Presentation is loading. Please wait.

Presentation is loading. Please wait.

E ARLY -O NSET S CHIZOPHRENIA Samuel J. Eckrich, M.S. Child Psychopathology University of Central Florida.

Similar presentations


Presentation on theme: "E ARLY -O NSET S CHIZOPHRENIA Samuel J. Eckrich, M.S. Child Psychopathology University of Central Florida."— Presentation transcript:

1 E ARLY -O NSET S CHIZOPHRENIA Samuel J. Eckrich, M.S. Child Psychopathology University of Central Florida

2 F AMOUS S CHIZOPHRENICS

3 H ISTORY OF P SYCHOSIS Trephination as early as 3,000-10,000 BC Incas (1350 AD) had 80% survival rate Emil Kraepelin (1893): Two types of psychosis- manic depressive and dementia praecox. Eugen Bleuler (1908) coined the term, “schizophrenia.” Kurt Schneider (1950s): 1 st rank symptoms: Delusions and hallucinations Included in all versions of DSMs Some Notable changes in the DSM-V

4 C HANGES IN DSM-V 1) Moved from categorical to spectrum approach: “Schizophrenia Spectrum and Other Psychotic Disorders” 2) Now includes the following disorders (Table 1):

5 T ABLE 1: DSM-V SZ SPECTRUM AND OTHER PSYCHOTIC DISORDERS. Bhati, 2012

6 C HANGES IN DSM-V 1) Moved from categorical to spectrum approach: “Schizophrenia Spectrum and Other Psychotic Disorders 2) Now includes the following disorders (Table 1): 3) Eliminated subtypes of schizophrenia: paranoid, disorganized, catatonic, undifferentiated, and residual Bhati, 2012

7 D IAGNOSTIC C RITERIA FOR S CHIZOPHRENIA

8 A SSOCIATED F EATURES Inappropriate affect (laughing without stimulus) Dysphoric mood (anxiety, depression, sleep disturbance) Lack of interest in eating Somatic concerns (depersonalization, derealization) Cognitive deficits (declaritive and working memory, language, executive fx, processing speed) Sensory processing, inhibitory capacity, and attention Social Cognition deficits (inferring intentions of others) Anosognosia (lack of insight or awareness of illness)

9 DSM-V’ S R ISK F ACTORS Genetic and Physiological (Miller et al. 2011) Conferred by a spectrum of “risk” alleles, common and rare, each contributing a small fraction of total variance. Hypoxia Greater paternal age Prenatal/perinatal adversity, stress, infection, malnutrition, maternal diabetes Environmental (Brown, 2011) Season of birth: late winter/early spring Urban environment

10 DSM-V INFORMED M ODEL Genetics Positive Symptoms Negative Symptoms Cognitive Decline Positive Symptoms Negative Symptoms Cognitive Decline Prenatal Stress, Hypoxia, Paternal age Environment: Birth Order and Urban Environment: Birth Order and Urban Schizophrenia

11 S CHIZOPHRENIA IN C HILDREN AND A DOLESCENTS Definitions and Classifications Very-early-onset (VEOS), beginning before 13 yrs. old. Early-onset (EOS), beginning before 18 yrs. old. Childhood-onset schizophrenia (COS) or “prepubertal” yet still defined as 12 yrs. or younger, not developmental age. Adolescent-onset schizophrenia (AOS) between yrs. * Not incorporated into DSM-V Werry et al., 1991

12 P REVALENCE Remained stable over past 50 yrs and occurs similarly across different countries and cultures (Hafner et al., 1997) 10-18% of all Sz arise before age 18 and 1% before 10yrs old. 42% occur between % between Remschmidt and Theisen 2011

13 S EX D IFFERENCES /O NSET About equally represented among children and adolescents however some studies: Under 13 and yr. old boys develop Sz more frequently (Hafner et al., 2007) More frequent in girls (Mehler-wex et al., 2004). Age of onset: Peaks in early-mid 20s for males, later 20s/ for females. Females more likely to have late onset (post 55yrs) Males generally worse premorbid adjustment, lower educational achievement, more prominent negative symptoms and cognitive impairment, and in general a worse outcome (Alvarez-Jimenez et al., 2012).

14 C LINICAL P RESENTATION OF P OSITIVE SYMPTOMS IN EOS Hallucinations Auditory (commands, threats, laughter, humming, whistling) Visual, olfactory, gustatory, and tactile are rare, but more common in COS Delusions Ideas of reference Belief of persecution Bodily change Delusions of control Systematized delusions are very rare Thought distortions Insertions, breaks and interpolations in train of thought Vague and incoherent thinking that is not expressed well.

15 C LINICAL P RESENTATION OF N EGATIVE S YMPTOMS IN EOS Speech Logorrhea or general paucity of speech Perseverations and stereotypies Echolalia Neologism Social functioning Withdrawal Emotional manifestations Blunted affect, apathetic, Irritable, fearful, suspicious Incongruent emotional responses

16 O THER C LINICAL P RESENTATIONS IN EOS Motor disturbances Clumsiness Catatonia Bizarre postures/movements (e.g. stereotypies of fingers) Rituals One study found very high incidences of hallucinations across all modalities in COS (David et al., 2011) 95% Auditory, 80% Visual, 61% tactile, 30% olfactory Tactile and olf. only occurred in those with visual Visual was associated with greater impairment/worse overall brain functioning. *Manifestations often occur long before initial hospitalization

17 V IDEO https://www.youtube.com/watch?v=UTUMt05_nC I Jani

18 D IFFERENTIAL D IAGNOSIS IN EOS Difficult. DSM-V: Delusions and hallucinations are usually less elaborate and must be distinguished from normal fantasy play. Disorganized speech and behavior commonly occurs in other disorders (See Table 3).

19 E TIOLOGY 1)Genetic factors Heritability Candidate gene regions 2)Neurobiological factors Brain morphology Biochemical 3) Neuropsychological factors Cognitive Impairment Neurointegrative deficits Attention deficits Communication deficits

20 G ENETICS More overlap with COS than Adult-onset Arsanow, 2013

21 A F EW P ROTEIN T ARGETS Genes scattered across all but 8 chromosomes have been implicated Most important: Neuregulin 1: NMDA, GABA, & ACh receptors Dysbindin: synaptic plasticity (esp. NMDAR) Catechol-O-methyl transferase: DA metabolism G72: regulates glutamatergic activity Others: myelination, glial function Paternal age thought to have an impact

22 D ISRUPTED IN S CHIZOPHRENIA -1 GENE (DISC-1) Expressed in forebrain. Affects cell growth, movement, positioning, and transport. Hikida et al., 2007 *Animals that expressed a mutated DISC-1 gene (tg) had significantly larger Lateral Ventricle volume at neo-natal stages than those who didn’t express the gene.

23 E XPRESSION PATTERN OF EXOGENOUS DN-DISC1 Exogenous DN-DISC1 is preferentially expressed in neonatal stages rather than in adulthood DISC1 expression naturally occurs in wild-type (wt) mice

24 E NLARGED V ENTRICLES IN HUMANS

25 O THER N EUROMORPHOLOGICAL D IFFERENCES Pyramidal cell organization in the hippocampus

26 P YRAMIDAL CELL ORGANIZATION IN HIPPOCAMPUS

27 M ORPHOLOGICAL DIFFERENCES IN A DOLESCENTS WITH S Z 1)Enlarged lateral ventricles 1)Reduced gray matter 2)Prefrontal connectivity (DLPFC, VMPFC) 3)Decreased hippocampal volume 4)Decreased cerebellar volume

28 E TIOLOGY 1)Genetic factors Heritability Candidate gene regions 2)Neurobiological factors Brain morphology Biochemical 3) Neuropsychological factors Cognitive Impairment Neurointegrative deficits Attention deficits Communication deficits

29 B IOCHEMICAL F ACTORS Three main hypotheses: Dopamine (DA), Serotonin (5-HT), and glutamate. Evidence for Dopamine Hypothesis: Amphetamines increase paranoia, delusions, auditory hallucinations and exacerbate Sz symptoms DA antagonists (chlorpromazine, thorazine, other typical antipsychotics) alleviate the positive symptoms. Schizophrenics had ~twice as many D 2 receptors occupied as normal (Meyer-Lindenberg et al., 2002)

30 5-HT AND G LUTAMATE H YPOTHESES Atypical antipsychotics (clozapine, olanzapine, etc.,) block 5-HT2 A receptors and increase DA! Negative symptoms were at first thought to be attenuated by AAs. Glutamate: PCP, Mk-801, Ketamine are NMDAr antagonists (decreases glutamate) cause hallucinations, paranoia, and depersonalization. Emulates chronic cognitive dysfunction and hypofrontality found in those with Sz. So why not give glutamate agonist?

31 P ROBLEMS WITH BIOCHEMICAL HYPOTHESES Approximately normal levels of DA in schizophrenics (Jaskiw & Weinberger, 1991). Antipsychotic drugs block DA synapses within minutes, but beneficial effects build up over 2 – 3 weeks. Most have very complicated mechanisms of actions: increasing D1 receptors while decreasing D2rs., tinkering with one of the 20 5-HT receptors, or combining. Dark secret…no one really knows what is going on.

32 E TIOLOGY 1)Genetic factors Heritability Candidate gene regions 2)Neurobiological factors Brain morphology Biochemical 3) Neuropsychological factors Cognitive Impairment Neurointegrative deficits Attention deficits Communication deficits

33 S UMMARY OF G ENETIC AND N EUROBIOLOGICAL F ACTORS Genetics obviously play a role, but it isn’t incredibly robust. Certain genes like DISC-1 can contribute to neuroanatomical differences at a young age. Large volume differences in Lateral Ventricle. Structural differences in frontal cortex, hippocampus, and cerebellum. DA, 5-HT, and glutamate hypotheses may account for positive, negative, and cognitive symptoms, respectively.

34 E TIOLOGY 1)Genetic factors Heritability Candidate gene regions 2)Neurobiological factors Brain morphology Biochemical 3) Neuropsychological factors Cognitive Impairment Neurointegrative deficits Attention deficits Communication deficits

35 C OGNITIVE I MPAIRMENT S PECIFIC TO EOS

36 C OGNITION T ESTS C OMMONLY USED IN EOS Frangou 2013 * A big problem with using consistent measurements: National Institute of Mental Health MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Dr. Green at UCLA is a world leader in Sz research

37 N EUROCOGNITIVE T ESTS IN C HILDREN WITH ANTECEDENTS TO S Z Meta-analysis of premorbid IQ measurements (assessed in childhood and later developed Sz) ~ 8 IQ points lower than TD individuals who did not go on to develop psychotic symptoms (dES =.55). (Woodberry et al., 2008) In one study by Cullen et al., children (9-12yrs.) At least one 1 “psychotic-like” episode Social, emotional, behavioral problems Early speech and/or motor developmental delays

38 Fig. 1 Scatterplots indicating the distribution of z-scores obtained on each neurocognitive domain by children presenting putative antecedents of schizophrenia (ASz) and by typically-developing children (TD) without the antecedents. Cullen et al., 2010 *Mean of all neurocog. tests: dES =.52 Effect Sizes: GI =.55; VM =.54; WM =.95; EF-I =.66

39 T RAJECTORY OF COGNITIVE DYSFUNCTION IN EOS Moving from premorbid to syndromal EOS had SD worse on IQ tests compared to Adult onset. Big picture: Earlier presentation of symptoms, the more dysfunction later in life. Some areas of cognitive functioning found to be more pervasive. (Frangou 2013).

40 E TIOLOGY OF C OGNITIVE D YSFUNCTION : H YPOFRONTALITY / CONNECTIVITY Kyriakopoulos et al., 2012

41 N EURAL U NDERPINNINGS C ONCLUSION During adolescence, significant remodeling and strengthening of neural circuits subserving higher cognitive functions. Functional imaging studies suggest a progressive deviance in prefrontal recruitment from adolescents to adulthood These functional changes along with anatomic differences in EOS show progressive loss in prefrontal gray volume and white matter integrity throughout adolescence and into young adulthood.

42 L ONGITUDINAL STUDIES /P ROGNOSIS Arsanow et al., 1999 Followed 18 children diagnosed with Sz Two follow-up assessments using K-SADS, K-SKIPS, and GAS at 1-7 years and yrs from initial diagnosis.

43 A S YSTEMATIC R EVIEW OF EOS P ROGNOSIS Global Function Scale, Global Assessment of Functioning, Children’s Global Assessment Scale, Global Assessment Scale, Study-Specific Functioning.

44 E NVIRONMENTAL R ISK F ACTORS Childhood environment Dunedin study atypical mother-child interactions (OR = 2.65, CI ) Physical/sexual abuse (Diathesis stress model) Drug use/abuse esp. Psychostimulants and Cannabis (RR = 2.4) Perinatal Maternal malnutrition (OR = 2.9), stress, diabetes, smoking, Dutch Hunger Winter studies Poor nutrition = more Sz Season of birth More plausible: Influenza, viruses, parasites Herpes simplex type 2, taxoplama gondii Obstetric complications Complications of pregnancy Fetal growth and development Complications of delivery Hypoxia (RR = 2-3) Very small effect sizes and OR < 2. Pooled OR = 1.07 Dean and Murray, 2005

45 E NVIRONMENTAL R ISK CONT. Migration Especially African-Caribbean in the UK Higher incidence rates ( ) when the group’s position in society was considered disadvantaged. Urbanicity One of the most consistent findings: 38-67% more likely to develop schizophrenia (Pederson et al., 2004). Dose-response fashion (causality?) Several validity/conceptual problems Most likely due to social isolation

46 T REATMENT None listed in Division 53 Pharmacological approach is generally the first line of defense. Second generation antipsychotics (atypical) are primarily antiserotonergic and dopamine altering. (e.g. clozapine, aripiprizole, resperidone, quietiapine, olanzapine) Originally thought to decrease positive and negative symptoms Extrapyramidal symptoms are less common Weight gain is common. First generation antipsychotics (typical) are antidopaminergic (e.g. Haloperidol, Chlorpromazine) Primarily work to decrease positive symptoms Tardive dyskinesia is a common side-effect

47 A NTIPSYCHOTIC INTERVENTION IN A DOLESCENT OS: A R EVIEW Very few studies. Generally use Atypical, only aripiprozole is FDA approved. Cochrane review looked at 13 RCTs with over 1,100 participants. Global state, mental state, adverse effects (weight gain, sedation, motor effects), drop out rate were assessed. (Datta et al., 2013) Atypical vs. Placebo: No difference (more dropped out in the placebo group). No difference between AAs, except aripiprozole had less weight gain. No difference in AAs vs. TAs. Need more studies!

48 R EVIEW ONLY LOOKING AT PANSS ( POSITIVE AND NEGATIVE SYMPTOM SCALE ) SCORES A GES Shimmelmann et al., 2013

49 C LINICAL A NTIPSYCHOTIC T RIALS OF I NTERVENTION E FFECTIVENESS (CATIE) Big recent (2013) finding from CATIE. No difference between AAs and TAs. Antipsychotic medications are more effective than placebo at reducing positive symptoms and relapse rates. Large meta-analyses studies show approx. 25% with AAs relapsed vs. 65% on placebo (Gilbert et al., 1995; Leucht et al., 2012). No change in cognitive functioning or negative symptoms Quality of life not improved

50 P SYCHOSOCIAL TREATMENT Very few studies for EOS Shimmelman et al., 2013 review *No one treatment is more effective than another. *Most experts suggest combined approach * Family intervention, social, and problem solving skills are probably efficacious.

51 N EW T REATMENT APPROACHES Targeting cognitive and negative symptoms. Metabotropic glutamate receptors (mGluRs), N- acetyl-cystein, phosphodiesterase inhibitors, modafinil, Omega-3, oxytocin. Depot shots to increase adherence. Psychoeducation in the community. Early identification and intervention in prodromal stages.

52 A LTERNATIVE E ARLY D IAGNOSTIC T OOLS ? Scratch-n-sniff: common odors (pizza, smoke, orange, bubble gum, gasoline, chocolate, clove, wintergreen, etc. Olfaction is processed in frontal and temporal lobes Can predict onset and severity 80+% Sz patients show deficit vs 10-15% in general population Some data suggest M Sz are particularly poor at emotional olfactory memories Venule Caliber Red Light Effect

53 DSM-V INFORMED M ODEL Genetics Positive Symptoms Negative Symptoms Cognitive Decline Positive Symptoms Negative Symptoms Cognitive Decline Prenatal Stress, Hypoxia, Paternal age Environment: Birth Order and Urban Environment: Birth Order and Urban Schizophrenia

54 Genetics: 1 st degree relative, paternal age GABA, glutamate, DA Perinatal: Stress, nutrition, influenza Obstetric: hypoxia Environment: urbanicity, abuse, parasites, cannabis, social isolation Antipsychotics Cognitive Dysfunction Positive Symptoms Negative Symptoms Neuroanatomical chemical: hypofrontality, gray matter, hippocampus, DA, glutamate Asymptomatic Prodromal 1 st Psychotic Episode Fully Symptomatic A New Model

55 T HE E ND

56 S PECIFIERS

57 E XECUTIVE F UNCTIONING Well-established in adults. Stroop and Wisconsin Card Sort Test (WCST)

58 C OGNITIVE I MPAIRMENT S PECIFIC TO EOS General intellectual ability (IQ) Executive Functioning Especially working memory (d = ), Attention (d = 1.47), rule discovery/perseveration (d =.7). Processing Speed (d =.66). Earliest detectable difference compared to HC. Associated impairments: verbal memory and learning (d = ), problem solving (d =.5)

59 T RAJECTORY OF COGNITIVE DYSFUNCTION IN EOS Big picture: Earlier presentation of symptoms, the more dysfunction later in life. Moving from premorbid to syndromal EOS had SD worse on IQ tests compared to Adult onset Processing speed (Digit Symbol): Two SDs worse compared to HCs in one study() and AOS ES =.66 () Working Memory (Digit Span and 1-back) EOS compared to HC

60 E LECTROPHYSIOLOGICAL F ACTORS Differences in skin conductance Slow habituation Evoked Potentials – debatable. Gamma Band asynchrony (40-70 hz)


Download ppt "E ARLY -O NSET S CHIZOPHRENIA Samuel J. Eckrich, M.S. Child Psychopathology University of Central Florida."

Similar presentations


Ads by Google