1. TREATMENT RESISTANT
SCHIZOPHRENIA: DIAGNOSIS AND
MANAGEMENT STRATEGIES
Presenter : Dr Gaurav Uppal
Chairperson : Dr Ravindra M Date : 17.02.2017

2. INTRODUCTION
• Earlier descriptions : schizophrenia tended to be chronic and with a poor
prognosis
• Prevalence studies found it to be stable in time and places with
prevalence 0.5-0.8% [Saha et al,2005]
• 70 % responded to medications in terms of positive symptoms , 30 % are
refractory or resistant [Meltzer et al ,1995]

3. INTRODUCTION
• Introduction of Chlorpromazine , improvement was seen
• With Second Generation antipsychotics both positive and negative
symptoms improved
•First definition of treatment resistance was given by Kane et al, 1988
after development of clozapine

4. DEFINING RESPONSE
RESPONSE: A score of 2 or 1 in the CGI-change or > 20 points
on FACT SCZ (functional assessment for comprehensive
treatment for schizophrenia ) or > 20 % decrease in BPRS or
PANSS [suzki et al,2012 ]
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 ]

5. 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 ]

6. DEFINING RESISTANCE

7. DEFINING RESISTANCE
Historical criteria Cross sectional Criteria Prospective criteria
• No preceding good
functioning period within
last 5 years
• At least 3 treatments
antipsychotics with two
different chemical classes
with dose equivalence of
1000 mg of
chlorpromazine for 6
weeks without relief
A BPRS >45 with two of
following 4 items :
Hallucinatory behaviour
Unusual thought content
Suspiciousness
Conceptual disorganization or
CGI > 4
• No improvement
( BPRS <35 or CGI <3)
after 6 weeks of
haloperidol >60mg/day
Treatments with
antipsychotics with two
different chemical classes
with dose equivalence of
1000 mg of chlorpromazine
for 6 weeks without relief
[Lehman et al, 2004 ]
Clozapine should be offered
to people with schizophrenia
who continue to experience
persistent and positive
symptoms [PORT , 2009]
Definition by Texas medical algorithm project , 2006
Definition by International psychopharmacological project ,2006

8. OPERATIONAL DEFINITION OF
RESISTANCE
• Well documented failure to respond to > 2 antipsychotics
• Clearly documented history of treatment failure with > antipsychotic plus
prospective validation of treatment failure with another antipsychotic (
different from one that previously failed )
• Dose and duration : each treatment with > 600 chlorpromazine equivalents
per day for > 6 weeks
• Lack of improvement in reducing CGI > 4 AND score of < 49 on FACT SCZ or <
50 on GAF

9. ASSESSMENTS TO BE CARRIED
OUT BEFORE LABELLING IT AS
DRUG RESISTANT
SCHIZOPHRENIA

10. ASSESS FOR PSEUDO-RESISTANCE
• treatment nonresponse due to reasons other than medication nonresponse
• Look for other factors causing or contributing to the persistence of
symptoms
RE EVALUATION OF THE PRIMARY DIAGNOSIS
• Look for conditions like schizophrenia

11. ASSESS FOR CO-OCCURRING
CONDITIONS
• substance use disorders
• Severe personality disorders
• Affective disorders with psychotic characteristics
• Comorbidity
• OCD
• Affective disorders [Dold et Leucht, Evid Based Mental Health May
2014]

12. ASSESS FOR ORGANIC CAUSES OF
PSYCHOSIS [DAVID AS,2009]
• Imaging: MRI head to SOL, CVA or others
• Endocrine: Thyroid function tests.
Biochemistry: B12, Folate, Calcium. Abnormalities
• Infection and inflammation: Syphilis, HIV, Hepatitis B, Hepatitis C
CRP, ESR.
• Autoimmune: NMDA, VGKC, ANA antibodies.
• EEG: clinical presentation has features suggestive of epilepsy.

13. ASSESS FOR ANTIPSYCHOTIC DRUG SIDE
EFFECTS
• Akathisia
• EPS
• Sedation and
• insomnia, can mimic negative symptoms

14. ASSESS FOR DRUG-DRUG INTERACTIONS
• Carbamazepine reduces the levels of all antipsychotics
metabolized by the liver except :
Amisulpride
Paliperidone
Smoking reduces levels of clozapine and olanzapine (Cytochrome P450
1A2 ).
• Fluoxetine and paroxetine can elevate levels of risperidone
and aripiprazole ( metabolized by Cyp 2D6)
[Jääskeläinen E,et al,2013 ]

15. ASSESS FOR MEDICATION
NONADHERENCE
●Ask the patient about missed or lower-than-prescribed medications
●Arrange for supervised medication intake( orally dissolving or
liquid formulation).
●Check a blood level of the antipsychotic drug. An absent level or a
low level despite relatively high doses indicate nonadherence (or
unusual metabolism). [kane JM et al, 2010]

16. [Haddad et al., 2014]
NON
ADHERENCE ?

17. OPTIMIZATION OF NON
PHARMACOLOGICAL MANAGEMENT
• Triggers and stressors identification leading to poor compliance
• potential impact of the support system needs to be evaluated and
utilized

18. OTHER PSYCHOSOCIAL INTERVENTIONS
• Cognitive-behavioral therapy :For persistent delusions
• Family psychoeducational interventions : during relapse
• Social skills training : deficits in skills
• Assertive community treatment : recent history of
repeated hospitalization
• Crisis intervention : acute psychosocial
stressor who are in emotional crisis [Joy CB, 2006]

19. OPTIMIZATION OF ANTIPSYCHOTIC DRUGS
• the duration, maximum dose, and response to previous trials
• a trial of at least six weeks on the maximally tolerated dose of antipsychotics
before calling it a treatment resistance
• Patients improve most rapidly during the first two weeks.
• If poor response in first two weeks , good response later on unlikely
[kinon BJ , 2008, PORT , 2009 ]

21. - Cloza vs First Generation Antipsychotics (FGA):
=> cloza > FGA (relapse rates and repeated hospitalisations) (Meltzer et al.,
2008).
- Cloza vs Second Generation Antipsychotics (SGA):
- Cloza > all SGA except olanzapine (OLZ) (Phase II CATIE).
- Cloza > OLZ on suicidal behaviors (Intersept: Meltzer et al., 2003)
- pro-cognitive “ effects of OLZ > cloza (anticholinergic properties).
CLOZAPINE, THE GOLD STANDARD

22. • BPRS improvement of < 20% despite a trial with clozapine for ≥ 8 weeks
and plasma levels > 350 μ g/L, no stable
• Period of good social and/or occupational functioning for ≥ 5 years
• Global assessment of functioning (GAF) ≤ 40
• BPRS total score ≥ 45, CGI score ≥ 4, and
• A score of ≥ 4 on 2 of 4 positive symptom items.
Ultra-resistant schizophrenia
(Mouaffak et al., 2006)
IF CLOZAPINE FAILS

23. For clinically significant positive symptoms despite trials of at least six weeks
duration with two antipsychotic drugs at the maximally tolerated dose,
Other considerations :
●Patient/family agreement along
●Absolute neutrophil count (ANC) ≥1500 cells/microliter
●Clozapine warranted despite relative contraindications, if present, based on
assessment of risks/benefits/alternatives
Guidelines for prescribing clozapine are described in detail separately.
ELIGIBILITY CRITERIA FOR CLOZAPINE

24. INDICATIONS FOR CLOZAPINE USE

25. STUDIES WITH CLOZAPINE.
John Kane 1988
Multicenter trial
Clozapine was compared with chlorpromazine.
After 6-week trial
30 percent of patients on Clozapine categorised as responders
compared with 4% of Chlorpromazine treated patients
Schooler et al 1993
60% with clozapine, but only 12% with haloperidol;

26. 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.

27. • RCTs show that clozapine is more effective than other antipsychotics in treating
patients with schizophrenia that has responded poorly to prior antipsychotic trials
[Souza JS, 2013].
• A meta-analysis of 14 trials with 1190 patients with schizophrenia resistant to
treatment with first-generation antipsychotics (FGAs) found that patients treated
with clozapine experienced greater clinical improvement compared with patients
treated with an FGA (relative risk [RR] = 0.72, CI 0.7-0.8, number needed to treat
[NNT] = 6, CI 5-8) [Essali A, 2009].
• In a series of related meta-analyses, clozapine led to greater reductions in symptoms
on the Brief Psychiatric Rating Scale (BPRS) in 16 eligible trials and in negative
symptoms in five short-term trials, compared with FGAs.
• Patients treated with clozapine experienced fewer relapses than those treated
with FGAs (RR = 0.62) and lower rates of all-cause discontinuation than with FGAs (RR
(RR = 0.60) in 16 trials.
EFFICACY OF CLOZAPINE

28. • Meta-analyses of randomized trials comparing
clozapine with second-generation antipsychotics in
schizophrenia have found mixed results:
• ●The clozapine group did not significantly differ from the olanzapine group in
rates (six trials), total PANSS scores (four trials), or mean change in total PANSS scores
(three trials). [Souza , 2013]
• ●A meta-analysis comparing clozapine to risperidone in five randomized trials of
patients with schizophrenia did not find a significant difference in the primary
outcome, total PANSS scores. A secondary analysis found evidence of greater
efficacy for clozapine in the two trials that used daily clozapine doses of at least 400

29. • higher levels of functioning before the onset of
schizophrenia,
• low levels of homovanillic acid and 5-hydroxyindoleacetic
acid in cerebrospinal fluid,
• reduced metabolism in the prefrontal cortex,
• reduced volume of the caudate, and
• the improvement of P50 gating at the 500-ms prepulse
interval [Chung C , 2005 ]
PREDICTORS OF CLOZAPINE RESPONSE

30. CLOZAPINE, gold
standard
(HAS, APA, PORT, TMAP, … )
ULTRA-RESISTANT
SCZ
Clozapine augmentation strategies
- with other antipsychotics
- with antidepressants
- with mood stabilizers
- with R-NMDA agents
- Non pharmacological strategies
(ECT, rTMS, Psychotherapy)
- High dose Antipsychotics
failure
Barnes et Dursun, Psychiatry, 2005; American Psychiatric Association, 2010; Mcilwain, Neuropsychiatr Dis Treat, 2011;
Mouaffak et al., Clin Neuropharmacol, 2006
ALGORITHM FOR TRS

31. Expert Opin. Pharmacother. (2014) 15(16):2329-2345
AUGMENTATION STRATEGIES IN PARTIAL RESPONDER
AND /OR TRS PATIENTS TREATED WITH CLOZAPINE
AUGMENTATION WITH ANTIPSYCHOTICS

32. • No current consensus regarding this strategy
• Promote pharmacologically synergistic associations
• Tolerance monitoring needed
AUGMENTATION WITH ANTIPSYCHOTICS

33. AUGMENTATION WITH MOOD STABILIZERS
Muscatello et al., Expert Opin. Pharmacother. (2014) 15(16):2329-2345;
Porcelli et al., European Neuropsychopharmacology (2012) 22, 165–182

34. • Interisting in clozapine treated patients with high epileptic risk
• Schizo-affective disorder
• Favor valproate, take care of lithium (tolerance).
AUGMENTATION WITH MOOD STABILIZERS

35. AUGMENTATION WITH ANTIDEPRESSANT
Muscatello et al., Expert Opin. Pharmacother. (2014) 15(16):2329-2345;
Porcelli et al., European Neuropsychopharmacology (2012) 22, 165–182

36. • Comorbid forms (depression, anxiety, OCD)
• Pharmacokinetic effects (inhibiting CYP1A2) with fluoxetine and
fluvoxamine ( CLZ norCLZ).
AUGMENTATION WITH ANTIDEPRESSANTS

37. • Antidepressant drugs — A meta-analysis of 23 randomized trials
with 819 participants found that antidepressants reduced negative
symptoms in patients with chronic schizophrenia (not limited to
treatment-resistant) [Singh SP et al ,2010].
• Mirtazapine, Reboxetine, Mianserin, Trazodone And Ritanserin.
• Subgroup analyses found statistically significant responses
resulting from treatment with Fluoxetine, Trazodone And
Ritanserin.
AUGMENTATION WITH ANTIDEPRESSANTS

38. • Adjunctive treatment with alpha-2 antagonist antidepressants,
mianserin and mirtazapine, have shown evidence of efficacy for
negative symptoms of schizophrenia [Hecht EM et al , 2012].
• A meta-analysis of eight randomized trials, with sample sizes
between 19 and 41 patients, found the medications to reduce
negative symptoms when added to an antipsychotic, in
comparison with placebo augmentation.
• Doses for negative symptoms were comparable to those used for
the treatment of depression.
AUGMENTATION WITH ANTIDEPRESSANTS

39. AUGMENTATION WITH OTHER AGENTS
Muscatello et al., Expert Opin. Pharmacother. (2014) 15(16):2329-2345;
Porcelli et al., European Neuropsychopharmacology (2012) 22, 165–182

40. • Agent involved in glutamatergic transmission
• glycine, D-serine,
• D-cycloserine, ampakine
• CX516
• memantine, N-methylglycine based on R-NMDA
hypofunctionning hypothesis.
AUGMENTATION WITH OTHER AGENTS

41. • N-acetyl cysteine (acetylcysteine) — A 24-week randomized trial in 140
patients with chronic schizophrenia (not limited to treatment-resistant)
found that patients treated with N-acetyl cysteine NAC; 1 gram taken
orally twice per day) experienced greater improvement on the PANSS
compared with patients treated with placebo[ Laan W, 2010].
• No difference was seen in change of positive symptoms. NAC, used as
mucolytic, is generally well tolerated; side effects include nausea,
vomiting, and diarrhea.
AUGMENTATION WITH N-ACETYL CYTEINE

42. • D-serine — A meta-analysis of five clinical trials with 80 patients
with chronic, antipsychotic-treated schizophrenia found that
adjunctive treatment with d-serine reduced negative symptoms
compared with placebo [Singh SP , 2011].
• D-serine is an experimental treatment, not available for general
clinical use.
AUGMENTATION WITH D- SERINE

43. • meta-analysis of eight clinical trials with 422 participants Patients receiving
topiramate (100 to 400 mg/day)
• experienced improvement in total psychopathology (standardized mean
difference [SMD] = -0.57 [95% CI -1.01 to -0.14]),
• positive symptoms (SMD = -0.56 [95% CI -1.0 to -0.11]), negative symptoms
(SMD = -0.62 [95% CI -1.13 to -0.10]) and
• general psychopathology (SMD = -0.69 [95% CI -1.27 to -0.11]) compared with
placebo. [Correl CU , 2016]
AUGMENTATION WITH TOPIRAMATE

44. ●As an example, a meta-analysis of four clinical trials with a total
of 330 patients found that augmentation of antipsychotic
medication with minocycline, compared with placebo, reduced
PANSS total scores and negative symptom subscores, but not
positive symptom subscores
[Corell, 2009]
OTHER ADJUNCTIVE MEASURES : WITH ANTI
INFLAMMTORY DRUGS

45. • Other – Negative results have been found in trials of the COX-
2 inhibitor celecoxib.
• Mixed or inconclusive results due to insufficient number of
studies have been reported for augmentation of antipsychotic
treatment of treatment-resistant schizophrenia
with aspirin [Sommer, 2012],
• Lamotrigine [Tiihonen, 2009 ], female sex steroids in females
[Chua WL, 2005], each for positive symptoms, and with N-
methyl-D-aspartate receptor modulators (glycine or sarcosine)
[Singh SP, 2005] for negative symptoms.
OTHER ADJUNCTIVE MEASURES : WITH OTHER
CLASSES OF DRUGS

46. • Nonclozapine antipsychotic drugs – Randomized trials have
yielded mixed results on the effects of augmenting an
antipsychotic other than clozapine with a second or third
antipsychotic drug [Correll, 2009].
• Evidence in support of antipsychotic augmentation of
clozapine is somewhat more positive compared with
augmentation of nonclozapine antipsychotics, but findings for
the strategy remain mixed, with one meta-analysis only finding
benefits of antipsychotic augmentation of clozapine in
nonblinded studies [Barbui C, 2009].
OTHER ADJUNCTIVE MEASURES : WITH NON
CLOZAPINE ANTIPSYCHOTICS

47. • Since the late 1990s,
• at doses between 25-45 mg/d -> as effective as clozapine (100-600mg/d) [Tollefson et
al., 2001]
• for cognitive deficit and hallucinations, better social functionning [Qadri et
al., 2006 ; Reich, 2009]
• Good tolerance even at very high doses [Batail et al., 2014]
 a worthwhile alternative for clozapine-resistant or intolerant patients
(Baldacchino et al., 1998; Dursun et al., 1999; Martin et al., 1997; Rodriguez-Perez et al.,
2002)
USE OF HIGH DOSE OLANZAPINE IN TREATMENT RESISTANT
SCHIZOPHRENIA

49. Question of the psychopharmacological mechanism behind the
therapeutic response at such high doses ?
A STUDY ON PHARMACOKINETICS OF HIGH DOSE OLANZAPINE IN PATIENT
SUFFERING FROM SCHIZOPHRENIA
Pharmacokinetics ?
Pharmacodynamics ?
Comparison of pharmacokinetics of olanzapine at both conventional and
high doses.
?

50. • Linear dose –
concentration
relationship (r = 0.83, p
< 0.001)
• Good concentration –
tolerance relationship
Pharmacodynamic characteristic of response to high dose olanzapine ?

51. ROLE OF LURASIDONE IN TRS

52. NON PHARMACOLOGICAL
AUGMENTATION
STRATEGIES

53. • A meta-analysis of ten trials involving 246 patients with schizophrenia
found rTMS to be more effective than sham treatment for auditory verbal
hallucinations (effect size = 0.49 [95% CI 0.11, 0.88]) [Otani VH et al,
2015].
• A 2014 meta-analysis of 13 sham-controlled randomized trials with 328
patients found rTMS to reduce negative symptoms in patients with
treatment-resistant schizophrenia (effect size = 0.532 [95% CI 0.191,
0.874]) [Shi C et al,2014].
AUGMENTATION WITH RTMS

54. The benefit of rTMS was greater when limiting the analysis to trials that:
●Used a frequency of stimulation of 10 Hz
●Used a 110 percent motor threshold
●Stimulated the left dorsolateral prefrontal cortex
●Had a longer duration of treatment (at least three consecutive weeks)
●Had a shorter duration of illness
AUGMENTATION WITH RTMS

55. ●A single-blind, eight-week trial randomly assigned 39 patients with
clozapine-resistant schizophrenia to continue clozapine or to receive
bilateral ECT along with continuing clozapine Fifty percent of patients
treated with ECT/clozapine met criteria for clinical response
[Petrides G et al, 2015 ]:
●A meta-analysis of 18 randomized trials with 1394 participants found that
ECT augmentation was superior to antipsychotic medication treatment alone
for achieving study-specific criteria of “clinical improvement” (risk ratio [RR]
= 1.25, 95% CI 1.14-1.37) [Wang W ,
2015 ]
AUGMENTATION WITH ELECTROCONVULSIVE
THERAPY

56. 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.

57. ● A metaanalysis of 12 randomized controlled trials showed that when
compared with controls , patients with medication resistant psychosis
had received CBT improved in terms of psychotic symptoms as well as
general symptoms
[Pinto A , 1999]
AUGMENTATION WITH COGNITIVE BEHAVIORAL
THERAPY

58. PSYCHOSOCIAL TREATMENT.
• COGNITIVE REMEDIATION AND THERAPY
1. Cognitive retraining
2. Cognitive therapy

59. PREDICTORS OF RELAPSE
(HIGH EE FAMILIES)
• Six or more critical comments
• Marked emotional over involvement,
• Presence of hostility
• LAND MARK STUDIES:
• Leff et al 1976
•
• RELAPSE RATE OF 50% IN FAMILY WITH HIGH EE
• ONLY 13% RELAPSE IN FAMILY WITH LOW EE
•
• Indian studies
• Wig et al 1987

60. OTHER NON PHARMACOLOGICAL
INTERVENTIONS

61. CONCLUSION
• Prior to making a diagnosis of treatment-resistant schizophrenia, the
clinician should rule out causes of pseudo-resistance
• The patient’s nonpharmacologic treatment should be evaluated and
optimized prior to diagnosing treatment resistance
• Initial management of residual schizophrenia symptoms includes adjusting
the antipsychotic dose and changing to another antipsychotic
• For patients with positive symptoms after adequate trials clozapine is
recommended , rather than other antipsychotics

62. CONCLUSION
• Non pharmacological measures have also shown good results in
augmentation with pharmacological measures.
• In addition to resistant positive symptoms, resistant negative symptoms,
cognitive symptoms also need to be addressed with same priority.
• Incomplete remission in patients depicts the complexity and diversity of
schizophrenia.
• Ongoing research is trying to address various symptom dimensions,
however, no single mode of intervention has emerged as holy grail for
managing all aspects of schizophrenia. It reiterates the need of
multidimensional intervention in all patients for better outcome.

63. DIRECTIONS FOR FUTURE
• More research is needed for prognosis of the condition
• The results from newer SGAs are awaited, probably can be a hope for further
management
• Biomarkers should be looked for ,so as to make early diagnosis of this condition
• Monoclonal antibodies can also be thought of for managing this condition once
targets are identified
• A combination of pharmacological and non pharmacological measures should be
continued

64. THANK YOU 

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