Download Schizophrenia - School of Psychiatry

Sarmad Nadeem
Consultant Psychiatrist
Overview of the presentation
 Introduction
 Pharmacological interventions
 NICE guidelines
 Non-pharmacological interventions
 Summary
Introduction
 Although antipsychotic medications are the mainstay
of the treatment for schizophrenia, research has found
that psychosocial interventions, including
psychotherapy, can augment the clinical improvement
Biopsychosocial approach
 The complexity of schizophrenia usually renders any
single therapeutic approach inadequate to deal with
the multifactorial disorder
 Psychosocial modalities should be integrated into
drug treatment regimen and should support it
Economic burden
 Schizophrenia costs society £11.8 billion a year, much
of which could be spent more effectively
 London School of economics report
Primary goals of hospitilisation
1.
Diagnostic purposes
2. Medication stabilization
3. Safety of patients and others
4. Grossly disorganized behaviour
5. Establishing an effective association between
patients and community support systems
Hospital treatment plans
 Should be oriented towards practical issues of:

Self-care

Quality of life

Employment

Social relationships
& coordinated with aftercare facilities
Pharmacotherapy
 Chlorpromazine 1952- the most important
contribution to treatment of psychiatric illnesses
 Antipsychotic medications are effective for decreasing
the severity of psychotic symptoms, reduce relapse rate
in acute and maintenance treatment of schizophrenia
Pharmacotherapy
 Placebo-controlled clinical trials with
antipsychotic medication in the acute phase of
schizophrenia have consistently demonstrated that
the active drug is significantly more effective

(Davis and Garver, 1978; Fleischhacker, 1999).
Pharmacotherapy
 The efficacy of antipsychotics in schizophrenia is not in
doubt, with a systematic review and meta-analysis of 38
RCTs that compared SGAs with placebo in schizophrenic
patients revealing a moderate effect size of around 0.5 and
a number needed to treat (NNT) of 6 for response

(Leucht et al., 2009a)
Pharmacotherapy
 Drugs used in schizophrenia have a wide variety of
pharmacological properties, but all share capacity to
anatagonise postsynaptic dopamine receptors in the
brain
 Nearly all patients on antipsychotic medications will
experience some burden from side effects
Pharmacotherapy
 A key pharmacologic property of antipsychotic drugs is
that they block the effects of dopamine at D2 receptors
 A consistent level of dopamine blockade being achieved
within a few days of starting treatment
What is the difference between
antipsychotics?

Pharmacology

Kinetics

Overall efficacy/effectiveness

Tolerability
Pharmacotherapy
 Most importantly response and tolerability differs
between patients
 This variability of individual response means that
there is no clear first line antipsychotic suitable for all
Early response
 Agid et al. (2003) a metanalysis of 42 double-blind,
controlled trials of antipsychotic response during the
first 4 weeks of treatment
 The findings suggested that antipsychotic response
begins within the first week of treatment and is
cumulative over the subsequent weeks
 In a multi-centre, double-blind, placebo-controlled study Kapur
et al. (2005) tested how early this response might be evident; 311
patients with an acute episode of schizophrenia were randomly
assigned to olanzapine (10 mg-I M), haloperidol (7.5 mg -IM) or
intramuscular placebo.
 Definite improvement in psychotic symptoms was observable
within the first 24 hours
First Vs Second generation
Antipsychotics
 Typicals and Atypicals were re-classified to first Generation
(FGAs) and Second Generation antipsychotics (SGAs)
 The essential difference between the two groups is the size
of therapeutic index in relation to acute Extra Pyramidal
Side effects
For example :
 Haloperidol has an extremely narrow index probably
less than 0.5 mg/day
 Olanzapine on the other hand have wide index
20-40mg/day
CATIE & CUtLASS
 Compared 51 FGAs vs 11 SGAs
 Concluded that there is no convincing evidence to
support any advantage for SGAs over FGAs
 (with possible exception of Clozapine & Olanzapine )
SGAs
 When individual (non-clozapine SGAs) are compared
with each other, Olanzapine is more effective than
aripiprazole, risperidone, quetiapine and ziprasidone
Recent network meta-analysis
 Ranked amisulpiride second behind clozapine, and
olanzapine third.
 Bear in mind the magnitude of these differences is
small but described as potentially substantial enough
to be clinically important
Leucj S et al. comparative efficacy & tolerability of 15 antipsychotic
drugs in schizophrenia: multiple treatment metanalysis lancet 2013
Adverse effects
 Both FGAs & SGAs are associated with a number of adverse
effects
 Exact profile is drug-specific
 It’s a common reason for treatment discontinuation
 Patients don not always spontaneously report side effects
 Psychiatrists views of prevalence & importance of adverse
effects differs markedly from patients’ experience
Phases of treatment
 Treatment of acute phase
 Treatment during stabelisation and maintenance
phase
Treatment of Acute phase
 Average duration of acute phase is 4-8 weeks
 Immediate attention is required
 Alleviate psychotic symptoms
 Manage agitation
 The longer the duration of untreated psychosis (DUP)
the worse the prognosis
 Leucht et al. (2003) reported a meta-analysis of the data
from 10 relapse prevention studies comparing FGAs and
SGAs in patients with established schizophrenia
 There was a modest but statistically significant reduction
in relapse rate with SGAs; the overall relapse rate with the
‘high-potency’ FGA haloperidol was 23% while the figure
for SGAs was 15%
First episode of psychosis
 First episode psychosis Early intervention in psychosis
services should be accessible to all people with a first
episode or first presentation of psychosis, irrespective
of the patient’s age or the duration of untreated
psychosis
First episode of psychosis
 The choice of antipsychotic medication should be
made by the patient and healthcare professional
together, taking into account the views of the carer
if the service user agrees
First episode of psychosis
 Provide information and discuss the likely benefits and possible side effects of
each drug, including:

Metabolic (including weight gain and diabetes)

Extrapyramidal (including akathisia, dyskinesia and dystonia)

Cardiovascular (including prolonging the QT interval)
 Hormonal (including increasing plasma prolactin)
 Other (including unpleasant subjective experiences)
First episode of psychosis
 Do not initiate regular combined antipsychotic
medication, except for short periods (for example,
when changing medication)
NICE- Recommendations for first-episode schizophrenia
 If the onset of psychosis is suspected the patient
should be referred to specialist mental health
services, ideally an early intervention in psychosis
service
 Assess the nature and impact of any substance use
 Choice of first-line antipsychotic drug should be
based on:




The evidence for relative liability for side effects,
particularly considering common and serious effects
such as extrapyramidal motor syndromes and metabolic
problems.
Individual patient preference
Individual patient risk factors for side effects
Relevant medical history.
 Antipsychotic medication should be initiated at the lower
end of the licensed dosage range
 An individual trial of the antipsychotic of choice should be
conducted:



The indications for oral antipsychotic medication
The expected benefits and risks
The anticipated timeframe for improvement of symptoms
and emergence of side effects should be considered and
documented
 Dosage titration should be within the dose range
identified in the BNF or Summary of Product
Characteristics (SmPC), and conducted gradually,
based on the response of symptoms or behaviour
and the nature and tolerability of side effects
 The results of symptom and side effect review should be
documented in the clinical records, with the rationale for
any change in medication or its continuation
 Aim to achieve an adequate trial: optimum dosage with
good adherence for 4 weeks.
 If an FGA is selected, this probably should be a medium- or
low-potency drug rather than a high potency drug
 Following antipsychotic drug initiation, side effects
should be closely monitored with regular, systematic
and comprehensive assessment
 Consideration should be given to the use of formal side
effect checklists or rating scales.
NICE- Recommendations: Acute psychotic episoderelapse
 Choice of antipsychotic drug should be based on the same
criteria as suggested for first-episode, but should
additionally take into account:


Any preference a patient may have for particular antipsychotic medication
A patient’s past experience of individual antipsychotic drugs in terms of relief of
symptoms and side effects, including aversive subjective experiences.
 Seek to conduct an adequate trial of the chosen
antipsychotic drug in terms of dosage, duration
(up to 4 weeks at optimum dosage) and
medication adherence
 Dosage should be titrated against side effects and efficacy
 If starting an antipsychotic that the patient has not previously
been prescribed, the initial dosage should be at the lower end of
the licensed range and slowly titrated upwards, if indicated, to
the optimal range for that drug, and not exceeding the maximum
licensed dose given in the BNF or SmPC.
 Initial loading doses (‘rapid neuroleptization’) should not be used
 The justification for dosages outside the range given in the BNF or
SmPC should be documented in the clinical records.
 Regular combined antipsychotic medication should not be prescribed
routinely, except for short periods when switching from one
antipsychotic to another.
 Anticholinergic agents should not be prescribed
prophylactically with antipsychotic medication,
but rather their use for emergent extrapyramidal
problems responsive to such medication
 Subsequent acute episodes of psychosis or schizophrenia and referral
in crisis Offer CBT to all people with psychosis or schizophrenia
 This can be started either during the acute phase or later, including in
inpatient settings
 Offer family intervention to all families of people with psychosis or
schizophrenia who live with or are in close contact with the patients
This can be started either during the acute phase or later, including in
inpatient settings
Pharmacotherapy
 Although many people with psychosis and
schizophrenia respond to antipsychotic drugs initially,
around 80% relapse within five years, partly because
they discontinue medication, which for many people
has unacceptable side effects
Pharmacotherapy
 However, although around 75% of people with
schizophrenia recurrently relapse and have continued
disability, there is a moderately good long term global
outcome in over half
Treatment during stabelisation and
maintenance phase
 Goals are


Prevent psychosis
Improve level of function
 Stable patients who are maintained on an antipsychotic
have a much lower relapse rate than patients who
discontinue their medications
Risk of relapse within a year
 16%-23% on treatment
 53%-72% without treatment
 Patients with one episode have a four in five chance of
relapsing
 Stopping the medications increases this risk five folds
How long should patient continue on antipsychotics
after the first episode?
 Given the absence of reliable predictors of
prognosis or drug response, consensus guidelines
recommend continued antipsychotic medication
for every patient diagnosed with schizophrenia for
1–2 years

(Buchanan et al., 2010; National Institute for Health and Clinical Excellence,2009b).
How long should maintenance
treatment continue?
 In the SOHO study (Ciudad et al., 2008; Suarez and
Haro, 2008), 4206 (65%) of 6516 patients achieved
remission with medication, of whom 25% relapsed
over a subsequent 3-year follow-up period.
 Most treatment guidelines recommend
continuation of antipsychotic medication for every
patient diagnosed with schizophrenia
(Buchanan et al., 2010; Gaebel et al., 2005;
 Smith et al. 2009, suggesting that this is
maintained for at least 6 months to 2 years
 Bosveld-van Haandel et al. (2001) criticized such
recommendations for being based on medium-term
studies lasting for less than 3 years, and on the basis of
their own systematic review of the relevant literature
concluded that it was reasonable to treat patients for
longer periods than indicated by current guidelines
 Recent data suggest 1-2 years maintenance is not
enough
 It is generally recommended that multiepsode patients
receiving maintenance treatment for at least 5 years and
many experts would recommend pharmacotherapy on
indefinite basis
Noncompliance
 Very high rate of non-compliance in long term antipsychotic
treatment
 Only 10 days after discharge from hospital up to 25% are
partially or non-compliant
 Up to 50% at one year
 Up to 75% at 2 years
Non-compliance increases the risk
of the following:
 Relapse
 Severity of relapse
 Duration of hospitalization
 Suicide attempts by four-fold
Dosage
 There is evidence that first-episode psychosis responds
to lower doses of antipsychotic medication than those
required for the treatment of established
schizophrenia, even when stringent criteria for
response are applied
 (Crespo-Facorro et al., 2006; Robinson et al. 1999; Schooler et al., 2005).
 There is a biological sensitivity to antipsychotics in the early
stages of the illness which applies to both the therapeutic
effects and the adverse effects
 Thus, there is a consensus that clinicians should use the
lowest recommended dosage of an antipsychotic when
initiating medication in an individual presenting with their
first episode of psychosis

(Lehman et al., 2004; Spencer et al., 2001; Taylor et al., 2009b).
Long-Acting depot injection
 Active drug in an oily suspension
 Depots are associated with a reduced risk of relapse
and rehospitilisation
 FGAs & SGAs are available
Continuation of antipsychotic medication
 Placebo-controlled trials with FGAs in first-episode
samples have consistently demonstrated a substantial
advantage for active medication in the prevention of
relapse
(Crow et al., 1986; Hogarty and Ulrich, 1998; Kane et al., 1982; Robinson et al., 2005)
Continuation of antipsychotic medication
 The same was found to be true in a placebo-controlled
RCT of the SGA- quetiapine
(Chen et al.,2010)
 There is no doubt that antipsychotic discontinuation is
strongly associated with relapse during this period
(RobinsonBarnes et al. 5et al., 1999)
Treatment resistant Schizophrenia
 TRS: Failure to respond to two or more antipsychotic
medications given in therapeutic doses for 6 weeks or
more
 Approximately 30% of patients respond poorly to
antipsychotics
 About 7% show total non-response
How to manage TRS?
 Clarify diagnosis
 Address comorbidity
 Consider non-compliance
 Pharmacological interventions: Clozapine then augment
 Rehabilitation
Continuing medication for relapse
prevention
 For the majority of first-episode patients treated with an antipsychotic
there will be a satisfactory response to antipsychotic medication within
4 weeks, and the aims of continued prescription of an antipsychotic are
to prevent relapse, maintain long-term control of symptoms and
behaviour and improve quality of life, with minimal adverse effects.
 One goal is to facilitate engagement in psychosocial
treatment; there is evidence that those individuals
achieving greater improvement in symptoms with
optimal pharmacotherapy can derive greater benefit
from psychosocial interventions such as social skills
training, CBT, cognitive remediation and social
cognition training

(Dixon et al., 2010; Hogarty et al., 1979; Kern et al., 2009; Marder et al., 2003; Rosenheck et al., 1998).
 Investigators in the Schizophrenia Outpatient
Health Outcomes (SOHO) study (Novick et al.,
2009) followed a large outpatient cohort study over
3 years
 Analysis of the follow-up data on 6642 patients
showed that long-lasting symptomatic remission had
been achieved in a third (33%), just over a quarter
(27%) had long-lasting adequate quality of life and 13%
achieved long-lasting functional remission
 Medium- to long-term cohort studies of this kind suggest
that around 20% of people diagnosed with schizophrenia
show complete recovery and, overall, 40% regain good
social functioning, with 16% of early unremitting cases
achieving late phase recovery

(Crumlish et al., 2009; Gaebel and Frommann, 2000; Harrison et al., 2001; Harrow et al., 2005; Hopper
and Wanderling, 2000).
 It is uncertain to what extent a better long-term prognosis might be
mediated by effective prevention of relapse
 Historical reviews of response rates reported over the 20th century
before and after the introduction of antipsychotic drugs suggest that
this medication may make only a limited contribution to such
outcomes

(Hegarty et al. 1994; Warner, 1994)
Choice of antipsychotic for relapse
prevention
 Only a relatively small number of longer-term,
relapse prevention trials have been conducted, and
the data are insufficient to allow assessment of the
relative merits of individual antipsychotics
Monitoring antipsychotic
medication-NICE
 The secondary care team should maintain responsibility for monitoring
service users’ physical health and the effects of antipsychotic
medication for at least the first 12 months or until the person’s
condition has stabilised, whichever is longer Thereafter, the
responsibility for this monitoring may be transferred to primary care
under shared care arrangements
Care across all phases—physical
health
 People with psychosis or schizophrenia, especially
those taking antipsychotics, should be offered a
combined programme of healthy eating and physical
activity by their mental healthcare provider
Non-pharmacological interventions
 For most individuals, antipsychotic medications
control the symptoms while non-pharmacological
treatments address the impairments in social,
vocational, and educational functioning
 The longstanding dependence of services on
antipsychotic drugs as the sole treatment for people
with psychosis and schizophrenia has led to
polypharmacy and inappropriate use, including as a
means to prevent psychosis.
 Patient and family education
 Skills training
 Supported employment
 Psychotherapies
 Offer people with psychosis or schizophrenia who
smoke help to stop smoking, even if previous attempts
have been unsuccessful
 Offer supported employment programs to people with
psychosis or schizophrenia who wish to find or return
to work
 Consider other occupational or educational activities,
including pre-vocational training, for people who are
unable to work or unsuccessful in finding employment
Support for carers
 As early as possible negotiate with patient and carers about
how information about the service user will be shared.
 Offer carers an assessment
 Offer a carer focused education and support programme,
which may be part of a family intervention for psychosis
and schizophrenia, as early as possible to all carers. The
intervention should - Be available as needed - Have a
positive message about recovery
Psychological therapies
 NICE guidelines

Offer CBT to all people with psychosis or schizophrenia

Offer family intervention to all families of people with psychosis or
schizophrenia who live with or are in close contact with the patient

Consider offering arts therapies to all people with psychosis or
schizophrenia, particularly for the alleviation of negative symptoms.
Family intervention
 Should include the person with psychosis or schizophrenia





if practical
To be carried out between 3 months and 1 year
Include at least 10 planned sessions
Take account of the whole family's preference for either
single-family intervention or multi-family group
intervention
Take account of the relationship between the main carer
and the person with psychosis or schizophrenia
Have a specific supportive, educational or treatment
function and include negotiated problem solving or crisis
management work
CBT
 CBT should be delivered on a one-to-one basis over at
least 16 planned sessions and it should follow a
treatment manual so that:

People can establish links between their thoughts, feelings or
actions and their current or past symptoms, and/or
functioning the re-evaluation of people's perceptions, beliefs
or reasoning relates to the target symptoms also include at
least one of the following components:
People monitoring their own thoughts, feelings or behaviours
with respect to their symptoms or recurrence of symptoms
 Promoting alternative ways of coping with the target symptom
 Reducing distress
 Improving functioning

 Studies by Drury et al showed that cognitive therapy
reduced positive symptoms at a faster rate during the initial
12-week period following hospital admission, and the
overall amount of positive symptoms were reduced during
this time compared to those patients that received an equal
amount of activity therapy and support
 There was no difference in the decrease in negative
symptoms between the groups during the initial 12-week
period
 At nine-month follow up, the group that received cognitive
therapy continued to have significantly fewer positive
symptoms than the control group
 At the follow up, there was no difference in negative
symptoms.
 In addition, Drury et al found more rapid improvement in
clinical recovery as measured by increased insight, less
dysphoria and “low level” psychotic thinking, and less
disinhibition
 Tai and Turkington summarize the results of the CBT
studies and reviews of these studies with the following
points:
 Randomized controlled trials (RCTs) have shown moderate
effect sizes for positive and negative symptoms at the end of
therapy and with sustained effects.
 CBT has been effective in clinical as well as research settings
 Hallucinations and delusions respond to CBT
 Negative symptoms respond initially, and improvement
remains at medium-term follow up
 Tai and Turkington acknowledge that
1) CBT is not as effective when people do not view
themselves as having a mental health problem, have
delusional systems, or have extreme primary
negative systems
2) When people have comorbid disorders, such as
substance misuse, because they are more difficult to
engage and treat. However, CBT does show promise
even in these more complex clinical situations
18. Tai S, Turkington D. The evolution of cognitive behavior therapy for schizophrenia:
current practice and recent developments. Schizo Bull. 2009;35(5):865–873.
Factors to predict improvement with CBTp
 In Drury et al,
 Early work with acutely psychotic inpatients,
 Female gender,
 Shorter duration of illness
 Shorter duration of untreated illness
Tarrier et al,
 A stable
 Outpatient population
 With persistent symptoms,
 Shorter duration of illness
 Less severe symptoms
 Brabban et al cited
 Female gender
 Low level of conviction in delusions as
predicting positive response to CBT
Tarrier N, Yusupoff L, Kinney C, et al. Randomised controlled trial of intensive
cognitive behaviour therapy for patients with chronic schizophrenia. BMJ. 1998;317:303–
307
Family therapy for Schizophrenia
 ‘The main benefit of family intervention for people
with schizophrenia is that it may decrease the risk of
relapse.’ It can also help to ensure that they take their
medication consistently, and may reduce family
tensions. ‘For this gain, which could be perceived as of
moderate certainty, people with schizophrenia and
their families should be willing to spend a significant
amount of time in contact with services.’
Family therapy for Schizophrenia
 Sixteen trials covering a total of 857 participants
suggest that family intervention may reduce the
frequency of relapse among patients although the
authors note that their searches may have failed to
uncover some small negative studies
Family therapy for Schizophrenia
 Eight trials (481 patients) indicate that family
intervention may reduce hospital admissions, and this
finding is in contrast to that of the ‘equivocal data’
reported in the previous version of the review
Family Intervention for Schizophrenia
 Seven trials (369 patients) suggest that family
intervention may also encourage compliance with
medication but six trials (481 patients) show that it
does not apparently affect the tendency of individuals
and families to drop out of care
Family Intervention for Schizophrenia
 It may also improve general social functioning and the
levels of expressed emotion within families, but there
is no evidence to suggest that it either promotes or
prevents suicide
Family intervention for schizophrenia (review) PHAROAH F., et al Publisher:John Wiley
and Sons , 2006, 107p., bibliog, Chichester
Cognitive Therapy for Psychosis
 CBT for psychosis (CBTp) is based on Beck’s
cognitive model of emotional disorders
 Educational and collaborative
 Aims to be time limited
 Uses guided discovery/Socratic questioning
 Structured and problem orientated
 Based on the principal of collaborative empiricism
Evidence Base for CBTp
 Jones et al. (2005) conducted a systematic review of 30
papers describing 19 trials of CBT for schizophrenia
 Concluded that CBT was a promising but under-
evaluated intervention for schizophrenia and other
psychotic illnesses
Evidence Base for CBTp
 SoCRATES trial (Lewis et al., 2002): 5-week course of CBTp for people
recently admitted to hospital
 More rapid improvement in symptoms for the group that received
CBTp
 Relatively modest effect size
Evidence Base for CBTp
 Wykes et al. (2008) conducted a meta-analysis of 34 trials
of CBTp
 Found a significant inverse relationship between effect size
and trial quality.
 Smaller, older and poorly funded trials showed a larger
effect size
Evidence Base for CBTp
 Wykes et al. (2008) did find that even rigorous CBTp
studies had a moderate effect size (around 0.4)
 This effect size was roughly the same irrespective of the
outcome being measured (positive symptoms, negative
symptoms, mood, or social functioning)
Evidence Base for CBTp
 Move away from generic CBT for psychosis towards a
symptom specific approach (Steel, 2008).
 E.g. CBT for command hallucinations
Summary
 Antipsychotics do not “Cure” schizophrenia
 Some antipsychotic drugs are more effective than others
 Range of antipsychotics are available
 Different drugs suit different patients
 Long-term treatment is generally required to prevent
relapses
 Antipsychotics should never be stopped suddenly
 Psychological and psychosocial interventions increases the
chances of staying well
 Any questions
References & further readings
 Kaplan & Sadock’s Synopsis of Psychiatry
 Revision notes in Psychiatry
 NICE Guidelines
 Oxford Shorter text book in psychiatry
 Oxford Handbook of Psychiatry
 The Maudsley: Prescribing Guidelines in Psychiatry
12th Edition 2015
Thank you