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Schizophrenia is a severe, persistent, debilitating, and poorly understood psychiatric disorder that probably comprises several separate illnesses. The hallmark symptoms of schizophrenia are psychotic ones, such as auditory hallucinations (voices) and delusions (fixed false beliefs). Impaired cognition or a disturbance in information processing is a less vivid symptom that is highly disruptive. People with schizophrenia have lower rates of employment, marriage, and independent living than other people do. Schizophrenia is a clinical diagnosis. It must be differentiated from other psychiatric and medical illnesses, as well as disorders such as heavy metal toxicity, adverse effects of drugs, and vitamin deficiencies. (See DDx and Workup.) Treatment of schizophrenia requires an integration of medical, psychological, and psychosocial inputs. The bulk of care occurs in an outpatient setting and probably is best carried out by a multidisciplinary team. Psychosocial rehabilitation is an essential part of treatment. The use of antipsychotic m edications, also known as neuroleptic medications or major tranquilizers, is the mainstay of medical treatment for schizophrenia. These medications diminish the positive symptoms of schizophrenia and prevent relapses. Unfortunately, they are also associated with a number of adverse effects. (See Treatment and Medication.)

Pathophysiology
Both anatomic and neurotransmitter system abnormalities have been implicated in the pathophysiology of schizophrenia.

Anatomic abnormalities
Neuroimaging studies in patients with schizophrenia show abnormalities such as enlargement of the ventricles, decreased brain volume in medial temporal areas, and changes in the hippocampus. [1, 2, 3] These findings are of interest more for research purposes than for clinical application. Interest has also focused on the various connections within the brain rather than on localization in a single part of the brain. Magnetic resonance imaging (MRI) studies show anatomic abnormalities in a network of neocortical and limbic regions and interconnecting white matter tracts. [4] A meta-analysis of studies using diffusion tensor imaging (DTI) to examine white matter found that 2 networks of whitematter tracts are reduced in schizophrenia.[5] In the Edinburgh High-Risk Study, brain imaging showed reductions in whole-brain volume and in left and right prefrontal and temporal lobe volumes in 17 of 146 people who were at high genetic risk for schizophrenia. The changes in prefrontal lobes were associated with increasing severity of psychotic symptoms.[6] In a meta-analysis of 27 longitudinal MRI studies comparing schizophrenic patients with control subjects, Olabi et al found that schizophrenia was associated with structural brain abnormalities that progressed over time. The abnormalities identified included loss of whole-brain volume in both gray and white matter and increases in lateral ventricular volume.[7]

Neurotransmitter system abnormalities

Abnormalities of the dopaminergic system are thought to exist in schizophrenia; however, there is little direct evidence to support this belief. The first clearly effective antipsychotic drugs, chlorpromazine and

reserpine, were structurally different from each other, but they shared antidopaminergic properties. Drugs that diminish the firing rates of mesolimbic dopamine D2 neurons are antipsychotic, and drugs that stimulate these neurons (eg, amphetamines) exacerbate psychotic symptoms. Hypodopaminergic activity in the mesocortical system, leading to negative symptoms, and hyperdopaminergic activity in the mesolimbic system, leading to positive symptoms, may coexist. (Negative and positive symptoms are defined below; see Presentation.) Moreover, the newer antipsychotic drugs block both dopamine D2 and 5-hydroxytryptamine (5-HT) receptors. Clozapine, perhaps the most effective antipsychotic agent, is a particularly weak dopamine D2 antagonist. Thus, other neurotransmitter systems, such as norepinephrine, serotonin, and gammaaminobutyric acid (GABA), are undoubtedly involved. Some research focuses on the N -methyl-Daspartate (NMDA) subclass of glutamate receptors because NMDA antagonists, such as phencyclidine and ketamine, can lead to psychotic symptoms in healthy subjects. [8]

Inflammation and immune function

Immune system function is disturbed in schizophrenia.[9] Overactivation of the immune system (eg, from prenatal infection or postnatal stress) may result in overexpression of inflammatory cytokines and subsequent alteration of brain structure and function. For example, schizophrenic patients have elevated levels of proinflammatory cytokines that activate the kynurenine pathway, by which tryptophan is metabolized into kynurenic and quinolinic acids; these acids regulate NMDA receptor activity and may also be involved in dopamine regulation. Insulin resistance and metabolic disturbances, which are common in the schizophrenic population, have also been linked to inflammation. Thus, inflammation might be related to both the psychopathology of schizophrenia and to metabolic disturbances seen in patients with schizophrenia. [10]

Etiology
The causes of schizophrenia are not known. Most likely, there are at least 2 sets of risk factors, genetic and perinatal. Undefined socioenvironmental factors may increase the risk of schizophrenia in international migrants or urban populations of ethnic minorities.[11, 12, 13]

Genetics
The risk of schizophrenia is elevated in biologic relatives of persons with schizophrenia but not in adopted relatives.[14] 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. Genome-wide association studies have identified many candidate genes, but the gene variants that have been implicated so far account for only a small fraction of schizophrenia cases, and these findings have not always been replicated in different studies. The genes that have been found mostly change a genes expression or a proteins function in a small way. Interactions with the rest of the genome and with the environment will doubtless prove to be important. Loci of particular interest include the following: The catechol-O-methyltransferase (COMT) gene The RELN gene The gene for nitric oxide synthase 1 adaptor, NOS1AP The COMT gene codes for the postsynaptic intracellular enzyme, COMT, which is involved in the methylation and degradation of the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. The several allelic variants of COMTaffect its activity. The valine-valine variant degrades dopamine faster than does the valine-methionine variant; subjects with 2 copies of the methionine allele

were less likely to develop psychotic symptoms with cannabis use than were other cannabis-using subjects without that variant.[15] The RELN gene codes for the protein reelin, which plays a role in brain development and GABAergic activity. In an international study using a genome-wide association scan, a common variant in this gene increased the risk of schizophrenia, but only in women.[16] The NOS1AP gene codes for the enzyme nitric oxide synthetase, which is found in high concentration in inhibitory neurons in the brain. Nitric oxide acts as an intracellular messenger. Using a newly developed statistical technique, the posterior probability of linkage disequilibrium, researchers have identified a single-nucleotide polymorphism associated with higher levels of expression of this gene in postmortem brain samples from individuals with schizophrenia.[17] 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. [18, 19] At most, however, these findings probably account for only a small part of the heritability of schizophrenia. In addition, the effects of some of these copy number variants are not restricted to schizophrenia. Other copy number variant disorders include autism, intellectual disability, attention-deficit hyperactivity disorder, and epilepsy.[20] 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 autism-related disorders. Subjects also had congenital anomalies.[21] Many studies have also looked for abnormalities in neurodevelopmental genes, in accordance with the neurodevelopmental hypothesis of schizophrenia. Disruptions in the DISC1, NRG1, DTNBP1, KCNH2, AKT1, and RGS4 genes have been associated with schizophrenia, albeit with significant variability between studies.[22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34] 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. Some people with schizophrenia have no family history of the disorder. These cases may be the result of new mutations. De novo mutations in the exome, which is the part of the chromosome that codes for proteins, seem to be more common in patients with schizophrenia than would otherwise be expected. [35, 36] As can be seen, working out the details of these genetic factors is difficult. Nonetheless, a meta-analysis of twin studies estimated that genetic factors account for about four fifths of liability to schizophrenia. [37]

Perinatal factors
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. [38] 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. [39] Obstetric complications may be associated with a higher incidence of schizophrenia. Children born in the winter months may be at greater risk for developing schizophrenia.[40] A study in Finnish women by Clarke et al supports an interaction between genetic and environmental influences on causation of schizophrenia. A review of the 9,596 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.[41] Clarke et al 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 both risk factors.[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.[11, 12, 13] People with schizophrenia have a 5% lifetime risk of suicide.[44] Mortality is also increased because of medical illnesses, which result from a combination of unhealthy lifestyles, side effects of medication, decreased health care, and perhaps even some fundamental vulnerability to medical comorbidities. To date, 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 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. The onset of schizophrenia usually occurs in adolescence, and symptoms remit somewhat in older patients. The first 5-10 years of the illness can be stormy; they are usually followed by decades of relative stability (though a return to baseline is unusual). Positive symptoms are more likely to remit than cognitive and negative symptoms are (see Presentation for a description of symptoms).

Prognosis
The prognosis for patients with schizophrenia is guarded. Full recovery is unusual. Early onset of illness, family history of schizophrenia, structural brain abnormalities, and prominent cognitive symptoms are associated with a poor prognosis. The prognosis is better for people living in low-income and middleincome countries.[45] Symptoms usually follow a waxing and waning course. A patients pattern of symptoms may change over years. Positive symptoms respond fairly well to antipsychotic medication, but the other symptoms are quite persistent. Because of vocational difficulties, many patients with schizophrenia also have to cope with the burdens of poverty. These include limited access to medical care, which may lead to poor control of the disease; homelessness; and incarceration, typically for minor offenses. People with schizophrenia have a 5% lifetime risk of suicide.[44] Other factors that contribute to an increased mortality in people with schizophrenia include lifestyle issues such as cigarette smoking, poor nutrition, and lack of exercise, and perhaps poorer medical care and complications of medications. A study from Britain shows that this mortality gap is increasing.[46] Schizophrenia is not well understood, and the available treatment is unacceptably poor. Research is ongoing into the pathophysiology and treatment of this illness. It is hoped that such efforts will eventually

allow earlier intervention with better pharmacologic agents, the goal being to achieve complete resolution of all symptoms of the illness and continuation or resumption of a full and meaningful life.

Patient Education
The nature of schizophrenia makes it a potentially difficult illness for patients to understand. Nevertheless, teaching the patient to understand the importance of medication compliance and abstinence from alcohol and other drugs of abuse is important. Working with the patient so that patient and family can learn to recognize early signs of a decompensation (eg, insomnia or increased irritability) is helpful. A review of 44 studies showed that education of patients about the nature of their illness and treatment, when added to standard care, led to reductions in rehospitalization and symptoms.[47] Education may help with adherence to medication and may help the patient cope with the illness better in other ways. Family members should be referred to the National Alliance on Mental Illness (NAMI) (or another appropriate support group, if one is available). These groups can provide many educational opportunities. Social skills training is helpful, but the effects are not long-lived. Such training, like other sorts of problemsolving therapy, may have to be continued on an indefinite basis, much as pharmacologic therapy is. People with schizophrenia have also championed self-help recovery-based approaches to care, with an emphasis on developing the personal strengths and resilience to combat this illness. Physical illnesses in schizophrenia are common. The importance of a healthy lifestyle and regular health care should be stressed. Counseling with respect to sexuality, pregnancy, and sexually transmitted diseases is important for patients with schizophrenia. Side effects of antipsychotic medications may affect physical appearance; this, in turn, can affect self-esteem and relationships with others.[48] The following resources may also be helpful: Mayo Clinic -Schizophrenia National Institute of Mental Health -Schizophrenia Medline Plus -Schizophrenia For patient education, see the Schizophrenia Health Center, as well asSchizophrenia.

Sumber: http://emedicine.medscape.com/article/288259-overview http://www.nimh.nih.gov/health/publications/schizophrenia/schizophrenia-booket-2009.pdf