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. 2019 Feb 26;10:67. doi: 10.3389/fpsyt.2019.00067

Table 1.

Summary of studies on predictive factors of treatment resistance.

Study design Patients (n)/type Trial duration Predictors of
PATIENT-RELATED FACTORS
Malla et al. (44) Longitudinal study 107 FEP SZ 2 years Response/remission
Better premorbid adjustment
Emsley et al. (45) Longitudinal study 57 FEP SSD 2 years Non-response/resistance
Single status, lower premorbid functioning
Crespo-Facorro et al. (40) RCT olanzapine vs. haloperidol vs. risperidone 172 FEP SSD 6 weeks acute phase (in the context of 3 years longitudinal intervention) Non-response/resistance lower premorbid functioning
Selten et al. (54) Longitudinal study 125 FEP SZ 30 months Non-response/resistance
Male gender (plus substance use)
Albert et al. (43) Longitudinal study 255 FEP 5 years Response/remission
Female gender, higher age, good premorbid function
Addington and Addington (42) Longitudinal study 240 FEP SSD 36 months Non-response/resistance Reduced social functioning and lower premorbid functioning
Levine et al. (46) Longitudinal study 263 SSD at recent onset 2 years Response/remission
Good premorbid functioning
Derks et al. (55) Randomized, open-label, prospective study olanzapine vs. haloperidol vs. risperidone 498 FEP SSD 1 year Non-response/resistance
Male gender
Verma et al. (50) Naturalistic study 1,175 FEP SSD 2 years Response/remission
Female gender, tertiary education
Teferra et al. (65) Longitudinal study 312 FEP SZ 5 years Response/remission
Single status
Crespo-Facorro et al. (41) RCT olanzapine vs. haloperidol vs. risperidone 375 FEP SSD 6 weeks Non-response/resistance
Poorer premorbid adjustment
Díaz et al. (51) Randomized, open-label, prospective study olanzapine vs. haloperidol vs. risperidone 174 FEP SSD 1 year Non-response/resistance
Male gender, single status, and low education level
Zhang et al. (53) Prospective cohort study 398 FEP SZ 1 year Response/remission
Higher age
Di Capite et al. (52) Longitudinal study 63 FEP SSD antipsychotic discontinuation 1 year Non-response/resistance
Male gender
Not related with educational level
Wimberley et al. (49) Cohort study 8,624 SZ at first hospital contact 9 years Non-response/resistance
Younger age, living in less urban area, low education level
Lally et al. (56) Longitudinal study 246 FEP SSD 5 years Non-response/resistance
Male gender
Lasalvia et al. (48) Retrospective study 444 FEP SSD 9 months Response/remission
Good premorbid adjustment and insight regardless of treatment, higher educational level
Friis et al. (79) Longitudinal study 301 FEP SSD 10 years Non-response/resistance
Lower premorbid functioning
DISEASE-RELATED FACTORS
Lambert et al. (69) Retrospective study 367 FEP SSD 18 months Non-response/resistance
High positive symptoms
Milev et al. (67) Longitudinal study 99 FEP SSD 7 years Non-response/resistance
Cognitive and negative symptoms
Siegel et al. (74) longitudinal study 208 FEP SZ 2–8 years (mean 3 years) Non-response/resistance
High positive, negative, and depressive symptoms
Selten et al. (54) Longitudinal study 125 FEP SZ 30 months Non-response/resistance
Substance use
Addington and Addinton (42) Longitudinal study 240 FEP SSD 36 months Non-response/resistance
High positive and negative symptoms
Boter et al. (82) Longitudinal study 498 FEP SSD 1 year Response/remission
Absence of use disorder
Strauss et al. (72) Longitudinal study 56 FEP SZ 20 years Non-response/resistance
Deficit syndrome
Levine and Rabinowitz (47) Longitudinal study 49 FEP SSD 2 years Non-response/resistance
Cognitive impairment
Diagnosis of schizophrenia
Early age at onset
Üçok et al. (62) Longitudinal study 93 FEP SZ 2 years Response/remission
High positive and low negative symptoms at onset
Galderisi et al. (73) RCT olanzapine vs. amisulpride vs. ziprasidone vs. quetiapina 345 FEP SSD 1 year Non-response/resistance
Persistent negative symptoms
Verma et al. (50) Naturalistic study 1,175 FEP SSD 2 years Non-response/resistance
Diagnosis of schizophrenia
Crespo-Facorro et al. (41) RCT olanzapine vs. haloperidol vs. risperidone 375 FEP SSD 6 weeks Non-response/resistance
High positive and disorganized symptoms, diagnosis of schizophrenia, and early age at onset
Gaebel et al. (78) RCT risperidone vs. haloperidol 166 FEP SZ 1 year Response/remission
Low positive and negative symptoms
Pelayo-Terán et al. (81) RCT risperidone vs. haloperidol 161 FEP SSD 6 weeks Non-response/resistance
Cannabis use
Austin et al. (70) longitudinal study 496 FEP SSD 10 years Non-response/resistance
Negative symptoms
Substance use
Chiliza et al. (7) Longitudinal study 126 FEP SSD 1 year Non-response/resistance
High negative symptoms
Ventura et al. (75) Longitudinal study 146 SZ recent onset 1 year + 7 years of follow-up Non-response/resistance
Early negative symptoms
Friis et al. (79) Longitudinal study 301 FEP SSD 10 years Non-response/resistance
Diagnosis of schizophrenia
Wimberley et al. (49) Cohort study 8,624 SZ at first hospital contact 9 years Non-response/resistance
Diagnosis of schizophrenia
Substance use
Demjaha et al. (8) Longitudinal study 323 FEP SSD 10 years Non-response/resistance
Negative symptoms at onset diagnosis of schizophrenia and early age at onset
Yoshimura et al. (76) Retrospective study 131 FEP SZ Not reported Non-response/resistance
High negative symptoms
Downs et al. (77) Cohort study 638 early-onset psychosis (10–17 years) 5 years Non-response/resistance
High negative symptoms
NEUROBIOLOGICAL FACTORS
Garner et al. (89) Controlled dose-finding study 42 FEP SZ with quetiapine 12 weeks Non-response/resistance
Larger pituitary volume
Palaniyappan et al. (90) Case-control study 126 (80 FEP) SSD 12 weeks Non-response/resistance
Hypogyria at bilateral insular, left frontal, and right temporal regions
Mondelli et al. (88) Longitudinal study 68 FEP
57 controls
12 weeks Non-response/resistance
Blunted cortisol awakening response and increased proinflammatory cytokines
Kim et al. (86) RCT 12 SZ—TR with clozapine vs. 12 SZ responders vs. 12 healthy controls 12 weeks Non-response/resistance
Lower dopamine synthesis capacity in striatum
Walker et al. (87) RCT (post-mortem) 14 SZ (6 TR)
9 healthy controls
Not available Non-response/resistance
Reduction of myelination in substantia nigra
TREATMENT-RELATED FACTORS
Bottlender et al. (101) Longitudinal study 58 FEP SZ 15 years Non-response/resistance
Longer DUP
Correll et al. (93) Open-label study 131 acute SSD with fluphenazine 4 weeks Non-response/resistance
Poor response at week 1
Malla et al. (44) Longitudinal study 107 FEP SZ 2 years Response/remission
Higher level of adherence
Leucht et al. (94, 95) Data analysis from 7 RCTs 1,708 SSD Not available Non-response/resistance
Poor response at week 1 and 2
Kinon et al. (26) Data analysis from 5 RCTs 1,077 SSD 6 months Non-response/resistance
Poor early response (but early response does not predict subsequent response)
Boter et al. (82) Longitudinal study 498 FEP SSD 1 year Response/remission
Higher level of adherence
Kinon et al. (96) RCT 628 SSD with risperidone. If non response switch to olanzapine 12 weeks + 10 weeks if non early response Non-response/resistance
Poor response within 2 weeks
Üçok et al. (62) Longitudinal study 93 FEP SZ 2 years Response/remission
Higher level of adherence
Zhang et al. (53) Prospective cohort study 398 FEP SZ 1 year Response/remission
Higher level of adherence
Austin et al. (70) Longitudinal study 496 FEP SSD 10 years Non-response/resistance
Longer DUP
Friis et al. (79) Longitudinal study 301 FEP SSD 10 years Non-response/resistance
Longer DUP
Demjaha et al. (8) Longitudinal study 323 FEP SSD 10 years Non-response/resistance
Longer DUP
Yoshimura et al. (76) Retrospective study 131 FEP SZ Not reported Response/remission
Shorter DUP

SZ, schizophrenia; SSD, schizophrenia spectrum disorders; FEP, first episode of psychosis; TR, treatment resistant; RCT, randomized-controlled study; DUP, duration of untreated psychosis.