Treatment resistant schizophrenia is defined as lack of satisfactory improvement despite trials of two antipsychotics for adequate duration and dose. Around 20-30% of schizophrenia patients are considered treatment resistant. Clozapine is currently the treatment of choice for such patients, though combination and augmentation strategies with other agents have limited evidence. Definitive treatment guidelines recommend establishing treatment resistance before trials of clozapine or other strategies for treatment resistant schizophrenia.

1. Treatment resistant
schizophrenia.

2. History
 19 th century till now.
 Divide into 2 groups – pre and post chlorpromazine.
 Post neuroleptic era studies -60-70% improve
 20-30% are resistant to treatment.
Kane J, Hognifeld G, Singer J, et al.1988
Miller A, McEvoy J, Jeste D,etal.2006
Hasan A, Falkai P, Wobrock T, et al.2012

3. Chronicity
vs
Refractoriness
vs
TRS

4. 1] INCOMPLETE RECOVERY
VS
TREATMENT REFRACTORY
RESPONSE TO TREATMENT
2] REMISSION
VS
RECOVERY

5. Epidemiology
 Prevalence:
20% doesn’t respond after one year of treatment.
Generally assumed to be around 20-30%.
Some authors report upto 60%.
Meltzer H, Kostacoglu A.2001.
 Age of onset: 17 yrs compared to 20 [ non TRS]
 Male predominance.

6. Definitions:Definitions:
Narrow definition: Kane et al,Narrow definition: Kane et al,
Clinical history
No functioning ------ 5 years,
Received 3 periods of treatment, At least 6 weeks,
Of at least 2 different chemical classes,
Equivalent of at least 1000 mg chlorpromazine daily,
Cross-sectional-
BPRS total score > 45 Rating, CGI score > 4
on at least 2 (score 4) of the following BPRS items:
Conceptual disorganization, Unusual thoughts,
Hallucinatory behavior, Suspiciousness
Prospective
Failure to reduce score by > 20%;
BPRS score > 35 or CGI score > 3
With 60mg haloperidol daily for 6 weeks

7. Present definition :
“ TRS is suggested by a lack of a satisfactory clinical improvement
despite the sequential use of the recommended doses for 6 to 8
weeks of at least two antipsychotics at least one of which should
be an atypical ”
(NICE, 2002)
 30% of patients fall under this category.

8. EARLY OPERATIONAL
DEFINITIONS:

9. American Psychiatric Association guidelines and the Schizophrenia
Patient Outcomes ResearchTeam guidelines, or algorithms, such
as theTexas Medication Algorithm Project state that:
“ A patient who has not responded to two or three treatments using
atypical antipsychotics for a duration of at least 4 to 6 weeks can be
considered as having TRS and is eligible for treatment with
clozapine.”
APA-2004

10. International Pharmacological Algorithm Project:
“who has not responded to two trials of 4 to 6 weeks’ duration using
monotherapy with two different SGAs (or two trials with an FGA,
if SGAs are not available) is considered to have TRS and is
eligible for treatment with clozapine, for a six month trial with
doses up to 900 mg/d.”
IPAP-2006

11. Clinical and biological correlates of TRS:
Adequate trial: Kinon and colleagues
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 weeks. [Kinon and colleagues 1994]

12. Apparent treatment resistance
or
Incomplete recovery.
 Poor compliance
 Lack of family support
 Substance abuse
 Physical comorbidity
 Intolerable side effects
 Incorrect dose schedule
 Poor therapeutic alliance
Elkis H, Treatment resistant schizophrenia, Psychiatr Clin N Am 30; 2007

13. Neuroimagimg correlates of TRS
TRS develops accoring to 3 stages:
 Childhood : cortical pathology and deficient neuro modulatory
capacity resulting from genetic/epigenetic etiologic factors.
 Adolescence: neuro chemical sensitization leading to dopamine
release and development
Of psychotic episodes.
 Adulthood: neurotoxicity with consequent development of
structural neuronal changes .
Sheitman and lieberman :1988

14. Neuroimagimg correlates of TRS
 Ventricular enlargement- non remitters.
Liebermann1996
[Prospective 18 months study]
 Retrospective study: ventricular enlargement-poor outcome
Crosthwaite CG, London 2000
 Prospective studies:
Ventricular enlargement: response to typicals
Cortical atrophy: response to atypicals
 Staal WG , AJP: 2001

15. other neurobiological correlates:
 HVA levels higher among responders in 1st
episode
 Liberman J and colleagues,1994.
 Altered ‘T’cell response.
 Altered inflammatory response due to interleukins.
Altamura AC, Bassetti R, Cattaneo E, etal,2004 .

16. REASONS FOR FAILURE TO
RESPOND: PATIENT FACTORS:
 Dual diagnosis.
 Organic factors.
 Poor adherence.
 Familial factors.
 Poor psychosocial support .
 Cultural backgrounds and expectations.
 Premorbid factors.

17. REASONS FOR FAILURE TO
RESPOND:Illness factors
 Negative symptoms
 Early onset
 Lack of early response
 Delay in 1st
treatment
 Type 1 v/s type 2 schizophrenia
 “Neurodevelopment” v/s “adult” type
 Cognitive impairment

18. REASONS FOR FAILURE TO
RESPOND:Treatment factors
 Improper dosage
 Inappropriate drug treatment
 Aberrant metabolism (necessary to monitor drug levels)

19. MANAGEMENT STRATERGIES
 Pharmacological
 Non pharmacological

21. Pharmacological methods:
 Increasing the dose
 Swtching the drug
 Combination
 Augmentation

22. Treatment guidelines:
[NICE]

23. Algorithm for the pharmacological treatment of patients with treatment-resistant
schizophrenia (modified from refs 3 and 4).
Markus Dold, and Stefan Leucht Evid Based Mental Health
2014;17:33-37
Copyright © by the BMJ Publishing Group Ltd, Royal College of Psychiatrists & British Psychological Society. All rights reserved.

24. Step 1:
Establish that therapy has failed to adequate trials of
antipsychotic drugs:
In terms of dosage, duration and adherence.
Other causes Of non-response as:
co-morbid substance misuse
concurrent use of other prescribed medicines and
physical illness.
NICE-2002

25. Step 2:
 Clozapine should be introduced at the earliest opportunity.
 The prescribing clinician and service user may
wish to consider an atypical antipsychotic in advance of a
trial of clozapine. in such cases, olanzapine or risperidone
may be worth considering.
 Service users should be informed:
evidence for improvement is more limited than for clozapine.
NICE-2002

26. Combination therapy:
Definition
 This refers to the concurrent administration of more than one
antipsychotic.
 The efficacy of combining two or more conventional
antipsychotics, or two or more atypical antipsychotics has not
been established.
 There is limited evidence that adding a conventional
antipsychotic to clozapine may produce benefits compared to
clozapine alone.
 Combining one antipsychotic with another antipsychotic may
increase the risk of adverse effects and pharmacokinetic
interactions
 NICE-2002

27. Summary:
 There is no convincing evidence to support the routine use of
combined antipsychotics .
 Doing so may increase the likelihood of adverse events and
high doses of drugs.
 There is some limited evidence to support the use of combined
antipsychotics for people TRS.
NICE-2002

28. CLINICAL PRACTICE
RECOMMENDATIONS
 More than one antipsychotic drug, whether atypical or typical,
should not be prescribed concurrently, except for short periods to
cover changeover.
 However, the addition of a second antipsychotic to clozapine
may be a supportable intervention in people with treatment
resistant schizophrenia for whom clozapine alone has proved
insufficiently effective.
NICE-2002

29. AUGMENTATION WITH CLOZAPINE:
 ANTIPSYCHOTICS:
OLANZEPINE
SULPIRIDE
AMISULPIRIDE
LOXEPINE
ZIPRAZIDONE
 ANTIDEPRESSANTS:
FLUOXETINE
MIRTAZEPINE
NICE-2002

30. Augmentation stratergies:
 MOOD STABLEZIRES:
LITHIUM
VALPROATE
CARBAMAZEPINE
LAMOTREGINE
 BENZODIAZEPINES
 OTHER AGENTS:
GLYCINE,SERINE, CYCLOSERINE
NICE-2002

31. Non pharmacological augmenters:
 ECT
 TMS
 Combination and augmentation strategies are only empirical
and are based on case reports and open label trials.
 Not enough data to support any of these strategies
 Needs further RCT to support these strategies.
NICE-2002

32. APA DEFINITION:
“Treatment resistance is defined as little or no symptomatic
response to multiple (at least two) antipsychotic trials of an
adequate duration (at least 6 weeks) and dose (therapeutic
range).”
APA-2004

33. APA GUIDELINES:
 Evaluate for adequacy of trial
 Establishing therapeutic alliance
 Improving treatment adherence
 APA-2004

34.  Because of clozapine’s superior efficacy, a trial of clozapine
should be considered for a patient with a clinically inadequate
response to antipsychotic treatment or for a patient with suicidal
ideation or behavior .
 Besides clozapine very limited options for individuals who have
significant residual symptoms.
 Various augmentation strategies with limited or no evidence are
tried.
 APA-2004

35. AUGMENTATION STRATERGIES:
 Depending on the type of residual symptom (eg.Positive,
negative, cognitive, or mood symptoms, aggressive behavior):
 Antipsychotic
 Anticonvulsants
 Benzodiazepine.
 NMDA receptor allosteric agonists.[D-serine]
 Glycine
 D- cycloserine
 Cholinergic agonists
 ECT
 CBT positive symptoms.
 Cognitive remediation- to reduce severity of cognitive deficits.
APA-2004

36. IPS GUIDELINES:
 Although there is some suggestion of efficacy of risperidone and
olanzapine in this condition, and despite recent doubts about the
effectiveness of clozapine, it still is the drug of choice in these
situations (Sartorius et al., 2002).

37. INDIAN DATA:
 Solanki and colleagues in a review concluded that :
“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

38. Canadian guidelines:2005
 To confirm diagnosis:
 To rule out schizoaffective disorder
 Bipolar disorder: mania
 Depression
 TREATMENT GUIDELINES FOR NON
RESPONDERS:
 Optimization,
 Substitution,
 Augmentation
 And combination.

39. Canadian guidelines: 2005
 If a trial of clozapine is not effective, the next steps are
augmentation,followed by combination strategies.
Augmentation : data available are case series only
Except for lamotrigene.
 Combination stratergies:
Limited evidence
Higher chances of side effects.
 ECT: There was limited evidence to support
its use as adjunctive treatment with antipsychotics for
those who show limited response to medication alone.

40. STUDIES WITH CLOZAPINE.STUDIES WITH CLOZAPINE.
John Kane 1992
Multicenter trial
Clozapine was compared with chlorpromazine.
30 percent of patients improved ---------- 6-week trial.
60 percent of patients improved ---------- 6 months.
Schooler et al 1993
60% with clozapine, but only 12% with haloperidol;
Rodriguez et al (1998)
Factors Clozapine responders
Cognitive disorganization ----- non-responders
Behavioral disorganization-----partial responders.

41. Jalenques et al (1992),
Improvement
Positive symptoms by 1 month
Negative symptoms by 3 months
Improvement in social functions by 4-6 months
Meltzer and Okayli (1995)
Clozapine treatment of 6 months to 7 years duration
Reported decrease in suicidality
Lieberman et al (1994)
Optimal trial of Clozapine ------------12 -24 weeks.

42. STUDIES OF CLOZAPINE WITH ECT:STUDIES OF CLOZAPINE WITH ECT:
Kales et al (1999)
Supplementing clozapine with ECTs
Effective in treatment resistant schizophrenia.
Its beneficial effects were short-lived.
Bhatia et al (1998)
Clozapine was combined with ECT.
Both the reports opined that such a combination is
safe.

43. ADJUVANT MEDICATIONS .ADJUVANT MEDICATIONS .
 Newer neuroleptic
 ECT’s
 Lithium
 Benzodiazepines
 Propranlol
 Carbamazepine
 Valproate
 Glycine (30gm/day)
Christinson et al (1991)

44. Schizophrenia Patient Outcomes Research Team (PORT)
A Trial of Adjunctive Pharmacotherapy With
BENZODIAZEPINES,
CARBAMAZEPINE,
PROPRANOLOL,
LITHIUM.

46. COGNITIVE REMEDIATION AND THERAPYCOGNITIVE REMEDIATION AND THERAPY
Two approaches to cognitive work
1. Cognitive retraining
2. Cognitive therapy
Comprehensive textbook ofpsychiatry,9th
edition.

47. Psychosocial intervention
 Family therapy
 Social skills and communication training
 Cognitive Behavior therapy
 Behavioral intervention
 Vocational training
 Anxiety management

48. Family therapy
 Reduces burden
 Better coping skills and problem solving abilities
 Reduces relapse rates by 50%
 Better compliance in the 1st
two years post discharge
Cochrane Meta-analysis

54. Cognitive Deficits :Cognitive Deficits :
Decreased attention,
Attention shifting tasks,
Working memory,
Scanning(Vigilance),
Executive function,
Language processing(Verbal fluency,
Poor Abstract ability,
Fine motor skills,
General intelligence
Comprehensive textbook ofpsychiatry,9th
edition.

55. NEURO COGNITIVE DEFICITS
Before the onset of illness.
Family studies-
Children of schizophrenia
First degree relatives
Shizotaxia
Comprehensive textbook ofpsychiatry,9th
edition.

56. Cognitive retraining.Cognitive retraining.
- Assessment
- Interventions
Attention enhancing tasks
Word fluency
Vigilance tasks
Card sorting
Picture completion
Memory recall retraining
Computer assisted training
Comprehensive textbook of psychiatry,9th
edition.

57. Cognitive therapy.Cognitive therapy.
Delusions
 Rapport building
 Psychopathology to be elicited and documented
 Empathizing
 Asking for evidence
 Asking for alternative explanations
 Reinforcing the alternative explanations
 Confrontation
Hallucinations
 Distraction techniques
 Sub vocalisation
 CBT-----Reattribution
 Comprehensive textbook ofpsychiatry,9th
edition.

58. SOCIAL SKILLS TRAININGSOCIAL SKILLS TRAINING
Social skills training involves behavioral techniques or
learning activities that enable patients to acquire
instrumental and affiliative skills in domains required to
meet the interpersonal, self-care, and coping demands of
community living.
Comprehensive textbook ofpsychiatry,9th
edition.

59. Social skills:Social skills:
Verbal:
Voice tone and pitch, affect, loudness, speech fluency, amount of
speech, Latency of response, content.
Nonverbal:
Eye contact, facial expression, gestures, interpersonal distance,
body posture, body orientation etc.
Comprehensive textbook ofpsychiatry,9th
edition.

60. Core skills:
Expressing positive feelings,
Making positive request,
Expressing negative feelings.
Supplementary skills:
Active listening,
Compromise and negotiation,
Requesting time out.
Comprehensive textbook ofpsychiatry,9th
edition.

61. Steps.Steps.
Done in treatment settings
 Providing rationale
 Live modeling, video , role play, drama etc
(Communication skill training)
 Rehearsals of skills,
 Coaching and feed back
 Problem solving techniques
 Group therapy
 Self help group
Done in natural environment
 In vivo exercise
 Home work assignment
 Booster sessions
Comprehensive textbook ofpsychiatry,9th
edition.

62. Treatment refractoriness:Treatment refractoriness:
Refractoriness may be defined as
Persisting positive and negative psychotic symptoms
Deficits in social functioning and bizarre behaviors
that interfere with community adaptation.
(Brenner et al 1999)

63. Brenner et al 1999 proposedBrenner et al 1999 proposed
criteria for refractoriness.criteria for refractoriness.
 ICD 10 diagnosis of schizophrenia
 Continuous hospitalization in the past 2 years
 Psychosocial functioning on GAS less than 40%
 Severe or moderate on at least 3 of the below items
Flattened affect
Psychomotor retardation
Delusions
Hallucinations
Poverty of speech
Incoherent speech

64. Vocational rehab
Sheltered workshops
Long-term hospitalization
5 -10 % requires institutional care

65. REFERENCES
 Sadock BJ, Sadock VA, Ruiz P. Comprehensive textbook of
Psychiatry,Schizophrenia. 9th Edition,VOL1:Lippincott
Williams ltd; 2009.
 IPS guidelines for management of schizophrenia.
 NICE guidelines: core interventions in treatment and
management of schizophrenia ,2002.
 APA guidelines: practice guidelines for treatment of patients
with schizophrenia,2004.

66. REFERENCES
 Canadian clinical practice guidelines: Treatment of
schizophrenia, canadian journal of psychiatry, vol50, no2,
supplement 1,Nov, 2005.
 Elkis H, Treatment resistant schizophrenia, Psychiatr Clin N
Am 30; 2007.
 Dold M,Leucht S. Evid Based Mental Health, Vol 17: No
2,May2014.

67. THANK YOU

68. Treatment resistant schizophrenia

69. Treatment resistant schizophrenia

70. Treatment resistant schizophrenia

71. Treatment resistant schizophrenia

74. THANK YOU