Table 1. Study characteristics.
1H-MRS – proton magnetic resonance spectroscopy; AP –antipsychotic; AVH – Auditory verbal hallucinations; BPRS – Brief Psychiatric Rating Scale; CNR – clozapine non responder; CPZ equiv – Chlorpromazine equivalents; DSM – Diagnostic and Statistical Manual of Mental Disorders; EEG – electroencephalogram; HC- healthy controls; MDD – major depressive disorder; MRI – Magnetic Resonance Imaging; PET – Positron Emission Tomography; Individuals with schizophrenia without auditory hallucinations; R – antipsychotic responders; Scz- unspecified whether responder/resistant; SPECT- single-photon emission computed tomography; TR – treatment resistant; TR-AVH, treatment resistant auditory verbal hallucinations.
| Authors | Year | Sample | Resistance criteria | Modality | Medication at time of scan | Diagnostic Criteria |
|---|---|---|---|---|---|---|
| Ahmed et al.17 | 2015 | 33 TR, 31 HC | Failed ≥2 Aps (≥1 atypical). Prolonged positive or negative symptoms of ≥moderate severity | MRI – Structural | Pre and post clozapine | DSM-IV-TR |
| Alonso-Solis et al.23 | 2015 | 19 TR-AVH, 14 R, 20 HC | Daily AVH AND failed ≥2 Aps (at dose equiv ≥600mg clozapine/day) | fMRI – resting state | Typical/Atypical Aps | DSM-IV-TR |
| Anderson et al.15 | 2015 | 15 CNR, 19 TR, 18 R, 20 HC | Lack of significant response despite trials (adequate dose and≥6 wk duration) of ≥2 Aps | MRI- structural | Atypical Aps (including clozapine) | DSM-IV-TR |
| Arango et al.51 | 2003 | 45 TR | Residual positive (≥8 BPRS psychotic) or negative symptoms (≥20 SANS) despite ≥2 6wk AP trials. Prospective trial fluphenazine 20mg/day – subjects with >30% improvement excluded. | MRI – Structural | Clozapine or Haloperidol | DSM-III-R |
| Bartlett et al.42 | 1998 | 7 TR, 7 R | Unmedicated BPRS ≥ 50 or medicated BPRS ≥ 42 AND no worsening when unmedicated. Prospective 4-wk AP trial for patients with no records | FDG-PET (haloperidol challenge) | Not specified | DSM-III-R |
| Buchsbaum et al.57 | 1992 | 12 Scz | Not specified | FDG-PET | Pre/post clozapine/thioxene | Not specified |
| Cachia et al.99 | 2008 | 30 TR-AVH, 28 HC | Kane et al (1988) | MRI-Structural | Typical /atypical Aps | DSM-IV |
| Chakos et al.54 | 1995 | 8 clozapine, 7 typical Aps | Not specified | MRI- Structural | Clozapine and typical Aps | Not specified |
| Demjaha et al.43 | 2012 | 12 TR, 12 R, 12 HC | Conley et al (2001) | FDOPA-PET | Non clozapine Aps | DSM-IV |
| Demjaha et al.34 | 2014 | 6 TR, 8 R, 10 HC | Conley et al (2001) | 1H-MRS | Typical and atypical Aps | DSM-IV |
| Ergun et al.62 | 2010 | 20 TR | Treatment refractory or AP intolerant | 99mTc-HMPAO SPECT | Pre and post clozapine | DSM-IV |
| Ertugrul et al.61 | 2009 | 22 TR | On clozapine due to treatment resistance or intolerance to previous Aps | 99mTc-HMPAO SPECT/ 1H-MRS | Typical and atypical Aps | DSM-IV |
| Fitzgerald et al.26 | 2007 | 3 TR, 4HC | Persistent severe refractory hallucinations that had not responded to ≥2 adequate courses of Aps | fMRI (word generation task) | Clozapine, amisulpride, sertraline, valproate, diazepam | Not specified |
| Friedman et al.50 | 1991 | 34 TR | Failure to respond to ≥2 different class Aps (each for ≥6 weeks, ≥ 800mg CPZ equiv). ≥4 on BPRS positive items | CT Scan | Clozapine | RDC |
| Galletly et al.36 | 2005 | 15 TR, 14 HC | Not specified | EEG | Pre and post clozapine | DSM-IV |
| Goldstein et al.35 | 2015 | 11 CNR, 16 TR, 15 R, 11 HC | NICE (2002), RANZCP (2005) | 1H-MRS | Atypical Aps including clozapine | DSM-IV |
| Gross et al.67 | 2004 | 16 TR | Kane et al (1988) | EEG | Risperidone or olanzapine | SCID + chart review |
| Holleran et al.22 | 2014 | 19 TR, 19 HC | Failure to respond to ≥2 Aps (≥1 atypical), prolonged moderate/severe positive or negative symptoms. | MRI- DTI | Atypical Aps, antidepressants | DSM-IV |
| Honer et al.48 | 1995 | 42 TR (inc 3 Schizoaffective) | Poor response to adequate AP dose for ≥6 months. May et al. (1988) scale. | CT scan | Antipsychotic class not specified | DSM-III-R |
| Hoptman et al.72 | 2005 | 49 TR | Kane et al (1988) | MRI-Structural | Typical and atypical Aps (including clozapine) | SCID + chart review |
| Horton et al.37 | 2011 | 21 TR, 19 HC | Not specified | EEG | Clozapine | DSM-IV and SCID |
| Kikuchi et al.100 | 2014 | 26 TR | Poor tolerance or poor response despite ≥2 Aps (≥1 atypical), ≥ 4 weeks and ≥600mg CPZ equiv. | EEG | Pre and post clozapine treatment | Not specified |
| Klirova et al28 | 2013 | 15 TR-AVH, 19HC | Non response to both typical and atypical Aps + ≥5 episodes AVH per day in the last month | FDG PET | Aps, Antidepressants, anticonvulsants | DSM-IV |
| Knott et al.68 | 2001 | 17 TR, 17 HC | Kane et al (1988) | EEG | Not specified | DSM-III-R |
| Knott et al.66 | 2002 | 17 TR | Kane et al (1988) | EEG | Pre/post clozapine | DSM-III-R |
| Konicki et al.49 | 2001 | TR 26 | Kane et al (1988) | CT scan | clozapine | DSM-III-R |
| Kubera et al.19 | 2014 | 10 TR-AVH, 10 nAVH, 14 HC | Persistent AVH despite ≥2 AP trials (adequate dose, ≥6 wks) | MRI Structural | Clozapine and other Aps | DSM-IV |
| Lacroix et al.101 | 1995 | 10 TR, 10 NR | 35% or more and a 30% or less reduction, respectively, on the Brief Psychiatric Rating Scale (BPRS) | EEG | Not specified | DSM-IV |
| Lahti et al.63,97 | 2003, 2004 | 6 partially responsive, 10 HV | Not specified | 15O-PET | Pre/post clozapine | DSM-III-R |
| Lauriello et al.53 | 1998 | 21 TR | Treatment intolerant or inadequate response. | MRI-Structural | Typical Aps | DSM-III-R |
| Lawrie et al.40 | 1995 | 20 TR, 20 R | May et al (1988) | MRI-Structural/ SPECT | Not specified | DSM-IV |
| Lee at al.46,47 | 2006, 2008 | 25 TR-AVH, 23 nAVH | Persistent AVH for ≥2yrs | EEG | Conventional neuroleptics | DSM-IV |
| Maller et al.18 | 2012 | 52 TR, 182 MDD, 76 HC | Not specified | MRI-Structural | Not specified | DSM-IV |
| MacCrimmon et al.69 | 2012 | 64 TR | Kane et al (1988) | EEG | Pre/post clozapine, (+ other psychotropics) | DSM-IV |
| Milovan et al.39 | 2004 | 13TR, 13 HC | Kane et al (1988) | EEG | Not specified | DSM-IV |
| Mitelman et al.41 | 2005 | 13 TR, 24 R, 27 HC | Keefe et al (1987) | MRI-Structural | Not specified | DSM-IV |
| Molina et al.59 | 1996 | 24 TR | Lack of adequate response to ≥2 chemically different Aps, ≥800mg CPZ equiv | 99mTc-HMPAO SPECT | Pre/post clozapine | DSM-IV |
| Molina et al.29 | 1997a | 36 TR, 28 HC | Kane et al (1988) | 99mTc-HMPAO SPECT | Not specified | DSM-IV-R |
| Molina et al.30 | 1997b | 39 TR (includes Molina et al. 1996 sample), 28 HC | Lack of response to ≥2 dissimilar Aps (≥800mg CPZ equiv), each one for ≥2 months over last year. | 99mTc-HMPAO SPECT | Pre/post clozapine | DSM-IV |
| Molina et al.102 | 2003 | 25 TR | Lack of response to ≥2 different Aps for ≥6 weeks in past 12 mths, dose ≥800mg CPZ equiv. Significant positive or disorganisation residual symptoms | MRI-structural FDG PET |
Pre/post clozapine | DSM-III-R |
| Molina et al.33,103 | 2005, 2007 | 23 TR, 17NN, 18HC | Lack of adequate response to ≥2 Aps for ≥4 weeks in preceding 12 months, dose ≥800mg CPZ equiv. All had haloperidol for ≥4wks before scan | FDG PET | Pre/post clozapine | DSM-IV |
| Molina et al.14 | 2008a | 30 TR, 19 R and 44 HC | Kane et al (1988) | MRI-structural, EEG | Haloperidol prior to first MRI, then olanzapine or clozapine | DSM-IV |
| Molina et al.31 | 2008b | 10 TR, 10 HC | A poor response during the previous year to haloperidol or risperidone followed by lack of response to 4 week trial of risperidone | 99mTc-HMPAO SPECT | Pre/post clozapine | DSM-IV |
| Potkin et al.58 | 1994 | 18 Scz | Not specified | FDG PET | Pre/post clozapine | Not specified |
| Potkin et al.64 | 2003 | 15 TR | Not specified | FDG PET | Not specified | DSM-IV |
| Quarantelli et al.16 | 2014 | 20 (TR + CNR), 15 R, 16 HC | <20 % improvement AND total > 45 on BPRS AND ≥4 in ≥2 BPRS psychotic items AND ≥2 yrs poor functioning despite 6-8 weeks with ≥2 Aps and good adherence. | MRI –structural | Typical and atypical Aps (including clozapine) | DSM-IV-TR |
| Ramos et al.44 | 2001 | 10 TR, 10 R | Keefe et al (1990) and Brenner & Merlo (1995) criteria | EEG | Not specified | DSM-IV |
| Ravan et al.98 | 2015 | 47 TR, 66 HC | Kane et al (1988) criteria | EEG (auditory evoked) | Pre/Post clozapine | DSM-IV |
| Scheepers et al.55 | 2001a | 26 TR | No response (CGI≥4) to ≥1 typical AP for ≥ 4 weeks OR severe EPSEs or TD | MRI-Structural | Pre/post clozapine | DSM-IV |
| Scheepers et al.56 | 2001 b | 28 TR | No response (CGI≥4) to ≥1 typical AP for ≥ 4 weeks OR severe EPSEs or TD | MRI-Structural | Pre/post clozapine | DSM-IV |
| Sun et al.21 | 2009 | 42 TR, 42 MDD, 30 HC | Kane et al (1988) criteria | MRI-Structural | Clozapine | DSM-III-R |
| Tsekou et al.104 | 2015 | 7 TR | Bremner et al (1990) criteria AND ≥70 on PANSS, and schizophrenia diagnosis for≥2 years | Sleep EEG | Pre/post clozapine | DSM-III-R |
| Umbricht et al.38 | 1998 | 11 TR, 6 R, 13 HC | Partially refractory –≥4 on any of the 4 BPRS positive symptom items | EEG | Clozapine and haloperidol | DSM-III-R |
| Vercammen et al.24 | 2010 | 27 TR-AVH, 27 HC | Daily AVH, ≥2 adequate AP trials | MRI-Resting state | Aps and benzodiazepines | DSM-IV |
| Wolf et al.25,27 | 2011, 2012 | 10 TR-AVH, 10 R, 14 HC | Kane et al (1988) | MRI-Resting state | Clozapine | DSM-IV |
| Zhao et al.32 | 2006 | 21 TR, 40 HC | Andreason’s negative symptom profile | SPECT | Medication free, follow up on clozapine | DSM-IV |
| Zugman et al.20 | 2013 | 61 TR, 67 R, 80 HC | Kane et al (1988) | MRI-Structural | Typical and atypical Aps (including clozapine) | DSM-IV |