Schizophrenia

1. Schizophrenia Dr Alin Mascas ST4 GAP

2. Definition • “Schizo” (split) and “phrene” (mind) to describe a fragmented pattern of thinking of people suffering from this disorder. • Schizophrenia is a severe form of mental illness affecting about 7 per thousand of the adult population, mostly in the age group 15-35 years.(WHO) • Schizophrenia is one of the terms used to describe a major psychiatric disorder(or cluster of disorders) that alters an individual’s perception, thoughts, affect and behaviour (NICE).

3. Historical perspective • Written documents describing symptoms of schizophrenia were traced back to Ancient Egypt and around 2000 BC. • Benedict Morel – “demence precoce” • Emil Kraepelin (German)-described schizophrenia (1887) as “dementia precox” and differentiated it from manic depression • Eugen Bleuler (Swiss)-coined the term “Schizophrenia”(1911)+ 4 “A”S (loosening of associations, apathy, autism(social withdrawal), blunt/incongruous affect) • Kahlbaum described catatonia (1868)

4. Demographics (WHO) • Schizophrenia affects about 24 million people worldwide. • More than 50% of persons with schizophrenia are not receiving appropriate care. • 90% of people with untreated schizophrenia are in developing countries.

5. Demographics • Incidence variable up to 5X depending on site (between 7-14:100 000) • Incidence 3-5 X higher in migrant population. AESOP study concluded that all psychoses are more common in the black and minority ethnic group compared to white population. • Incidence 2 X higher in urban vs rural born population. Marcelis et al. (1998) (Dutch National Psychiatric Register study) found that the effect of urbanicity on all psychoses was greater for men than for women. • Male: female difference in incidence of schizophrenia is estimated to be around 1.4:1. • Prevalence: around 1%(variations depending on the study) • Catatonia 10% (developing countries) vs 1% (developed countries) • Hebephrenia 13 % (developing countries) vs 4% (developing countries)

6. Demographics • No evidence to support an overall change in the incidence of psychotic disorder over time, though diagnostic shifts (away from schizophrenia) were reported. • Incidence of psychotic disorders varied markedly by age, sex, place and migration status/ethnicity.  • Raised rates of psychotic disorders across several ethnic minority groups. Effects were strongest, and most consistent, amongst migrants and their descendants of black Caribbean and black African origin. Although the evidence in England for raised rates amongst ethnic minority groups descendant from the Indian subcontinent has been interpreted as equivocal, our review suggested some elevation in rates for this group a phenomenon potentially restricted to women  • There was emerging evidence of raised rates amongst people of mixed ethnicity, a possible marker of ‘third-generation’ descendants, and some suggestion of a smaller, though significant elevation in rates amongst non-British white migrant groups.  Incidence of Schizophrenia and Other Psychoses in England, 1950–2009: A Systematic Review and Meta-Analyses James B. Kirkbride mail,Antonia Errazuriz, Tim J. Croudace, Craig Morgan,Daniel Jackson,Jane Boydell, Robin M. Murray,Peter B. Jones

7. Incidence of schizophrenia by age and gender in England, 1950-2009, pooled and per relevant citation Incidence of Schizophrenia and Other Psychoses in England, 1950–2009: A Systematic Review and Meta-Analyses James B. Kirkbride mail,Antonia Errazuriz, Tim J. Croudace, Craig Morgan,Daniel Jackson,Jane Boydell, Robin M. Murray,Peter B. Jones

8. Aetiology • Genes (Neuregulin and Dysbindin) • Environment(obstetric complications, maternal influenza, winter birth, early cannabis use, paternal age) • Social(migration, urban birth/living, recent life events) • Structural (smaller brain size, reduced synaptic markers) • Functional imaging (hypofrontality) • Neurophysiological (abnormal eye tracking and sensory evoked potentials) • Neurochemical (Dopamine-”hyperdopaminaergia” and Glutamate-NMDA receptor dysfunction) Shorter Oxford Textbook of Psychiatry-5th edition, Michael Gelder, p281

9. Hypotheses • Neurodevelopmental • Aberrant connectivity (failure of integration of mental functions) • Stress vulnerability(interaction between early factors and later life stresors) Shorter Oxford Textbook of Psychiatry-5th edition, Michael Gelder, p281

10. Genetic risk in relatives (Source: Gottesman, 1991)

11. Schizophrenia genetics • In Down’s syndrome the risk of schizophrenia is same as or lower than general population (probably less than 0.6%). • A number of studies have shown higher familial risk to be associated with earlier age of onset. Sham et al. (1994) showed that the morbid risk of schizophrenia is greater among the relatives of those probands who had an onset before rather than after age 21 years. • Severity of schizophrenia is not directly associated with family history or genetic loading. • Broad heritability = 80% Murray et al (ed). The epidemiology of Schizophrenia. Cambridge University Press, 2003. p212

12. Shared genes – BPAD and Schizophrenia • DAO & BDNF – seen more in mood disorders than schizophrenia • DISC 1 & NRG – shared with schizophrenia; seen in schizoaffective disorder • Dysbindin – seen more in schizophrenia than mood disorders • CREB1 (chr2) – unipolar depression Craddock N, et al (2005) The genetics of schizophrenia and bipolar disorder: dissecting psychosis. JMed Genet, 42, 193–204.

13. Dopamine pathways • Nigrostriatal from sustantia nigra to striatum (movement-EPS , tardive dyskinesia), • Mesocortical from ventral tegmental area( VTA) to frontal cortex (motivation and emotions- negative symptoms of schizophrenia) • Mesolimbic from the (VTA) to the limbic system via the nucleus accumbens. (reward pathway-positive symptoms of schizophrenia). • Tuberoinfundibular from hypothalamus to pituitary gland (prolactin inhibiting- hyperprolactinaemia) • Incertohypothalamic in hypothalamus (sexual behaviour) • Amacrine cells in retina, olfactory system.

14. Dopamine pathwaysDopamine- mechanisms of action Ann D. Crocker, Associate Professor and Reader, Department of Clinical Pharmacology, Flinders University of South Australia, Adelaide

15. Neuroanatomy of schizophrenia • A decrease in brain weight, brain length and volume of the cerebral hemisphere enlargement of the lateral ventricles • Enlarged lateral ventricles and third ventricle • Smaller medial temporal lobes • Decreased cortical grey matter • Reduced cerebral asymetry (Some evidence from postmortem examinations indicate disturbed cerebral asymmetry (planum temporale). Planum temporale (the posterior superior surface of the superior temporal gyrus) is a brain structure involved with language. In schizophrenia there was noted a reversal of the normal left surface area.

16. Histological changes • No evidence for astrogliosis • Reduced cell numbers or cell size especially affecting neurons in the hippocampus and DLPFC. • Increase in neurone density, which may relate to the observed decrease in neurone size (with decreased dendritic arborization and a decreased neuropil compartment) • Subtle cytoarchitectural anomalies were described in the hippocampal formation, frontal cortex • Synaptic studies in the hippocampus and DLPFC in schizophrenia show decrements in presynaptic markers. These changes may reflect a reduction in the number of synaptic contacts formed and received in these areas which supports hypotheses of excessive synaptic pruning. • Glutamatergic synapses may be especially vulnerable in the hippocampus and perhaps the DLPFC, with predominantly GABAergic involvement in the cingulate gyrus. Harrison PJ. “The neuropathology of schizophrenia. A critical review of the data and their interpretation.” Brain 1999; 122:593-624

17. Relapse Duration, Treatment Intensity, and Brain Tissue Loss in Schizophrenia: A Prospective Longitudinal MRI StudyNancy C. Andreasen, M.D., Ph.D.; Dawei Liu, Ph.D.; Steven Ziebell, B.A.; Anvi Vora, M.D.; Beng-Choon Ho, M.D.Am J Psychiatry 2013;170:609-615.  • The primary focus of the Andreasen et al. study was on clinical associations of atrophic anatomic changes with duration of persistent psychosis and intensity of antipsychotic treatment. • Findings: • Antipsychotic treatment intensity was related to brain volume reductions in the frontal and temporal cortex and in parietal white matter. • Antipsychotic-related effects on brain volume were notably smaller than those reported in rodent and nonhuman primate models; this difference may reflect species differences, an interaction with disease, more variable dosing clinically, or underreporting of treatment nonadherence. In any case, it is reassuring to see that progressive atrophic effects associated with antipsychotic treatment are less than those seen in animal models. • Effects of relapse duration and antipsychotic treatment intensity on anatomic measures were of similar magnitude.

18. Diagnostic criteria-ICD 10 • ICD10-Schizophrenia, Schizotypal and delusional disorders F20-F29 • Minimum 1symptom (a-d) or at least 2 symptoms(e-h) present most of the time during a period of 1 month or more

19. Diagnostic criteria-ICD10 • a) Thought insertion, withdrawal, broadcasting, echo. • b)Delusions of control, influence, pasivity, clearly referred to body or limb movements or specific thoughts, actions or sensations, delusional perception. • c) Hallucinatory voices giving a running commentary on patient’s behaviour, or discussing patient among themselves, or other types of hallucinatory voices coming from some part of the body. • d) Persistent delusions of other kinds that are culturally inappropriate and completely impossible

20. Diagnostic criteria – ICD 10 • e) Persistent hallucinations in any modality when accompanied either by fleeting or half formed delusions without clear affective content, or by persistent overvalued ideas, or when occurring every day for weeks or months on end. • f) Breaks or interpolations in the train of thought resulting in incoherence or irrelevant speech or neologisms. • g )Catatonic behaviour such as excitement, posturing, or waxy flexibility, negativism, mutism and stupor. • h) “Negative” symptoms such as marked apathy, paucity of speech, and blunting or incongruity of emotional responses, usually resulting in social withdrawal and lowering of social performance. Should not be secondary to depression or to neuroleptic medication. • i) significant and consistent change in overall quality of some aspects of personal behaviour, manifest as loss of interest, aimlesness, idleness,a self absorbed attitude and social withdrawal.

21. Sub-types • Paranoid (the commonest type, persecutory delusions and hallucinations) • Hebephrenic(thought disorder and affective sx are prominent. Negative Sx occur early and mannerisms common) • Catatonic • Undiferentiated • Residual (at least a year of persistent negative Sx) • Simple(insidious onset with odd behaviour, social withdrawal and functional decline) • Postschizophrenic depression • Other Schizophrenia • Unspecified • But…ICD11 will change Schizophrenia classification

22. The most significant recommendations that are being made on the basis of evidence review and WGPD consensus (Working Group on the Classification of Psychotic Disorders ) • The ICD-10 section “F2 Schizophrenia, schizotypal and delusional disorders” will be renamed “Schizophrenia spectrum and other primary psychotic disorders.” • Accordingly, non-primary (ie, “secondary”) psychotic disorders such as psychotic disorders in general medical conditions and psychotic disorders due to substance use or withdrawal will be placed in the sections (or “blocks”) of the Mental and Behavioural Disorders chapter corresponding to “Substance-induced disorders” and “Mental and behavioural disorders associated with disorders or diseases classified elsewhere.” • The overall structure being proposed for the ICD-11 block on “Schizophrenia spectrum and other primary psychotic disorders” is as follows: • Schizophrenia • Schizoaffective disorder • Acute and transient psychotic disorder (ATPD) • Schizotypal disorder • Delusional disorder • Other primary psychotic disorders • Unspecified primary psychotic disorders • Status of Psychotic Disorders in ICD-11, Wolfgang Gaebel, Schizophr Bull (2012) 38 (5): 895-898.

23. The most significant recommendations that are being made on the basis of evidence review and WGPD consensus (Working Group on the Classification of Psychotic Disorders ) • Single disorders will continue to be categorized on the basis of their psychopathological profile and duration. • For ICD-11 schizophrenia, the WGPD recommends, in accordance with DSM-5, that the 9 ICD-10 subtypes—paranoid, hebephrenic, catatonic, etc.—be omitted because of their longitudinal instability and prognostic invalidity.6 These would be replaced by a system of coded qualifiers (see below). Although de-emphasizing the importance of first-rank symptoms,7 a diagnosis of schizophrenia would require the presence of at least 2 out of 8 symptoms, including at least one core symptom. • The WGPD is recommending that in ICD-11 a diagnosis of “Schizoaffective disorder” should be made only when the definitional requirements of schizophrenia and of a mood disorder of moderate or severe degree are met simultaneously or within a few days of each other. The total duration requirement would be 4 weeks, including both mood and schizophrenic symptoms.

24. Schneider’s First Rank symptoms • TI/TW/TB • 3rd person auditory hallucinations + running commentary +Thought eco • Somatic hallucinations • Delusional perception • Feelings or actions experienced as made by an external agency

25. Negative symptoms • Alogia • Affective blunting • Asociality • Anhedonia • Avolition These predict: • Poor life quality • Poor social functioning • Poor interpersonal relationships • Poor work performance • Poor overall outcome

26. Definition of catatonic symptoms • Excitement -Extreme hyperactivity, constant motor unrest that is apparently nonpurposeful • Immobility/stupor -Extreme hypoactivity, immobility. Minimally responsive to stimuli • Mutism - Verbally unresponsive or minimally responsive • Staring-Fixed gaze, little or no visual scanning of environment, decreased blinking • Posturing/catalepsy - Maintains posture(s), including mundane (e.g., sitting or standing for hours without reacting) • Grimacing-Maintenance of odd facial expressions • Echopraxia/echolalia- Mimicking of examiner’s movements/speech

27. Definition of catatonic symptoms • Ambitendency - The patient seems stuck in indecisive, hesitant motor movements • Grasp reflex - Strike open palm of patient with two extended fingers of examiner’s hand. Automatic closure of patient’s hand • Perseveration - Repeatedly returns to the same topic or persists with same movements • Combativeness - Usually in an undirected manner, without explanation • Autonomic abnormality - Abnormality of temperature (fever), blood pressure, pulse rate, respiratory rate, inappropriate

28. Definition of catatonic symptoms • Stereotypy- Repetitive, nongoal-directed motor activity (e.g., finger play, repeatedly touching, patting, or rubbing self) • Mannerisms Odd, purposeful movements (hopping or walking tiptoe, saluting passers-by, exaggerated caricatures of mundane movements) • Verbigeration Repetition of phrases or sentences • Rigidity (Fig. 27.4 and 27.5) Maintenance of a rigid position despite efforts to be moved • Negativism Apparently motiveless resistance to instructions or to attempts to move/examine the patient. Contrary behavior, does the opposite of the instruction • Waxy flexibility (Fig. 27.6, 27.7 and 27.8) During reposturing, patients offers initial resistance before allowing himself to be repositioned (similar to that of bending a warm candle)

29. Definition of catatonic symptoms • Withdrawal Refusal to eat, drink, and/or make eye contact • Impulsivity Patient suddenly engages in inappropriate behavior (e.g., runs down the hallway, starts screaming, or takes off clothes) without provocation. Afterward, cannot explain • Automatic obedience Exaggerated cooperation with examiner’s request, or repeated movements that are requested once • Passive obedience (mitgehen) Raising arm in response to light pressure of finger, despite instructions to the contrary • Gegenhalten/counterpull Resistance to passive movement that is proportional to strength of the stimulus; response seems automatic rather than willful

30. Schizophrenia and suicide The estimate of lifetime suicide prevalence in those observed from first admission or illness onset - 5.6%. Factors with robust evidence of increased risk of suicide were • previous depressive disorders • previous suicide attempts • drug misuse • agitation or motor restlessness • fear of mental disintegration • poor adherence to treatment • recent loss “Schizophrenia and suicide: systematic review of risk factors” HAWTON Keith, et al , British Journal of Psychiatry, 187(1), July 2005, pp.9-20.

31. Schizophrenia and suicide Prevention of suicide in schizophrenia is likely to result from treatment of affective symptoms, improving adherence to treatment, and maintaining special vigilance in patients with risk factors, especially after losses. “Schizophrenia and suicide: systematic review of risk factors” HAWTON Keith, et al , British Journal of Psychiatry, 187(1), July 2005, pp.9-20.

32. Predictors of quality of life in schizophrenia • This Canadian study aims to clarify the relationships between socio-demographics, clinical characteristics, stressors, coping strategies, social support and quality of life (QOL) in 143 patients with a diagnosis of either schizophrenia or schizoaffective disorders. The research design is cross-sectional with repeated measures on the same subjects after a 6-month interval. A regression analysis generated a model that accounts for 50% of the variance in QOL at Time 1 and 43% at Time 2. The best predictors of QOL were two components of social support: attachment and reassurance of worth. Severity of daily hassles, the coping strategy of changing the situation, level of education and life-time hospitalization length were also related to QOL.

33. Management (NICE)

34. Indicators of good prognosis • Sudden onset • Short episode • No past psychiatric Hx • Prominent affective Sx • Paranoid type • Older age • Married • Good psychosexual adjustment • Good premorbid personality • Good work record • Good social relationships • Compliance with treatment Shorter Oxford Textbook of Psychiatry-5th edition, Michael Gelder, p295

35. Indicators of poor prognosis • The opposite of above indicators +….. • Negative Sx • Enlarged lateral ventricles • Male gender

36. Prognosis of EOS “In contrast to the adult manifestation, the early manifestation of schizophrenia in childhood and adolescence still carries a particularly poor prognosis. According to these aggregated data analyses, longer follow-up periods, male sex, and patients having been diagnosed before 1970 contribute predominantly to the rather poor course of EOS. “ A systematic review of the long-term outcome of early onset schizophrenia Lars Clemmensen1†, Ditte Lammers Vernal2† and Hans-Christoph Steinhausen234*† BMC Psychiatry 2012, 12:150 doi:10.1186/1471-244X-12-150 Published: 19 September 2012

37. Characteristics of individuals at high risk who fell ill, according to presence or absence of psychotic symptoms on entryPredicting schizophrenia: findings from the Edinburgh High-Risk Study, Eve C. Johnstone, FRCPsych, Klaus P. Ebmeier, MD, Patrick Miller, PhD, David G. C. Owens, FRCPsych and Stephen M. Lawrie, MRCPsych The British Journal of Psychiatry (2005)186: 18-25

38. CLINICAL IMPLICATIONS of Edinburgh High-Risk study • Among individuals at enhanced genetic risk of schizophrenia, a state of vulnerability, including transient and partial symptoms, will occur in many more individuals than will develop florid schizophrenia. • It is possible, using simple behavioural assessments of schizotypal and anxiety cognitions, to predict with some accuracy those of a high-risk group who will (and with considerable accuracy those who will not) develop schizophrenia, some years before the development of the psychosis. • Neuropsychological and neurodevelopmental measures are more successful in distinguishing individuals at high risk from healthy controls than they are in distinguishing high-risk individuals who will develop schizophrenia from those who will not.