Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis

“To further assess the robustness of the results, we performed sensitivity analyses by sequentially removing each study and re-running the analysis, when at least 5 studies were included (Higgins and Green, 2011).”

“Publication biases were tested with the Duval and Tweedie “trim and fill” method (Duval and Tweedie, 2000), when at least 3 studies were included.”

“As meta-analysis of observational studies is supposed to be characterized by significant heterogeneity, random effect models were used (Cooper et al., 2009).”

“They are released in systemic circulation through the posterior pituitary gland, where they act as hormones regulating a range of physiological functions (Gimpl and Fahrenholz, 2001; Leng et al., 2015).”

“, 2005) and MDD (Carroll et al., 1981; Dinan, 1994; Holsboer, 2000).”

“…cues (Zak et al., 2005) and has an effect on emotion recognition/theory of mind (Domes et al., 2007; Guastella et al., 2010b), fearful face processing (Evans et al., 2010), social anxiety (Heinrichs et al., 2003), paranoia (Legros et al., 1992), and trust behaviour (Baumgartner et al., 2008).”

“These neuropeptides are associated with complex social and emotional processing in healthy people which if impaired may account for some of the symptoms present in psychiatric disorders (Meyer-Lindenberg et al., 2011).”

“Heterogeneity among study point estimates was assessed using Q statistics (Paulson and Bazemore, 2010) and the proportion of the total variability in the effect size estimates evaluated with the I(2) index (Lipsey and Wilson, 2000).”

“, 2005) and has an effect on emotion recognition/theory of mind (Domes et al., 2007; Guastella et al., 2010b), fearful face processing (Evans et al.”

“, 2004) investigated peripheral levels of ADH in first-episode, drug naïve patients and eight (Beckmann et al., 1985; Elman et al., 2003; Jobst et al., 2014; Kudoh et al., 1998; Ohsawa et al., 1993; Rubin et al., 2014; Sarai and Matsunaga, 1989; Walsh et al., 2005) in chronic patients.”

“…and independent neuropeptide synthesis and vesicle routing and targeting have been shown in the somata (for peripheral secretion and somatic release) and in dendrites (for dendritic release), which might account for independent central and peripheral release patterns (Landgraf and Neumann, 2004).”

“For example, OT alters response to social cues (Zak et al., 2005) and has an effect on emotion recognition/theory of mind (Domes et al., 2007; Guastella et al., 2010b), fearful face processing (Evans et al., 2010), social anxiety (Heinrichs et al., 2003), paranoia (Legros et al., 1992), and trust…”

“…authors, about the lack of neurophysiological evidence of a direct relationship between peripheral levels of OT and ADH and their central release and activity (Grinevich et al., 2015; Kagerbauer et al., 2013; Leng and Ludwig, 2015; Ludwig and Leng, 2006; McCullough et al., 2013; Neumann, 2007).”

“…Rutigliano et al. / Psychiatry Research 241 (2016) 207–220 217 domains, namely emotion recognition (Guastella et al., 2010a), social cognition (Andari et al., 2010), and core autistic repetitive behaviours (e.g. ordering, compulsion to tell/ask and touching) (Hollander et al., 2003), to…”

“An increasing number of studies have also began to dissect the roles of OT and ADH in human social behaviour (Heinrichs et al., 2009).”

“Specifically, plasma/serum (Rubin et al., 2014), saliva (Fujisawa et al., 2014), urine (Hoffman et al., 2012) or cerebrospinal fluid (CSF) (Sasayama et al., 2012) OT and ADH levels have been recently tested as putative biomarkers in ASD (Alabdali et al., 2014; Boso et al., 2007; Modahl et al., 1998), Psychosis (Elman…”

“ordering, compulsion to tell/ask and touching) (Hollander et al., 2003), to modest (Anagnostou et al.”

“…207 –220 215 G. Rutigliano et al. / Psychiatry Research 241 (2016) 207–220216 On the other hand plasma OT levels are stable, except in pregnancy (Leng and Ludwig, 2015), but may be regulated independently from central OT as suggested by converging evidence from animal studies (Ludwig et al.,…”

“For example, OT alters response to social cues (Zak et al., 2005) and has an effect on emotion recognition/theory of mind (Domes et al., 2007; Guastella et al., 2010b), fearful face processing (Evans et al., 2010), social anxiety (Heinrichs et al., 2003), paranoia (Legros et al., 1992), and trust…”

“Further, peptides appear to have a short plasma half-life (1–2 min) and a slightly longer central half-life ( 30 min) (MacDonald and MacDonald, 2010).”

“Originally, ADH and OT have been described as hormones, involved respectively in antidiuresis, osmolality regulation, direct vasoconstriction and hepatic glycogenolysis (Appelgren, 1982; Robertson, 2001) and labor (Husslein, 1984), lactation (Crowley, 2015), and sexual activity (Carmichael et al., 1987).”

“They are also released in the central nervous system, acting on multiple brain regions as neuromodulators and influencing a range of neurophysiological processes and behaviours (Stoop, 2012), including feeding, anxiety, aggression, social recognition and the stress/fear response to social stimuli (Hashimoto et al.”

“Axonal and dendritic/soma release may be independently regulated by the MCNs through inhibitory mechanisms – mediated by corticosterone, GABA, endogenous opioids, the atrial natriuretic peptide and ADH itself – which selectively block the peripheral secretion (Wotjak et al., 1998).”

“Furthermore, the blood-brain barrier prevents ADH and OT to reflow into the central compartment (i. e. brain parenchyma and CSF) once they have reached the peripheral one (i. e., blood and peripheral organs) (Kagerbauer et al., 2013; Mens et al., 1983).”

“Priming persisting for at least 90 min (Ludwig et al., 2002) allows peptides to survive for long enough to diffuse to distant sites.”

“Axonal and dendritic/soma release may be independently regulated by the MCNs through inhibitory mechanisms – mediated by corticosterone, GABA, endogenous opioids, the atrial natriuretic peptide and ADH itself – which selectively block the peripheral secretion (Wotjak et al., 1998).”

“ADH has been shown to alter reciprocation of cooperation in males (Rilling et al., 2014) while the ADH Avpr-1a gene, which is involved in social bonding in humans (Walum et al., 2008), has been shown to influence the money people will give to others in an economic game (Knafo et al., 2008).”

“intracerebral microdialysis (Veenema and Neumann, 2008), targeted delivery of neuropeptide agonists or antagonists (Song et al.”

“, 2005) and MDD (Carroll et al., 1981; Dinan, 1994; Holsboer, 2000).”

“Specifically, plasma/serum (Rubin et al., 2014), saliva (Fujisawa et al., 2014), urine (Hoffman et al., 2012) or cerebrospinal fluid (CSF) (Sasayama et al., 2012) OT and ADH levels have been recently tested as putative biomarkers in ASD (Alabdali et al., 2014; Boso et al., 2007; Modahl et al., 1998), Psychosis (Elman…”

“…authors, about the lack of neurophysiological evidence of a direct relationship between peripheral levels of OT and ADH and their central release and activity (Grinevich et al., 2015; Kagerbauer et al., 2013; Leng and Ludwig, 2015; Ludwig and Leng, 2006; McCullough et al., 2013; Neumann, 2007).”

“…of two recent clinical trials of exogenous OT (intranasal administration; dose: 24 IU twice daily (Pedersen et al., 2011) and 40 IU twice daily (Feifel et al., 2010)) in patients with schizophrenia suggest a therapeutic effect across different symptom domains with good safety and tolerability…”

“Finally, the results of two recent clinical trials of exogenous OT (intranasal administration; dose: 24 IU twice daily (Pedersen et al., 2011) and 40 IU twice daily (Feifel et al.”

“ADH has been shown to alter reciprocation of cooperation in males (Rilling et al., 2014) while the ADH Avpr-1a gene, which is involved in social bonding in humans (Walum et al., 2008), has been shown to influence the money people will give to others in an economic game (Knafo et al., 2008).”

“Studies investigating plasma OT and ADH levels during the menstrual cycle in different species, including humans, found that these fluctuate across the ovarian cycle (Wathes and Swann, 1982).”

“ADH is involved in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, which has been found to be overactive in BD (Cervantes et al., 2001; Daban et al., 2005) and MDD (Carroll et al., 1981; Dinan, 1994; Holsboer, 2000).”

“…there is also growing interest in the potential for synthetic neuropeptides in treatment of psychosis (for a comprehensive review see (Gumley et al., 2014)), autism spectrum disorders (ASD) (Thompson et al., 2006; Uzunova et al., 2015), and affective and anxiety disorders (Griebel et al., 2012).”

“Also long-lasting changes induced in other transmitter systems may further extend their biological activity and behavioural effects (MacDonald and MacDonald, 2010; Uvanas-Moberg et al., 2005).”

“, 2009) and OT levels have been shown to correlate inversely with symptomatology (including suspiciousness and paranoia) and prosociality (Rubin et al., 2010), as well as capacity to identify facial emotions (Goldman et al.”

“Three studies (Emsley et al., 1989; Rubin et al., 2013; Ryan et al., 2004) investigated peripheral levels of ADH in first-episode, drug naïve patients and eight (Beckmann et al., 1985; Elman et al., 2003; Jobst et al., 2014; Kudoh et al., 1998; Ohsawa et al., 1993; Rubin et al., 2014; Sarai and…”

“…et al. / Psychiatry Research 241 (2016) 207–220216 On the other hand plasma OT levels are stable, except in pregnancy (Leng and Ludwig, 2015), but may be regulated independently from central OT as suggested by converging evidence from animal studies (Ludwig et al., 1994; Moos et al., 1989).”

“…2014; Turan et al., 2013), major depressive disorder (MDD) (Goldstein et al., 2000; Ozsoy et al., 2009; Yuen et al., 2014), as well as in anxiety (Hoge et al., 2012, 2008), personality (Bertsch et al., 2013) and eating disorders (anorexia nervosa, AN and bulimia nervosa, BN) (Frank et al., 2000;…”

“…authors, about the lack of neurophysiological evidence of a direct relationship between peripheral levels of OT and ADH and their central release and activity (Grinevich et al., 2015; Kagerbauer et al., 2013; Leng and Ludwig, 2015; Ludwig and Leng, 2006; McCullough et al., 2013; Neumann, 2007).”

“…in the trust-related increases in OT seen in controls (Keri et al., 2009) and OT levels have been shown to correlate inversely with symptomatology (including suspiciousness and paranoia) and prosociality (Rubin et al., 2010), as well as capacity to identify facial emotions (Goldman et al., 2008).”

“…social anxiety (GSAD) (Hoge et al., 2012), borderline personality disorder (BPD) (Bertsch et al., 2013), attention deficit and hyperactivity disorder (ADHD) (Taurines et al., 2014), Tourette syndrome (TS) (Leckman et al., 1994) and Prader-Willi syndrome (PWS) (Martin et al., 1998) (eTable 4).”

“…ADH and OT have been described as hormones, involved respectively in antidiuresis, osmolality regulation, direct vasoconstriction and hepatic glycogenolysis (Appelgren, 1982; Robertson, 2001) and labor (Husslein, 1984), lactation (Crowley, 2015), and sexual activity (Carmichael et al., 1987).”

“, 2002), and viral gene transfer (Pagani et al., 2014)).”

“…CSF Antidiuretic Hormone in Obsessive-Compulsive Disorder Altemus et al. (1992a) 3 ⋆ / / ⋆ / / ⋆ / (b) Leckman et al. (1994) 5 ⋆ / / / ⋆⋆ ⋆ ⋆ / Overall 4.00 (71.414) CSF Antidiuretic Hormone in Anorexia Nervosa (a) Gold et al. (1983) 2 / / / / ⋆ / ⋆ / (c) Frank et al. (2000) 6 ⋆ / ⋆ ⋆ ⋆⋆ /…”

“, 2012), borderline personality disorder (BPD) (Bertsch et al., 2013), attention deficit and hyperactivity disorder (ADHD) (Taurines et al.”

“…al. (1998) 3 / / / / ⋆⋆ / ⋆ / Elman et al. (2003) 5 ⋆ / ⋆ ⋆ / / ⋆ ⋆ Ryan et al. (2004) 6 ⋆ / / ⋆ ⋆⋆ ⋆ ⋆ / Walsh et al. (2005) 5 ⋆ / / ⋆ ⋆ ⋆ ⋆ / (b) Rubin et al. (2013) 6 ⋆ ⋆ ⋆ ⋆ ⋆ / ⋆ / (b) Jobst et al. (2014) 4 ⋆ / / / ⋆⋆ / ⋆ / (d) Rubin et al. (2014) 7 ⋆ / / ⋆ ⋆⋆ ⋆ ⋆ ⋆ Overall 4.09 (71.814) CSF…”

“Research with ADH in human social cognition is less prevalent but there is evidence that intranasal ADH biases emotional face perception (Thompson et al., 2004)), enhances memory encoding of human faces (Guastella et al.”

“Specifically, plasma/serum (Rubin et al., 2014), saliva (Fujisawa et al., 2014), urine (Hoffman et al., 2012) or cerebrospinal fluid (CSF) (Sasayama et al., 2012) OT and ADH levels have been recently tested as putative biomarkers in ASD (Alabdali et al., 2014; Boso et al., 2007; Modahl et al., 1998), Psychosis (Elman…”

“In schizophrenia, patients have been shown to produce a failure in the trust-related increases in OT seen in controls (Keri et al., 2009) and OT levels have been shown to correlate inversely with symptomatology (including suspiciousness and paranoia) and prosociality (Rubin et al., 2010), as well…”

“…authors, about the lack of neurophysiological evidence of a direct relationship between peripheral levels of OT and ADH and their central release and activity (Grinevich et al., 2015; Kagerbauer et al., 2013; Leng and Ludwig, 2015; Ludwig and Leng, 2006; McCullough et al., 2013; Neumann, 2007).”

“, 2012) or null clinical improvement (Anagnostou et al., 2014).”

“Postmortem brain tissues of patients with MDD and BD contain a greater number of ADH-immunoreactive neurons in the hypothalamic PVN (Merali et al., 2006).”

“…et al. / Psychiatry Research 241 (2016) 207–220216 On the other hand plasma OT levels are stable, except in pregnancy (Leng and Ludwig, 2015), but may be regulated independently from central OT as suggested by converging evidence from animal studies (Ludwig et al., 1994; Moos et al., 1989).”

“(a) Miller et al. (2013) 2013 USA OT Plasma ASD 75 40 35 12 12.”

“…authors, about the lack of neurophysiological evidence of a direct relationship between peripheral levels of OT and ADH and their central release and activity (Grinevich et al., 2015; Kagerbauer et al., 2013; Leng and Ludwig, 2015; Ludwig and Leng, 2006; McCullough et al., 2013; Neumann, 2007).”

“…(1997) 4 ⋆ / / ⋆ / / ⋆ ⋆ van Londen et al. (1998) 4 ⋆ / / ⋆ / / ⋆ ⋆ Rubin et al. (1999) 5 ⋆ / / ⋆ ⋆⋆ / ⋆ / Goldstein et al. (2000) 4 ⋆ / / / ⋆ / ⋆ ⋆ Goekoop et al. (2006) 3 ⋆ / / / / / ⋆ ⋆ Overall 3.67 (71.033) CSF Antidiuretic Hormone in Psychosis (b) Beckmann et al. (1985) 3 ⋆ ⋆ / / / / ⋆ /…”

“For example, OT alters response to social cues (Zak et al., 2005) and has an effect on emotion recognition/theory of mind (Domes et al., 2007; Guastella et al., 2010b), fearful face processing (Evans et al., 2010), social anxiety (Heinrichs et al., 2003), paranoia (Legros et al., 1992), and trust…”

“Specifically, plasma/serum (Rubin et al., 2014), saliva (Fujisawa et al., 2014), urine (Hoffman et al., 2012) or cerebrospinal fluid (CSF) (Sasayama et al., 2012) OT and ADH levels have been recently tested as putative biomarkers in ASD (Alabdali et al., 2014; Boso et al., 2007; Modahl et al., 1998), Psychosis (Elman…”

“Specifically, plasma/serum (Rubin et al., 2014), saliva (Fujisawa et al., 2014), urine (Hoffman et al., 2012) or cerebrospinal fluid (CSF) (Sasayama et al., 2012) OT and ADH levels have been recently tested as putative biomarkers in ASD (Alabdali et al., 2014; Boso et al., 2007; Modahl et al., 1998), Psychosis (Elman…”

“(a) Demitrack et al. (1990) 1990 USA OT CSF AN 25 14 11 24.”

“Administration of OT either intracerebrally or subcutaneously effectively reverted behavioural deficits in rodent models of schizophrenia (Macdonald and Feifel, 2012).”

“…manipulate central OT and ADH levels and their effects on behaviour (e.g. intracerebral microdialysis (Veenema and Neumann, 2008), targeted delivery of neuropeptide agonists or antagonists (Song et al., 2014), gene knockout (Wersinger et al., 2002), and viral gene transfer (Pagani et al., 2014)).”

“…levels as biomarkers of AN is weakened by the global hypothalamic-pituitary dysfunction, the impact of fluid and sodium restriction and purging behaviours observed in AN and the putative role of the two hormones in the regulation of the gut brain axis and energy homeostasis (Blevins and Ho, 2013).”

“Plasma oxytocin levels in autistic children.”

“%) failed to control for alcohol intake (not applicable to 2 studies which had recruited only children), which was reported to induce degeneration in numerous neurons in the hypothalamic magnocellular system in rats (Silva et al., 2002).”

“, 2010b), fearful face processing (Evans et al., 2010), social anxiety (Heinrichs et al.”

“%) failed to control for alcohol intake (not applicable to 2 studies which had recruited only children), which was reported to induce degeneration in numerous neurons in the hypothalamic magnocellular system in rats (Silva et al., 2002).”

“, 1994) and Prader-Willi syndrome (PWS) (Martin et al., 1998) (eTable4).”

“They are released in systemic circulation through the posterior pituitary gland, where they act as hormones regulating a range of physiological functions (Gimpl and Fahrenholz, 2001; Leng et al., 2015).”

“As regard OT, preclinical studies in rats found that a systemic injection of lithium leads to a significant elevation of peripheral OT levels (Cui et al., 2001; You et al., 2001).”

“During pregnancy dramatic structural and functional changes occur in the OT system of the mother's brain (Hillerer et al., 2014; Rocchetti et al., 2014).”

“In humans no correlation was found between central and plasma OT in pregnant women (Altemus et al., 2004) and suicide attempters (Jokinen et al., 2012).”

“(Spruce et al., 1985).”

“…there is also growing interest in the potential for synthetic neuropeptides in treatment of psychosis (for a comprehensive review see (Gumley et al., 2014)), autism spectrum disorders (ASD) (Thompson et al., 2006; Uzunova et al., 2015), and affective and anxiety disorders (Griebel et al., 2012).”

“…(1977) 1 / / / / / / ⋆ / (c) Rubin et al. (2014) 7 ⋆ / / ⋆ ⋆⋆ ⋆ ⋆ ⋆ Overall 4.00 (74.243) CSF Antidiuretic Hormone in Major Depressive Disorder (a) (Sorensen et al. (1985) 2 ⋆ / / / / / ⋆ / (b) Pitts et al. (1995) 4 ⋆ / / ⋆ / / ⋆ ⋆ Heuser et al. (1998) 4 ⋆ / / ⋆ / ⋆ ⋆ / Overall 3.33 (71.155)…”

“van Londen et al. (1998) 1998 The Netherlands ADH Plasma MDD 89 52 37 44.”

“…lithium exerts adverse effects on the kidney, leading to nephrogenic diabetes insipidus (NDI) in up to 10% of the patients on long term treatment (Bendz and Aurell, 1999; Bendz et al., 1996), which may be expected to be associated with a compensatory increase in ADH release (Watson et al., 2007).”

“Evidence from animal studies has demonstrated the significant role that OT and ADH play in the regulation of social behaviour and cognition (Chang and Platt, 2014).”

“…2012, 2008), personality (Bertsch et al., 2013) and eating disorders (anorexia nervosa, AN and bulimia nervosa, BN) (Frank et al., 2000; Lawson et al., 2011, 2012), with highly heterogeneous and conflicting results (Al-Ayadhi, 2005; Alabdali et al., 2014; Emsley et al., 1989; Watson et al., 2007).”

“Since the main methodological concern specifically regards the use of extraction (Christensen et al., 2014), we performed a sensitivity analysis on the studies investigating serum/plasma ADH levels in Psychosis, which seemed to confirm that the extraction technique could have had an effect on the…”

“, 2013), bipolar disorder (BD) (Rubin et al., 2014; Turan et al., 2013), major depressive disorder (MDD) (Goldstein et al.”

“…example, despite evidence that patients with schizoaffective psychoses may have clear distinctive features as compared to schizophrenic psychoses (Pagel et al., 2013), they were included in some of the articles in the Psychosis subgroup (OT: 6 out of 11 (Goldman et al., 2008; Rubin et al., 2014,…”

“A comprehensive systematic review and preliminary meta-analysis Rutigliano Graziaa,b,1, Rocchetti Matteoa,c,1, Paloyelis Yannisd, Gilleen Jamesa,f, Sardella Albertoa, Cappucciati Marcoa,c, Palombini Erikaa,c, Dell’Osso Lilianab, Caverzasi Edgardoc, Politi Pierluigic, McGuire Philipa, Fusar-Poli Paoloa,e,n a Department…”

“It has been argued that psychotic exacerbations may be concurrent with a transient reset of the osmostasis for ADH secretion, elevated plasma levels of the neuropeptide and eventually water imbalance, as an epiphenomenon of dysfunctions in hypothalamic pituitary adrenal (HPA) axis response to psychological stimuli(Gol…”

“…al. (1998) 3 / / / / ⋆⋆ / ⋆ / Elman et al. (2003) 5 ⋆ / ⋆ ⋆ / / ⋆ ⋆ Ryan et al. (2004) 6 ⋆ / / ⋆ ⋆⋆ ⋆ ⋆ / Walsh et al. (2005) 5 ⋆ / / ⋆ ⋆ ⋆ ⋆ / (b) Rubin et al. (2013) 6 ⋆ ⋆ ⋆ ⋆ ⋆ / ⋆ / (b) Jobst et al. (2014) 4 ⋆ / / / ⋆⋆ / ⋆ / (d) Rubin et al. (2014) 7 ⋆ / / ⋆ ⋆⋆ ⋆ ⋆ ⋆ Overall 4.09 (71.814) CSF…”

“Specifically, plasma/serum (Rubin et al., 2014), saliva (Fujisawa et al., 2014), urine (Hoffman et al., 2012) or cerebrospinal fluid (CSF) (Sasayama et al., 2012) OT and ADH levels have been recently tested as putative biomarkers in ASD (Alabdali et al., 2014; Boso et al., 2007; Modahl et al.,…”

“Moreover, high levels of oxytocinase secreted by the placenta might further contribute to the final serum/plasma OT levels (Nomura et al., 2005).”

“…4 ⋆ / / ⋆ / ⋆ ⋆ / Overall 3.33 (71.155) Plasma/Serum Antidiuretic Hormone in Major Depressive Disorder (b) Sorensen et al. (1985) 2 ⋆ / / / / / ⋆ / Inder et al. (1997) 4 ⋆ / / ⋆ / / ⋆ ⋆ van Londen et al. (1998) 4 ⋆ / / ⋆ / / ⋆ ⋆ Rubin et al. (1999) 5 ⋆ / / ⋆ ⋆⋆ / ⋆ / Goldstein et al. (2000) 4…”

“Neuroleptics have also been reported to normalise raised ADH plasma levels in patients with schizophrenia (Raskind et al., 1987).”

“We did not perform analyses on diagnoses where there was only one study available: generalized social anxiety (GSAD) (Hoge et al., 2012), borderline personality disorder (BPD) (Bertsch et al., 2013), attention deficit and hyperactivity disorder (ADHD) (Taurines et al., 2014), Tourette syndrome (TS)…”

“Specifically, plasma/serum (Rubin et al., 2014), saliva (Fujisawa et al., 2014), urine (Hoffman et al., 2012) or cerebrospinal fluid (CSF) (Sasayama et al., 2012) OT and ADH levels have been recently tested as putative biomarkers in ASD (Alabdali et al., 2014; Boso et al., 2007; Modahl et al.,…”

“, 2013), they were included in some of the articles in the Psychosis subgroup (OT: 6 out of 11 (Goldman et al., 2008; Rubin et al., 2014, 2013, 2010; Strauss et al., 2015; Walss-Bass et al., 2013)); ADH (4 out of 13 (Emsley et al.”

“, 2013), they were included in some of the articles in the Psychosis subgroup (OT: 6 out of 11 (Goldman et al., 2008; Rubin et al., 2014, 2013, 2010; Strauss et al., 2015; Walss-Bass et al., 2013)); ADH (4 out of 13 (Emsley et al.”

“…Hormone in Major Depressive Disorder (b) Sorensen et al. (1985) 2 ⋆ / / / / / ⋆ / Inder et al. (1997) 4 ⋆ / / ⋆ / / ⋆ ⋆ van Londen et al. (1998) 4 ⋆ / / ⋆ / / ⋆ ⋆ Rubin et al. (1999) 5 ⋆ / / ⋆ ⋆⋆ / ⋆ / Goldstein et al. (2000) 4 ⋆ / / / ⋆ / ⋆ ⋆ Goekoop et al. (2006) 3 ⋆ / / / / / ⋆ ⋆ Overall…”

“…et al./ Psychiatry R esearch 241 (2016) 207 –220 214 Plasma/Serum Antidiuretic Hormone in Autism Spectrum Disorder (b) Al-Ayadhi (2005) 3 ⋆ / / / ⋆ / ⋆ / Boso et al. (2007) 7 ⋆ / ⋆ ⋆ ⋆ ⋆ ⋆ ⋆ (b) Miller et al. (2013) 4 ⋆ / / / ⋆ / ⋆ ⋆ Overall 4.67 (72.082) Plasma/Serum Antidiuretic Hormone in…”

“R utigliano et al./ Psychiatry R esearch 241 (2016) 207 –220 214 Plasma/Serum Antidiuretic Hormone in Autism Spectrum Disorder (b) Al-Ayadhi (2005) 3 ⋆ / / / ⋆ / ⋆ / Boso et al. (2007) 7 ⋆ / ⋆ ⋆ ⋆ ⋆ ⋆ ⋆ (b) Miller et al. (2013) 4 ⋆ / / / ⋆ / ⋆ ⋆ Overall 4.67 (72.082) Plasma/Serum Antidiuretic Hormone in Bipolar Disord…”

“, 2003), paranoia (Legros et al., 1992), and trust behaviour (Baumgartner et al.”

“R utigliano et al./ Psychiatry R esearch 241 (2016) 207 –220 214 Plasma/Serum Antidiuretic Hormone in Autism Spectrum Disorder (b) Al-Ayadhi (2005) 3 ⋆ / / / ⋆ / ⋆ / Boso et al. (2007) 7 ⋆ / ⋆ ⋆ ⋆ ⋆ ⋆ ⋆ (b) Miller et al. (2013) 4 ⋆ / / / ⋆ / ⋆ ⋆ Overall 4.67 (72.082) Plasma/Serum Antidiuretic Hormone in Bipolar Disord…”

“…ADH and OT have been described as hormones, involved respectively in antidiuresis, osmolality regulation, direct vasoconstriction and hepatic glycogenolysis (Appelgren, 1982; Robertson, 2001) and labor (Husslein, 1984), lactation (Crowley, 2015), and sexual activity (Carmichael et al., 1987).”

“…/ / / / ⋆ / Overall 2.50 (70.707) Plasma/Serum Antidiuretic Hormone in Psychosis (d) Sorensen et al. (1985) 2 ⋆ / / / / / ⋆ / Emsley et al. (1989) 2 / / / / / / ⋆ ⋆ Sarai and Matsunaga (1989) 2 ⋆ / / / / / ⋆ / Ohsawa et al. (1993) 3 ⋆ / / / ⋆ / ⋆ / Kudoh et al. (1998) 3 / / / / ⋆⋆ / ⋆ / Elman et…”

“…(Pagel et al., 2013), they were included in some of the articles in the Psychosis subgroup (OT: 6 out of 11 (Goldman et al., 2008; Rubin et al., 2014, 2013, 2010; Strauss et al., 2015; Walss-Bass et al., 2013)); ADH (4 out of 13 (Emsley et al., 1989; Ohsawa et al., 1993; Rubin et al., 2014, 2013)).”

“As regard OT, preclinical studies in rats found that a systemic injection of lithium leads to a significant elevation of peripheral OT levels (Cui et al., 2001; You et al., 2001).”

“They are also released in the central nervous system, acting on multiple brain regions as neuromodulators and influencing a range of neurophysiological processes and behaviours (Stoop, 2012), including feeding, anxiety, aggression, social recognition and the stress/fear response to social stimuli (Hashimoto et al., 20…”

“, 2014), gene knockout (Wersinger et al., 2002), and viral gene transfer (Pagani et al.”

“Specifically, plasma/serum (Rubin et al., 2014), saliva (Fujisawa et al., 2014), urine (Hoffman et al., 2012) or cerebrospinal fluid (CSF) (Sasayama et al., 2012) OT and ADH levels have been recently tested as putative biomarkers in ASD (Alabdali et al., 2014; Boso et al., 2007; Modahl et al., 1998), Psychosis (Elman…”

“, 2004) investigated peripheral levels of ADH in first-episode, drug naïve patients and eight (Beckmann et al., 1985; Elman et al., 2003; Jobst et al., 2014; Kudoh et al., 1998; Ohsawa et al., 1993; Rubin et al., 2014; Sarai and Matsunaga, 1989; Walsh et al., 2005) in chronic patients.”

“, 2013), major depressive disorder (MDD) (Goldstein et al., 2000; Ozsoy et al., 2009; Yuen et al., 2014), as well as in anxiety (Hoge et al.”

“A recent systematic review has concluded that studies using ELISA on unex-tracted samples have produced no convincing evidence that peripheral vasopressin or oxytocin might be reliable biomarkers in psychiatric disorders (135).”

“Methodological differences and a lack of standardization across studies of human (and nonhuman animal) endogenous oxytocin concentrations have made it challenging to synthesize our current state of knowledge of the role of oxytocin in human social processes and psychiatric illness [142].”

“Yet, studies investigating the potential use of OXT as a biochemical biomarker for social dysfunction in ASD have reported mixed results (see Rutigliano et al. 2016 for a review).”

“A recent systematic review has concluded that studies using ELISA on unextracted samples have produced no convincing evidence that peripheral oxytocin might be reliable biomarkers in psychiatric disorders (Rutigliano et al., 2016).”

“To date, only one formal meta-analysis has addressed whether baseline OT levels differ in autistic and neurotypical people (Rutigliano et al., 2016).”

“A common target of efforts to identify biomarkers of psychiatric disorders is the oxytocin system [2].”

“A meta-analysis of 64 studies of several psychiatric disorders, including MDD but not PTSD, showed no significant differences in peripheral OT between healthy and psychiatric groups (except in anorexia).(40) Compared with trauma-exposed controls, lower peripheral OT levels have been observed in men, but not women, wit…”

“…in central and peripheral body fluids has become a popular tool with the aim to assess the general activity of the OXT system in both healthy and clinical populations, either at rest or after an experimental challenge (Crockford et al., 2014; de Jong et al., 2015; Rutigliano et al., 2016).”

“vary with clinical aspects of disease (Rutigliano et al., 2016).”

“Still, a recent meta-analysis revealed that there were no substantial differences in peripheral OXT levels between psychiatric patients and healthy controls (Rutigliano et al., 2016).”

“In patients with bulimia nervosa, no alterations in CSF and circulating oxytocin levels have been found [84, 86, 87, 90-92], while up to now there is to the best of our knowledge no mechanistic study on oxytocin function in patients with binge eating disorder (see also 5.”

“A meta-analysis review has recently shown the possibility of using oxytocin and vasopressin as biomarkers; however, this is heterogeneous in psychiatric disorders and does not provide convincing findings that peripheral OT or ADH levels are altered in ASD compared to healthy controls [14].”

“Altered OT and AVP synthesis and release appear to be among the core dysfunctions underpinning the impairments in social and communication behavior of individuals with ASD [9,11,37], although it remains unclear whether OT neuropeptide can be used as biochemical marker for ASD [38].”

“It is released into the bloodstream, entering peripheral circulation, as well as directly into the nervous system (9).”

“…et al., 2015), the concern about the lack of neurophysiological evidence of a direct relationship between peripheral levels of oxytocin and its central release and activity, widely expressed in the literature, cannot be ignored also in the interpretation of our findings (Rutigliano et al., 2016).”

“Moreover, a meta-analysis on the subject published in 2016, and summarizing the results from 404 patients from 4 clinical trials found no overall differences in the levels of plasma oxytocin between the patients with ASD and the neurotypical controls (29).”

“Some meta-analyses point out that it is not reliable, regardless of the type of sample taken (Rutigliano et al., 2016).”

“05).(37) There is some evidence to suggest that over the course of recovery from AN the oxytocin system returns to normal levels.”

“Commercially available immunoassays have been questioned on their validity due to high variability (e.g., McCullough et al., 2013; Christensen et al., 2014; Rutigliano et al., 2016).”

“However, a recent meta-analysis found no robust evidence of alterations to oxytocin in cases of psychosis, possibly reflecting the heterogeneity of these studies and indicating that more analyses are needed to define oxytocin as a biomarker for a FEP (Rutigliano et al., 2016).”

“The co-secreted and synergistically at this level acting CRH and AVP cannot be simply measured because of their pulsatile secretion pattern, small molecular size, avid binding to platelets, rapid plasma clearance, degradation, and instability (28, 29).”

“[111] came to the conclusion that vasopressin preparations may be promising for communicability improvement, however, they noted inconsistency of data in various studies about the role of vasopressin in ASD development.”

“…may play a role in the pathophysiology of BDD. Oxytocin has also been implicated as a candidate biomarker of certain psychiatric disorders associated with BDD, such as psychosis, depression, anxiety disorders, and eating disorders, although the evidence has been mixed (Rutigliano et al., 2016).”

“However, a recent meta-analysis that include 64 studies with several psychiatric disorders, showed no significant differences in peripheral OT between a healthy adult and the MDD groups [33].”

“, 2001), while others have found no relationship or altered correlations to symptoms (Rutigliano et al., 2016).”

“…(BN) have been observed for years, as well as a different pattern of postprandial OXT secretion, correlating, among other things, with the level of depressive and anxiety symptoms (Maguire et al., 2013; Rutigliano et al., 2016; Monteleone et al., 2016; Lawson et al., 2012; Lawson et al., 2011).”

“Furthermore, some studies have found that children suffering from ASD have lower concentrations of circulating OXT [8] and they were shown to be associated with annotated ASD risk genes [9].”

“…role in regulating cognitive, emotional and behavioral responses to social stimuli, there has been increasing interest in the potential relevance of oxytocin regarding psychopathology (see reviews by Cochran et al., 2013; Rutigliano et al., 2016; Engel et al., 2019; John and Jaeggi, 2021).”

“1 3 2020), and potentially also in human ASD cases (Husarova et al. 2016; Rutigliano et al. 2016; Zhang et al. 2016).”

“According to a recent meta-analysis [67], which combined currently available data from a total of 556 participants and corrected effect sizes for publication bias, the OT deficiency hypothesis in autism lacks solid evidence.”

“Different subtypes of ADH receptors have been detected not only in the hypothalamus, but also in the cerebral cortex and the hippocampus where it may be involved in responses to stress, depression, and anxiety (Rutigliano et al., 2016).”

“Patients with AN have reduced central ([12]; see [13] for a systematic review and meta-analysis) and peripheral level [14] of OT at baseline and in response to stimulation with estrogens [15].”

“On the oth‐ er hand, peripheral levels of oxytocin are often found to be unaltered in the same patients as well as in patients with psychotic disorders (Rutigliano et al., 2016).”

“For urinary levels insufficient data are available to draw further conclusions (Rutigliano et al., 2016; Valstad et al., 2017).”

“A correlation between peripheral levels and central activity is still questionable (104).”

“Extensive research has explored the potential role of peripheral oxytocin levels as a biomarker of several psychiatric disorders, but the findings so far do not support this hypothesis (Rutigliano et al., 2016).”

“A meta-analysis pooling the two aforementioned studies in adults also found no significant difference 29 , however, a more recent meta-analysis also including the study by Marazziti et al., found significantly higher levels in patients with OCD compared to healthy controls 30 .”

“Researchers have also failed to agree whether oxytocin is a reliable correlate of psychiatric constructs (Rutigliano et al., 2016), likely due to its pulsatile release (i.e., a pulse every 3 – 5 min, not continuous release) into the periphery that complicates measurement and increases the…”