TREATMENT RESISTANT SCHIZOPHRENIA: DIAGNOSIS AND

MANAGEMENT STRATEGIES

Presenter : Dr Gaurav Uppal Chairperson : Dr Ravindra M Date : 17.02.2017

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]

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

DEFINING RESPONSERESPONSE: 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 ]

DEFINING REMISSIONREMISSION: 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 ]

DEFINING RESISTANCE

DEFINING RESISTANCE Historical criteria

Cross sectional Criteria

Prospective criteria

• No preceding good functioning period within last 5 years

• At least 3 treatments with 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

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

ASSESSMENTS TO BE CARRIED OUT BEFORE LABELLING IT AS DRUG

RESISTANT SCHIZOPHRENIA

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

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]

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.

ASSESS FOR ANTIPSYCHOTIC DRUG SIDE EFFECTS

• Akathisia

• EPS

• Sedation and

• insomnia, can mimic negative symptoms

ASSESS FOR DRUG-DRUG INTERACTIONS • Carbamazepine reduces the levels of all antipsychotics

metabolized by the liver except : Amisulpride PaliperidoneSmoking 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 ]

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]

[Haddad et al., 2014]

NON ADHERENC

E ?

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

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]

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 ]

- 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

• 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

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/alternativesGuidelines for prescribing clozapine are described in detail separately.

ELIGIBILITY CRITERIA FOR CLOZAPINE

INDICATIONS FOR CLOZAPINE USE

STUDIES WITH CLOZAPINE.

John Kane 1988Multicenter 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  199360% with clozapine, but only 12% with haloperidol;

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

durationReported decrease in suicidality

Lieberman et al (1994) Optimal trial of Clozapine ------------12 -24 weeks.

• 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 = 0.60) in 16 trials.

EFFICACY OF CLOZAPINE

•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 dropout 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 466 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 mg/day [Lecht S , 2009]

• 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

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

Expert Opin. Pharmacother. (2014) 15(16):2329-2345

AUGMENTATION STRATEGIES IN PARTIAL RESPONDER AND /OR TRS PATIENTS TREATED WITH CLOZAPINE

AUGMENTATION WITH ANTIPSYCHOTICS

• No current consensus regarding this strategy

• Promote pharmacologically synergistic associations

• Tolerance monitoring needed

AUGMENTATION WITH ANTIPSYCHOTICS

AUGMENTATION WITH MOOD STABILIZERS

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

• Interisting in clozapine treated patients with high epileptic risk

• Schizo-affective disorder

• Favor valproate, take care of lithium (tolerance).

AUGMENTATION WITH MOOD STABILIZERS

AUGMENTATION WITH ANTIDEPRESSANT

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

• Comorbid forms (depression, anxiety, OCD)

• Pharmacokinetic effects (inhibiting CYP1A2) with fluoxetine and fluvoxamine ( CLZ norCLZ).

AUGMENTATION WITH ANTIDEPRESSANTS

• 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

• 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

AUGMENTATION WITH OTHER AGENTS

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

• 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

• 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

• 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

• 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

●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

• 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

• 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

• 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

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.

?

• Linear dose –concentration relationship (r = 0.83, p < 0.001)

• Good concentration – tolerance relationshipPharmacodynamic characteristic of response to high dose olanzapine ?

ROLE OF LURASIDONE IN TRS

NON PHARMACOLOGICALAUGMENTATION

STRATEGIES

• 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

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

●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

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.

● A metaanalysis of 12 randomized controlled trials showed that when compared with controls , patients with medication resistant psychosis who had received CBT improved in terms of psychotic symptoms as well as general symptoms

[Pinto A , 1999]

AUGMENTATION WITH COGNITIVE BEHAVIORAL THERAPY

PSYCHOSOCIAL TREATMENT.

• COGNITIVE REMEDIATION AND THERAPY

1. Cognitive retraining2.Cognitive therapy

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

OTHER NON PHARMACOLOGICAL INTERVENTIONS

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

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. •  •  

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

THANK YOU

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