|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 43
| Issue : 2 | Page : 63-69 |
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Oxytocin and obsessive–compulsive disorder
Mohamed R Soltan
Department of Psychiatry, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| Date of Submission | 22-Jun-2021 |
| Date of Decision | 30-Jun-2021 |
| Date of Acceptance | 18-Jul-2021 |
| Date of Web Publication | 24-Jun-2022 |
Correspondence Address:
MD Mohamed R Soltan
Department of Psychiatry, Faculty of Medicine, Fayoum University, PO Box 63514, Fayoum
Egypt
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ejpsy.ejpsy_28_21
Attention has recently been focused on central nervous system neuropeptides as potential mediators of the symptom profile of obsessive–compulsive disorder (OCD). OCD includes a range of cognitive and behavioral symptoms that bear some relationship to dimensions of behavior associated with oxytocin (OT). Increased cerebrospinal fluid levels of the anxiolytic neuropeptide OT have been reported in OCD. OT is a neurosecretory nonapeptide synthesized in hypothalamic cells, which project to widely distributed sites in the central nervous system as well as the neurohypophysis. Central OT affects a variety of cognitive, grooming, affiliative, sexual, and reproductive behaviors in animals. OT is associated with the regulation of complex sociocognitive processes such as attachment, social exploration, social recognition, anxiety, and other stress-related behaviors. Based on these data, we hypothesized that OCD is mediated by OT. The aim of this review is to define possible involvements of OT in the pathophysiology of OCD.
Keywords: obsessive–compulsive disorder, neurobiology, oxytocin
How to cite this article:
Soltan MR. Oxytocin and obsessive–compulsive disorder. Egypt J Psychiatr 2022;43:63-9 |
| Introduction | |  |
Neurobiology of oxytocin
Oxytocin (OT) is a pleiotropic, peptide hormone with broad implications for general health, adaptation, development, reproduction, and social behavior. Endogenous OT and stimulation of the OT-receptor supports patterns of growth, resilience, and healing (Abramova et al., 2020; Carter et al., 2020).
OT is a 9-amino-acid neuropeptide made primarily in magnocellular neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) and secreted into the peripheral bloodstream from the posterior pituitary. Within the brain, OT that is not routed to the pituitary is synthesized by and transported from smaller, parvocellular neurons located in PVN and elsewhere (Caldwell and Young, 2006).
OT produced in the parvocellular neurons of the PVN projects to several other areas in the brain, including the amygdala, hippocampus, striatum, and brainstem, where it acts as a neuromodulator exerting effects on social behavior (Swanson and Sawchenko, 1980; Castel and Morris, 1988; Peñagarikano et al., 2015). Accumulating evidence highlights the significant role OT plays in the human limbic system, including the amygdala (Bale et al., 2001; Domes et al., 2007).
Once in the bloodstream, OT is defined as a hormone, interacting with distal targets over relatively long timescales. Peripheral OT release is important during parturition and lactation; central OT release can affect maternal behavior and learning and memory (Morris and Ludwig, 2004; Caldwell and Young, 2006).
OT has a key role in female-reproductive functions as well as in social memory in the brain. In our recent Communications Biology article, we reported that OT is transported from the peripheral blood into the brain by the receptor for advanced glycation end products in endothelial cells at the blood−brain barrier. Additionally, we found that oral OT is absorbed by receptor for advanced glycation end products on intestinal epithelial cells at the blood−intestinal barrier (Yamamoto and Higashida, 2020).
Research has recently found that OT also plays an important role in the digestive system, regulating appetite and, indirectly, body weight (Blevins and Baskin, 2015). Besides neural networks, within the last decade, various sets of data have highlighted the possible role of OT and vasopressin, two small neuropeptides composed by nine amino acids and synthesized in the paraventricular and in the SON of the hypothalamus (Buijs et al., 1983; Marazziti et al., 2006), in linking social signals with cognition, behaviors, and reward (Insel and Fernald, 2004).
OT and vasopressin, in fact, have been shown to be involved in the creation of pair bonding in monogamous rodents, such as prairie voles (Insel and Shapiro, 1992), in maternal behavior in rats (Insel and Harbaugh, 1989), in the postpartum acceptance of offspring in sheep (Keverne and Kendrick, 1992), and the relief of distress vocalization in rat pups (Insel and Winslow, 1991).
The relevance of these intriguing findings for humans has not been clarified as yet (Young and Wang, 2004). OT receptors in the human brain are mainly distributed in the substantia nigra, globus pallidus, anterior cingulate, and medial insula, areas that have been shown to be activated in adults while looking at pictures of their partners, or in mothers while looking at their children (Brown, 2005), and belong to the recently hypothesized circuits of the ‘social brain’ (Adolphs, 2001).
It is interesting to note that OT seems to be released during sexual intercourse and orgasm (Carmichael et al., 1987) and during the application of different relaxation techniques (Turner et al., 1999), so that it is thought to be one of the promoters of attachment and/or mediators in the decrease of the stress responses that are related to positive social bonding (Kosfeld et al., 2005).
Oxytocin and psychiatric disorder
Lower levels of peripheral OT have been reported in some studies on autism-spectrum disorder (ASD), depression, and schizophrenia, although the findings vary (MacDonald and Feifel, 2012; Yamasue et al., 2012; Stavropoulos and Carver, 2013).
An association between the severity of positive symptoms and elevated serum OT levels was shown in patients with schizophrenia (Rubin et al., 2010).
Various studies have suggested that OT reduces aggressiveness, and enhances social relations and interactions in autism (Kuehn, 2011; Kosaka et al., 2012). Intranasal OT, when administered to male patients with autism, enhanced the ability to recognize other individuals’ emotions (Guastella et al., 2010).
Serum OT levels were found to have been elevated in manic episodes of bipolar-affective disorder when compared with the levels in healthy controls, emphasizing that the elevation could be associated with increased dopamine levels during manic episodes and is responsible for impulsive behaviors such as hypersexuality and aggressiveness observed in clinical settings (Turan et al., 2013).
In addition, it was reported that plasma OT levels were low in female patients diagnosed with borderline personality disorders, suggesting that decreased OT levels were a result of childhood trauma and attachment, as well as derangements in serotonin and dopamine levels, and could be associated with declined social cognition and impaired award system (Bertsch et al., 2013).
It was reported that men with conduct disorder had higher OT-reactive autoantibody levels compared with men without conduct disorder (Fetissov et al., 2006).
There is evidence in the literature that genes for OT-receptor SNPs rs6770632 and rs1042778 are associated with persistent and pervasive aggressive behaviors in females and males (Malik et al., 2012). OT moderated reactive aggression in women with high-state anxiety (Campbell and Hausmann, 2013; Alcorn et al., 2015).
Moreover, OT causes enhanced emotional recognition and increased empathy (Bartz et al., 2010). OT plays an important role in the modulation of social behavior in both typical and atypical contexts. Also, the quality of early parental care sets the foundation for long-term psychosocial development. Here, we review studies that investigated how OT receptor interacts with early parental care experiences to influence the development of psychiatric disorders (Ilaria et al., 2018).
Evidence from animal studies has demonstrated the significant role that OT and antidiuretic hormone (ADH) play in the regulation of social behavior and cognition (Chang and Platt, 2014). An increasing number of studies have also begun to dissect the roles of OT and ADH in human social behavior (Heinrichs et al., 2009).
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).
Furthermore, there is also growing interest in the potential for synthetic neuropeptides in the treatment of psychosis (Gumley et al., 2014), ASD (Thompson et al., 2006; Uzunova et al., 2015), and affective and anxiety disorders (Griebel et al., 2012).
OT and ADH levels have been recently tested as putative biomarkers in ASD (Boso et al., 2007; Alabdali et al., 2014), psychosis (Goldman et al., 2008; Rubin et al., 2013), bipolar disorder (Turan et al., 2013; Rubin et al., 2014), and major depressive disorder (MDD) (Goldstein et al., 2000; Yuen et al., 2014), as well as in anxiety (Hoge et al., 2012), personality (Bertsch et al., 2013), and eating disorders (anorexia nervosa and bulimia nervosa) (Lawson et al., 2012), with highly heterogeneous and conflicting results (Al-Ayadhi, 2005; Watson et al., 2007; Alabdali et al., 2014).
Oxytocin and obsessive–compulsive disorder
Anxiogenic and stressful stimuli significantly activate the body’s OT system, as reflected by increased electrophysiological activity of OT neurons, increased OT gene expression within the SON and PVN, and stimulated peripheral and intracerebral OT release (Wotjak et al., 1998).
For example, exposure of male rats to novelty, forced swimming, or social defeat rapidly increases OT release into blood but also within the PVN and/or SON and in other limbic brain regions, such as the central amygdala or septum (Neumann, 2007).
Similarly, increased OT release into blood and within the PVN and central amygdala has also been found in female rats exposed to psychosocial stress (maternal defeat by an aggressive lactating resident dam) (Bosch et al., 2004).
Magnocellular OT neurons within the PVN (or SON) themselves may provide the neuroanatomical basis for these observations: in addition to their projections to the neurohypophysis, they can also release OT locally within the PVN (or SON) from dendrites and perikarya, as well as from axon collaterals that project to distinct brain regions, for example, the central amygdala (Knobloch et al., 2012).
Recently, there is growing evidence that the neuropeptide OT modulates fear and extinction in humans and rodents through actions in corticolimbic circuits, including the central amygdala (Gunduz-Cinar et al., 2020).
This is an important observation with implications for human studies, as it speaks in favor of peripheral OT measures being a global biomarker for the general activity of the endogenous OT system also, at least partly, reflecting the central (re)activity of an individual’s OT system to stress. However, we have to be aware of the fact that plasma OT may, at best, only roughly reflect the temporal dynamics of central release patterns, which was shown to substantially differ from peripheral release patterns of OT (Neumann, 2007).
Further, plasma OT necessarily ignores brain-region-dependent events, which play an important role in the behavioral effects of OT. Paradoxically, while OT is linked to anxiolytic effects and to improvement of repetitive behaviors in autism, elevated OT levels are also putatively involved in the etiology of obsessive–compulsive disorder (OCD)-repetitive behaviors. Clinical trials that investigated the therapeutic use of OT in OCD found no effect of this molecule over the frequency of repetitive symptoms (neither improvement nor worsening) (Den Boer and Westenberg, 1992; Epperson et al., 1996). In contrast, Leckman et al. (1994a) reported that levels of OT in ventricular cerebrospinal fluid (CSF) are higher in OCD patients than in healthy controls and identified a positive correlation between higher CSF levels of OT and higher frequency of repetitive behaviors.
Some (Marazziti et al., 2015), but not all (Leckman et al., 1994a), studies have found elevated CSF OT levels in patients with OCD, but a direct correlation between CSF OT levels and OCD severity has not been established (Marazziti et al., 2015). In a 1992 study, CSF-OT of 43 children/adolescents correlated positively with depression, but not with OCD-symptom severity. In a study 2 years later, CSF OT was elevated compared with controls in 22 adult patients with OCD and without history of tic disorders, and in these patients, CSF OT was also positively related to OCD severity, as measured by the Yale–Brown Obsessive–Compulsive Scale (Goodman et al., 1989).
This finding supports an oxytocinergic OCD hypothesis, but a study in 1999 found no CSF OT difference between OCD and control cases and no relation to Yale–Brown Obsessive–Compulsive Scale ratings; however, only 14 patients with OCD were included (Altemus et al., 1999).
Recently, an animal model suggested supporting that OT gives rise to grooming compulsions through links between the PVN and the central nucleus of amygdala (Humble et al., 2013).
There are many different theories as to how OT levels might correlate with specific OCD phenotypes. For instance, OT has been reported to attenuate memory consolidation and retrieval. It might be that pathological doubting associated with the need to repeatedly carry out checking compulsions is a clinical manifestation of the cognitive effects of a dysregulated OT system in some forms of OCD. Additionally, violent and horrific thoughts, images, and impulses are also common types of obsessions. Central OT injections in mother hamsters were associated with increased maternal aggression toward intruders. A dose–response increase in aggression has also been reported in dominant male squirrel monkeys given intracerebroventricular OT. Blockade of OT receptors reduced aggressive behavior in these same monkeys (McDougle et al., 1999).
Current evidence regarding intranasal OT modulation of social–cognitive processes, behavior, and related neurocircuitry is mixed with some studies suggesting benefits (e.g. improved social perception/interactions, emotion processing), depending on contextual (e.g. social stimuli) and interindividual factors (e.g. age, sex, and clinical status) (Horta et al., 2020).
Thus, given the putative role of OT in ‘affiliative/mothering’ behavior, with regard to our patient, the pathological doubting she had about being a competent mother with thoughts of possibly harming her baby could be attributed to one manifestation of a pathologically dysregulated OT syndrome (McDougle et al., 1999).
Finally, in the nonpathological state, estrogens can act in a synergistic manner with OT, not only by enhancing its anxiolytic effects, but also by increasing OT-receptor levels in the mouse brain (Acevedo-Rodriguez et al., 2015).
Notably, during peripartum, elevated levels of estrogen are present. Thus, this hypoestrogenism could result in a dysregulated OT system. However, in a subsequent study, Altemus et al. (1999) were unable to replicate those findings.
The aforementioned inconsistences in findings relating OT to OCD-repetitive behaviors highlight the potential complexity of such association. The absence of the effects of the acute administration of OT in neither improvement nor worsening of OCD symptoms suggests that current variation of this neuropeptide may not be relevant for the better understanding of OCD etiology (Den Boer and Westenberg, 1992; Epperson et al., 1996). However, despite the lack of significance of current OT levels, prenatal and early natal exposure to high levels of OT could still be potentially related to the future outbreak of OCD-repetitive behaviors. Corroborating this hypothesis, OT has been previously shown to moderate the effects of early social experiences in later life (Cushing and Kramer, 2005).
Oxytocin levels in treated patients
Only three previous studies have investigated OT changes during SSRI treatment in humans (Keating et al., 2013).
In the first of these, 16 children/adolescents with OCD were studied. Clomipramine treatment, ranging between 8.5 and 34 months, caused an overall increase in CSF OT by 11%. Intriguingly, however, the individual clinical response was negatively correlated to CSF OT changes (i.e. those with the least increase in CSF OT were the most improved). Since this study only included treatment responders and no placebo group, conclusion regarding the pharmacological effects of SSRIs on the OT system should be considered with caution (Altemus et al., 1999).
In the next study, plasma OT was measured in 40 patients with MDD before and after successful pharmacological treatment, of which 19 cases were treated with SRIs (venlafaxine or SSRI) in 19 cases. When compared with a control group, the active-treatment patients had significantly lower plasma OT at baseline; however, no difference between pretreatment and posttreatment OT levels was found. All included patients were treatment responders, and the time span between samples was not conveyed (Ozsoy et al., 2009).
A third study was reported on plasma OT at baseline and after 12 weeks of SSRI treatment in 16 adult patients who were successfully treated for MDD. No difference was found (Keating et al., 2013).
Consequently, placebo-treated patients were not used as controls in any of these three studies, nor were responders compared with nonresponders. Two of the studies were for depression, and only one applied a fixed time interval for the second OT sample. Most recently, a study concluded that SSRIs have highly variable effects on plasma OT between individuals. The authors stated that the associations between baseline OT and OCD severity and between OT changes and treatment response support the theories that OT is involved in OCD pathophysiology and that the antiobsessive effects of SSRIs might be partly exerted through oxytocinergic mechanisms (Humble et al., 2013).
Increased OT activity has been linked to anxiolytic effects (e.g. in the amygdala or the median raphe nucleus) (Humble et al., 2013).
OCD onset is common during the peripartum period, with ranges up to four times the expected rate in the nonperipartum population (Miller et al., 2015).
The acute onset of OCD in the peripartum period might be attributed to the dramatic rise and fall in steroid hormone levels, resulting in serotonergic dysfunction, which is compounded by a predisposition to psychiatric illness. Some research suggests that the rapid increase in OT seen during pregnancy, particularly at nine months, and during the puerperium, might trigger the exacerbation or onset of OCD; however, the exact pathophysiology is unclear, and future research could elucidate this relationship (Brandes et al., 2004).
Clinical trials that investigated the therapeutic use of OT in OCD found no effect of this molecule over the frequency of repetitive symptoms (neither improvement nor worsening). In contrast, a study reported that levels of OT in ventricular CSF are higher in patients with OCD than in healthy controls and identified a positive correlation between higher CSF levels of OT and higher frequency of repetitive behaviors (Leckman et al., 1994a).
However, a subsequent study was unable to replicate those findings (Cappi et al., 2016).
Ultimately, it is unknown whether OT is critically involved in OCD pathogenesis, and, if so, whether the oxytocinergic activity should be increased, decreased, or changed in other ways to improve the clinical state. In various experiments, elevated OT has been linked to relaxed, affiliative situations, implying anxiolytic and antidepressant effects, but, in other experiments, OT is increased in relation to stress. These disparate findings indicate that different segments of the central OT system might act in different direction (Goodman et al., 1989).
In summary, the evidence for the role of OT in a broad range of neuropsychiatric disorders is accumulating, and further research is needed to determine the exact nature of its role and to translate these findings into a better understanding of the underlying pathophysiology of the disorders and effective treatment strategies targeting the oxytocinergic system.
Acknowledgements
The authors thank participants for their participation and cooperation.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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