update on schizophrenia
DESCRIPTION
focus on neurolepticsTRANSCRIPT
‘NATURAL’ COURSE OF SCHIZOPHRENIA
Dr. Walid Sarhan
Natural history of schizophrenia
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 schizophrenia
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
Treatment stages of patients with schizophrenia
Advances in interventions have raised outcome expectations.Remission has become achievable for many patients
Recovery in schizophrenia
• Jääskeläinen et al meta analysis of 50 studies‐• Primary aims were to: – Identify the proportion of individuals with schizophrenia and 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
DIFFICULTIES WITH DIAGNOSING SCHIZOPHRENIA
DSM V diagnostic criteria: defining ‐features
• ≥2 symptoms present*, at least one of these must be 1, 2 or 3:
1.Delusions2.Hallucinations3.Disorganized speech4.Disorganized or catatonic behaviour5.Negative symptoms
Criterion A. Characteristic symptoms
• Functioning in ≥1 major area significantly below the level achieved prior to onset*
• Occupational/academic• Interpersonal relations• Self care‐
Criterion B. Social/occupational dysfunction
• Continuous signs of disturbance persist for at least 6 months
• This must include 1 month of symptoms and may include periods of prodromal or residual symptoms
Criterion C. Duration
TREATMENT AND GUIDELINES
Treatment recommendations from the guidelines in multiple-episode patients: treatment durationGuidelines Recommendation
American Psychiatric Association (APA)1
•Indefinite maintenance of antipsychotic medication•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)
Guideline recommendations on use of LAI APs
CONTINUOUS VERSUS INTERMITTENT TREATMENT
Maintaining treatmentThe treatment for patients with schizophrenia often involves the long term ‐
administration of antipsychoticsRisks 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
Continuous medication was associatedwith important HRQoL benefits at 3 years
• Changes in HRQoL may be linked to impact of clinical changes on social functioning
• SOHO study– Conducted in 10 European countries– HRQoL* assessed at study entry a
nd at 6 monthly intervals‐
• Mean EQ‐5D scores increased over time:– Largest improvement occurred in
the first 6 months
• Adjusted mean change in EQ-5D tariff score after continuous antipsychotic treatment for 6–36 months
CONSEQUENCES AND PREDICTORS OF RELAPSE
Consequences of relapseLoss of
self-esteem (due to stigma)
Potentialdanger to selfand others
Increasedcost of care
Loss offunctional
achievements
Illness maybecome resistantto treatment
Harder tore-establish
previous gains
Family burdenand
estrangement
Potentialneurobiological
sequelae
Social stigma leading to
discrimination
Carers’ views on the impact of relapseSurvey 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
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
ROLE OF EARLY INTERVENTION:IMPACT OF RELAPSE
First episode patients are at high risk ‐of relapse
There is a high rate of relapse within 5 years after a first episode
Relapse rates following transition to intermittent treatment after 2 years’ optimal
maintenance treatment
94% of patients relapse within 2 years of receiving intermittent treatment
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 relaxed
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%)
Meta‐analysis of relapse rates at the longest study time point
• Fluphenazine‐LAI showed significant superiority over OAPs (studies=8, n=826, RR=0.79, 95% CI 0.65–0.96, p= 0.02)
• Other LAIs were not significantly superior to OAPs (pooled RRs for each LAI ranged from 0.99 to 1.28)
• When pooled together, the risk for LAI was similar to the risk for OAPs (studies=21, n=4950, RR=0.93, 95% CI 0.80–1.08, p= 0.35)
• FGA-LAIs (not SGA-LAIs) outperformed OAPs. However, the difference in effect was not statistically relevant and may be due to a cohort effect
ANTIPSYCHOTICS: MONITORING SIDE EFFECTS
Trends in treatmentData collected from 2895 newly treated patients with schizophrenia
spectrum disorder from 1999 to 2006
• The percentage of SGA prescriptions 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 2006Pharmacological treatments have changed over the years with the introduction
of second-generation antipsychotics
Antipsychotics: relative adverse effectsAntipsychotic Sedation Weight gain Extra-
pyramidal symptoms
Hypotension Prolactin elevation
Flupentixol + ++ ++ + +++
Fluphenazine + + +++ + +++
Haloperidol + + +++ + +++
Zuclopenthixol ++ ++ ++ + +++
Amisulpride ‐ + + ‐ +++
Aripiprazole ‐ +/‐ +/‐ ‐ ‐
Clozapine +++ +++ ‐ +++ ‐
Olanzapine ++ +++ +/‐ + +
Paliperidone + ++ + ++ +++ Quetiapine IR/XR
++ ++ ‐ ++ ‐
Risperidone + ++ + ++ +++
Ziprasidone + +/‐ +/‐ + +/‐
THE USE OF POLYPHARMACY IN SCHIZOPHRENIA
Guideline recommendations: treatment forco morbid conditions in acute care‐
Benzodiazepines May be used to
manage catatonia, anxiety and agitation until antipsychotic
medication reaches therapeutic efficacy
Antidepressants With the increasing availability of antidepressant agents which provide a more acceptable side effect profile than the older tricyclic molecules/drugs/compounds, antidepressants can be more widely prescribed
Mood stabilizers and beta-blockers May be considered for reducing the severity of recurrent hostility and aggression
AnticholinergicsShould not be prescribed prophylactically, only for treatment of EPS
Careful attention Should be paid to potential drug–drug
interactions, especially those related to metabolism by
cytochrome P450 enzymes
Polypharmacy to monotherapy•Adult outpatients (n=127) receiving two antipsychotics were randomized 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 BMI of 0.5 points)
HOW TO HANDLE SWITCHING ANTIPSYCHOTICS
Guideline recommendations for antipsychotic switching
Three aspects to remember when switching antipsychotics: 1. half life, 2. receptor binding‐
profile and 3. the patient
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? adherence?)1
The patient/clinical situation
Switching strategies: three techniquesTo achieve success when choosing a switching strategy, the half life and receptor ‐
binding profiles of antipsychotics needs to be considered
ROLE OF PSYCHOSOCIAL INTERVENTIONS
Does care in the community reduce burden on healthcare systems?
• Integrated care is the combination of psychosocial and pharmacological treatment, 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‐effectiveness 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 healthcare systems
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 inpatient to outpatient setting
Cognitive Behavioural Therapy
(CBT)Helps patients
identify and modify negative thoughts
about medication and improve adherence
PsychoeducationCan change medication attitudes, therefore improving medication adherence
Motivational interviewingAssesses patients’ motivation to makechanges in behaviour related to adherence
Meta-cognitive therapy4Aims to change the way in which people experience and regulate their thoughts
Integrated care and patient outcomes
• 1268 patients with early‐stage schizophrenia randomized to either:
• Antipsychotic medication alone, or with added psychoeducation, 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 functioning, activities of daily living and four domains of QoL assessment
• Significantly improved likelihood of obtaining employment or accessing education
Can functional recovery be achieved using integrated treatment?
• 1 year follow up of first‐ ‐ ‐episode patients without prior treatment:– Integrated care (n=39) including pharmacotherapy, psychosocial treatment and psychoeducation
–Medication only (n=34)
Integrated care (%)
Medicationonly (%)
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