This document provides an overview of treatment resistant schizophrenia, including definitions, prevalence, factors leading to treatment resistance, and management approaches. It notes that approximately 30% of schizophrenia patients do not adequately respond to initial treatment. Clozapine is identified as the gold standard treatment for resistant cases, though some patients remain resistant even to clozapine. The document discusses criteria for defining treatment resistance and response, as well as strategies for managing patients who are clozapine-resistant, including augmentation with other pharmacological or psychosocial approaches.

1. TREATMENT RESISTANT
SCHIZOPHRENIA
Presenter: Dr. Kaushik Nandi

2. OVERVIEW
 Introduction
 Prevalence
 Evolution of the concept of
TRS
 Pseudo-resistance
 Pharmacological
management
 Adjunctive treatment
 Use of Clozapine
 Clozapine resistance
 Psychosocial approaches
 The Indian Scenario
 Conclusion
 References

3. INTRODUCTION
 Schizophrenia is a chronic disease for which treatment
rarely provide a complete cure, but can lead to clinical
improvement.
 Schizophrenia is a heterogeneous disorder with regards to
etiology, clinical picture, course, treatment response and
outcome, the course being usually marked by discrete
episodes of intensification of psychopathology with positive
symptoms and disorganization.

4.  Treatment resistance is one of the most important clinical
challenges in the pharmacological management of
schizophrenia.
 Although precise estimates are missing, authors assume that
approximately 20–30% of all patients with schizophrenia do
not respond adequately to an initial antipsychotic trial.
 At present, a uniform definition of treatment resistance in the
pharmacotherapy of schizophrenia is not available.

5. PREVALENCE
 Treatment-resistant schizophrenia (TRS) affects ~30% of
people with a diagnosis of schizophrenia.
(Meltzer HY. 1997)
 Recovery rates in schizophrenia remain suboptimal with
up to one-third resistant to standard treatments, a
population prevalence of 0.2%
(Larry J 2018)

6. TREATMENT RESPONSE
 RESPONSE:
A score of 2 or 1 in the CGI-change (Clinical Global
Impression Scale) or > 20 points on FACT SCZ (functional
assessment for comprehensive treatment for schizophrenia )
or
> 20 % decrease in BPRS or PANSS
[Suzki et al,2012]

7.  PARTIAL RESPONSE:
A score of 3 in the CGI-change or 10 - 20 points
increase on FACT SCZ (functional assessment for
comprehensive treatment for schizophrenia )
or
GAF or >10% decrease in BPRS or PANSS
[Suzki et al,2012]

8. DEFINING REMISSION
 REMISSION:
Reduction of symptoms to a level that does not
interfere with patient’s psychosocial functions, quantified by
using 8 symptoms of PANSS which may reach upto
maximum level of 3 ( mild).
[Suzki et al,2012]

9. EVOLUTION OF CONCEPT
 Itil and colleagues (1966) proposed a definition of Resistant
Schizophrenia as those patients having active psychotic
symptoms despite at least 2 years of treatment and dosages
above 600mg/d for Chlorpromazine and 80-mg/d for
Trifluoperazine.
 Chronic hospitalization (more than 2 years) was considered
to be roughly equivalent to treatment resistance (Carman et
al. 1981; Small et al. 1975)

10. Kane's criteria (Kane et al. 1988)
1. Persistent positive psychotic symptoms: item score > 4
(moderately on at least 2 of 4 positive symptom items) on
the BPRS.
2. Current presence of at least moderately severe illness as
rated by total BPRS score (> 45) and a score of > 4 on the
CGI scale.
3. Persistence of illness: no stable period of good social
and/or occupational functioning within the last 5 years.

11. 4. Drug refractory condition: at least 3 periods of
treatment in the preceding 5 years with conventional
antipsychotics (from 2 chemical classes) at doses >
1000 chlorpromazine equivalent per day for 6 weeks
without significant symptom relief, or intolerance to 6
week prospective trial of haloperidol at a dose of 10-60
mg per day.

12. Modified Kane criteria (Conley and Kelly 2001)
 At least 2 drug trials of 4-6 weeks, at 400-600 mg CPZ
equivalents
 > 5 years with no period of good social or occupational
functioning
 Persistent psychosis: Total BPRS > 45 and scores of ≥ 4
on 2 out of 4 positive item scores

13. ADEQUATE TRIAL
Adequate dose:
 Risperidone: 4 to 6 mg/d
 Olanzapine: 10 to 20 mg/d
 Quetiapine: 300 to 600 mg/d
 Ziprasidone: 80 to 160 mg/d
 Aripiprazole: 15 to 30 mg/d
Adequate period:
 Min 4-6 weeks.
[Kinon and colleagues 1994]

14. FACTORS LEADING TO TRS
 Early age at onset
 Male gender
 Higher number of hospitalizations
 Number of episodes of illness
 Long duration of untreated psychosis
 History of substance abuse
(Elkis et al 2007)

15. CONFOUNDING FACTORS - TRS
Patient factors:
 Illicit substance misuse
 Psychosocial milieu
 Physical comorbidity
Illness factors:
 Intellectual disability
 Marked cognitive impairment
 Poor premorbid adjustment

16. CONFOUNDING FACTORS - TRS
Treatment factors :
 Non-compliance
 Side effects (e.g., extrapyramidal symptoms, weight
gain, diabetes)
 Incorrect dose
 Drug–drug interactions
 Drug bioavailability problems
 Inadequate rehabilitation program
(Pantelis et al 2003)

17. PHARMACOLOGICAL MANAGEMENT OF TRS
PHASE 1

18. PHASE 2

19. PHASE 3

20. ADJUNCTIVE PHARMACOLOGICAL TREATMENTS
Mood Stabilizers
Lithium:
 Adjunctive use of Lithium in earlier uncontrolled studies
showed a favorable response (Growe et al. 1979)
 Response was seen to be more prominent with affective
symptoms though functional areas also improved to some
extent (Delva and Letemendia, 1986).

21.  Recent reports have found no benefit with adjunctive
lithium therapy (Schulz, 1999).
 Concomitant use of lithium with conventional
antipsychotics carries a risk of delirium and
neurotoxicity (Barnes and McEvedy, 1996; Small et al.
2003).

22. Anticonvulsants :
 Carbamazepine and sodium valproate are considered as
adjunct therapy in patients with schizophrenia (Freeman et al.
1992; Post, 1990).
 In a meta-analysis it was found that valproate might be useful
in the control of aggression in schizophrenia (Schulz et al.
1990; Wassef et al. 2000).

23.  A review (Hosak and Libiger, 2002) mentions that
carbamazepine is effective in affective symptoms of
schizophrenia and influences violent behavior; valproate
treatment leads to a decrease in positive symptoms and
hostility.
 Lamotrigine as an adjunct can be used to influence the
positive, negative, affective and cognitive symptoms
whereas Topiramate been especially effective in negative
symptoms and antipsychotic induced weight gain (Drusun
and Devarjan, 2000; Drapalski et al. 2001).
 Drugs are used in usual antiepileptic doses.

24. Benzodiazepines:
 Adjunctive benzodiazepines have proven evidence for a
positive treatment effect; in short term (Lingjaerde et al. 1979)
and long term trials in treatment refractory schizophrenia
(Paton et al. 2000).
 Their long-term use is associated with side effects like chronic
sedation, fatigue, ataxia, and dependence, at time also leading
to behavioral disinhibition (Pato, 1989).

25. Antidepressants:
 Selective serotonin reuptake inhibitors when added to
conventional antipsychotics led to substantial improvement in
negative symptoms in treatment resistant schizophrenia with
Fluoxetine and Fluvoxamine being the most beneficial agents
(Evins and Goff, 1996).
 They are also used to treat comorbid depression, obsessive-
compulsive disorder and substance abuse in treatment resistant
schizophrenia.

26. Electroconvulsive Therapy (ECT):
 If a patient remains resistant to treatment due to failed
clozapine trial, adjunctive electroconvulsive therapy should be
considered (Conley and Buchanan, 1997).
 Improvement was found more in positive symptoms though
beneficial effects were short lived with significant relapse
after stopping ECTs (Meltzer, 1993; Chanapattana et al.
1999).
 Maintenance ECT in resistant schizophrenia led to
improvement in the form of less hospitalization and better
functioning (Dean, 2000).

27. MANAGEMENT OF TRS
Clozapine:
 Evidence of efficacy
 What is the adequate trial?
 What is the adequate serum concentrations?
 What if it does not work?

28. EFFICACY OF CLOZAPINE
 Wahlbeck K et al conducted a meta-analysis including 2530
participants in 30 trials and confirmd that clozapine is more
effective than conventional neuroleptics in reducing
symptoms of patients with both treatment-resistant and
nonresistant schizophrenia.
 Phase II trial CATIE: Clozapine was confirmed as the most
effective drug for individuals with a poor symptom response
to previous antipsychotic drug trials, although clozapine was
also associated with troublesome adverse effects.

29.  A study was conducted by Leucht and colleagues in a meta-
analysis that included 150 trials and 21,533 participants, and
clozapine, amisulpride, risperidone, and olanzapine proved to
be superior to haloperidol, a standard antipsychotic for the
treatment of schizophrenia, with clozapine showing the highest
efficacy in terms of improvement of positive, negative,
depressive, and total symptoms

30.  “Clozapine exhibits superiority over typical antipsychotics
in terms of both efficacy (as shown by an improvement in
overall psychopathology) and safety.
 However the magnitude of its effect is not consistent.
Efficacy data for other SGA’s in the treatment of refractory
schizophrenics were inconclusive.”
(Solanki et al, IJP, Nov-Dec:2009)

31. CLOZAPINE – ADEQUATE TRIAL
 About 30% respond - first 6 weeks of treatment
 Another 20% respond between 6 weeks and 3 months
 Another 10 to 20% by the end of 6 months
(Meltzer et al 1990)
 A trial of 8 weeks – plasma conc > 350ng/ml
(Mouaffak et al 2006)
 An trial of 12 weeks - adequate
(APA guidelines 2004)

32. CLOZAPINE – PLASMA LEVELS
Lack of consensus
 Threshold plasma level of 350-420 ng/ml - associated
with an increased probability of a good clinical response
(Miller et al 1996; Bell et al 1998)
 Optimal plasma clozapine levels lie between 200 and 250
ng/ml (Task Force of the WPA 2002)
 Optimal plasma clozapine levels lie between 200 – 400
ng/ml (APA guidelines 2004)

33. Ultra resistant (Clozapine resistant) schizophrenia
(Mouaffak et al 2006)
 At least 8 weeks treatment with Clozapine, plasma level
≥ 350 ng/ml, and <20% fall in BPRS scores
 Score ≥ 4 on 2 out of 4 of the positive symptom items of
BPRS
 Total BPRS ≥ 45 and CGI ≥ 4
 No stable period of functioning over 5 years
 GAF of 40 or less

34. EVALUATION OF CLOZAPINE RESISTANCE
 Diagnostic clarification
 Medical co-morbidities
 Substance use
 Serum clozapine levels
 Drug interactions
 Adequacy of psychosocial interventions

35. BEYOND CLOZAPINE: CLOZAPINE AUGMENTATION
STRATEGIES
 Approximately 40-70% of treatment resistant
schizophrenics are also clozapine resistant having deficits in
all domains despite clozapine monotherapy for adequate
dose and duration (Kontaxalis et al. 2005).
 During the last several years, adjunctive agents have been
used to enhance the antipsychotic efficacy of clozapine
(Buckley et al. 2001).

36. Clozapine and Atypical Antipsychotics:
 Risperidone with a dose of 6 mg per day has been used in
various uncontrolled trials with significant improvement and
recently in a double blind, randomized, placebo-controlled
study (Josiassen et al. 2005).
 There are only few reports of augmentation with high dose
olanzapine added to, upto 600 mg clozapine per day with
variable results (Gupta et al. 1999).

37. CLOZAPINE AND MOOD STABILIZERS
 Lithium: Evidence is strongest for major affective component
(Fuchs, 1994). A recent RCT for 16 weeks revealed
significant improvement (Small et al. 2003).
 Valproate: Used in adjunct with clozapine to increase the
seizure threshold and to increase the efficacy of drug regimen.
Reinstein et al. (1998) documented a better outcome,
contrasting Wilson (1995) who concluded that patient on
adjunctive valproate have poorer outcome.

38.  Lamotrigine : A randomized trial using upto 200 mg
lamotrigine revealed favorable response in a 28 weeks trial
(Tiihonen et al. 2003).
 Topiramate: Topiramate might present as a useful agent in
adjunct with atypical antipsychotics due to weight reducing
properties.
 Amisulpride: Amisulpride augmentation of clozapine for
schizophrenia that had an insufficient response to a trial of
clozapine monotherapy has shown satisfactory response,
mostly in managing the negative symptioms.

39. CLOZAPINE AND SSRIS
 Fluvoxamine augmentation causes threefold increase in
clozapine and its metabolites causing worsening of side
effects though the results should not be extrapolated to
clinical settings (Byerly and Derave, 1996).
 Fluoxetine augmentation gave no evidence of superior
improvement in the augmentation group (Buchanan et al.
1996).

40. CLOZAPINE AND ECT /REPETITIVE
TRANSCRANIAL MAGNETIC STIMULATION
 Preliminary evidence suggests that ECT can safely enhance
the efficacy of clozapine and rTMS can be used to target
specific treatment resistant positive symptoms like auditory
hallucinations (Buckley et al. 2001).
 Combined treatment of clozapine with ECT appears to be
safe and well tolerated, with around 20% patients reporting
improvement than clozapine alone (Tharyan, 2000).

41. CLOZAPINE AND GLYCINERGIC AGENTS
 Based on NMDA receptor hypothesis of schizophrenia
(Olney and Farber 1995) double blind, placebo controlled
trials combining glycine.
 D-cycloserine and D-serine to antipsychotics have been
associated with improvement in negative symptoms (Tsai et
al. 1998; Hereseco-Levy et al. 1999).

42. NEW DRUG: NEW HOPE
 Levomepromazine: Holds promise in treatment resistant
cases. Its sedative properties are particularly suitable for
psychiatric intensive care. (Green et al. 2004)
 Melperone: An effective antipsychotic of the
butyrophenone class with properties of an atypical. In an
open study, Meltzer et al (2001) have tried melperone in
treatment resistant cases and found it to be effective in
significantly reducing overall psychopathology status,
without associated increase in side effects.

43.  Gallantammine: A non-competitive agonist / allosteric
modulator at nicotinic cholinergic receptors. Bhat & Galang
(2002) have reported cases of treatment resistance where
successful treatment with clozapine has been discontinued due
to agranulocytosis-have shown therapeutic benefit with
addition of gallantamine with resperidone.
 Secretin: Alamy et al (2004) have reported possible role of
this G.I. peptide as a novel adjunctive treatment in treatment
resistant schizophrenia patients especially with autistic
features.

44. PSYCHOSOCIAL APPROACHES IN MANAGING TRS
 The treatment unresponsive patient may need intensive
psychosocial interventions than medication responsive
patients because of their disabilities.
 Family living with a person may also require extra support,
so psychosocial approach for the management of treatment
resistant schizophrenia should be carefully selected.

45. WORKING WITH THE INDIVIDUAL
Managing persistent positive symptoms: Cognitive behaviour
therapy (CBT)
 Garety et al. (2000) reviewed the RCTs using CBT and
concluded that CBT has significant benefits in terms of
symptom reduction in the form of delusions and
hallucinations.
 A study comparing CBT and supportive psychotherapy
among clozapine partial responders revealed that CBT has
more favorable long-term effects (Sensky et al. 2000).
 Cognitive flexibility and less negative symptoms predict
response to CBT.

46. Managing negative and cognitive symptoms:
 It has been documented that people with treatment resistant
schizophrenia perform substantially below normal in a
number of cognitive domains (Harvey and Keefe, 2001).
 Cognitive remediation techniques targeting executive
functions deficit have been useful in reducing cognitive
deficits leading to improved social outcome (Wykes et al.
1999).
 It was found that using compensatory or cognitive adaptation
training in addition to medication showed significantly better
outcomes in cognitive dysfunctions and social functioning
(Velligan et al. 2000).

47. Managing affective symptoms: Emotion management training
(EMT)
 EMT is an avenue addressing deficient emotional perception
and its functional consequence by self evaluation of
maladaptive emotions followed by developing coping
strategies to deal with poor social and limited stress
management in schizophrenics (Hodel et al. 1998).
 Showing its efficacy in first episode clients, it has been used
in TRS where preliminary results reveal significant efficacy as
measured by emotions perception tests, however, long term
effect are still to be ascertained (Hodel et al. 2004).

48. WORKING WITH THE FAMILY
 Early work examined the association of high expressed
emotion (EE) among caregivers and poor clinical outcome
with good compliance to medications (Brown et al. 1972;
Vaugh and Jeff, 1976).
 Various strategies utilizing psychoeducation and family
therapy approaches to reduce EE, facilitating problem-
solving techniques and diminishing isolation have been
reported (Schulz et al. 1986; Hogarty et al. 1991).

49.  McFarlen et al. (1995) and Telles et al. (1995) have shown
beneficial effects of the family interventions in managing
treatment resistant patients in the community setting.
 In a recent RCT using occupational therapy as an adjunct to
clozapine, group with above intervention scored better than
patients with clozapine alone (Buchain et al. 2003)

50. WORKING WITH THE SYSTEM: COMMUNITY BASED
INTERVENTIONS
 The broad aim of such intervention is to improve quality of
life, stabilize mental health, minimize relapses, and
rehopitalizations.
 "Early symptoms and sign monitoring" (Birchwood and
Shepherd, 1992) to recognize early sign of relapse and
"Assertive community Training Programmes" (Wykes and
Carson, 1996) aimed at delivering services in an assertive
manner and crisis intervention programmes are used to help
treatment resistant patients.

51. TRS– THE INDIAN SCENE
 India’s contribution to the existing literature is mostly
restricted to case series reports and few isolated trials
(Andrade C., 1990; Painuly et al., 2004; Sonawalla and.
Parikh, 1995).
 Srivastava et al. (2002) have found a significant
improvement in psychopathology and social functioning in
treatment resistant patients with much lower dose of
clozapine than has been reported elsewhere (average daily
dose being 248.21 mg) and the incidence of side effects like
neutropenia rarer.

52.  Goswami et al. (2003) has thrown light on efficacy of ECT
in treatment resistant schizophrenia in India. They have
found ECT augmentation have a significant impact on the
clinical course of patients with treatment resistance which
may be reinforced and maintained by maintenance ECTs.
 Though, Indian study of Agarwal and Winny (1985) has
failed to find an advantage for ECT- neuroleptic combination
in broadly defined schizophrenic non-responders.

53. CONCLUSION
 The concept of treatment resistant schizophrenia is a working
concept, which has significantly evolved substantially over
years, but current advances in treatment have not been
operationalized to have appreciable impact on different
variables in such patients.
 Available evidence suggests that the atypical antipsychotics
other than clozapine are at least as effective as typical
antipsychotics, conceptualizing a second level of refractory
patients, unresponsive to typical antipsychotics

54.  The question of whether any atypical antipsychotic other than
clozapine is more efficacious than the other still needs to be
answered.
 The sequences in which the drugs should be used in poorly
responsive patients still need to be answered.
 On current evidence, clozapine stands alone as a treatment of
choice, though a third level refractory patients unresponsive
to clozapine still challenge the mental health professionals.

55.  Finally, substantial developments in psychosocial therapies
have led to the challenge of optimizing treatment response
so as to give an integrated and comprehensive approach to
the care of patients with treatment resistant schizophrenia.

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61. THANK YOU