Schizophrenia (1)

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Schizophrenia (1)

  1. 1. Schizophrenia Ni dheesha T 1 st year msc nursing Nursing college kottayam
  2. 2. Definition <ul><li>fundamental and characteristic distortions of thinking and perception, and affects that are inappropriate or blunted. </li></ul><ul><li>Clear consciousness and intellectual capacity are usually maintained although certain cognitive deficits may evolve in the course of time. </li></ul>
  3. 3. contd <ul><li>The most important psychopathological phenomena include </li></ul><ul><ul><li>thought echo </li></ul></ul><ul><ul><li>thought insertion or withdrawal </li></ul></ul><ul><ul><li>thought broadcasting </li></ul></ul><ul><ul><li>delusional perception and delusions of control </li></ul></ul><ul><ul><li>influence or passivity </li></ul></ul><ul><ul><li>hallucinatory voices commenting or discussing the patient in the third person </li></ul></ul><ul><ul><li>thought disorders and negative symptoms. </li></ul></ul>
  4. 4. Schizophrenia <ul><li>Schizophrenia occurs with regular frequency nearly everywhere in the world in 1 % of population and begins mainly in young age (mostly around 16 to 25 years). </li></ul><ul><li>Schizophrenia is defined by </li></ul><ul><ul><li>a group of characteristic positive and negative symptoms </li></ul></ul><ul><ul><li>deterioration in social, occupational, or interpersonal relationships </li></ul></ul><ul><ul><li>continuous signs of the disturbance for at least 6 months </li></ul></ul>
  5. 5. History <ul><li>Emil Kraepelin : This illness develops relatively early in life, and its course is likely deteriorating and chronic; deterioration reminded dementia („Dementia praecox“), but was not followed by any organic changes of the brain, detectable at that time. </li></ul><ul><li>Eugen Bleuler : He renamed Kraepelin’s dementia praecox as schizophrenia (1911); he recognized the cognitive impairment in this illness, which he named as a „splitting “ of mind. </li></ul><ul><li>Kurt Schneider : He emphasized the role of psychotic symptoms, as hallucinations, delusions and gave them the privilege of „the first rank symptoms” even in the concept of the diagnosis of schizophrenia. </li></ul>
  6. 6. 4 A (Bleuler) <ul><li>Bleuler maintained, that for the diagnosis of schizophrenia are most important the following four fundamental symptoms: </li></ul><ul><ul><li>affective blunting </li></ul></ul><ul><ul><li>disturbance of association (fragmented thinking) </li></ul></ul><ul><ul><li>autism </li></ul></ul><ul><ul><li>ambivalence (fragmented emotional response) </li></ul></ul><ul><li>These groups of symptoms, are called „four A’ s” and Bleuler thought, that they are „primary” for this diagnosis. </li></ul><ul><li>The other known symptoms, hallucinations, delusions, which are appearing in schizophrenia very often also, he used to call as a “secondary symptoms”, because they could be seen in any other psychotic disease, which are caused by quite different factors — from intoxication to infection or other disease entities. </li></ul>
  7. 7. Course of Illness <ul><li>Course of schizophrenia: </li></ul><ul><ul><li>continuous without temporary improvement </li></ul></ul><ul><ul><li>episodic with progressive or stable deficit </li></ul></ul><ul><ul><li>episodic with complete or incomplete remission </li></ul></ul><ul><li>Typical stages of schizophrenia: </li></ul><ul><ul><li>prodromal phase </li></ul></ul><ul><ul><li>active phase </li></ul></ul><ul><ul><li>residual phase </li></ul></ul>
  8. 8. Clinical Picture <ul><li>Diagnostic manuals: </li></ul><ul><ul><li>lCD-10 („International Classification of Disease“, WHO) </li></ul></ul><ul><ul><li>DSM-IV („Diagnostic and Statistical Manual“, APA) </li></ul></ul><ul><li>Clinical picture of schizophrenia is according to lCD-10, defined from the point of view of the presence and expression of primary and/or secondary symptoms (at present covered by the terms negative and positive symptoms) : </li></ul><ul><ul><li>t he negative symptoms are represented by cognitive disorders, having its origin probably in the disorders of associations of thoughts, combined with emotional blunting and small or missing production of hallucinations and delusions </li></ul></ul><ul><ul><li>t he positive symptom are characterized by the presence of hallucinations and delusions </li></ul></ul><ul><ul><li>t he division is not quite strict and lesser or greater mixture of symptoms from these two groups are possible </li></ul></ul>
  9. 9. Positive and Negative Symptoms Negative Positive Alogia Hallucinations Affective flattening Delusions Avolition-apathy Bizarre behaviour Anhedonia-asociality Positive formal thought disorder Attentional impairment
  10. 10. Positive symtoms <ul><li>Those that appear to reflect an excess or distortion of normal functions . Positive symptoms are those that have a positive reaction from some treatment. In other words, positive symptoms respond to treatment. </li></ul><ul><li>Delusions . Those where the patient thinks he is being followed or watched are common; also the belief that people on TV, radio are directing special messages to him/her. </li></ul>
  11. 11. <ul><li>Hallucinations . Distortions or exaggerations of perception in any of the senses. </li></ul><ul><li>Often they hear voices within their own thoughts followed by visual hallucinations. </li></ul>
  12. 12. <ul><li>Disorganized thinking/speech . </li></ul><ul><li>AKA loose associations; speech is tangential, loosely associated or incoherent enough to impair communication. </li></ul>
  13. 13. Grossly disorganized behavior . Difficulty in goal directed behavior (ADLs), unpredictable agitation or silliness, social disinhibition, or bizarre behavior. There is a purposelessness to behavior.
  14. 14. <ul><li>Catatonic behavior . </li></ul><ul><li>Marked decrease in reaction to immediate environment, sometimes just unaware of surroundings, rigid or bizarre postures, aimless motor activity. </li></ul>
  15. 15. <ul><li>Inappropriate response to stimuli </li></ul><ul><li>Unusual motor behavior (pacing, rocking) </li></ul><ul><li>Depersonalization </li></ul><ul><li>Derealization </li></ul><ul><li>Somatic preoccupations </li></ul>
  16. 16. Negative Symptoms <ul><li>Those that appear to reflect a diminution or loss of normal functions . </li></ul><ul><li>May be difficult to evaluate because they are not as grossly abnormal as positive symptoms. </li></ul><ul><li>Currently there is no treatment that has a consistent impact on negative symptoms </li></ul>
  17. 17. <ul><li>Affective flattening . </li></ul><ul><li>Reduction in the range and intensity of emotional expression, including facial expression, voice tone, eye contact and body language. </li></ul>
  18. 18. <ul><li>Alogia (poverty of speech) </li></ul><ul><li>Lessening of speech fluency and productivity, thought to reflect slowing or blocked thoughts; often manifested as short, empty replies to questions. </li></ul>
  19. 19. <ul><li>Avolition </li></ul><ul><li>The reduction, difficulty or inability to initiate and persist in goal-directed behavior. Often mistaken for apparent disinterest. </li></ul>
  20. 20. <ul><li>No longer interested in going out with friends </li></ul><ul><li>No longer interested in activities that the person used to show enthusiasm </li></ul><ul><li>No longer interested in anything </li></ul><ul><li>Sitting in the house for hours or days doing nothing </li></ul>
  21. 21. Disorganized Symptoms <ul><li>This one is somewhat new and may not be considered valid. </li></ul><ul><li>It is thought disorder, confusion, disorientation and memory problems. </li></ul>
  22. 22. Cognitive Symptoms <ul><li>Difficulties in concentration and memory: </li></ul><ul><ul><li>Disorganized thinking </li></ul></ul><ul><ul><li>Slow thinking </li></ul></ul><ul><ul><li>Difficulty understanding </li></ul></ul><ul><ul><li>Poor concentration </li></ul></ul><ul><ul><li>Poor memory </li></ul></ul><ul><ul><li>Difficulty expressing thoughts </li></ul></ul><ul><ul><li>Difficulty integrating thoughts, feelings, behaviors </li></ul></ul>
  23. 23. The Criteria of Diagnosis <ul><li>For the diagnosis of schizophrenia </li></ul><ul><li>presence of one very clear symptom - from point a) to d) the hearing of own thoughts, the feelings of thought withdrawal, thought insertion, or thought broadcasting </li></ul><ul><li>the delusions of control, outside manipulation and influence, or the feelings of passivity, which are connected with the movements of the body or extremities, specific thoughts, acting or feelings, delusional perception </li></ul>
  24. 24. COND C] hallucinated voices, commenting permanently the behavior of the patient or they talk about him between themselves, or the other types of hallucinatory voices, coming from different parts of body. D] permanent delusions of different kind, which are inappropriate and unacceptable in given culture
  25. 25. F20-F29 Schizophrenia, Schizotypal and Delusional Disorders <ul><li>F20 Schizophrenia </li></ul><ul><li>F20.0 Paranoid schizophrenia </li></ul><ul><li>F20.1 Hebephrenic schizophrenia </li></ul><ul><li>F20.2 Catatonic schizophrenia </li></ul><ul><li>F20.3 Undifferentiated schizophrenia </li></ul><ul><li>F20.4 Post-schizophrenic depression </li></ul><ul><li>F20.5 Residual schizophrenia </li></ul><ul><li>F20.6 Simple schizophrenia </li></ul><ul><li>F20.8 Other schizophrenia </li></ul><ul><li>F20.9 Schizophrenia, unspecified </li></ul>
  26. 26. The Criteria of Diagnosis <ul><li>the lasting hallucination of every form </li></ul><ul><li>blocks or intrusion of thoughts into the flow of thinking and resulting incoherence and irrelevance of speach, or neologisms </li></ul><ul><li>catatonic behavior </li></ul><ul><li>„ the negative symptoms”, for instance the expressed apathy, poor speech, blunting and inappropriatness of emotional reactions </li></ul><ul><li>expressed and conspicuous qualitative changes in patient’s behavior, the loss of interests, hobbies, aimlesness, inactivity, the loss of relations to others and social withdrawal </li></ul>2. the presence of the symptoms from at least two groups below for one month or more:
  27. 27. <ul><li>Diagnosis of acute schizophorm disorder (F23.2) – if the conditions for diagnosis of schizophrenia are fulfilled, but lasting less than one month </li></ul><ul><li>Diagnosis of schizoaffective disorder (F25) - if the schizophrenic and affective symptoms are developing together at the same time </li></ul>
  28. 28. F20-F29 Schizophrenia, Schizotypal and Delusional Disorders <ul><li>F21 Schizotypal disorder </li></ul><ul><li>F22 Persistent delusional disorders </li></ul><ul><li>F22.0 Delusional disorder </li></ul><ul><li>F22.8 Other persistent delusional disorders </li></ul><ul><li>F22.9 Persistent delusional disorder, unspecified </li></ul><ul><li>F23 Acute and transient psychotic disorders </li></ul><ul><li>F23.1 Acute polymorphic psychotic disorder with symptoms of schizophrenia </li></ul><ul><li>F23.2 Acute schizophrenia-like psychotic disorder </li></ul><ul><li>F23.3 Other acute predominantly delusional psychotic disorders </li></ul><ul><li>F23.8 Other acute and transient psychotic disorders </li></ul><ul><li>F23.9 Acute and transient psychotic disorder, unspecified </li></ul>
  29. 29. F20-F29 Schizophrenia, Schizotypal and Delusional Disorders <ul><li>F24 Induced delusional disorder </li></ul><ul><li>F25 Schizoaffective disorders </li></ul><ul><li>F25.0 Schizoaffective disorder, manic type </li></ul><ul><li>F25.1 Schizoaffective disorder, depressive type </li></ul><ul><li>F25.2 Schizoaffective disorder, mixed type </li></ul><ul><li>F25.8 Other schizoaffective disorders </li></ul><ul><li>F25.9 Schizoaffective disorder, unspecified </li></ul><ul><li>F28 Other nonorganic psychotic disorders </li></ul><ul><li>F29 Unspecified nonorganic psychosis </li></ul>
  30. 30. F20.0 Paranoid Schizophrenia <ul><li>Paranoid schizophrenia is characterized mainly by delusions of persecution, feelings of passive or active control, feelings of intrusion, and often by megalomanic tendencies also. The delusions are not usually systemized too much, without tight logical connections and are often combined with hallucinations of different senses, mostly with hearing voices. </li></ul><ul><li>Disturbances of affect, volition and speech, and catatonic symptoms, are either absent or relatively inconspicuous. </li></ul>
  31. 31. F20.1 Hebephrenic Schizophrenia <ul><li>disorganized thinking with blunted and inappropriate emotions. </li></ul><ul><li>adolescent age, the behavior is often bizarre. </li></ul><ul><li>There could appear mannerisms, grimacing, inappropriate laugh and joking, pseudophilosophical brooding and sudden impulsive reactions without external stimulation. There is a tendency to social isolation. </li></ul><ul><li>Usually the prognosis is poor because of the rapid development of &quot;negative&quot; symptoms, particularly flattening of affect and loss of volition. Hebephrenia should normally be diagnosed only in adolescents or young adults . </li></ul><ul><li>Denoted also as disorganized schizophrenia </li></ul>
  32. 32. F20.2 Catatonic Schizophrenia <ul><li>Catatonic schizophrenia is characterized mainly by motoric activity, which might be strongly increased (hypekinesis) or decreased (stupor), or automatic obedience and negativism. </li></ul>We recognize two forms :
  33. 33. COND <ul><ul><li>productive form — which shows catatonic excitement, extreme and often aggressive activity. Treatment by neuroleptics or by electroconvulsive therapy. </li></ul></ul><ul><ul><li>stuporose form — characterized by general inhibition of patient’s behavior or at least by retardation and slowness, followed often by mutism, negativism, fexibilitas cerea or by stupor. The consciousness is not absent. </li></ul></ul>
  34. 34. F20.3 Undifferentiated Schizophrenia <ul><li>Psychotic conditions meeting the general diagnostic criteria for schizophrenia but not conforming to any of the subtypes in F20.0-F20.2, or exhibiting the features of more than one of them without a clear predominance of a particular set of diagnostic characteristics. </li></ul><ul><li>This subgroup represents also the former diagnosis of atypical schizophrenia. </li></ul>
  35. 35. F20.4 Postschizophrenic Depression <ul><li>A depressive episode, which may be prolonged, arising in the aftermath of a schizophrenic illness. Some schizophrenic symptoms, either „ positive “ or „ negative “ , must still be present but they no longer dominate the clinical picture. </li></ul><ul><li>These depressive states are associated with an increased risk of suicide. </li></ul>
  36. 36. F20.5 Residual Schizophrenia <ul><li>A chronic stage in the development of schizophrenia with clear succession from the initial stage with one or more episodes characterized by general criteria of schizophrenia to the late stage with long-lasting negative symptoms and deterioration (not necessarily irreversible). </li></ul>
  37. 37. F20.6 Simple Schizophrenia <ul><li>Simple schizophrenia is characterized by early and slowly developing initial stage with growing social isolation, withdrawal, small activity, passivity, avolition and dependence on the others. </li></ul><ul><li>The patients are indifferent, without any initiative and volition. There is not expressed the presence of hallucinations and delusions . </li></ul>
  38. 38. F21 Schizotypal disorder <ul><li>According to lCD-10 this disorder is characterized by eccentric behavior and by deviations of thinking and affectivity, which are similar to that occurring in schizophrenia, but without psychotic features and expressed symptoms of schizophrenia of any type . </li></ul>
  39. 39. F22 Persistent Delusional Disorders <ul><li>Includes a variety of disorders in which long-standing delusions constitute the only, or the most conspicuous, clinical characteristic and which cannot be classified as organic, schizophrenic or affective. </li></ul><ul><li>Their origin is probably heterogeneous, but it seems, that there is some relation to schizophrenia . </li></ul>
  40. 40. F22.0 Delusional Disorder <ul><li>A disorder characterized by the development of one delusion or of the group of similar related delusions, which are persisting unusually long, very often for the whole life. </li></ul><ul><li>Other psychopathological symptoms — hallucinations, intrusion of thoughts etc. are not present and are excluding this diagnosis. </li></ul><ul><li>It begins usually in the middle age. </li></ul>
  41. 41. F23 Acute and Transient Psychotic Disorders <ul><li>The criteria should be the following features: </li></ul><ul><ul><li>acute beginning (to two weeks) </li></ul></ul><ul><ul><li>presence of typical symptoms (quickly changing “polymorphic symptoms”) </li></ul></ul><ul><ul><li>presence of typical schizophrenic symptoms. </li></ul></ul><ul><li>Complete recovery usually occurs within a few months, often within a few weeks or even days. </li></ul><ul><li>The disorder may or may not be associated with acute stress, defined as usually stressful events preceding the onset by one to two weeks. </li></ul>
  42. 42. F24 Induced Delusional Disorder <ul><li>A delusional disorder shared by two or more people with close emotional links. Only one of the people suffers from a genuine psychotic disorder; the delusions are induced in the other(s) and usually disappear when the people are separated. </li></ul><ul><li>The psychotic disorder of the dominant member of this dyad is mainly, but not necessarily, of schizophrenic type. The original delusions of dominant member and his partner are usually chronic, either persecutory or megalomanic. </li></ul>
  43. 43. F25 Schizoaffective Disorders <ul><li>Episodic disorders in which both affective and schizophrenic symptoms are prominent ( during the same episode of the illness or at least during few days ) but which do not justify a diagnosis of either schizophrenia or depressive or manic episodes. </li></ul><ul><li>Patients suffering from periodic schizoaffective disorders, especially with manic symptoms, have usually good prognosis with full remissions without any remaining defects. </li></ul><ul><li>They are divided in different subgroups: </li></ul><ul><ul><li>F25.0 Schizoaffective disorder, manic type </li></ul></ul><ul><ul><li>F25.1 Schizoaffective disorder, depressive type </li></ul></ul><ul><ul><li>F25.2 Schizoaffective disorder, mixed type </li></ul></ul><ul><ul><li>F25.8 Other schizoaffective disorders </li></ul></ul><ul><ul><li>F25.9 Schizoaffective disorder, unspecified </li></ul></ul>
  44. 44. Etiology of Schizophrenia <ul><li>The etiology and pathogenesis of schizophrenia is not known </li></ul><ul><li>It is accepted, that schizophrenia is „the group of schizophrenias“ which origin is multifactorial: </li></ul><ul><ul><li>internal factors – genetic, inborn, biochemical </li></ul></ul><ul><ul><li>external factors – trauma, infection of CNS, stress </li></ul></ul>
  45. 45. Genetics of Schizophrenia <ul><li>Many psychiatric disorders are multifactorial (caused by the interaction of external and genetic factors) and from the genetic point of view very often polygenically determined. </li></ul>
  46. 46. Genes x Environment Behavior Emotion Cognition Perception Development
  47. 47. Schizophrenia susceptibility genes: Current candidates Whole genome linkage 1q,2p,5q,6p,6q,8p,10p,11q,13q,15q,22q Finer mapping SNP association dysbindin (6p) ( seven )* neuregulin (8p) ( six)* G72 (13q) ( three )* MRDS1 (6p) ( four )* Functional candidates COMT (22q) ( eight )* GRM3 (7q) ( four )* GAD 1 (2q) ( four )* CNRNA7 (15q) ( two )* PPP3CC (8p) ( two )* Akt1 (two) Chromosomal translocation DISC1 (1q) ( three )* PRODH (22q) (two ) Expression profiling RGS4 (1q) ( four )* * Number of positive samples worldwide
  48. 48. Etiology of Schizophrenia - Dopamine Hypothesis <ul><li>The most influential and plausible are the hypotheses, based on the supposed disorder of neurotransmission in the brain, derived mainly from </li></ul><ul><ul><li>the effects of antipsychotic drugs that have in common the ability to inhibit the dopaminergic system by blocking action of dopamine in the brain </li></ul></ul><ul><ul><li>dopamine-releasing drugs (amphetamine, mescaline, diethyl amide of lysergic acid - LSD) that can induce state closely resembling paranoid schizophrenia </li></ul></ul><ul><li>Classical dopamine hypothesis of schizophrenia: Psychotic symptoms are related to dopaminergic hyperactivity in the brain. Hyperactivity of dopaminergic systems during schizophrenia is result of increased sensitivity and density of dopamine D2 receptors in the different parts of the brain . </li></ul>
  49. 49. Etiology of Schizophrenia - Contemporary Models <ul><li>Dopamine hypothesis revisited: various neurotransmitter systems probably takes place in the etiology of schizophrenia (norepinephric, serotonergic, glutamatergic, some peptidergic systems); based on effects of atypical antipsychotics especially. </li></ul><ul><li>Contemporary models of schizophrenia conceptualize it as a neurocognitive disorder, with the various signs and symptoms reflecting the downstream effects of a more fundamental cognitive deficit: </li></ul><ul><ul><li>the symptoms of schizophrenia arise from “cognitive dysmetria” </li></ul></ul><ul><ul><li>concept of schizophrenia as a neurodevelopmental disorder . </li></ul></ul>
  50. 50. Etiology of Schizophrenia - Neurodevelopmental Model <ul><li>Neurodevelopmental model supposes in schizophrenia the presence of “silent lesion” in the brain, mostly in the parts, important for the development of integration (frontal, parietal and temporal), which is caused by different factors (genetic, inborn, infection, trauma...) during very early development of the brain in prenatal or early postnatal period of life. </li></ul><ul><li>It does not interfere too much with the basic brain functioning in early years, but expresses itself in the time, when the subject is stressed by demands of growing needs for integration, during formative years in adolescence and young adulthood. </li></ul>
  51. 51. Structural changes in brain <ul><li>Hippocampus, amygdala, parahippocamp. </li></ul><ul><ul><li>Smaller in affected twin (static trait) </li></ul></ul><ul><ul><li>Disordered hippocampal pyramidal cells </li></ul></ul><ul><ul><li>Also in entorhinal, cingulate, parahippocampal cortex </li></ul></ul>
  52. 52. Structural changes in brain <ul><li>Shrinkage of cerebellar vermis </li></ul><ul><li>Thicker corpus callosum </li></ul><ul><li>Frontal lobes </li></ul><ul><ul><li>Abnormal neuronal migration in one study </li></ul></ul><ul><ul><li>Dendrites have fewer spines </li></ul></ul><ul><ul><li>But no major structural abnormalities </li></ul></ul><ul><ul><li>Measures of frontal function impaired </li></ul></ul>
  53. 56. Mental disorders are brain disorders: Loss of gray matter in childhood schizophrenia
  54. 57. Functional changes in brain <ul><li>Hypofrontality hypothesis </li></ul><ul><ul><li>Discordant twins: low frontal blood flow only in affected twin </li></ul></ul><ul><ul><li>Wisconsin card sorting task </li></ul></ul><ul><ul><ul><li>Schizophrenics can’t shift attn. to other criterion </li></ul></ul></ul><ul><ul><ul><li>Functional imaging: frontal lobe activity lower at rest, esp. in right hemisphere, does not increase during task. </li></ul></ul></ul><ul><ul><ul><li>Drug treatment increased activation of frontal lobes </li></ul></ul></ul>
  55. 59. Treatment of Schizophrenia <ul><li>The acute psychotic schizophrenic patients will respond usually to antipsychotic medication. </li></ul><ul><li>According to current consensus we use in the first line therapy the newer atypical antipsychotics, because their use is not complicated by appearance of extrapyramidal side-effects, or these are much lower than with classical antipsychotics. </li></ul><ul><li>The newest medication is Invega </li></ul><ul><li>In general it may take up to 6 months for medications to show consistent effects </li></ul>
  56. 60. Atypical neuroleptics <ul><li>Clozapine blocks 5-HT2A receptors > D2 </li></ul><ul><li>As effective as typical neuroleptics on (+) symptoms, more effective on (-) symptoms </li></ul><ul><li>Fewer motor side effects (tardive dyskinesia) </li></ul><ul><li>Actually increase DA release in frontal cortex </li></ul><ul><ul><li>L-DOPA can even be beneficial </li></ul></ul>
  57. 61. <ul><li>conventional antipsychotics </li></ul><ul><li>(classical neuroleptics) </li></ul><ul><li>chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine </li></ul><ul><li>droperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazine </li></ul><ul><li>atypical antipsychotics </li></ul><ul><li>amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride </li></ul>
  58. 62. Psychotherapy - an adjunct to meds and is very useful to keep the patient on the meds. Group therapy Family therapy Community support groups Treatments
  59. 63. <ul><li>Early detection and treatment has the best results/response to treatment. </li></ul><ul><li>Per patients, once you have schizophrenia you have it for life. The best you can hope for is control. </li></ul>
  60. 64. <ul><li>THANK YOU </li></ul>

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