1) A study of mortality rates in patients with schizophrenia in Sweden found rates were 2-3 times higher than the general population, with suicide rates being particularly elevated. 2) Recovery from schizophrenia is possible for many patients with appropriate treatment, though a meta-analysis found only 13.5% of patients met strict recovery criteria. 3) Guidelines provide no clear consensus on the optimal duration of antipsychotic treatment for multi-episode schizophrenia. Long-term treatment aims to reduce relapse rates but risks include brain tissue reduction.

1. ‘NATURAL’ COURSE OF
SCHIZOPHRENIA
Dr. Walid Sarhan

2. Natural history of schizophrenia

3. Schizophrenia mortality: data from
Stockholm County, Sweden
• Mortality rates have previously been shown to be two to three times higher in patients
with schizophrenia than that in the general population
• This study aimed to assess mortality over time after a first admission to hospital with sc
hizophrenia
All causes Natural Cardiovascular Suicide Unspecified
violence
Year Male Female Male Female Male Female Male Female Male Female
1976–80 2.6 2.1 1.7 1.7 1.7 1.7 13.2 17.1 12.1 7.4
1981–85 2.7 2.6 1.8 2.0 2.0 2.1 16.9 28.5 12.6 9.9
1986–90 4.3 3.0 2.0 2.0 4.2 3.1 27.7 35.3 21.1 15.8
1991–95 9.4 3.6 4.4 2.1 8.3 5.0 47.8 58.6 45.2 15.8
Table shows observed over expected number of deaths for different causes in patients first
admitted to hospital with schizophrenia between 1976–1995

4. Treatment stages of patients with
schizophrenia
Advances in interventions have raised outcome expectations.
Remission has become achievable for many patients

5. Recovery in schizophrenia
• Jääskeläinen et al meta‐analysis of 50 studies
• Primary aims were to:
– Identify the proportion of individuals with schizophrenia a
nd related psychoses who met recovery criteria
– Examine which factors were associated with recovery
This review concluded that 42% of patients had a good outcome
13.5% of patients met recovery criteria
Recovery may be treatment‐related or spontaneous
No signs that we are ‘getting better’ at getting our patients better

6. DIFFICULTIES WITH DIAGNOSING
SCHIZOPHRENIA

7. DSM‐V diagnostic criteria: defining
features
• ≥2 symptoms present*, at least one of these mus
t be 1, 2 or 3:
1.Delusions
2.Hallucinations
3.Disorganized speech
4.Disorganized or catatonic behaviour
5.Negative symptoms
Criterion A. Characteristic symptoms

8. • Functioning in ≥1 major area significantly below
the level achieved prior to onset*
• Occupational/academic
• Interpersonal relations
• Self‐care
Criterion B. Social/occupational dysfunction

9. • Continuous signs of disturbance persist for at l
east 6 months
• This must include 1 month of symptoms and
may include periods of prodromal or residual s
ymptoms
Criterion C. Duration

10. TREATMENT AND GUIDELINES

11. Treatment recommendations from the guidelines
in multiple-episode patients: treatment duration
Guidelines Recommendation
American Psychiatric
Association (APA)1
•Indefinite maintenance of antipsychotic me
dication
•Monitor for signs and symptoms of relapse
British Association for
Psychopharmacology (BAP)2
• Not stated
National Institute for Health and Care
Excellence (NICE)3
• Not stated
World Federation of Societies of Biological
Psychiatry (WFSBP)4
• 2–5 years in patients with one relapse
• >5 years in multiple‐episode patients
Treatment guidelines do not offer a consensus on duration of treatment
for multi-episode schizophrenia (or for patients with
first-episode schizophrenia)

12. Guideline recommendations on use of
LAI APs

13. CONTINUOUS VERSUS
INTERMITTENT TREATMENT

14. Maintaining treatment
The treatment for patients with schizophrenia often involves the long‐term
administration of antipsychotics
Risks Benefits
• Reduction of brain tissue
• Antipsychotics have a subtle but
measurable influence on brain
tissue loss over time1
• Poor outcomes and higher
cumulative intake of antipsychotics
is associated with more
pronounced cortical thinning2
• Dysregulation of myelination
trajectory may contribute to the
aetiology of schizophrenia
• Antipsychotics increase
intracortical myelin in first‐episode
patients with schizophrenica3
• Atypical antipsychotic drugs may
enhance cellular resilience and
ameliorate the pathophysiology of
schizophrenia4
Long-term use of antipsychotics
is associated with the risk of brain
tissue reduction
Maintaining treatment with
antipsychotics is associated with fewer
recurrent episodes

15. Continuous medication was associated
with important HRQoL benefits at 3 years
• Changes in HRQoL
may be linked to impact of cli
nical changes on social functi
oning
• SOHO study
– Conducted in 10 European
countries
– HRQoL* assessed at study entry
and at 6‐monthly intervals
• Mean EQ‐5D scores increased
over time:
– Largest improvement occurred i
n the first 6 months
• Adjusted mean change in EQ-
5D tariff score after continuo
us antipsychotic treatment f
or 6–36 months

16. CONSEQUENCES AND PREDICTORS
OF RELAPSE

17. Consequences of relapse
Loss of
self-esteem
(due to stigma)
Potential
danger to self
and others
Increased
cost of care
Loss of
functional
achievements
Illness may
become resistant
to treatment
Harder to
re-establish
previous gains
Family burden
and
estrangement
Potential
neurobiological
sequelae
Social stigma
leading to
discrimination

18. Carers’ views on the impact of relapse
Survey of 982 family carers of patients with schizophrenia,
bipolar disorder and schizoaffective disorder
Impact of relapse
(carers’ perspective)
Patients unable to
work, hospitalized,
suicidal and/or
incarcerated
Deterioration of
carers’ financial w
ell-being
Deterioration of carers’
physical and emotional
health
Chaos of relapse:
more attention
should be focused
on long-term care,
not crisis
management

19. Predictors of relapse:
lack of adherence to treatment regimen
• Patient‐related factors
– Poor insight
– Cognitive impairment
– Psychiatric and other co‐morbidities
– Substance misuse
– Duration of untreated illness
– Stigma (both internal and social)
• Treatment‐related factors
– Efficacy and tolerability of antipsychotics
• Environmental factors
– Degree of family and social support available
– Healthcare setting

20. ROLE OF EARLY INTERVENTION:
IMPACT OF RELAPSE

21. First‐episode patients are at high risk
of relapse
There is a high rate of relapse within 5 years after a first episode

22. Relapse rates following transition to
intermittent treatment after 2 years’ optimal
maintenance treatment
94% of patients relapse within 2 years of receiving intermittent treatment

23. Early intervention study
• The first 3 years of illness (treated or untreated) offer a critical period in which to
prevent or limit potential long‐term decline
• The OPUS trial hypothesized that the critical period for early
• intervention is up to 5 years from onset2
• Results from the OPUS II trial are not currently available, however,
• extending specialized assertive treatment for up to 5 years may allow the
• beneficial effects to continue beyond the high‐risk period
Early intervention
during the critical
period can:
•Improve the course of psychosis and lead to a new plateau
• Prevent mental and social decline
• Result in a better outcome than intervention after the
critical period
•Prevent return to baseline if the intensity of intervention is r
elaxed

24. Relapse rates in patients treated with
LAI and oral medication
Significantly fewer participants receiving depot formulations (21.6%)
experienced relapse compared with oral formulations (33.3%)

25. Meta‐analysis of relapse rates at the lo
ngest study time point
• Fluphenazine‐LAI showed signific
ant superiority over OAPs (studies
=8, n=826, RR=0.79, 95% CI 0.65–
0.96, p= 0.02)
• Other LAIs were not significantly s
uperior to OAPs (pooled RRs for
each LAI ranged from 0.99 to 1.2
8)
• When pooled together, the risk fo
r LAI was similar to the risk for O
APs (studies=21, n=4950, RR=0.9
3, 95% CI 0.80–1.08, p= 0.35)
• FGA-LAIs (not SGA-
LAIs) outperformed OAPs. Howe
ver, the difference in effect was
not statistically relevant and may
be due to a cohort effect

26. ANTIPSYCHOTICS: MONITORING
SIDE EFFECTS

27. Trends in treatment
Data collected from 2895 newly treated patients with schizophrenia
spectrum disorder from 1999 to 2006
• The percentage of SGA prescripti
ons increased significantly from
1999 to 2006
• The percentage of FGAs,
anticholinergics
and those on >1 antipsychotic
for more than 6 weeks declined
• Adherence increased from 23.2%
in 1999 to 38.9% in 2006
Pharmacological treatments have changed over the years with the introduction
of second-generation antipsychotics

28. Antipsychotics: relative adverse effects
Antipsychotic Sedation Weight gain Extra-
pyramidal
symptoms
Hypotension Prolactin
elevation
Flupentixol + ++ ++ + +++
Fluphenazine + + +++ + +++
Haloperidol + + +++ + +++
Zuclopenthixol ++ ++ ++ + +++
Amisulpride ‐ + + ‐ +++
Aripiprazole ‐ +/‐ +/‐ ‐ ‐
Clozapine +++ +++ ‐ +++ ‐
Olanzapine ++ +++ +/‐ + +
Paliperidone + ++ + ++ +++
Quetiapine
IR/XR
++ ++ ‐ ++ ‐
Risperidone + ++ + ++ +++
Ziprasidone + +/‐ +/‐ + +/‐

29. THE USE OF POLYPHARMACY
IN SCHIZOPHRENIA

30. Guideline recommendations: treatment for
co‐morbid conditions in acute care
Benzodiazepines
May be used to
manage catatonia, anxiety and a
gitation until antipsychotic med
ication reaches therapeutic
efficacy
Antidepressants With the increasing availability of
antidepressant agents which provide a more acceptable side effec
t profile than the older tricyclic molecules/drugs/compounds, anti
depressants can be more widely prescribed
Mood stabilizers
and beta-blockers
May be considered
for reducing the seve
rity of recurrent
hostility and aggressi
on
Anticholinergics
Should not be
prescribed
prophylactically, on
ly for treatment of
EPS
Careful attention
Should be paid to
potential drug–drug
interactions, especially
those related to
metabolism by
cytochrome P450
enzymes

31. Polypharmacy to monotherapy
•Adult outpatients (n=127) receiving two antipsychotics were random
ized to switch to monotherapy or stay on polypharmacy
• Although switching to monotherapy
treatment resulted in a significantly
higher rate of treatment
discontinuation
• Two‐thirds of participants
successfully switched to monotherapy
• Switched patients did not have a po
orer symptom control
• Switching to monotherapy resulted i
n weight loss (average decrease in B
MI of 0.5 points)

32. HOW TO HANDLE SWITCHING
ANTIPSYCHOTICS

33. Guideline recommendations
for antipsychotic switching

34. Three aspects to remember when switching
antipsychotics: 1. half‐life, 2. receptor binding
profile and 3. the patient

35. Three aspects to remember when switching
antipsychotics: 1. half‐life, 2. receptor binding profile
and 3. the patient
• Urgency of clinical situation
• Past and current response to medication1,3
• Severity of illness
• Current stability of patient2,3
• Are plasma levels of pre‐switch antipsychotic
at steady state? (duration of treatment? adh
erence?)1
The patient/clinical
situation

36. Switching strategies: three techniques
To achieve success when choosing a switching strategy, the half‐life and receptor
binding profiles of antipsychotics needs to be considered

37. ROLE OF PSYCHOSOCIAL
INTERVENTIONS

38. Does care in the community reduce
burden on healthcare systems?
• Integrated care is the combination of psychosocial and pharmacological treatm
ent, which varies based on the patient’s:
– Stage of disease
– Frequency of relapse
– Level of treatment adherence
– Presence of treatment‐resistant symptoms
– Presence of co‐morbid substance abuse
• Adherence to antipsychotic medication and receipt of psychosocial
thrapies
– Can reduce the number and duration of hospitalizations for patients with
schizophrenia
• Antipsychotic medication that is taken as prescribed can increase the cost‐effe
ctiveness of schizophrenia treatment
– By reducing hospitalizations and inpatient care
– Even in spite of higher medication costs
Providing integrated care in the community setting can reduce the burden on healthc
are systems

39. Integrated care
• Management of integrated care is important to
balance continuous delivery of medication with
therapies that support social rehabilitation
– Is key to ensuring a successful transition from the in
patient to outpatient setting
Cognitive
Behavioural Therapy
(CBT)
Helps patients
identify and modify
negative thoughts
about medication and
improve adherence
Psychoeducation
Can change
medication attitudes,
therefore improving
medication
adherence
Motivational
interviewing
Assesses patients’
motivation to make
changes in behaviour
related to adherence
Meta-cognitive
therapy4
Aims to change
the way in which pe
ople
experience and
regulate their
thoughts

40. Integrated care and patient outcomes
• 1268 patients with early‐stage schizophrenia randomiz
ed to either:
• Antipsychotic medication alone, or with added psychoe
ducation, family intervention, skills training and CBT
• Combined therapy resulted in:
• Significantly lower risk of all‐cause discontinuation and
relapse
• Significantly greater improvements in insight, social fun
ctioning, activities of daily living and four domains of
QoL assessment
• Significantly improved likelihood of obtaining employm
ent or accessing education

42. Can functional recovery be achieved using
integrated treatment?
• 1‐year follow‐up of first‐episode patients with
out prior treatment:
– Integrated care (n=39) including pharmacotherapy
, psychosocial treatment and psychoeducation
– Medication only (n=34)

43. Integrated
care (%)
Medication
only (%)
p value
Relapse 10.3 35.7 <0.01
Rehospitalization 5.1 10.7 NR
Adherence 85 67.6 <0.01
Symptomatic remission 94.9 58.8 NR
Functional remission 56.4 3.6 <0.01
Functional recovery 56.4 2.9 <0.01
Integrated care provided additional benefits compared
with medication alone