Overview of Psychosis and Schizophrenia Prodromal State

1. Psychosis
High Risk State &
Schizophrenia Prodrome
Dr, B
0ctober 2018

2. Objectives
• Define psychosis as a syndrome
• Differentiate paranoid, disorganized/excited, and depressive
psychosis
• Review symptoms and diagnostic criteria for schizophrenia
and related psychotic disorders
• Study the clinical high risk (HR) state for psychosis and
define at-risk subgroups
• List potential therapeutics in prodromal phase of psychosis

3. Psychosis

4. Psychosis is
a syndrome
Psychosis is a defining feature in:
• Schizophrenia
• Substance-induced psychotic disorders
• Schizophreniform disorder
• Schizoaffective disorder
• Delusional disorder
• Brief psychotic disorder
• Psychotic disorder due to a general medical
condition
Psychosis is an associated feature of:
• Mania
• Depression
• Cognitive disorders
• Alzheimer’s dementia

5. Paranoid Psychosis
• Paranoid projection
• Hostile belligerence
• Grandiose expansiveness

6. Disorganized/Excited Psychosis
• Conceptual disorganization
• Disorientation
• Excitement

7. Depressive Psychosis
• Psychomotor retardation
• Apathy
• Anxious self-punishment and blame

8. Positive Symptoms
• Delusions
• Hallucinations
• Distortions or exaggerations in
language and communication
• Disorganized speech
• Disorganized behavior
• *Catatonic behavior*
• Agitation
Negative Symptoms
• Blunted affect
• Emotional withdrawal
• Poor rapport
• Passivity
• Asociality
• Difficulty in abstract thinking
• Lack of spontaneity
• Stereotyped thinking
• Alogia
• Avolition
• Anhedonia
• Attentional impairment

9. “Positively Catatonic”
https://siberiantimes.com/other/others/news/how-a-unique-line-of-schizophrenic-rats-may-help-unlock-
secrets-of-complex-disease/
https://www.frontiersin.org/articles/10.3389/fnbeh.2016.00007/full

10. Localization of Symptom Domains
Stahl’s Essential Psychopharmacology, 4th Ed

11. Stahl’s Essential Psychopharmacology, 4th Ed
Dopamine Pathways
A. Nigrostriatal
 Substantia nigra to basal ganglia/striatum
 Part of extrapyramidal nervous system
 Controls motor function and movement
B. Mesolimbic
 Midbrain ventral tegmental area to nucleus accumbens
 Pleasure, euphoria of drug abuse
 Delusions/hallucinations of psychosis
C. Mesocortical
 Midbrain VTA to prefrontal cortex
 Cognitive sxs (DLPRF)
 Affective sxs (VMPFC)
D. Tuberoinfundibular
 Hypothalamus to anterior pituitary gland
 Prolactin secretion

12. http://slideplayer.com/slide/4332390/14/images/23/Major+Dopamine+Pathways.jpg

13. Schizophrenia
DSM-V Criteria

14. https://nobaproject.com/modules/schizophrenia-spectrum-disorders

15. Psychosis High-Risk State

16. JAMA PSYCHIATRY/VOL 70 (NO. 1) JAN 2013

17. HR Diagnosis

19. Model of Psychosis Onset

20. Outcomes

21. o 2500 HR individuals
o Mean (95% CI) transition risk
• 6 months follow-up: 18% (12%-25%)
• 1 year follow-up: 22% (17%-28%)
• 2 year follow-up: 29% (23%-36%)
• 3 year follow-up: 32% (24%-35%)
• After 3 years: 36% (30%-43%)
o (independent of psychometric instruments)

22. Outcomes Discussion
• Study participants are help-seeking
• # of individuals in community meeting HR criteria unknown
– Available instruments NOT indicated for screening in the
general population
• Little known about nonconverters
– Significant improvement in attenuated positive symptoms,
negative symptoms, social/role functioning
– Lower functioning compared to nonpsychiatric comparison
– Some resolve, but later develop psychotic disorder
• “Outpost” syndrome

23. Clinical and Functional Characteristics
• Comorbidities may include anxiety, depression,
substance abuse
• May have high levels of negative symptoms, impaired
academic/occupational functioning, interpersonal
relationship difficulties
• HR symptoms associated with psychosocial functioning
• Social impairment tends to be resistant to
pharmacological and psychosocial treatment
• HR state may also be associated with increased
suicidality

25. Reasons to include HR state
in DSM-V
• Ameliorate presenting symptoms,
problems, and functional deficits
• Reduce treatment delays if
individual later develops psychosis
– Less traumatic first-episode
• Grant access to health care system
• Allow establishment of rules to guide
treatment
– Avoid under- or overtreatment
Counter-arguments against
inclusion of HR State
• Concern for false-positive
patients
• Evidence suggesting declining
transition risk over recent years
• Concern that people meeting HR
criteria may be incorrectly
conceptualized as psychosis
spectrum
– Stigma
– Discrimination
– Unnecessary treatment

26. Prodromal Phase of
Schizophrenia

28. Duration of Untreated Psychosis (DUP)
• Longer duration of illness associated with persistent
symptoms and functional disabilities
• Longer DUP directly associated with:
– Worse functional outcomes
– Greater symptoms
– Poorer QOL
– Less response to antipsychotic medications
• Controlling for potential confounders (e.g. premorbid
functioning) does not negate association

29. Pharmacological Interventions
• “…treatments should be tailored to the patient’s needs
with safer and simpler treatments preceding psychotic
onset and increasingly intensive and aggressive
treatments following psychosis onset.”
Expert Rev Neurother. 2010 Aug;10(8):1347-59

30. Antipsychotics for Prodrome
• Five studies have examined the effects of antipsychotic
medications during the prodrome…

31. 1. McGorry PD, Yung AR, Phillips LJ, et al.; Arch. Gen. Psychiatry 2002;59:921–928.
• Open-label treatment study examining low doses of risperidone augmented by ‘enriched psychosocial treatment’ (cognitive–
behavioral therapy) compared with a standard supportive psychosocial intervention
– Standard intervention includes basic problem solving, case management, symptom monitoring, active listening, reflection and
support
• 59 individuals who evidenced subthreshold psychotic symptoms were randomized; antidepressant medications were allowed in
both groups
• Results indicated that of the 31 participants receiving medication and enriched psychosocial intervention, three (9.7%)
transitioned to a psychotic disorder over the 6-month period of the active treatment phase of the study
• By contrast, of the 28 participants receiving standard supportive psychosocial treatment, ten (35.7%) converted to a psychotic
disorder (results significant, p <0.05) over the 6-month period of the active treatment phase of the study.
• At the 12-month follow-up (during which no treatment was administered over the second 6-month period), three more of the
participants in the experimental group had converted while no additional control participants converted.
• This study does not allow for determination of the relative contribution of antipsychotic medication versus the enriched
psychosocial intervention, and the design did not include a ‘no treatment’ group. However, the results suggest that combined
pharmacologic and psychosocial treatment may delay or avert the onset of psychosis.
• The authors of this study found a NNT of four

32. 2. Cannon TD, van Erp TG, Rosso IM, et al.; Arch. Gen. Psychiatry 2002;59:35–41.
• Small, nonrandomized, open-label clinical trial/pilot study of risperidone provided evidence for the
potential efficacy of this antipsychotic medication for prodromal patients.
• Six first-episode schizophrenia patients were compared with four participants deemed to be at
UHR for psychosis. Participants were not on any other medications.
• At follow-up (8 weeks for schizophrenia patients, 12 weeks for prodromal patients) both groups of
participants evidenced significant reductions in positive symptoms and improvements in
neurocognition
• Limited by small sample size, lack of blinding, and absence of a control group

33. 3. Woods SW, Breier A, Zipursky RB, et al.; Biol. Psychiatry 2003;54:453–564.
• Double-blind, randomized, parallel-groups, placebo-controlled study conducted across four sites to examine the effect of
olanzapine on symptom severity in the prodrome (SOPS and PANSS scores).
• 30 patients in the olanzapine-treated group evidenced a significant improvement in symptoms relative to the placebo-
administered group over the 8-week treatment period. The participants were not currently on antidepressant medication, although
40% of the sample had previously been prescribed antidepressants.
• Researchers also examined the effect of olanzapine versus placebo on conversion rates over a longer time period (2 years) in a
randomized, double-blind trial of 60 treatment-seeking participants.
• After the first year of treatment, five out of 31 (16.1%) of the olanzapine-treated group converted to psychosis. By contrast, 11 out
of 29 (37.9%) of the placebo-administered group converted. These results did not reach statistical significance, but were
suggestive of a potentially meaningful effect.
• 17 of the original 60 participants continued the study into the second year, during which no active treatment was administered.
The conversion rate did not differ between the two groups (33% for the experimental group, 25% for the control group) after this
additional year. The olanzapine group’s conversion rate increased and the prodromal symptoms were significantly higher in
severity after the drug was stopped. The overall conversion rate for the whole sample was 35% (21 out of 60).
• These results suggest that the treatment did not afford protection after it ceased. Thus, active treatment may delay conversion to
psychosis, but there is no evidence that short-term treatment will avert conversion.
• The NNT found in this study 4.5

34. 4. Woods SW, Tully EM, Walsh BC, Hawkins KA, Callahan JL, Cohen SJ.; Br. J.
Psychiatry 2007;191:S96–S101.
• Small, nonrandomized study examined 15 participants after 8 weeks of receiving aripiprazole
• Results indicated reductions in positive, negative, disorganization and general symptoms and a
significant functional improvement

35. 5. Ruhrmann S, Bechdolf A, Kuhn K-U, Wagner M, Schultze-Lutter F, Janssen B.; Br. J.
Psychiatry 2007;191:S88–S95.
• Randomized parallel-group study comparing amisulpride plus needs-based treatment (n = 61) to
needs-based treatment alone (n = 40).
• Needs-based treatment included psychoeducation, crisis intervention, family counseling and
assistance with education or work-related difficulties.
• None of the participants were taking antidepressant medications
• At the 12-week outcome, amisulpride plus needs-based treatment was associated with a
reduction in positive, basic, negative and depressive symptoms, as well as an improvement in
functional deficits.

36. Antipsychotics for Prodrome
• Results from these studies suggest that intervention may
delay conversion to psychosis and ameliorate symptoms
during the active phase of treatment
• No evidence of lasting effects after treatment cessation.
• Long-term use of even low doses of antipsychotic
medication can cause sensitization of dopamine
receptors in the brain.
– May lead to “supersensitivity psychosis” or “rapid-onset
psychosis” following cessation of antipsychotic
medication

37. Antidepressants for Prodrome
• Three studies suggest that antidepressant medications
are associated with symptomatic improvement among
potentially prodromal adolescents and young adults.
• Causal relationship has not been determined
• Evidence suggests that antidepressants are better
tolerated in prodromal participants compared with
antipsychotics
– double-blind, randomized, parallel-group, placebo-
controlled trials are warranted

38. Psychological Interventions
• “…even individuals with psychosis who are adherent to
medication and whose symptoms respond to well to
antipsychotics commonly evidence residual symptoms
and functional impairments.”
Expert Rev Neurother. 2010 Aug;10(8):1347-59

39. Social skills, cognition, and interaction
training improve social functioning
• Psychoeducation
– Improved social adjustment
– Increased QOL
– Decreased family burden
• Cognitive Remediation
– Improved psychosocial functioning, functional outcomes, and
cognition
• Cognitive Behavioral Therapy (CBT)
– Guides patients to challenge/modify thoughts, emotions, and
behaviors
– Improves coping strategies to decrease level of conviction of
delusions/hallucinations

40. Expert Commentary
“Adolescents and young adults who appear to be prodromal or at UHR should be
monitored and provided with symptom-targeted treatments (e.g., antidepressants,
psychosocial treatments). Antipsychotics should be used as soon as frank
psychosis emerges. For the investigational treatments reviewed herein,
prodromal-appearing adolescents and young adults should be referred to
specialized research programs when possible. The potential benefits, and
minimal risks, associated with omega-3 fatty acids suggest that this treatment is
promising as an early intervention.”
Expert Rev Neurother. 2010 Aug;10(8):1347-59

41. Proposed Treatment Guidelines for HR State

42. Thank You