Table 1.
The endogenous OT system in patients with schizophrenia: relation to symptom domains. Adapted from [58].
| Authors | N | OT Parameter | Main Findings | Implications |
|---|---|---|---|---|
| Positive Symptoms | ||||
| Rubin et al. 2010 [40] | 50 SCZ (27 M, 23 F) 58 CTL |
pOT | Female patients with higher pOT levels had less severe positive symptoms and overall psychopathology | Sex differences in clinical course of SCZ [90, 91]. Estrogen and prolactin regulate OT and OXTR expression [92–95] |
| Souza et al. 2010 [46] | 140 M and F SCZ | OT and OXTR SNPs | Variants in the OXTR (rs237887) were nominally associated with positive symptoms | Supports a role for OT system in regulating positive symptoms |
| Rubin et al. 2013 [55] | 38 SCZ (24 M, 14 F) 38 CTL |
pOT | pOT did not differ between patients and CTL and were unrelated to severity of positive symptoms | Discrepant with [40] |
| Rubin et al. 2014 [41] | 57 SCZ (M 35 F 22) 34 SCZA (M 15, F 19) 75 BP (M 24, F 8) CTL (M 28, F 14) |
pOT | pOT did not differ between patients and CTL and were unrelated to severity of positive symptoms | Does not support a role of endogenous OT in manifestation of positive symptoms |
| Negative Symptoms | ||||
| Keri et al. 2009 [45] | 50 SCZ (16M, 34 F) 50 CTL |
pOT | Low pOT after trust-related interactions were associated with negative symptoms | Suggests endogenous OT counteracts negative symptoms |
| Souza et al. 2010 [46] | Vide supra | OT and OXTR SNPs | An OT gene variant (rs2740204) was associated with clozapine response and was nominally associated with negative symptoms | The endogenous OT system may mediate the effects of APDs [96, 97] |
| Sasayama et al. 2012 [43] | 27 SCZ, 17 MDD 21 CTL |
cOT | More severe negative symptoms (PANSS) related to lower cOT | |
| Montag et al. 2013 [47] | 406 SCZ (285 M, 121 F) 406 CTL |
OT and OXTR SNPS | Significant association between OXTR variant rs237902 and negative symptoms scores (PANSS), and OTR variants rs53576 and rs237885 and SCZ | |
| Haram, et al. 2015 [48] | 265 SCZ (Sex not indicated) 412 CTL (208 M, 204 F) |
OT, OXTR, AVP, CD38 SNPS | Significant association between OXTR risk allele A in rs53576 and emotional withdrawal No significant associations between OT pathway gene variants and SCZ |
More evidence for role for OT in the negative symptoms of SCZ |
| Strauss, et al. 2015 [44] | 39 SCZ (28 M, 11 F) 21 CTL (14 M, 7 F) |
pOT | pOT levels higher in SCZ compared to controls. Lower OT levels associated with greater severity of asociality in SCZ | |
| Jobst, et al. 2015 [42] | 41 M SCZ 45 CTL |
pOT | More severe negative symptoms, e.g., emotional and social withdrawal (PANSS), related to lower pOT | |
| Cognitive Deficits | ||||
| Goldman et al. 2008 [49] | 15 SCZ (6 PHS, 4 PNS, 5 NNS), 7 CTL | pOT | pOT increased in PHS patients compared to PNS or NNSA or controls, and higher pOT associated with greater accuracy in rating facial emotions. pOT inversely correlated with anterior hippocampal volume |
Along with [73], indicates potential of differential role of OT in various subtypes, especially PHS. PHS also exhibit impaired hippocampal function and structural pathology in amygdala, and anterior and lateral hippocampus |
| Keri et al. 2009 [45] | Vide supra | pOT | CTL subjects exhibited elevated pOT after trust related interactions, whereas SCZ subjects did not | Suggest a defect in OT systems ability to respond to interactions promoting trust consistent with OT effects on facial affect recognition [72–75, 65, 68] |
| Rubin et al. 2010 [40] | Vide supra | supra pOT | In both sexes, patients with higher pOT exhibited more prosocial behaviors (PANSS) | Suggests endogenous OT promotes pro-social behavior |
| Rubin et al. 2011 [50] | 48 SCZ (26 M, 22 F) 57 CTL |
pOT | Higher pOT related to perceiving faces as happier in both female patients and CTL | Sex differences reported in other studies of pOT [98, 99] and in [100] but not other studies of IN OT [101, 102] |
| Rubin et al. 2013 [55] | Vide supra | pOT | pOT unrelated to cognition in SCZ | Association of endogenous AVP and worse cognition in untreated female but not male patients |
| Walss-Bass et al. 2013 [103] | 60 SCZ (45 M, 15 F) 20 CTL |
pOT | Significant correlations between social cognitive bias and pOT in control group and SCZ with delusions. Social cognitive capacity correlated with pOT in SCZ with delusions, only | |
| Rubin et al. 2014 [41] | Vide supra | pOT | Higher pOT associated with better emotion recognition in healthy controls but not in proband or relative group | |
| Davis et al 2014a [56]. | 74 SCZ (M 53, F 21) | OXTR SNPs | OXTR variant (rs2268493) was significantly associated with poorer performance on a social cognition index, as well as tests of mentalizing and social perception | |
| Frost et al. 2014 [54]. | 31 SCZ (Sex not specified), 21 CTL | pOT | Higher pOT associated with superior processing speed, working memory, and social cognition | |
| Brown et al. 2014 [51] | 28 SCZ M | pOT | In an approach-avoidance task, patients with SCZ with higher pOT levels exhibited increased avoidance of angry faces | Suggested elevated levels of endogenous OT increased social awareness in patients with SCZ |
| Strauss et al. 2015 [52] | 41 SCZ (Sex not specified), 22 CTL | pOT | Higher pOT levels associated with better emotion recognition in CTL and SCZ (female only). | Individual differences in endogenous OT predict emotion perception accuracy |
| Strauss et al. 2015 [53] | 40 SCZ (28 M, 12 F) 22 CTL |
pOT | SCZ had higher pOT compared to CTL Fewer false positives for concrete items on SCRT associated with higher pOT in SCZ |
In SCZ, accurate encoding of socially relevant information predicted by pOT |
| Montag et al. 2012 [57] | 145 SCZ (91 M, 54 F),145 CTL (79 M, F 66) | OXTR SNPS | OXTR variant rs22544298 significantly associated with empathic concern | |
| Domain Not Specified | ||||
| Linkowski, et al. 1984[104] | 12 SCZ (9 M, 3 F), 12 CTL (8 M, 4 F) | Plasma Np1 | Basal NpI levels were decreased compared to CTL | |
| Beckman et al. 1985 [105] | 28 M SCZ, 15 CTL | cOT | cOT increased in patients with SCZ and higher in patients on APDs (butyrophenones) | Relevance of cOT to central function in patients on APDs - see [106] |
| Legros et al. 1992 [106] | 9 M SCZ, 14 M CTL | Plasma Np1 | Basal NpI levels were decreased compared to CTL | |
| Mai et al. 1993 [107] | 11 SCZ (sex not indicated) 10 CTL |
Neurophysin staining in post mortem brain samples | Altered neurophysin staining in PVN, globus pallidus, substantia nigra SCZ brains | Primarily untreated patients so not due to effects of medication |
| Glovinsky et al. 1994 [108] | 40 SCZ (31 M, 9 F) 15 CTL |
cOT | cOT levels did not differ within subjects based on APD status (treated or withdrawn), nor between SCZ and CTL | |
| Souza et al. 2010 [109] | 179 SCZ, 358 CTL | OT, OXTR genes | OT variants rs4813625 and rs3761248 nominally associated with SCZ | |
| Watenabe et al. 2012 [110] | 1) Case-Control 544 SCZ (M 290, 254 F), 674 CTL (341 M, 333 F) 2) 105 family based trios consisting of patients (59 M, 46 F) and both parents |
OXTR | No significant associations in either the case control or trio study. Meta analysis detected nominal significance between rs9840864 and SCZ | |
| Teltsh et al. 2012 [111] | 1) Extended pedigree 25 SCZ spectrum, 31 unaffected family members 2) 52 families (90 SCZ, 96 unaffected) 3) 272 SCZ (177 M, 95 F), 273 CTL |
OT, AVP | 1) Two OT variants (rs4813626, rs2740204) and one AVP variant (AVP3011589) significantly associated with SCZ 2) One OT variant (rs4813626) significantly associated with SCZ 3) One OT variant (rs4813626) significantly associated in male SCZ |
One SNP (rs4813626) in OT gene significantly associated with SCZ in all three samples. However, its minor and major alleles in samples 2 and 3 were opposite to the extended pedigree in sample 1. |
Abbreviations: APD, antipsychotic drug; AVP, arginine vasopressin; CTL, controls; NNS, normonatremic nonpolydipsic schizophrenia; NP1, neurophysin for oxytocin; OT, oxytocin; cOT, cerebrospinal fluid oxytocin; pOT, plasma oxytocin; OXTR, oxytocin receptor; pOT, plasma oxytocin; PANSS, Positive and Negative Symptoms Survey; PHS, polydipsic hyponatremic schizophrenia; PNS, polydipsic normonatremic schizophrenia; PVN, paraventricular nucleus; SCZ, schizophrenia;, SCRT; Social Cue Recognition Test; UPSIT, University of Pennsylvania Smell Identification Test