRENIA including clinical features and

Schizophrenia including mechanism of action and etiology and clinical features and management
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1. SCHIZOPHRENIA: ETIOLOGICAL ASPECT By- Dr.Ankita Bajpai (JRII) Deptt . of Psychiatry RMCH&RC

2. INTRODUCTION More than any other mental illness, schizophrenia is synonymous in the public’s mind with madness. Schizophrenia is neither new nor rare; it has likely existed for centuries. It affects approximately 1% percent of the world’s population—2.6 million people in the United States and 27 million worldwide affecting all segments of the population. Once thought to be due to spiritual affliction or moral deviance, schizophrenia today is known to be a brain disorder arising from multiple avenues. The cause of schizophrenia is not known. Many believe its aetiology is heterogeneous, possibly with multiple causative mechanisms causing different aspects of the disorder. Alternatively, multiple causative mechanisms may interact resulting in a common illness pathway. The causes of schizophrenia are complex and heterogeneous, with a multitude of potential risk and protective factors .

3. A large body of literature points to genetic and environmental risk factors and their interactions. In a review of this extensive literature, it is important to note some key caveats. First , most of what we know about causality comes from epidemiological data wherein guidelines exist about how to evaluate the strength of causal relationships. Second , a distinction needs to be made between risk indicators and risk factors. Third , causal factors rarely work in isolation. Finally , a distinction needs to be made between cause ( etiology ) and mechanism (pathophysiology).

4. PSYCHODYNAMIC THEORIES OF SCHIZOPHRENIA According to the psychodynamic approach, abnormality is caused when trauma from unresolved conflict between the id, ego, and superego ; the ego is repressed into the unconscious and this causes regression to an earlier stage of the Freudian stages of psychosexual development. In particular, schizophrenia is linked to an early part of the oral stage called primary narcissism during which the ego has not separated from the id. The ego is the rational part of the mind and so the person ceases to operate on the basis of the reality principle, therefore losing touch with reality as the ego is the rational element of the tripartite apparatus. This explains some of the symptoms of schizophrenia.

5. THE VARIOUS PSYCHODYNAMIC THEORIES ARE- CLASSICAL PSYCHOANALYSIS INTERPERSONAL PSYCHOANALYSIS OBJECT RELATIONS THEORIES FAMILY TRANSACTON MODELS THEORY

6. CLASSICAL PSYCHOANALYSIS SIGMUND FREUD Psychoanalytic formulation and the tripartite model of the mind The psychodynamic explanation suggests that very harsh childhood experiences result in inner turmoil in the patient giving rise to a conflict between the id, ego and superego (tripartite apparatus). If this conflict remains unresolved, it leads to fixation or regression to early stages of psychosexual development. In particular, schizophrenia is linked to an early part of the oral stage called primary narcissism during which the ego had not separated from the id. Due to this the person ceases to operate on the basis of the reality principle .

7. The psychodynamic approach views schizophrenia as the result of the disintegration of the ego. It is the ego’s job to keep control of the id’s impulses and strike a compromise between the demands of the id and the moral restrictions of the superego. According to Freud, a weak and fragile ego, whose ability to contain the id’s desires is limited, can be ‘broken apart’ by its attempt to contain the id, leaving the id in overall control of the psyche. If this happens, the person loses contact with reality as they can no longer distinguish between themselves and others, their desires and fantasies and reality (which is one of the many functions of the ego). They regress to a state of ‘primary narcissism’ little different from that of a newborn infant, dominated by their animal instincts, incapable of organizing their own behavior and hallucinating as a result of their basic inability to distinguish between their imaginations and reality. Freud viewed psychotic symptoms as a manifestation of unresolved conflict, the resolution of which results in defective object-relations. He maintained that a delusion is like a patch applied over the tear between the ego and external world which reflects on his viewpoint of symptoms as restitutional , i.e., an attempt to reforge object ties .

8. MARGARET MAHLER Margaret Mahler was also a central figure as far as psychoanalysis was concerned. Her main interest was in normal childhood development and how children arrive at the concept of self . Mahler developed the separation–individuation theory of child development. Her work included psychoanalysis with young disturbed children. As per Mahler when there are distortions in the reciprocal relationship between the infant and the mother, the child is unable to separate from, and progress beyond, the closeness and complete dependence that characterizes the mother-child relationship in the oral phase of development. As a result, the person's identity never becomes secure . She attributed the symptomatology of schizophrenia to a derailment of the normal process whereby self-representations (the representation of one's self) and object representations (the representation of a familiar person) become distinct.

9. HEINZ HARTMANN Heinz Hartmann believed the ego included innate capacities that facilitated an individual's ability to adapt to his or her environment. These included perception, attention, memory, concentration, motor coordination, and language. Under normal conditions, what Hartmann called an average expectable environment, these capacities developed into ego functions and had autonomy from the libidinal and aggressive drives; that is, they were not products of frustration and conflict, as Freud (1911) believed . Through Hartmann's focus on ego functions, and how an individual adapts to his or her environment, he worked to create both a general psychology and a clinical instrument with which an analyst could evaluate an individual's functioning and formulate appropriate therapeutic interventions. Based on Hartmann's propositions, the task of the ego psychologist was to neutralize conflicted impulses and expand the conflict-free spheres of ego functions. By doing so, Hartmann believed psychoanalysis facilitated an individual's adaptation to his or her environment.

10. INTERPERSONAL PSYCHOANALYSIS Interpersonal psychoanalysis accents the nuances of interpersonal interactions, particularly how individuals protect themselves from anxiety by establishing collusive interactions with others, and the relevance of actual experiences with other persons developmentally (e.g. family and peers) as well as in the present. This is contrasted with the primacy of intrapsychic forces, as in classical psychoanalysis. Interpersonal theory was first introduced by Harry Stack Sullivan and developed further by Frieda Fromm- Reichmann, Erich Fromm who contributed to the school of Interpersonal Psychoanalysis.

11. HARRY STACK SULLIVAN Sullivan laid the groundwork for understanding an individual, based on the network of relationships in which he or she is enmeshed. He developed a theory of psychiatry based on interpersonal relationships where cultural forces are largely responsible for mental illnesses. In his words, one must pay attention to the ‘interactional’, not the ‘intrapsychic’. This search for satisfaction via personal involvement with others led Sullivan to characterize loneliness as the most painful of human experiences. He also extended the Freudian psychoanalysis to the treatment of patients with severe mental disorders, particularly schizophrenia .

12. FRIEDA FROMM-REICHMANN According to her schizophrenia has its root in the failure of the parents - commonly the mother figure – to provide emotional security in infancy. This causes a weak ego organization, inability to give and receive love on an adult level .

13. ERICH FROMM Erich Fromm postulated eight basic needs: Relatedness - This includes relationships with others, care, respect, knowledge. 2. Transcendence – Humans have to transcend their nature by destroying or creating people or things. Humans can destroy through malignant aggression, or killing for reasons other than survival, but they can also create and care about their creations. 3. Rootedness - Rootedness is the need to establish roots and to feel at home in the world. Productively, rootedness enables us to grow beyond the security of our mother and establish ties with the outside world. With the nonproductive strategy, we become fixated and afraid to move beyond the security and safety of our mother or a mother substitute.

14. 4. Sense of Identity - The drive for a sense of identity is expressed non-productively as conformity to a group and productively as individuality. 5. Frame of orientation - Understanding the world and our place in it. 6. Excitation and Stimulation - actively striving for a goal rather than simply responding. 7. Unity - A sense of oneness between one person and the natural and human world outside. 8 . Effectiveness - The need to feel accomplished. When the above basic needs are not fulfilled properly schizophrenia develops.

15. OBJECT RELATIONS THEORIES This theory in psychoanalytic psychology is the process of developing a psyche in relation to others in the environment during childhood. Based on psychodynamic theory, the object relations theory suggests that the way people relate to others and situations in their adult lives are shaped by family experiences during infancy.

16. MELANIE KLEIN Klein believed that both good and bad objects are introjected by the infant, the internalization of good object being essential to the development of healthy ego function. Klein conceptualized the depressive position as “the most mature form of psychological organization”, which continues to develop throughout the life span. The depressive position occurs during the second quarter of the first year. Prior to this the infant is in the paranoid-schizoid position, which is characterized by persecutory anxieties and the mechanisms of splitting, projection, introjection, and omnipotence—which includes idealizing and denial—to defend against these anxieties. Depressive and paranoid-schizoid modes of experience continue to intermingle throughout the first few years of childhood .

17. The paranoid-schizoid position is characterized by part object relationships. Part objects are a function of splitting, which takes place in fantasy. At this developmental stage, experience can only be perceived as all good or all bad. As part objects, it is the function that is identified by the experiencing self, rather than whole and autonomous others. The anxieties of the paranoid schizoid position are of a persecutory nature with fear of the ego’s annihilation. Splitting allows good to stay separate from bad. Projection is an attempt to eject the bad in order to control through omnipotent mastery. Splitting is never fully effective, according to Klein, as the ego tends towards integration

18. FAMILY TRANSACTON MODELS THEORY DOUBLE BIND THEORY Double bind theory was first described by Gregory Bateson and Donald Jackson in 1950s. It can be described as an emotionally distressing dilemma in communication in which an individual (or group) receives two or more conflicting messages, and one message negates the other. This creates a situation in which a successful response to one message results in a failed response to the other (and vice versa), so that the person will automatically be wrong regardless of response. The double bind occurs when the person cannot confront the inherent dilemma, and therefore can neither resolve it nor opt out of the situation . Double binds are often utilized as a form of control without open coercion—the use of confusion makes them both difficult to respond to as well as to resist. In the long run this manifests itself as schizophrenic symptoms, e.g. flattened effect, delusions, hallucinations, incoherent thinking and speaking and in some cases, paranoia.

19. MARITAL SCHISM AND SKEWED FAMILIES Theodore Lidz described two abnormal patterns of family behavior . In one family type, with a prominent schism between the parents, one parent is overly close to a child of the opposite gender. In the other family type, a skewed relationship between a child and one parent involves a power struggle between the parents and the resulting dominance of one parent. These dynamics stress the tenuous adaptive capacity of the schizophrenic person .

20. PSEUDO-MUTUALITY AND PSEUDO-HOSTILITY Communication deviance (CD) occurs when a speaker fails to effectively communicate meaning to their listener with confusing speech or illogical speech patterns. These disturbances can range from vague linguistic references, contradictory statements to more encompassing non-verbal problems. A recent meta-analysis reported that communication deviance is highly prevalent in parents of patients diagnosed with schizophrenia and adoption studies have reported significant associations between CD in the parent and thought disorder in the offspring, however, the mechanisms by which CD impacts on the offspring's cognition are still unknown . The research of psychiatrists and psychoanalysts Lyman Wynne and Theodore Lidz on communication deviance and roles (e.g., pseudo-mutuality, pseudo-hostility, schism and skew) in families of people with schizophrenia also became influential with systems-communications oriented theorists and therapists .

21. GENETICS Many studies were done to find the genetic relationship : 1. FAMILY STUDIES. 2. TWIN STUDIES. 3. LINKAGE STUDIES 4. ADOPTION STUDIES. 5. GENE ASSOCIATION STUDIES. 6. COPY NUMBER VARIENTS.

22. FAMILY STUDIES ( to establish familial genetics ) TWIN/ADOPTION STUDIES ( for specific genetic basis rather than environmental factors) After genetic basis establishment To find out the genes (gene mapping) Linkage studies Association studies Genome wide association studies Chromosomal aberration/Copy number variant.

23. 1. FAMILY STUDIES : To establish family genetics. The first systematic family study was published in 1916 by Ernst Rüdin , who was working in Munich with Kraepelin . Several researchers conducting these studies spent decades of their lives in research and achieved the monumental task of gathering information on tens of thousands of relatives.

24. Pre 1980 studies : Morbidity risk for schizophrenia in the relatives of schizophrenic probands . The numbers are based on Gottesman and Shields and used with permission by Irving Gottesman .

25. In the 1980s the validity of these early studies was questioned on methodological grounds. No control groups. Diagnostic criteria. No structured interviews. It was not clear in many of the studies how many patients had been examined in person. FAMILY HISTORY METHOD : In this approach, the rates of illness in family members of a proband are determined by systematically questioning the proband about his or her family. This method is inherently less accurate than the direct interview method in which each family member is interviewed to make a diagnosis.

26. Post 1980 studies :

27. Conclusion : Schizophrenia runs in families. Significantly higher morbidity risks in relatives of patients compared with relatives of controls. Total number of people affected in a family. 1 st degree relatives. Very high in children with both the parents being diagnosed as schizophrenia = 45% Siblings = 10%

28. If a condition is found to be more common in the relatives of probands , this could be due to shared genes or to shared environmental factors. These shared environmental factors could be psychological, infectious, social, or other. Therefore, in order to confirm that a disorder is genetic, other types of studies need to be conducted, such as twin and/or adoption studies, which control for the environmental factors.

29. 2. TWIN STUDIES : Twins who are reared together share the same environment. Monozygotic (MZ) twins share all their genes, while dizygotic (DZ) twins share on average only 50 percent. Twin studies compare the concordance rates in MZ and DZ twins.

30. Conclusion : MZ twins = 40-50 % DZ twins = 6-10 % If one assumes that MZ and DZ twins share their environments to a roughly equal extent, then a higher concordance in MZ twins implies that the disorder is genetic, while a concordance of less than 100 percent in MZ twins indicates that environmental factors are also at play.

31. After genetic basis has been established by family, twin and adoption studies: Linkage studies. Genome wide association studies. copy number varients . Epigenetics

32. 4. LINKAGE STUDIES : ( To find out the gene responsible / inheritance ) Genetic linkage is the tendency of the alleles that are located close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. DNA markers distributed across all 23 human chromosomes . Several LINKAGE studies were done. Several meta-analyses have reached somewhat different conclusions.

33. STUDIES SHOW : Existence of susceptibility genes on chromosomes 8p, 13q, and 22q. Evidence was also obtained for linkage to regions on chromosomes 1q, 3p, 5q, 6p, 8p, 11q, 14p, 20q, and 22q. The 8p and 22q regions were supported little more than other chromosomes in meta-analyses.

34. Conclusion : No single gene for schizophrenia exists, confirming that it is not a single gene disorder. Several genomic loci have received support from several studies. Genetic overlap. The inability of linkage studies to unambiguously identify linkage signals and the absence of a clear mode of transmission in the vast majority of families affected with schizophrenia indicate that this is not a simple Mendelian disorder, but a disorder of complex inheritance.

35. 5. ASSOCIATION STUDIES : ( comparison of the defective gene between cases/controls ) Genetic association is when one or more genotypes within a population co-occur with a phenotype trait, more often than it would be expected by chance occurrence. Despite the inconclusive results produced by linkage studies, these have led to the identification of the most plausible candidate genes to date. Identified the genes dysbindin (DTNBP1) and neuregulin 1 (NRG1) , which are so far the two most consistently confirmed findings.

36. Dystrobrevin -Binding Protein 1 / Dysbindin : (DTNBP 1) Dystrophin -associated protein complex (DPC) of skeletal muscle cells. The dystrophin complex is found in the sarcolemma of muscle but is also located in the brain.  Gene required for the development of dendritic spines. Presynaptic dysbindin is reduced in schizophrenic brain within certain glutamatergic neurones of the hippocampus and may alter presynaptic glutamate function.

37. NEUREGULIN 1 Found on chr8p22-p21 Functions : Cell–cell signaling. Axon guidance. Synaptogenesis. Glial differentiation. Myelination. Neurotransmission.

38. Rest other candidate genes are-   GENE CHROMOSOME 1 Neuregulin 1 (NRG1) chr8p22-p21 2 Dystrobrevin-binding protein 1 gene (DTNBP1) chromosome 6. 3 Disrupted in Schizophrenia (DISC1) chromosome 1 4 D-amino-acid oxidase activator (DAOA, formerly called G72 or G30) chromosome 13q 5 G protein signaling (RGS4) chromosome 1q 6 ZNF804A (It encodes a zinc finger protein) chromosome 2q 7 major histocompatibility complex (MHC) chromosome 6p 8 Histone H2A type 1 gene (HIST1H2AG)-Also on chromosome 6p 9 TCF4- On chromosome 18q

39. Copy Number Variants Additional research has focused on copy number variants, structural variations in the genome that include insertions, deletions, and duplications. These variations are common (involving up to 12% of the human genome) and are hypothesized to contribute to phenotypic variation. Copy number variants can be inherited or can arise de novo , and can upregulate, downregulate, or otherwise disrupt normal gene function. The first copy number variant identified was a microdeletion at 22q11.2. Deletion at 22q11.2 causes velocardiofacial syndrome, and 20% of patients with this deletion develop schizophrenia. Since then many additional copy number variants have been associated with schizophrenia: 1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p13.1.

40. 1. Chromosome 22q11.2 Deletion Syndrome : Several studies have shown that adults with 22q11.2 deletions have a high risk of schizophrenia. DiGeorge / velocardiofacial syndrome (VCFS). Cardiac abnormality (especially tetralogy of Fallot) Abnormal facies. Thymic aplasia. Cleft palate. Hypocalcemia/Hypoparathyroidism. Developmental delay (speech), renal abnormalities, low IQ and skeletal abnormalities.

41. Epigenetics Epigenetics refers to ways that gene activity is regulated without altering the nucleotide sequence. Frequently this involves methylation of gene promoters or covalent modification of chromatin. This modification is often a response to hormonal, enzymatic, or second-messenger cascades linking the external environment (biochemical or psychosocial exposures) with gene expression. Data suggest epigenetic processes are involved with schizophrenia. The evidence includes: high methionine diets can exacerbate psychosis, hypermethylation of gamma-aminobutyric acid (GABA) genes causes GABA deficit in cortical neurons among schizophrenia patients, monozygotic twins discordant for schizophrenia show widespread DNA methylation differences in relevant neurobiological networks, and psychotic patients show brain-wide methylation abnormalities. Researchers have identified aberrant DNA methylation at about 100 loci in schizophrenia, including genes regulating glutamatergic and GABAergic systems, stress responses, and neurodevelopment .

42. NEUROANATOMICAL THEORIES T he brain structures most often implicated in the pathophysiology of schizophrenia are- The most consistent morphological finding in the literature of schizophrenia is enlarged ventricles which was reported by past generations of researchers using pneumoencephalography, and confirmed in recent decades by a large number of CT and MRI studies. Various studies indicate medium ventricular volume increases in chronic schizophrenia relative to controls for total ventricular volume, especially the lateral, third, and fourth ventricles.

43. Prefrontal Cortex The prefrontal cortex (PFC) contains a heteromodal association area that is responsible for integrating information from all other cortical areas as well as from several subcortical regions for the execution of purposeful behavior . Among its specific functions are working memory, which involves the temporary storage (seconds to minutes) of information, attention, and suppression of interference from internal and external sources. The most inferior portion of the PFC, termed the orbital frontal cortex (OFC), is involved in emotional expression. Dorsolateral prefrontal cortex (DLPFC) is involved in working memory and other executive functions. Schizophrenia patients show deficits in each of these functions. Several lines of evidence have implicated the PFC in schizophrenia.

44. Limbic System The limbic structures that have been implicated in schizophrenia are the hippocampus, entorhinal cortex, anterior cingulate, and amygdala. These structures have important functions for memory (hippocampus), attention (anterior cingulate), and emotional expression and social affiliation (amygdala). The entorhinal cortex serves as a “way station” between hippocampus sand neocortex in that neurotransmission between these regions synapse in the entorhinal cortex. The entorhinal cortex, hippocampus, and other components of the Para hippocampal gyrus are often considered “ mesiotemporal ” structures because of their close anatomical and functional relationship. Postmortem studies of the hippocampus have reported a number of pathological changes, but many of the findings have not been replicated.

45. Temporal Lobe The superior temporal gyrus (STG) is involved in auditory processing and, with parts of the inferior parietal cortex, is a heteromodal association area that includes Wernicke’s area, a language centre. It is involved in the production, interpretation, and self-monitoring of language. Dysfunction in the superior temporal gyrus or its network of connections is closely linked to auditory hallucinations and thought disorder. MRI studies have shown reduced volumes of the anterior, posterior, and total superior temporal gyrus, as well as subregions of the temporal plane in schizophrenia. Volume loss may progress over time, but the evidence for this is limited. Some studies report a correlation between volume loss and clinical symptoms, especially delusions, auditory hallucinations (left superior temporal gyrus volume loss), thought disorder (left posterior superior temporal gyrus),

46. NEUROTRANSMITTER HYPOTHESIS 46 Dopamine pathways

47. Mesolimbic pathway: it projects from the midbrain (ventral tegmental area) to limbic system, increased dopamine in this area is considered to be responsible for delusions and hallucinations in psychosis. It mainly involves D2 receptors. Associated with motivation, pleasure and reward. 47

48. Mesocortical pathway : it project from midbrain to areas of the limbic cortex. Prominent dopamine receptors in this area are the D1 and D4 receptors. It is believed that this pathway may be responsible for the negative and cognitive symptoms of schizophrenia, probably due to a deficit of dopamine. DLPFC: COGNITIONS AND EXECUTIVE FUNCTIONS VMPFC: EMOTIONAL REGULATION 48

49. 49

50. Nigrostriatal pathway: it projects from substantia nigra to basal ganglia, & forms part of the extrapyrimidal system. Increased dopamine in this pathway is said to cause hyperkinetic disorders like tics, chorea & deficiency of dopamine causes parkinsonism (tremors, rigidity, bradykinesia). 50

51. Tuberoinfundibular pathway: it projects from hypothalamus to anterior pituitary. Normally dopamine imhibits prolactin release, so antipsychotics that block dopamine action, cause rise in prolactin levels leading to glactorrhoea , amenorrhoea and sexual dysfunction. 51

52. Glutamate Phencyclidine (PCP), which is an antagonist of the NMDA(N-methyl-D-aspartate receptor complex ) subtype of glutamate receptors, produces a psychosis resembling schizophrenia. This suggests that in schizophrenia there should ideally be a reduction in glutamate receptors and glutamate. Excess glutamate produces neurotoxicity, so now it has been hypothesized that glutamate dysfunction is seen in different brain areas. 52

53. Cortico-brainstem Pathway Communicates with Mesolimbic pathway in VTA Hypoactive NMDA receptors Excess Glutamate Excess DA, NA 53

54. NMDA Receptor Hypofunction Negative Symptoms • Hypoactive NMDA receptors • Cortico-brainstem – Overactive • Excess Glutamate at VTA • Excess stimulation of brainstem pyramidal neurons • Inhibition of Mesocortical DA neurons 54

55. Serotonin The serotonin hypothesis for schizophrenia has attracted renewed interest since the serotoninergic properties of atypical antipsychotics were characterized. A high affinity for 5HT, receptor may explain the therapeutic advantages of atypical antipsychotics. It is postulated that serotonin stimulates the 5HT, receptors in the prefrontal cortex. This inhibits the release of dopamine, and leads to negative symptoms. Atypical antipsychotics act as serotonin antagonist and effectively help in reducing these negative symptoms. 55

56. Blocking 5HT2A Receptors Increase DA Release 56

57. Raphe 5HT1A Increase DA release, Serotonin binding at raphe nucleus inhibits serotonin release 57

58. ENVIRONMENTAL RISK FACTORS Environmental risk factors have been relatively ignored in the investigations of the aetiology of schizophrenia. Research from the last few decades suggests that genetic factors do not explain all of the variance associated with the onset of schizophrenia. Although schizophrenia is highly heritable, the contribution of genetic factors varies considerably depending on the type of genetic factor involve. Schizophrenia is the result of an interaction between multiple genetic and environmental factors. The various environmental factors implicated are-

59. Seasonality of birth Approximately 5%–8% winter birth are associated with schizophrenia, suggesting increased risk with winter seasonality. Seasonality of birth is one of the most replicated findings. Neurobiological underpinnings are unclear; implications for treatment development are uncertain. Shifting seasonality patterns make selection of control subjects difficult. Obstetric Complications A variety of obstetric complications, including preeclampsia, bleeding, Rh incompatibility, diabetes, asphyxia, uterine atony, emergency caesarean section, and other obstetric abnormalities that lead to low birth weight, congenital malformations, and a small head circumference, have been associated with schizophrenia.

60.   Infectious Agents Infectious agents are prototypical examples of discretely defined environmental factors. Prenatal and postnatal exposures to infections have been examined using ecological as well as birth cohort data. Researchers have investigated early prenatal exposure in children conceived during the influenza epidemic in 1957 and found a higher prevalence of schizophrenia among subjects who were in utero during the second trimester when the epidemic occurred than in those who were not in utero. data show that influenza exposure in the first half of pregnancy may be associated with three times the risk for schizophrenia. Similarly, exposures to rubella, Toxoplasma gondii, and herpes simplex virus (HSV) type 2 have been linked to higher risk for schizophrenia. Postnatal exposures to HSV type 1 have consistently been associated with cognitive impairments observed in schizophrenia, suggesting that some infections may add to poor outcomes even if they do not elevate the risk for schizophrenia.  

61. Prenatal Stress Prenatal stress has been examined extensively in relation to risk for schizophrenia. Maternal exposure to stressors such as serious illness, war, and famine has been associated with increased risk for schizophrenia, although causal relationships are far from clear. Maternal stress during pregnancy has been linked to changes in corticosteroids and to the consequent association with small-for-gestational age births. Cannabis Use Adolescent cannabis use has been identified as a risk factor for schizophrenia, a finding that has been replicated in multiple analyses. Early evidence came from a study conducted in 1987, which reported nearly six times the risk for schizophrenia among heavy cannabis users compared with nonusers.  

62. Malnutrition A meta-analysis showed a vitamin D deficiency in nearly two-thirds of patients with schizophrenia. Prenatal protein deprivation in animals was associated with interesting changes in the brain, including altered dendritic architecture with associated decrease in sensorimotor gating. Micronutrient deficiencies of folate and iron, as well as elevations of homocysteine, have also been related to an elevated risk for schizophrenia.  Autoimmune Disorders Autoimmune disorders have been associated with an increased risk for schizophrenia . Specifically, type 1 diabetes, celiac disease, autoimmune thyroid diseases, and systemic lupus erythematosus have ranked high in contributing to risk for schizophrenia. Interestingly, even a family history of autoimmune disorders is associated with elevated risk for schizophrenia. An exception to this is rheumatoid arthritis, which is associated with decreased risk for schizophrenia.

63. Childhood Trauma Childhood trauma of various kinds has been associated with the risk for schizophrenia. Overall, a threefold to sevenfold increase in risk for schizophrenia has been found when the trauma occurred before age 16 years. Studies have differed in their inclusion of different types of trauma, with some focusing solely on childhood sexual abuse and others including additional varieties of trauma. Urban Birth An association between urban birth and elevated risk for schizophrenia has been reported in many population cohort studies. Interestingly, a positive relationship has been seen between the degree of urbanicity and the risk for psychosis. Factors that have been proposed to underlie such elevated risk include overcrowding, increased stress, and infections; however, none of these have been conclusively proven to be causal. A recent study suggested that such associations of urbanicity and schizophrenia may be found in developed countries but not in developing countries.

64. Socioeconomic Status Socioeconomic status has long been associated with schizophrenia, although the nature of the relationship remains unresolved. The direction of a possibly causal connection is unclear: it could be due to either social causation or social drift, with the former explanation implying that low socioeconomic status is a causative factor for schizophrenia, and the latter suggesting that individuals with schizophrenia gravitate toward low socioeconomic status due to job loss and other financial hardships sustained while living in more affluent neighbourhoods. Immigration The risk of schizophrenia is shown to be higher in both first-generation and second-generation immigrants. Also immigrants moving from developing to developed countries had higher risk of the disease compared with immigrants from developed countries who moved to another developed country.

65. Advanced Paternal Age Advanced paternal age was initially observed in 1958 as a risk factor for schizophrenia in offspring, but it was not until 1979 that the separate contributions of maternal and paternal age could be teased apart. It is found that offspring of fathers ages 45–49 years had twice the risk for schizophrenia, and offspring of fathers age 50 years and older had three times the risk compared with children of fathers who were age 25 years or younger. Although precise mechanisms are unclear, accumulation of several point mutations during the replications of spermatogonial stem cells and epigenetic changes related to methylation, demethylation, and histone modifications have been proposed.

66. Conclusion Even after extensive research in the field of aetiology of schizophrenia none of the above factors can be implicated with confirmation as the cause of the disease. Further researches are still going on and the results are awaited. A better prognosis and treatment of schizophrenia would be possible when we can attribute the disease to a specific aetiological factor.

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