1. Back to Basics: Psychotic Spectrum Disorders Sharman Robertson Bsc MD FRCPC

2. Format: Summary of Kaplan and Sadock’s “ Synopsis of Psychiatry” Schizophrenia Other Psychotic Disorders Schizophreniform disorder Brief psychotic disorder Schizoaffective disorder Delusional disorder Psychosis NOS

3. Schizophrenia: Epidemiology Lifetime prevalence 1% Annual incidence 0.5-5/10,000 Male = female Disproportionate number in low SES in industrialized nations Onset males 10- 25 years, mean=21 years females 25-35 years, mean=27 years

4. Epidemiology (Cont.) Fertility rates close to that of general population 80% have significant concurrent medical illness and only 50% of this is diagnosed >75% smoke Suicide is leading cause of mortality 15% success rate

5. Epidemiology (Cont.) Incidence and prevalence roughly similar world-wide Substance use 30-50% alcohol dependence Cannabis dependence 15-25% Cocaine dependence 5-10%

6. Etiology Likely not single illness, but group of disorders with heterogeneous causes Patients show a range of presentations, response to treatment and outcomes Stress-diathesis model: Diathesis or vulnerability is acted on by stressful event resulting in production of the illness

7. Neurobiology Dysfunction in one area can lead to dysfunction in interconnected area Limbic system-may be primary site of pathology Frontal cortex:impaired abstraction Basal ganglia : abnormal involuntary mvts Cerebellum : cognitive dysmetria

9. Neurobiology (Cont.) ? Abnormal cell migration along radial glial cells during embryo-genesis Hippocampal pyramidal cell disarray ? Early pre-programmed cell death Loss of associative neuron axons and dendrites ->decreased brain volume Environment plays part as evidenced by only 50% concordance rate in MZ twins

10. Neuroanatomy Limbic system: Decreased size of amygdala, hippocampus, parahippocampal gyrus on MRI Basal ganglia and cerebellum: 25% of drug naïve patients have abnormal involuntary movements Huntington’s associated with basal ganglia pathology, psychosis and AIM

11. Neuroanatomy CT scan evidence of Increased size of lateral and third ventricles Decreased cortical, cerebellar volume More negative symptoms, soft neurological signs, increased EPS with meds, poor premorbid adjustment if CT scan shows abnormalities

12. Neurochemistry; Dopamine Dopamine (DA) hypothesis: Over-activity of DA in certain brain areas ie mesolimbic and mesocortical areas Evidence: Efficacy of DA blocking medications Psychotomimetic effect of stimulants ? Too much DA release, too many DA receptors DA levels actually low in prefrontal cortex

13. Serotonin 5HT-2 blockade reduces psychotic symptoms and prevents movement D/O’s caused by D2 blockade Second generation anti-psychotics (SGA’s) have potent 5HT-2 blockade ie: Risperidone, olanzapine, seroquel Older: clozapine

14. Norepinephrine (NE) Long term anti-psychotic use  decreased activity in alpha-1 and alpha- 2 receptors in locus ceruleus NA system modulates DA system ? NA system abnormalities may affect relapse rate

15. GABA,Glutamate, CCK, Neurotensin Loss of inhibitory GABA-ergic cells in hippocampus  hyperactivity of DA and NA neurons Several hypotheses; hyperactivity, hypoactivity, glutamate-induced neurotoxicity linked with schizophrenia CCK and neurotensin levels altered in psychosis

16. Eye Movement Disorders Frontal eye fields implicated Patients and unaffected relatives have disorders of smooth visual pursuit and disinhibition of saccades ? Trait marker for schizophrenia independent of treatment and clinical state

17. ? Viral Most controlled neuro-immunological studies do not support this No genetic evidence of viral infection Circumstantial evidence: More physical anomalies at birth More winter/late-spring births geographical clusters of adult cases 2 nd trimester influenza exposure

18. Other Theories Immunological abnormalities: Some data support auto-immune brain anti-bodies in a subset of schizophrenia Neuro-endocrine abnormalities: Blunted release of GH and PRL following GnRH or TRH stimulation Decreased LH/FSH concentrations

19. Other Theories Genetic factors: 50% concordance in MZ twins 40% if both parents have schizophrenia 10% if DZ twin or other first degree relative Multiple chromosomal sites support polygenic origin of schizophrenia

20. Emil Kraeplin: Dementia Praecox One of first to characterize a psychotic illness separate from BAD; Early onset Chronic deteriorating course Primary sx delusions and hallucinations Cognitive impairment Not clearly episodic as was BAD

21. Eugen Bleuler: Schizophrenia Schizophrenia = split-mind Split between thought, emotion and behavior Not necessarily deteriorating Most important symptoms 4 A’s: autism, affective flattening, ambivalence, associations loose Accessory symptoms: hallucinations and delusions

22. Kurt Schneider First rank symptoms: Audible thoughts Voices commenting Voices arguing, discussing Somatic passivity Thought broadcasting, insertion and withdrawal Delusional perceptions Volitional problems: made affect and impulses

23. Second Rank Symptoms Sudden delusional thoughts Perceptual disturbances Perplexity Depressive and euphoric feelings Emotional impoverishment

24. DSMIV Diagnosis of Schizophrenia A Criteria: two or more during a significant portion of one month (less if successfully treated) 1) delusions 2) hallucinations 3) disorganized speech 4) grossly disorganized or catatonic behavior 5) negative symptoms (affective flattening, alogia, avolition)

25. DSMIV Diagnosis of Schizophrenia Only one A criterion needed if delusions are bizarre or hallucinations are of a running commentary or voices conversing with each other B: Social/ Occupational Dysfunction

26. DSMIV Diagnosis of Schizophrenia C: continuous signs of the disturbance for >= 6 months, prodromal, active, residual symptoms D: not due to mood disorder or schizoaffective disorder (mood symptoms are brief relative to duration of active and residual symptoms) E: not due to substance or general medical condition F: if PDD is present must have clear cut delusions and hallucinations for one month

27. Subtypes of Schizophrenia Paranoid Disorganized Catatonic Undifferentiated Residual Based on clinical presentation NOT closely correlated with different prognoses

28. Paranoid Preoccupation with one encapsulated delusional system or auditory hallucinations Delusional content = persecution or grandeur Later onset than catatonic or disorganized Less impairment of emotional responses, and behavior Later onset usually means established social life and supports, better coping skills

29. Disorganized (Hebephrenic) Primitive, disorganized, disinhibited, vague, aimless behavior Onset <25 years Pronounced thought disorder Poor reality contact Poor self-care Inappropriate affect, grimacing

30. Catatonic Relatively rare Marked disturbance of motor functioning Require supervision to prevent physical harm to self or others, exhaustion, hyperpyrexia Stupor, mutism Rigidity Waxy flexibility, stereotypies, mannerisms Posturing Stupor alternating with agitation

31. Undifferentiated Not clearly fitting any other single type of schizophrenia Residual Type: Schizophrenia is still evident, but patient does not meet full A criteria or specific subtype Cognitive impairments common Attenuated and negative symptoms

32. Clinical Picture No one symptom is pathognomonic of schizophrenia, symptoms can change with time Must take signs and symptoms as part of patient’s context: IQ and developmental level Culture Educational level

33. Positive Symptoms Delusions: Firm, fixed, false beliefs Paranoid Grandiose Religious Somatic Referential Pseudo-philosophical Control

34. Positive Symptoms Hallucinations: sensory perceptions in absence of external stimuli Auditory (most frequent) Visual Cenesthetic Olfactory* Gustatory* * ? metabolic or neurological causes Less association with CT abnormalities, better response to treatment

35. Negative Symptoms (Deficit Symptoms) Affective flattening, blunting Alogia: poverty of rate or content of speech Thought blocking Autism Ambivalence

36. Negative Symptoms (Deficit Symptoms) Anhedonia-asociality Avolition-apathy Poor self-care Inattention Associated with CT abnormalities, less treatment responsiveness

37. Disturbances of Affect/Mood Reduced emotional responsiveness Unregulated, inappropriate emotional discharge: Terror, rage Anxiety, depression Perplexity Happiness, euphoria, ecstasy

38. Thought Disorders Core symptoms of schizophrenia Thought content Thought form Thought process Visible in speech and written language

39. Thought Content Overvalued ideas Delusions Loss of ego boundaries ie where patients own body, mind and influence begin and where those of other animate and inanimate objects begin

40. Thought Form Loosening of associations Derailment Circumstantiality Tangientiality Neologisms Word salad Echolalia Mutism Clanging Verbigeration Incoherence

41. Though Process Flight of ideas Though blocking Prolonged response latency Inattention Perseveration Impaired abstraction Over-inclusion

42. Violence Rates of violence in schizophrenia are higher than rates in the general public Risk factors act synergistically; Untreated Active substance use Active alcohol use Past history of violence Persecutory or erotomanic delusions Neurological deficits

43. Suicide 50% attempt 10-15% succeed Risk factors: Undiagnosed depression Command auditory hallucinations Need to escape symptoms Young, male, well educated, awareness of losses, living alone

44. Differential Diagnosis Substance intoxication or withdrawal Cocaine, amphetamines, ecstasy, LSD, PCP, anabolic steroids Alcohol, benzodiazepine, barbiturate, GHB withdrawal Prescription medications: L-dopa, steroids, anti-retrovirals, anti-tubercular agents

45. General Medical Conditions Neurological: Epilepsy, esp. TLE Neoplasm Trauma to frontal or limbic areas Wernike-Korsakoff’s Infectious: HIV, neurosyphilis, CJD, herpes encephalitis

46. General Medical Conditions Metabolic: Hyper/hypothyroidism, hyper/hypoparathyroidism Acute intermittent porphyria Homocystinuria Wilson’s disease Auto-immune: SLE Cerebral lipoidosis

47. General Medical Conditions Poisoning: Heavy metals CO Solvents Nutritional: B12, folate deficiency

48. Psychiatric Illness Mood: BAD Major Depression with psychotic features Schizoaffective disorder Psychotic Spectrum Disorders: Delusional disorder Brief psychotic disorder Schizophreniform disorder

49. Psychiatric Disorders Personality Disorders: Paranoid PD Schizotypal PD Schizoid PD Anxiety Disorders: OCD Panic disorder

50. Psychiatric Disorders Pervasive developmental disorders: Asperger’s disorder Infantile autism Factitious disorder Malingering ($ or legal gain)

51. Course Prodrome Active Phase: active positive and negative symptoms Residual Phase: attenuated positive symptoms and negative symptoms

52. Prodrome Lead in to schizophrenia Marked by variable symptoms: Depression, anxiety, conduct disorder symptoms, confusion, substance and alcohol misuse, attenuated positive symptoms, negative symptoms, cognitive impairment May last a year or more Onset adolescence usually Often difficult to determine due to poor specificity

53. Course First episode: Duration of untreated psychosis associated with worse outcome Associated with greatest potential for full recovery to baseline Treat early and aggressively with multi- modal approach Pattern of illness during the first 5 years indicates course

54. Course Relapses: Harder to treat Longer duration Less responsive to medication Less likely to return to baseline

55. Prognosis Lifelong vulnerability to illness Episodes of active psychosis Residual symptoms Cognitive impairment and negative symptoms: Longest lasting, most difficult to treat Failure to return to baseline demarcates schizophrenia from mood disorders

56. Prognosis Twelve month relapse rates; No medication: 75% Medication: 15-25% 1/3 able to lead relatively normal lives 1/3 moderate symptoms 1/3 deteriorating course 25% of this population are drug resistant 50% of drug resistant respond well to clozapine

57. Good Prognositic Signs -Late onset -Obvious precipitating factors -Acute onset -Good pre-morbid social, academic, work function -Mood sx -Married Family hx mood disorder Good supports Positive symptoms

58. Poor Prognostic Signs Early onset No precipitant Insidious onset Poor premorbid function Withdrawn, autistic behavior Single, divorced, widowed assaultiveness Family hx schizophrenia Poor support systems Negative symptoms Neurological S+Sx Perinatal trauma No remission in 3 years Many relapses

59. Assessment Assessment of predisposing, precipitating, perpetuating and protective factors: Genetic: family medical and psychiatric hx General medical conditions eg head injury, seizure disorder Substance misuse Learning disorders Perinatal illness, trauma Psychological trauma, abuse Legal problems Past psychiatric history Supports, strengths

60. Assessment Physical with full neurological exam CBC, lytes, BUN, Cr, AST, ALT, Ca, PO4, TSH, B12, folate, fasting glucose and lipid profile Urinalysis and drug screen EKG EEG +/- CT, MRI

61. Treatment Patient and family psychoeducation: Definition of schizophrenia Provision of information and available supports Schizophrenia society Reading materials

62. Treatment Group and individual therapy: Social skills training Vocational rehabilitation Supportive therapy Managing anxiety groups CBT Family therapy Supervised living, Case management, ACTT

63. Pharmacology Dopamine receptor antagonists: Older classes of medications Extra pyramidal symptoms Tremor, parkinsonism, rigidity, akathesia TD, NMS Work well on positive symptoms May cause negative symptoms in higher dose

64. Dopamine Receptor Antagonists Haloperidol Zuclopenthixol Fluanxol Perphenazine Loxapine Methotrimeprazine Chlorpromazine Low potency meds have more sedative, anticholinergic and alpha blocking properties Higher potency drugs have higher rates of EPS and TD

65. 5HT/DA Blocking Drugs, Second Generation Antipsychotics, Atypicals As effective on positive symptoms as first generation antipsychotics Perhaps superior on negative symptoms Less potential for EPS, TD, NMS (although it can occur) More potential for endocrinological illness: Obesity, DM, Dyslipidemia, CVS disease

66. Atypical Antipsychotics Clozapine Risperidone Olanzapine Quetiapine Ziprasidone (USA) Aripiprazole (USA) Some evidence points to neuroprotective effects and cognitive enhancement

67. Treatment Acute phase, emergency: Safety-suicide, aggression Use intra-muscular antipsychotics (haldol, olanzapine) and benzodiazepines Watch for EPS and have cogentin available May need restraints Have staff available

68. Treatment Acute, non-emergent: Choose medication based on: Past response Side effect profile Patient preference Route Cost Availablity

69. Antipsychotic selection Usually choose second generation ie risperidone, seroquel, olanzapine based on side effects and patient characteristics: ? Obese, family hx DM, Obesity CVS disease olanzapine not first choice ? sexual dysfunction, menstrual irregularity risperidone not first choice

70. Antipsychotic Trials Define target symptoms Try mono therapy first Trial length = 4-6 weeks at adequate dosage Usually start with SGA If medication ineffective or SE’s present switch to another SGA Use lowest possible dose Higher doses needed in acute phase and may be lowered in maintenance

71. Brief Psychotic Disorder Acute, transient psychotic disorder 1 day- < 1 month Symptoms may resemble schizophrenia with delusions and hallucinations May develop in response to a traumatic stressor Symptoms often reflect stressful event

72. Brief Psychotic Disorder Temporal relationship to the trauma Usually benign course, eventual return to baseline function Uncommon Pts in 20’s and 30’s ? More in women and lower SES Often seen in patients with histrionic, narcissistic, borderline, paranoid, schizotypal PD

73. Brief Psychotic Disorder Similar to “Bouffee Delirante” Emotional lability, confusion, inattention more common Rule out delirium 50% go on to have a mood disorder or schizophrenia 50-80% will not have further problems

74. Brief Psychotic Disorder Not due to: Schizophrenia Schizoaffective disorder Mood disorder A general medical condition Substance abuse, intoxication or withdrawal Treat with antipsychotics and benzos

75. Schizophreniform Disorder Duration >= 1 month < 6 months Similar to schizophrenia Less than half as common as schizophrenia 0.2% lifetime prevalence

76. Schizophreniform Disorder Usually young adults Family members more likely to have mood disorders Better outcome than schizophrenia More affective symptoms Episodic presentation like mood disorders

77. Clinical Presentation Rapid onset, no prodrome Delusions, hallucinations, negative symptoms-similar to schizophrenia Prodrome, active and residual phases last at least one month but less than 6 months Patient is back to baseline by 6 months 60-80% progress to schizophrenia

78. Treatment May respond to treatment more rapidly May need to use mood stabilizer if mood component and recurrence are an issue Treat as for schizophrenia

79. Schizoaffective Disorder Has features of both schizophrenia and affective disorders 0.5-0.8% lifetime prevalence ? Bipolar type more common in younger patients and depressive type more common in older F>M

80. Schizoaffective Disorder Etiology unknown Heterogeneous group: ? Related to mood disorders ? Related to schizophrenia ? An entity unto itself ? All of these Difficult diagnosis to make as require temporal course Bipolar type, depressive types possible Prognosis intermediate to schizophrenia and mood disorders

81. Schizoaffective Disorder: Clinical Picture Contiguous period of illness with: Criteria A for schizophrenia + Major depressive episode OR Mania OR Mixed episode OR During this same episode there were delusions and hallucinations for 2 weeks without prominent mood symptoms

82. Schizoaffective Disorder: Clinical Picture Mood symptoms are there for a “substantial” part of the active and residual period ( 15-20 % of total episode) Not due to substance or general medical condition

83. Schizoaffective Disorder: Treatment Mood stabilizers Antidepressants: use SSRI’s due to possibility of switch to mania with TCA’s Antipsychotics Benzodiazepines

84. Delusional Disorder Patient experiences nonbizarre (situations that could occur in real life) delusions for at least 1 month Criteria A for schizophrenia never met Can have tactile and olfactory hallucinations if congruent with delusion Function is not markedly impaired, behavior not obviously bizarre

85. Delusional Disorder Etiology unknown Less common than schizophrenia and mood disorders Prevalence 0.03 % Later onset than schizophrenia, mean age 40y Associated with recent immigration Many married and employed

86. Delusional Disorder More suspiciousness, jealousy in relatives of affected patients Diagnosis changes to schizophrenia or mood disorder in < 10 % Family studies do not support link to either mood disorders or schizophrenia

87. Delusional Disorder Hallucinations transient, not prominent Moods congruent to delusional content and brief in duration No marked though form disorganization Cognition intact Sensorium intact MSE remarkably normal given the intensity of delusional system

88. Delusional Disorder: Risk Factors Advanced age Sensory impairment Isolation Recent immigration Family history

89. Delusional Disorder Types: Erotomanic “de Clerambault’s syndrome” Jealous “ Othello syndrome” Persecutory Somatic Grandiose Mixed Capgras: familiar people replaced by doubles Fregoli’s phenomena: family can transform themselves to look like strangers Cotard’s syndrome: pt believes they have lost loved ones, status, job, internal organs

90. Shared Psychotic Disorder “Folie a Deux”: Pt develops delusion of another after associating closely with them Secondarily delusional pt Is gullible, passive, less intelligent May abandon delusion once separated Primary delusional pt is more dominant, chronically delusional

91. Delusional Disorder: Treatment Difficult to treat Antipsychotics ? Pimozide more effective in somatic delusions Separation for Shared Psychotic Disorder Psychotherapy