This presentation discuss in brief the criteria, predictors and management approaches for treatment resistant psychosis. The presentation is an overview for readers to search more regarding this important topic.

1. Resistant psychosis
“Criteria, Predictors and approach”
Shokry Alemam, MD.
Sutherland Hospital 01/07/20
Shokry

2. Objectives
• Definition and criteria
• Predictors of resistance
• Pharmacological management
• Psychotherapy in TRP
• ECT in TRP
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3. Definition and criteria
• The definition and criteria vary according to the guideline
describing them.
• It can be linked with higher risk of a clinical deterioration,
chronicity, neurotoxic effects of relapse, suicide, aggressive
conducts, poor quality of life and low level of functioning.(1)
• 3 keys for the definition of treatment resistant psychosis:
1. Confirmed diagnosis
2. Adequate pharmacological treatment
3. Persistence of significant symptoms despite this treatment.
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4. guidelines Minimum
number of
failed APs
Specified AP Adeqaute treatment
episode duration
Dose Severity of illness others
APA 2 At least one of which is a
second- generation AP
≥6 weeks Therapeutic dose A clinically
inadequate
response” “and for
patients with
persistent suicidal
ideation or
behaviour that has
not responded to
other treatments
-
RANZCP 2 Recommends both first and
second trial to be of an
atypical
6-8 weeks Specified dosages Poor response If poor adherence,
or persistent suicide
risk, positively offer
trial of clozapine
NICE 2 One of the drugs should be a
non- clozapine second-
generation AP
≥4 weeks Adequate Inadequate response 2 trials should be
given “sequentially”
MAUDSLEY 2 Consider use of either first
generation or second-
generation AP
2-3 weeks for trial of
first AP in FEP. 6-
week trial for
subsequent 2nd AP
before clozapine.
At least minimum
effective dose, then
titrated to response
Not specified -
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5. • Poor responders (8.2%), the majority of patients have a
moderate response (76.4%), and only 15.4% can be
considered rapid responders with the greatest magnitude of
response. (2)
• In FEP 25% of patients’ symptoms of psychosis persist with a
worse long-term course of illness. (3)
• Temporal development:
Resistance can be present from the illness onset and can be
developed later after initial response.(4)
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6. • Duration:
Each AP trial should last at least 6 weeks.
• Dose:
In first episode psychosis, minimum therapeutic dose which equals 600 mg of
chlorpromazine daily.
• Number of past treatment episodes:
At least 2 adequate treatment episodes.
Incomplete episodes due to non-compliance (adherence: ≥80% of prescribed
doses for ≥12 weeks) developed side effects should be excluded.
Shokry
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7. Patient related predictors (cont.)
• Premobid functioning:
Lower premorbid functioning is one of the most important factors related to
poor or no response to antipsychotic medications (5)
• Yonger age at the onset of disorder and living in a less urban area:
few studies support this and results were controversial with other studies. (6)
• Lower education level:
La Salvia et al. (5), Verma et al. (7) and Diaz et al. (8) found a relationship
between lower educational level and treatment resistance.
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8. Patient related predictors (cont.)
• Gender:
Male gender was found as a predictor of worse response, poor
outcome and higher risk of relapse after discontinuation of
antipsychotic.
Also, Lally et al.(12) for FEP in patients with schizophrenia concluded
that treatment resistance was strictly connected with male sex.
• Marital status:
Controversial findings of relation between single marital status and
treatment resistance as this factor is changeable.
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9. Disorder related factors (cont.)
• Type of symptoms:
Some studies found theat patients with high levels of both positive
and negative symptoms have poor outcomes. (13)
Patients with negative symptoms at the onset of disorder and
resistant in nature have higher rates of treatment resistance.(14,15)
Cognitive and disorganized symptoms are predictors of treatment
resistance. (16, 17, 18)
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10. Disorder related factors (cont.)
• Diagnosis of schizophrenia was found significantly related to
treatment resistance. (6)
• Comorbidity:
40% of patients with schizophrenia meet criteria of alcohol
use disorder and 30% for substance use disorder especially
cannabis which was considered as a predominant factor of
treatment resistance. (19)
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11. Neurobiological Predictors
• Decreased plasma level of dopamine metabolites.(20)
• Decreased level of dopamine syntesis in striatum.
• Greater decrease of myelination in substantia nigra.(21) ??!!
Greater decrease of myelination of substantia nigra was
observed in cases with schizophrenia with poor response
• Cortisol and inflammatory markers:
Blunted cortisol awakening response and increased
proinflammatory cytokines were predictors of resistance in
the early phases of psychosis . (22)
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12. Neurobiological Predictors (cont.)
• Pituitary volume:
It has inverse relation with decrease of symptoms severity. (23)
• Decreased volume of grey matter:
Hypogyria in bilateral insular regions, left frontal area and
right temporal area.
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13. Treatment related predictors
• Adherence:
Higher level of adherence since FEP predicted response and
remission of the illness. (24)
LAI can be considered in patients with risk factors of relapse.(3)
• Early response:
Samara et al. (25) showed association between lack of
symptoms improvement at week 2 and later non-response.
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14. Treatment related predictors (cont.)
• Duration of untreated psychosis (DUP)
A more prolonged DUP has been related to a longer time of
response to treatment in patients who presented a first-
episode of psychosis and to an impaired course of the disorder
such as higher levels of positive, negative symptoms and lower
global functioning. (26)
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15. Changeable factors Unchangeable factors
• Lower educational level
• Single marital status
• Negative symptoms
• Substance use disorder
• Non-adherence
• Early non-response (within
week 2)
• Duration of untreated
psychosis
• Poor premorbid functioning
• Male gender
• Younger age at onset
• Diagnosis of schizophrenia
• Neurobiological factors
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16. Management of resistant psychosis
Clozapine:
• It is the first line medication in TRP
• Not tolerable by many patients with sometimes serious side
effects
• Some patients are resistant to clozapine as well
• Pharmacological augmentation:
Mainly to reduce clozapine side effects such as weigh gain and
dyslipidemia and decrease used doses of clozapine; however,
it can increase the burden of side effects.(cont.)
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17. Management of resistant psychosis (cont.)
• Amisulpride, Sertindole, Pimozide and ziprasidone may increase
cardiac side effects.(27)
• Aripiprazole has limited therapeutic evidence but decrease weight
and LDL cholesterol.(28)
• 2 RCTs support use of MEMANTINE.(29,30)
• Haloperidol has a modest effect.
• Lamotrigine has moderate effect and may reduce alcohol
consumption.
• Risperidone effect is controversial.
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18. Management of resistant psychosis (cont.)
ECT:
• A study showed that 50% of the patient received bilateral ECT
as augmentation to clozapine had 40% or more reduction of
symptoms.(31)
• ECT augmentation is a safe and efficacious in TRS
• Adverse effects such as transient memory impairment(32),
headache, increased blood pressure after ECT and prolonged
seizures. (33)
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19. Management of resistant psychosis (cont.)
CBT:
• Cognitive behavioral psychotherapy is very effective particularly in the
treatment of positive symptoms in TRS and/or TRP patients. (34)
• The same efficacy was not found in the treatment of negative symptoms
while it was only partial in achieving an improvement in the total scores of
patients evaluated in the PANSS.
• CBT in augmentation with the usual treatment (TAU) works well in the
initial stages and then gradually loses effectiveness.(35)
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20. References
1. Demjaha A, Leppin JM, Stahl D, Patel MX, MacCabe JH, Howes OD, et al. Antipsychotic treatment resistance
in first-episode psychosis: prevalence, subtypes and predictors. Psychol Med. (2017) 47:1981-9.
2. Murray R, Correll CU, Reynolds GP, Taylor D. Atypical antipsychotics: recent research findings and
applications to clinical practice: proceedings of a symposium presented at the 29th Annual European College of
Neuropsychopharmacology Congress, 19 September 2016, Vienna, Austria. Ther Adv Psychopharmacol. (2017)
7:1–14.
3. Fusar-Poli P, McGorry PD, Kane JM. Improving outcomes of first- episode psychosis: an overview. World
Psychiatry (2017) 16:251–65.
4. Agid O, Arenovich T, Sajeev G, Zipursky RB, Kapur S, Foussias G, Remington G. An algorithm- based approach
to first-episode schizophrenia: Response rates over 3 prospective antipsychotic trials with a retrospective data
analysis. J Clin Psychiatry. 2011; 72:1439–1444.
5. Lasalvia A, Bonetto C, Lenzi J, Rucci P, Iozzino L, Cellini M, et al. Predictors and moderators of treatment
outcome in patients receiving multi- element psychosocial intervention for early psychosis: results from the
GET UP pragmatic cluster randomised controlled trial. Br J Psychiatry (2017)
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21. 6. Wimberley T, Støvring H, Sørensen HJ, Horsdal HT, MacCabe JH, Gasse C. Predictors of treatment resistance in patients
with schizophrenia: a population-based cohort study. Lancet Psychiatry (2016) 3:358–66.
7. Verma S, Subramaniam M, Abdin E, Poon LY, Chong SA. Symptomatic and functional remission in patients with first-
episode psychosis. Acta Psychiatr Scand. (2012) 126:282–9.
8. Díaz I, Pelayo-Terán JM, Pérez-Iglesias R. Predictors of clinical remission following a first episode of non-affective
psychosis: sociodemographics, premorbid and clinical variables. Psychiatry Res. (2013) 206:181–7.
9. Di Capite S, Upthegrove R, Mallikarjun P. The relapse rate and predictors of relapse in patients with first-episode
psychosis following discontinuation of antipsychotic medication. Early Interv Psychiatry (2016) 12:893–9.
10. Selten JP, Veen ND, Hoek HW. Early course of schizophrenia in a representative Dutch incidence cohort. Schizophr
Res. (2007) 97:79–87.
11. Derks EM, Fleischhacker WW, Boter H, Peuskens J, Kahn RS. EUFEST Study Group. Antipsychotic drug treatment in
first-episode psychosis: should patients be switched to a different antipsychotic drug after 2, 4, or 6 weeks of
nonresponse? J Clin Psychopharmacol. (2010) 30:176–80.
12. Lally J, Ajnakina O, Di Forti M, Trotta A, Demjaha A, Kolliakou A, et al. Two distinct patterns of treatment resistance:
clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychol Med. (2016)
46:3231–40.
13. Addington J, Addington D. Symptom remission in first episode patients. Schizophr Res. (2008) 106:281–5
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22. 14. Strauss GP, Harrow M, Grossman LS, Rosen C. Periods of recovery in deficit syndrome schizophrenia: a 20-year multi-
follow-up longitudinal study. Schizophr Bull. (2010) 36:788–99.
15. Ventura J, Subotnik KL, Gitlin M, Gretchen-Doorly D, Ered A, Villa KF, et al. Negative symptoms and functioning during
the first year after a recent onset of schizophrenia and 8 years later. Schizophr Res. (2015) 161:407–13.
16. Chiliza B, Asmal L, Kilian S, Phahladira L, Emsley R. Rate and predictors of non-response to first-line antipsychotic
treatment in first-episode schizophrenia. Hum Psychopharmacol. (2015) 30:173–82.
17. Levine SZ, Rabinowitz J. Trajectories and antecedents of treatment response over time in early-episode psychosis.
Schizophr Bull. (2010) 36:624–32.
18. Iasevoli F, Giordano S, Balletta R, Latte G, Formato MV, Prinzivalli E, et al. Treatment resistant schizophrenia is
associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the
most relevant predictor of poorer achievements in functional milestones. Prog Neuropsychopharmacol Biol Psychiatry
(2016) 65:34–48
19. Pelayo-Terán JM, Diaz FJ, Pérez-Iglesias R, Suárez-Pinilla P, Tabarés- Seisdedos R, de León J, et al. Trajectories of
symptom dimensions in short-term response to antipsychotic treatment in patients with a first episode of non-affective
psychosis. Psychol Med. (2014) 44:37–50.
20. Yoshimura R, Ueda N, Shinkai K, Nakamura J. Plasma levels of homovanillic acid and the response to risperidone in first
episode untreated acute schizophrenia. Int Clin Psychopharmacol. (2003) 18:107–11.
21. Walker CK, Roche JK, Sinha V, Roberts RC. Substantia nigra ultrastructural pathology in schizophrenia. Schizophr Res.
(2017)
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23. 22. Mondelli V, Ciufolini S, Belvederi-Murri M, Bonaccorso S, Di Forti M, Giordano A, et al. Cortisol and inflammatory
biomarkers predict poor treatment response in first episode psychosis. Schizophr Bull. (2015)
23. Garner B, Berger GE, Nicolo JP, Mackinnon A, Wood SJ, Pariante CM, et al. Pituitary volume and early treatment
response in drug- naïve first-episode psychosis patients. Schizophr Res. (2009) 113:65–71.
24. Zhang HX, Shen XL, Zhou H, Yang XM, Wang HF, Jiang KD. Predictors of response to second generation antipsychotics in
drug naïve patients with schizophrenia: a 1 year follow-up study in Shanghai. Psychiatry Res. (2014) 215:20–5.
25. Samara MT, Leucht C, Leeflang MM, Anghelescu IG, Chung YC, Crespo- Facorro B. Early improvement as a predictor of
later response to antipsychotics in schizophrenia: a diagnostic test review. Am J Psychiatry (2015) 172:617–29
26. Schennach R, Riedel M, Musil R, Möller HJ. Treatment Response in first- episode schizophrenia. Clin Psychopharmacol
Neurosci. (2012) 10:78–87.
27. Assion HJ et al. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to
clozapine. A randomized, double‐blind, placebo‐controlled trial. Pharmacopsychiatry 2008; 41:24–28.
28. Srisurapanont M et al. Efficacy and safety of aripiprazole augmentation of clozapine in schizophrenia: a systematic
review and meta‐analysis of randomized‐controlled trials. J Psychiatr Res 2015; 62:38–47.
29. de Lucena D et al. Improvement of negative and positive symptoms in treatment‐refractory schizophrenia: a
double‐blind, randomized, placebo‐controlled trial with memantine as add‐on therapy to clozapine. J Clin Psychiatry 2009;
70:1416–1423.
30. Veerman SR et al. Adjunctive memantine in clozapine‐treated refractory schizophrenia: an open‐label 1‐year extension
study. Psychol Med 2017; 47:363–375.
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24. 31. Petrides G et al. Electroconvulsive therapy augmentation in clozapine‐resistant schizophrenia: a prospective,
randomized study. Am J Psychiatry 2015; 172:52–58.
32. Kaster TS et al. Clinical effectiveness and cognitive impact of electroconvulsive therapy for schizophrenia: a large
retrospective study. J Clin Psychiatry 2017; 78:e383–e389.
33. Grover S et al. Effectiveness of electroconvulsive therapy in patients with treatment resistant schizophrenia: a
retrospective study. Psychiatry Res 2017; 249:349–353.
34. Polese D, Fornaro M, Palermo M, De Luca V and de Bartolomeis A (2019) Treatment-Resistant to
Antipsychotics: A Resistance to Everything? Psychotherapy in Treatment-Resistant Schizophrenia and Nonaffective
Psychosis: A 25-Year Systematic Review and Exploratory Meta-Analysis. Front. Psychiatry 10:210.
35. Morrison AP, Pyle M, Gumley A, Schwannauer M, Turkington D, MacLennan G, et al. Cognitive behavioural therapy
in clozapine- resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial. Lancet Psychiatry
(2018) 5(8):633–64.
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