The document discusses treatment resistant schizophrenia, defining it as when patients do not respond to conventional antipsychotics or at least two different antipsychotics. It provides various definitions and criteria for treatment resistance proposed over time. It also discusses factors associated with poor outcomes in schizophrenia like biological, symptomatic, environmental, and illness factors. The neurobiology of treatment resistant schizophrenia is explained, involving the dopaminergic and glutamatergic systems. Evaluation of treatment resistant schizophrenia involves assessing patient factors, treatment factors, and conducting further investigations.

1. T R E AT M E N T R E S I S TA N T
S C H I Z O P H R E N I A
D I PA N W I TA B I S W A S
R E S I D E N T, D E PA R T M E N T O F P S Y C H I AT R Y
R G K M C H

2. INTRODUCTION
 20-30% of patients with schizophrenia do not respond to
conventional antipsychotics.
 Those patients have high rates of smoking (56 %), alcohol
abuse (51%), substance abuse (51%), suicide ideation (44%) and
poor quality of life.
 Annual costs for patients with treatment resistant schizophrenia
(TRS) are 3-11-fold higher compared to patients with
schizophrenia in general and they often have long
hospitalizations.
 Treatment resistance represents the greatest unmet need in
schizophrenia care

3. DEFINING RESPONSE, REMISSION,RESISTANCE
RESPONSE
 Not more than mild symptom severity and no functional impairment for atleast 12
weeks,
 ≥20% decrease on PANSS or BPRS
 A score of 2 or 1 on CGI- Global improvement sub scale OR
 ≥20-point increase on FACT Sz or GAF
PARTIAL RESPONSE
 ≥10% to 20% decrease on PANSS or BPRS
 A score of 3 on CGI- Global improvement subscale OR
 ≥10 to 20-point increase on FACT-Sz or GAF
REMISSION
 Not more than mild positive and negative symptoms or no symptoms for ≥ 6 months
 A patient is in remission if 8 items of the PANSS is ≤3 or
 Corresponding items on the BPRS/SAPS/SANS are rated as "mildly present" or better.

5. Functional Assessment for
ComprehensiveTreatment of Schizophrenia: The
FACT-sz
90-100 No impairments, with or without some
subjective efforts
80-89 Acceptable social functioning and
independence
70-79 Minimal impairments
60-69 Mild Impairments
50-59 Moderate impairments
40-49 Marked impairments
30-39 Significant impairments
20-29 Extreme impairments
10-19 Frank dysfunction
0-9 Life threatening dysfunction

6. CONCEPT OF TREATMENT RESISTANT
SCHIZOPHRENIA
 The concept of treatment-resistant schizophrenia was associated
with the development of antipsychotic drugs.
 Although previous attempts had been made, the first definition
acknowledged in the scientific literature, was linked to the
development of an antipsychotic drug, clozapine.
 A study carried out in 1988 by Kane et al defined “treatment-
resistance” and indicated clozapine as the gold standard treatment
for these patients.
 This recommendation remains in the clinical guidelines.
 It is a dichotomous definition of response/no response.

7. Other dimensional definitions, such as by Brenner et al, appeared
later, and were more applicable to daily practice.
The leverage effect of psychotherapeutic and psychosocial
interventions has been successively integrated with antipsychotic
drugs and resilience to stress factors in the overall response.
This has finally led to an integrated biopsychosocial approach and a
multi-level assessment of treatment response.
This evolution reflects changes in the way treatment-resistance is
conceptualized, and ranges from dichotomy to dimensional .

8. The various criterias of treatment resistant schizophrenia proposed by
different researchers over due course of time
1) KANE’S CRITERIA
Operational criteria most widely used for TRS.
It is three dimensional
A)HISTORICAL
• Atleast three treatments with antipsychotics of
• Atleast two different chemical classes
• Doses equivalent to 1000mg/day of chlorpromazine
• For a period of 6weeks without significant relief
• No period of good function within the preceeding 5years
B)CROSS SECTIONAL
A score of atleast 45 in the BPRS with score≥4 on atleast 2 out of 4 positive symptoms
hallucinatory behavior
unusual thought content
suspiciousness
conceptual disorganization
C)PROSPECTIVE CLINICAL RESPONSE
Failure to achieve BPRS ≤35 in BPRS or CGI≥3 with trial of haloperidol 60mg daily for

9. EQUIVALENT ORAL DOSES FOR SGA FOR AN
ADEQUATE TRIAL
Risperidone: 4 to 6mg /day
Olanzapine: 10 to 20mg/day
Quetiapine: 300 to 600mg/day
Aripiprazole: 15 to 30mg /day
Ziprasidone: 80 to 160mg/day

10. 2)MODIFIED KANE’S CRITERIA
A)HISTORICAL
• Atleast two treatments with antipsychotics of
• Atleast two different chemical classes
• Doses equivalent to 400-600mg/day of chlorpromazine
• For a period of 4-6weeks without significant relief
• No period of good function within the preceeding 5years
B)CROSS SECTIONAL
A score of atleast 45 in the BPRS with score of ≥4 on atleast 2 out of 4
positive symptoms
hallucinatory behavior
unusual thought content
suspiciousness
conceptual disorganization
C)PROSPECTIVE CLINICAL RESPONSE
Failure to achieve BPRS ≤35 in BPRS or CGI≥3 with trial of haloperidol 60mg
daily for 6weeks.

11. • They used a psychosocial approach, rather than solely a pharmacological one.
• They defended the existence of different degrees of treatment response, ranging
from clinical remission to severe treatment-refractoriness.
3)BRENNER ET AL, 1990

12. 4)MELTZER 1992
• Set forth the idea from Brenner et al.
• Proposed to assess treatment-resistance according
to different parameters:
• His criteria are less strict and more useful in
clinical practice.
1) Psychopathology,
2) Cognitive function,
3) Extrapyramidal functions,
4) Social functioning,
5) Independence and work
functioning, Quality of life,
6) Reinstatement,
7) Dependences,
8) Cost of the illness, as well as
treatment.
5)INTERNATIONAL STUDY GROUP CRITERIA
1. Persistent moderate to severe positive, negative,disorganization symptoms.
2. Cognitive dysfunction in multiple spheres.
3. Recurrent mood disturbance and suicidality.
4. Poor work and social function.
5. Poor (subjective) quality of life.
6. Bizarre behavior.
7. One adequate trial of a typical neuroleptic
at doses of 2-20 mg/day of haloperidol or equivalent
for duration of 6-12 weeks

13. 5)With advent of clozapine and atypicals definiton
has been changed to:

14. 6)NICE 2002
stated that "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 atleast two antipsychotics
• Atleast one of which should be an atypical
7)AMERICAN PSYCHIATRIC ASSOCIATION 2004
A patient who has not responded to two or three treatments using atypical
antipsychotics for duration of at least 4 to 6 weeks can be considered as having
TRS and is eligible for treatment with clozapine."

15. FACTORS ASSOCIATED WITH POOR OUTCOME IN SCHIZOPHRENIA
BIOLOGICAL FACTORS
1. Structural brain
abnormalities
2. Family history
SYMPTOMATIC FACTORS
1. Early onset
2. Lack of precipitating
factors
3. Severe negative
symptoms
4. Marked cognitive
impairment
5. Absence of affective
symptoms
6. Neurological soft signs
ENVIRONMENTAL FACTORS
1. Lack of social network (e.g.
homelessness, lack of family
support)
2. Migration
OTHER ILLNESS FACTORS
1. Poor premorbid adjustment
2. Increased no of episodes of psychosis
3. Long duration of untreated
psychosis(DUP)
4. Childhood onset schizophrenia
5. Obstetric complications
6. Advanced paternal age
7. Comorbidity (eg. substance abuse)

16. PHARMACOLOGICAL PREDICTORS
1. Delay in initiating pharmacological
therapy
2. Incorrect choice, dose and duration
of psychotropic treatment
3. Non adherence
4. Psychotropic drug-drug interactions
5. Appearance of EPS
PSYCHOSOCIAL PREDICTORS
1. Delay of psychosocial intervention
2. Insufficient quality of treatment
and rehabilitation
3. Poor therapeutic alliance
FAMILY FACTORS
1. High family expressed
emotion (EE)Situational
stress
2. Aggression
3. Reluctance against
treatment
OTHER FACTORS
1. Male gender
2. Lack of insight
3. Negative attitude towards
treatment
4. Adverse life events

17. NEUROBIOLOGY OF TRS
Involvement of dopaminergic
system
 SCZ patients with high
dopamine release were more
responsive to antipsychotics
than who had lower dopamine
levels.
 Striatal dopamine synthesis
capacity in TRS was lower than
in remission.
 Ineffectiveness of antipsychotics
in TRS is due to lack of
increased presynaptic striatal
dopamine synthesis.
 Post-mortem study found a
higher density of dopaminergic
synapses in caudate nucleus in
treatment response, compared
to those with TRS.

18.  DOPAMINE SUPERSENSITIVITY
PSYCHOSIS (DSP)
 DSP was reported 50% of patients
with TRS.
 The dopaminergic changes
following continuous receptor
blockade with an antipsychotic
medication are proposed to involve
increases in DRD2 receptor density
 In turn, increases in antipsychotic
medication doses to control break-
through symptoms are thought to
lead to further increases in DRD2
density, resulting in increased
dopamine super sensitivity, and
consequently, the reemergence of
symptoms
 This implies that TRS is related to
duration of antipsychotic treatment

19. INVOLVEMENT OF GLUTAMINERGIC SYSTEM
Higher glutamate levels in the ACC in patients with TRS compared to those whose
symptoms remitted. They also have a range of abnormalities in glutaminergic system
in different parts of the brain.
GENETIC RISK
Increased genetic loading for schizophrenia is also a risk factor for TRS.
Among a set of 74 candidate genes suggested by the CATIE study, only the BDNF
gene (low levels)was associated with antipsychotic treatment resistance.
INFLAMMATION AND OXIDATIVE STRESS
Serum IL-6 found to be significantly higher in resistant schizophrenia.
Schizophrenia may be associated with significant immunological alterations like impaired
T-cell functions, showing the activation of the inflammatory response system (IRS),
particularly in treatment-resistant schizophrenia.

20. NEUROANATOMY
 Grey matter volumes were significantly smaller in patients with TRS, compared
with responders to first-line treatment.
 This grey matter loss was the most extensive in superior temporal gyrus
 Patients resistant to clozapine showed significantly larger ventricular CSF volumes
 widespread reduction in cortical thickness in frontal, parietal, temporal and
occipital regions bilaterally.
 Patients with TRS also had decreased thickness in the left DLPFC) ,which was
proposed as a putative for treatment resistance

21. EVALUATION OF TREATMENT RESISTANT
SCHIZOPHRENIA

22. Patient factors
Illicit substance misuse
Psychosocial milieu
Physical comorbidity
Treatment factors
Non-compliance
Side effects (eg, extrapyramidal
symptoms, weight gain, diabetes)
Incorrect dose
Incorrect diagnosis
Drug–drug interactions
Delay in initiating treatment
Drug bioavailability problems
Inadequate rehabilitation program
Poor therapeutic alliance between doctor
and patient
Illness factors
Severity of psychopathology for each symptom
domain
Poor prognosis of patients, who are typically single
men with:
Intellectual disability
Marked cognitive impairment
Poor premorbid adjustment
Early and/or insidious onset of disorder
Longer duration of prodrome
Longer duration of untreated psychosis
Negative symptoms at first admission
Organic disorders (eg, temporal lobe abnormalities,
brain injury) (suspected after abnormal CT scan, MRI
scan or EEG)
CONFOUNDERS

23.  It is recommended as first-line treatment
for TRS in all guidelines and remains the
gold standard
 Particularly effective against aggression
and violence in patients with TRS.
 Also unique due to anti suicidal
properties
PHARMACOLOGY
 Clozapine is a dibenzothiazepine.
 Antagonist of 5-HT2A, D1, D3, D4, and
α(especially α1) receptors,
 Relatively low potency as a D2 receptor
antagonist.
 Data from PET scanning show10 mg of
haloperidol-80 % occupancy of striatal D2
receptors,
 Clinically effective dosages of clozapine
occupy & only 40 to 50% of striatal D2
receptors.
 This is why clozapine does not cause EPS.
CLOZAPINE
WHY CLOZAPINE WORKS IN
RESISATANT CASES?
 NOVEL MECHANISM OF
ACTION
 P-glycoprotein transports
antipsychotics out of brain
 Inhibitors of Pgp can cause reversal
of drug resistance
 Clozapine is NOT transported by
PgP

24. NICE GUIDELINES
• Before initiating therapy,
• WBC ≥3,500/mm3 and ANC ≥2,000/mm3
• First 6 months, weekly monitoring,
• Six to 12 months, every 2 week monitoring,
• Then every 4 weeks or monthly
• Monitoring for at least 1 month after it is discontinued.
• Any fever or sign of infection (e.g., pharyngitis) is an immediate
indication for a WBC count,
particularly in the first 18 weeks of treatment.
• If WBC < 3000 cells/ mm3 or ANC < 1500 cells/mm3, clozapine
must be discontinued.

25. CLOZAPINE: DOSING REGIMEN
Male smokers
550mg/day

26. DRUG INTERACTIONS
 Other drugs causing agranulocytosis or bone marrow suppression-carbamazepine,
phenytoin, propylthiouracil, sulphonamides.
 Lithium clozapine increase the risk of seizures, confusion, and movement
disorders.
 Risperidone, fluoxetine, fluvoxamine, and paroxetine increase serum
concentrations of clozapine.
EFFICACY OF CLOZAPINE
30% improve by 6weeks
60% improve by 6 months
ADEQUATE TRIAL OF CLOZAPINE –
9MONTHS

27. SPECIAL OBSERVATION IN INDOOR WHILE CLOZAPINE DOSE ESCALATION
 Temperature>38c (very common & not a valid reason to stop clozapine solely on its
basis)
 Pulse>100bpm (also very common & not solely on its own a reason to stop clozapine
except if signs of myocarditis is present)
 Postural drop of BP of > 30 mm of Hg
 Patient is clearly over sedated
 Any other adverse effects that the patient complains of being intolerable.
PLASMA LEVELS
Most studies indicate that threshold for response is in the range 350–420 ug/l. Can be high
as 500 ug/l.

31. PREDICTORS OF RESPONSE
 Severe clinical symptoms,
 Higher levels of functioning before the onset of
schizophrenia, Low levels of HVA and 5-HIAA in CSF,
 Reduced metabolism in the prefrontal cortex,
 Reduced volume of the caudate, and
 The improvement of P50 gating at the 500-ms prepulse
interval

32. CLOZAPINE RESISTANT SCHIZOPHRENIA/ULTRA RESISTANT SCHIZOPHRENIA/SUPER
REFRACTORY SCHIZOPHRENIA
Clozapine is still very much the “last resort”
However as much as 40-70% patients suffering from TRS respond inadequately to
Clozapine
DEFINITION: Persistent active psychotic features despite daily doses of 300 to 900
mg for 8 weeks to 6 months, with plasma drug levels of 350 ng/mL or higher.

33. STRATIGIES TO TACKLE CLOZAPINE RESISTANT
SCHIZOPHRENIA:
 CORRECTION OF FACTORS CAUSING APPARENT RESISTANCE
 AUGMENTATION
 AUGMENTATION WITH ECT & rTMS
 SWITCHING TO SGA/OTHER COMBINATIONS
TREATING APPARENT RESISTANCE
Ensure compliance
Check for adverse effects
Psychoeducation and counselling of family
Regular monitoring of adverse effect and prompt management of disconserting
adverse effect
Check plasma level

34. AUGMENTATION
1)WITH ANTIPSYCHOTICS
 AMISULPIRIDE(400-800 mg/day)- allowed 24% reduction in clozapine dose. Reduces hypersalivation
 ARIPIPRAZOLE(15-30 mg/day)Limited role, mainly improves dislipidemia and obesity
 HALOPERIDOL(2 mg/day)Modest benefit
 RISPERIDONE(2-6 mg/day) Doubtful
 SULPIRIDE (400mg/day)-single RCT in English study; overall effect is modest
 Add Ziprasidone (80-160 mg/day)- supported by two RCTs ; rarely used, causes QTc prolongation
2)AUGMENTATION WITH MOOD STABILIZERS
 Lamotrigine (25-300 mg/day)
• Aids the glutamate antagonism demonstrated by clozapine.
• May reduce alcohol consumption.
• "Meta-analyses suggest moderate effect size.“
 Lithium
• Used for clozapine re-challenge in patients with previous clozapine-induced neutropenia*
• Benefits as an augmenting agent in schizoaffective patients, with improvements in negative symptom
and cognitive domains

35.  Valproic Acid
• Is indicated for use in prophylaxis against seizures in individuals on high doses of
clozapine
• In combination with clozapine it results in Less weight gain, greater Improvement in
BPRS scores after 6 months of therapy, and reducing hostility and anxiety
• The combination of valproate and clozapine is safe and well-tolerated
.
3)AUGMENTATION WITH ANTIDEPRESSANTS
There are three potential benefits for the usage of SSRI with clozapine.
1. All the SSRIs are, inhibitors of the hepatic cytochrome (CYP) system increases
clozapine levels,which is metabolized by CYP1A2
2. Clozapine has anti-serotoninergic effects-worsens the Obsessive compulsive
symptoms of somepatients. The SSRIs could decrease this
3. Antidepressant effects of SSRIs promote rehabilitation and social integration
Fluvoxamine and Fluoxetine- Improvement in negative symptoms
Mirtazapine (30 mg a day) was shown to improve avolition, anhedonia and
cognition

36. 4)OTHER DRUGS
 Topiramate (50-300 mg/day)
• Robust effect on positive and negative symptoms
• Greatest potential lies in its ability to induce weight loss
• Can worsen psychosis in some.
• Memory impairment and deficits in cognitive processing
 Omega-3 triglycerides (2-3 g EPA dally)
• The phospholipid hypothesis of schizophrenia-genetically determined
abnormality of phospholipid metabolism
• Modest evidence
 Glutamatergic agents
• Glycine and D-cycloserine.
• The rationale is, in schizophrenia is a decrease in NMDA (glutamate
receptor) activity. Glycine is a full NMDA receptor agonist and D-cycloserine
is a partial agonist
 Ginkgo blloba,Memantine,Acetyl-L-carnitine,Thyroxine

37. ClOZAPINE WITH ECT
 Was effective in half of TRS patients
 Highest response rate reported with any type of clozapine augmentation.
 A review of 36 published cases → 67% of patients benefited from the combination.
 The number of ECT sessions was 12 ± 6
 Clozapine dose during ECT was 385+ 172 mg/day.
MECHANISMS OF EFFICACY
 Clozapine induces lowering of the seizure threshold
 ECT compromises the BBB so that greater amounts of clozapine penetrate into the brain.
 It may potentiate GABA B neurotransmission
THEORETICAL CONCERNS
1) Risk of prolonged seizures during ECT
2) The potent anticholinergic effect of clozapine may exacerbate the cognitive adverse
effects of ECT
3) Clozapine increases heart rate & prolongation of the QTc interval .ECT causes
sympathetic hyperactivity. The combination increase the risk of cardiac arrhythmias.

38. rTMS WITH CLOZAPINE
 rTMS involves focal, non-invasive stimulation of cortical regions by
rapidly changing magnetic fields.
 Repetitive stimulation can either increase or decrease the cortical
excitability depending on the frequency of stimulation.
 High frequency stimulation (25Hz) has an excitatory effect, and
 Low frequency stimulation (S1Hz) has an inhibitory effect on the cortical
region targeted the stimulation.
 Due to the focal nature of stimulation, specific symptom clusters can be
be targeted. Auditory hallucinations and negative symptoms are
important targets for rTMS in schizophrenia.
 Low frequency rTMS over Lt temporoparietal cortex medication-resistant
AH.
 High frequency rTMS over the Lt or B/L dorsolateral prefrontal cortex
(DLPFC)→ attenuate negative symptom burden in schizophrenia.

39. SWITCHING TO OTHER ANTIPSYCHOTICS
 Done when:
 Augmentation fails
 Intolerable adverse effect occurs
 Burden of treatment excessive
DRUGS USED
1)OLANZAPINE-Normal doses modestly effective. Higher doses(30-60 mg/day) can be
tried. Side effects is a problem. May also be used in combination with risperidone, lamotrigine, sulpiride,
amisulpride
2)RISPERIDONE(2-8 mg/day)May be used alone or combined with olanzapine/lamotrigine
3)QUETIAPINE very high doses(1200 mg/day) to be used
4)AMISULPIRIDE (upto 1200 mg/day)
5)ARIPIPRAZOLE (15-30 mg/day) can be combined with Olanzapine . Even higher doses
like 60 md/day used rarely though.
6)RISPERIDONE+CELECOXIB: Promising may prevent cell-death
7)ZIPRASIDONE(80-160 mg/day)

40. PSYCHOLOGICAL TREATMENT
1) CBT
2) Family therapy
3) Personal therapy
PSYCHOSOCIAL TREATMENT
1) Social skill training
2) Assertive community therapy
3) Stress reduction
4) Vocational rehabilitation
PSYCHOSOCIALAPPROACHES FOR TREATMENT RESISTANT SCHIZOPHRENIA
CBT:
 Not as much helpful as in Depression
 Not useful if patient is too paranoid, withdrawn or cognitively impaired
 Stresses on developing therapeutic alliance with a neutral stance
 Alternative explanation for patients experiences
 Starts with “peripheral questioning” and “inference chaining”
 Graded reality testing
 Reduce the impact of positive symptoms

41. FAMILY THERAPY
Primary environment where disease is expressed
Family dysfunctions can cause and exacerbate illness e.g Expressed emotion cause
increased chance of relapse.
Adequate functioning can buffer many symptoms
Aim: To reduce familial stress and ensure collaborative approach provide
psychoeducation
Advantage: Cost effective & increases compliance
PERSONAL THERAPY
A variety of supportive psychotherapy
Individualized for patient
Stress reductionCognitive restructuringVocational rehabilitation
Weekly sessions(30-45 mins)
Largely replacing individual therapy as it ensures compliance and social
adjustment and is not anxiety provoking

42. SOCIAL SKILLS TRAINING(SST)
 Social skills ---specific response capabilities necessary for effective social
performance(BellackandMueser,1993)
 Social skill deficits are well known in schizophrenia
 Explained by
1)problem in “theory of mind” skills
2)Attributional style and
3)Inability to perceive facial affect in others
3 MODELS OF SST USED:
BASIC MODEL:
 Complex social scenarios broken down to simpler components
 Combination with drugs prevent relapse
 However improvement lasts for only 1 yr(Bellack and Meuser 1993)
SOCIAL PROBLEM-SOLVING MODEL:
 Emphasizes in cognitive disturbances resulting in poor social life
 Defects in receptive and expressive communication addressed in spheres of recreation, social interaction,
personal care and drug compliance
COGNITIVE RESTRUCTURING:
 Corrects key cognitive errors as in attention concentration, memory and executive
functions
 Effect lasts for few years

43. ASSERTIVE COMMUNITY TREATMENT
 Candidates identified in community
 Multidisciplinary team Case manager, psychiatrist, nurse,social worker, psychologist
 Fixed caseload with high staff-to-patient ratio, providing care 24 x 7 in residence,clinics and
hospital
 Reduce time spent in hospital(Bustillo et al 2001)
VOCATIONAL REHABILITATION
 Unemployment is the major problem in resistant cases
 Rate of continuous employment is very low
 Sheltered work setting used where work and social demands are manageable for schizophrenic
patients
 This includes Job clubs and part-time/transitional employment programs
 Allows focus on individual brilliance found in some patients
 ART THERAPY is a form of vocational rehabilitation
 Successful employment signifies recovery
STRESS REDUCTION
 General modes can be applied as these patients are exceptionally vulnerable to stress
 Relaxation training and Jacobson’s PMR technique can help

44. THANKYOU