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Keywords:

  • brain/physiology;
  • double-blind method;
  • humans;
  • intranasal;
  • oxytocin/administration and dosage;
  • schizophrenia;
  • social perception

Abstract

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References

MacDonald K, Feifel D. Oxytocin in schizophrenia: a review of evidence for its therapeutic effects.

Background: The suggestion that the neurohormone oxytocin may have clinical application in the treatment of schizophrenia was first published in 1972. Since then, a considerable body of research on a variety of fronts – including several recent double-blind treatment trials – has buttressed these early reports, providing support for the assertion that the oxytocin system is a promising and novel therapeutic target for this devastating malady. Herein, we review the diverse, convergent lines of evidence supporting the therapeutic potential of oxytocin in psychotic illness.

Methods: We performed a systematic review of preclinical and clinical literature pertaining to oxytocin's role in schizophrenia.

Results: Multiple lines of evidence converge to support the antipsychotic potential of oxytocin. These include several animal models of schizophrenia, pharmacological studies examining the impact of antipsychotics on the oxytocin system, human trials in patients examining the aspects of the oxytocin system and several double-blind, placebo-controlled clinical treatment trials.

Conclusions: There exists considerable, convergent evidence that oxytocin has potential as a novel antipsychotic with a unique mechanism of action. Auspiciously, based on the few chronic trials to date, its safety profile and tolerability appear very good. That said, several critical clinical questions await investigation before widespread use is clinically warranted.


Summations

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References
  • Substantial preclinical evidence from a variety of animal models indicates that oxytocin (OT) has a role in processes related to schizophrenia. Dopaminergic or glutamatergic systems appear to mediate these effects.
  • Examination of aspects of the OT system in humans (i.e. OT levels, OT genes) also suggests links between OT and schizophrenia.
  • Recently, several randomised, double-blind clinical trials of adjunctive intranasal OT have shown OT's efficacy in reducing core symptoms in patients with schizophrenia.

Considerations

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References
  • Both the neurobiological underpinnings of schizophrenia as well as the dynamics of the human OT system are complex and inadequately characterised.
  • Before treatment of schizophrenia with OT can be recommended, large-scale trials in a wide variety of patients are needed.
  • These future studies need to clarify the effects of OT in different subpopulations with schizophrenia (i.e. first-break, women) and on different parameters of the illness (i.e. cognition, social function) as well as validate issues around the safety and side effects of chronic use of OT.

Introduction

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References

Schizophrenia is one of the most disabling disorders in psychiatry, with a disturbingly small proportion of patients afflicted with this disorder able to maintain independent function (1). Despite decades of intensive research, a precise, comprehensive, systems-level understanding of its aetiology and pathophysiology remains elusive (2,3). In terms of the treatment of schizophrenia, though psychosocial interventions add significant value (4), psychopharmacological treatment remains the backbone of care (1,5). Regarding antipsychotic psychopharmacology, despite a long program of intense drug discovery, all established medications to date rely on D2 receptor antagonism – either exclusively or in conjunction with antagonism of serotonin 2A (5-HT2A) receptors – as the mechanism of action (1,6). This with the possible exception of clozapine (7,8), an antipsychotic of note in that data reviewed below indicate that clozapine may have a unique relationship with the subject of this review: the oxytocin (OT) system. Recent years have seen a groundswell of clinically oriented research on this system, opening the possibility for a genuinely novel treatment for psychotic illness.

In the context of the current fervent interest in OT as a therapy in psychiatry, it is interesting to note that it was first proposed as a potential treatment for schizophrenia in the early seventies (9), 20 years before the structure of its receptor was discovered (10) and 10 years before the sequencing of its gene (11). Almost 40 years since that initial report, following several decades of basic science and animal research, two recent double-blind placebo-controlled trials have confirmed and bolstered this initial finding, pointing towards OT as having genuine therapeutic potential (12,13). In the following review, after a brief summary of the OT system, we will summarise the data that support the therapeutic use of OT in schizophrenia.

Oxytocin fundamentals

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References

Evolutionarily, the nine-amino-acid (nonapeptide) family of which OT is part is ancient, with slight variants found in species from mollusks to meerkats (14–16). Demonstrating a surprising homology of behavioural effects, OT and its homologues have been linked to social and reproductive behaviours in a truly remarkable diversity of species (17–19). Structurally, OT is very similar to arginine vasopressin (AVP), and together these nonapeptides share four phylogenically related receptors (AVPR1a, AVPR1b, AVPR2, OTR) (15). This structural homology is important, as some of OT's central effects (20,21), as well as potential side effects (i.e. hyponatraemia) (22,23), may be mediated by binding to AVP receptors (24,25).

When considering the therapeutic use of OT in psychiatric illness in general–and schizophrenia in particular – several facets of its central neurophysiology warrant brief mention. These include its synthesis and release, its receptor system, its modes of central action and its regulation by and interaction with other important systems of interest, including gonadal hormones, dopamine and glutamate. Given other comprehensive reviews on these topics (15,26–30), these issues are addressed only briefly here.

In humans, OT acts as both a hormone and a neurotransmitter, and has been used therapeutically for decades based on its effects on the smooth muscle of the uterus (in the context of delivery) and breast (in the context of lactation) (31,32). These peripheral actions are effected when endogenous OT is synthesised in magnocellular neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, moved by axonal transport to the posterior pituitary and released into the systemic circulation (Fig. 1). Worth noting in this context is that there is some controversy regarding the extent to which peripheral and central release of OT are coordinated, and thus how much peripheral OT levels can be considered a surrogate marker for central activity. In brief, though there is evidence that the activity of the central and peripheral OT systems can be dissociated (33–35), there is also accumulating evidence in humans that its central activity and peripheral release are often correlated (36–39) [see (40,41) for reviews of this topic]. Of interest here, correlations between peripheral OT levels and neurobehavioural outcomes include interesting associations in patients with schizophrenia (discussed below) (42–44).

image

Figure 1. Oxytocin: central synthesis and peripheral effects. Although there is evidence for oxytocin synthesis outside the brain (45), oxytocin is predominantly synthesised by specialised neurons in two nuclei in the hypothalamus: the PVN and SON. Once synthesised, oxytocin serves dual roles as both a central neurotransmitter/neuromodulator (see Fig. 2) as well as a peripheral hormone. In point of fact, there are receptors for oxytocin throughout the body, although its primary therapeutic uses to date have been been in the gravid uterus and lactating breast, where it stimulates contractions and milk ejection, respectively. Of note, the correlation and coordination of peripheral and central oxytocin release (and therefore the relevance of peripheral oxytocin levels to brain-based illness) is complex and a matter of active research [see (41,46,47) for contemporary perspectives]. Figure reprinted with permission from Oxford University Press.

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Besides its vital role as a hormone, OT also acts in an important central network as a peptide neurotransmitter (48,49) (Fig. 2). These central actions, which have been elaborated in a growing variety of human magnetic resonance imaging (MRI) studies (39,50–57), occur via mechanisms that differ significantly from classical neurotransmitters (i.e. gamma-amino butyric acid) (29) (Fig. 2). That is, unlike classical neurotransmitters, neuropeptide neurotransmitters such as OT have both direct effects via axonal release from parvocellular neurons in the PVN as well as diffuse ‘volume’ effects due to somatodendritic release from magnocellular neurons (35,47) (Fig. 2). These latter effects uniquely occur with neuropeptides because unlike classical neurotransmitters, neuropeptides have no reuptake system and a longer extracellular half-life. As such, they are able to produce a range of effects in areas at some distances from their release due to short-range diffusion in the extracellular fluid and cerebrospinal fluid (CSF) (29,41).

image

Figure 2. Oxytocin: central effects. Oxytocin has at least two modes of central activity: (a) direct axonal transmission from parvocellular neurons in the PVN (solid arrows above) and (b) volume diffusion effects (i.e. ‘volume transmission’), which has effects in areas with oxytocin receptors. This latter set of ‘volume effects' are the result of somatodendritic release of oxytocin from both SON and PVN, and may partially occur via short-range diffusion in the CSF (41,47,58). As discussed in the text, the amygdala (with important connections in pull-out box) is a critical node of oxytocin's central activity in humans, and plays a role in some theories about oxytocin's role in schizophrenia (59). Other areas of overlap between schizophrenia and oxytocinergic function include the hippocampus and the dopaminergic ventral tegmental area/striatum. Only selected oxytocin receptor-containing brain areas are shown here (indicated with * in diagram); for a more complete list, see reviews in (15,60,61). Figure reprinted with permission from Oxford University Press. ACC, anterior cingulate cortex; AMG, amygdala; mPFC, medial prefrontal cortex; NAS, nucleus accumbens; OFC, orbitofrontal cortex; SN, substantia nigra; STR, striatum; VMH, ventromedial hypothalamus; VTA, ventral tegmental area.

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As noted in Fig. 2, oxytocin receptors (OTRs) have been located in a number of brain areas relevant to schizophrenia, including the substantia nigra, the nucleus of the solitary tract, the central nucleus of the amygdala (CeA), the lateral septal nucleus and parts of the basal ganglia (15,62–65) (Fig. 2). Several factors about OTRs warrant mention here. First, although only one OTR has been identified and cloned, recent research has identified polymorphisms of the OTR in the human population, and the role of genetic variations in human OTRs is an area of intense interest, with several studies showing these variations have associations with important central functions in humans (66–70). Besides polymorphisms in the OTR, basic science research by Insel and others has also shown that a second factor – the spatial distribution and density of OTRs in different brain areas – is a critical parameter determining OT's species-specific central effects (71) as well as dynamic effects based on developmental stages (i.e. parturition) (72,73). Lastly, epigenetic variations in the OTR system can occur as the result of environmental influences like early caregiving, part of the way nurture is transformed into nature (74,75) and part of the complex role OT plays in the translation of social factors (isolation and social defeat) into neurobiology (76,77). All told, a greater understanding of variations in the plastic, socially sensitive OT system may be illuminative in understanding the considerable role different social and environmental stressors (i.e. prenatal stress, childhood trauma, social defeat) play in the development of schizophrenia (78–80).

When considering the treatment of humans with intranasal OT, it is worth noting that although the precise mechanism wherein intranasal OT exerts its central effects is underspecified (81,82), the central OT system is regulated as feed-forward system, with synchronous bursting of neural networks leading to spikes of OT release (83). As such, small amounts of exogenous OT delivered to the brain may prime and trigger sustained, endogenous release from the central system. This may account for the interesting fact that in some experiments, intranasal OT increases peripheral OT levels for an extended time (>1 h) (36), well beyond OT's short plasma half-life, which is on the order of 2–12 min (84–86). Furthermore, due to its evolutionary role in plastic and long-lasting developmental brain processes (87), the time frame of therapeutic effects of exogenous OT may differ from that of treatments based on classical neurotransmission.

Finally, regarding OT and schizophrenia, it is important to note that OT has significant interactions with other systems of interest in the illness, including oestrogen [which regulates synthesis of both OT and OTRs (88,89), serotonin (90), dopamine (91–93) and glutamate (94,95)]. These interactions, explored in the experiments reviewed below, are helpful to keep in mind when considering the‘final common pathway’ by which OT may exert its therapeutic effects.

Preclinical models of schizophrenia and oxytocin

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References

Although all animal models of schizophrenia contain theoretical and translational challenges, they provide an invaluable way to discern putative antipsychotic effects and allow the use of techniques (intracerebral microdialysis, gene knockout, maternal deprivation) not available in humans (12). In the case of OT, several animal models predictive of antipsychotic efficacy both support its antipsychotic-like effects and point towards putative mechanisms of action (Table 1). These models include a variety of pharmacologic, environmental and genetic manipulations, all of which induce different aspects of the syndrome of schizophrenia.

Table 1.  Preclinical studies supporting antipsychotic effects of OT
AuthorsModel /parameterMain findingsNotes
  1. APD, antipsychotic drug; DA, dopamine; ICV, intracerebroventricular; MOA, mechanism of action; mPFC, medial prefrontal cortex; pOT, plasma oxytocin level; SC, subcutaneous.

Sarnyai et al. (96)Cocaine-induced hyperactivityBoth pimozide (DA receptor antagonist) and OT blocked cocaine-induced hyperactivity, the latter in a ‘U’ shaped, dose-response mannerAlong with (91,92,97–101), supports dopaminergic MOA for OT
  Effects of OT on DA were centred in nucleus accumbens 
Uvnas-Moberg et al. (102)APD effect on pOT levelsClozaril and amperozide (clozaril-like antipsychotic) increased pOT levels, whereas haloperidol did notAlong with (103,104), supports unique relationship between OT and clozapine
Feifel and Reza (105)PPI modelSC OT restored PPI that had been reduced by dizocilpine (NMDA antagonist), and amphetamine (indirect DA agonist), but not apomorphine (direct DA agonist)Along with (106,107), supports glutamatergic/NMDA receptor MOA
Lee et al. (107)PCP modelPCP-induced social dysfunction caused decreases in hypothalamic OT mRNA expression and increases in OTR binding in the CeAPCP (a non-competitive NMDA receptor antagonist) induces social deficits in animals (108) and psychosis in humans (109). Along with (105,106), supports a glutamatergic/NMDA receptor MOA for OT
  Infusion of OT into the CeA restored social behaviour in PCP-treated rats 
Lee et al. (110)Prenatal stress modelPrenatal-stressed rats, which show decreased social interaction, showed less OT mRNA in the PVN and increased OTR binding in the CeAA variety of prenatal and early childhood stressors may play a role in the development of schizophrenia (111,112)
  As in (107), OT injected into the CeA reversed social deficits 
Qi et al. (101)MAP-induced hyperactivityICV OT inhibited MAP hyperactivity in a dose-dependent mannerAlong with (96)– and see other references in that note – supports a dopaminergic MOA for OT
  Atosiban, a selective OTR antagonist, attenuated this effect 
  OT inhibited the MAP-induced reduction of DA turnover in the striatum and accumbens 
Caldwell et al. (106)PPI modelMice with disruption of the OT gene (OTKO mice) showed unique PPI deficits with PCP, but not amphetamine or apomorphineAlong with (105,107), supports glutamatergic/NMDA receptor MOA
Qi et al. (113)MAP-induced CPPOT inhibited the acquisition and facilitated the extinction and stress-induced reinstatement of MAP-induced CPPThis study joins (105–107) in pointing to a gluatmatergic MOA for OT, and, like (95) locates glutamatergic effects in the mPFC
  OT blocked stress-induced elevations in glutamate in the mPFC, an effect blocked by atosiban (an OTR antagonist)Human studies note PFC dysfunction linked to DA dysregulation (114), part of the ‘functional dysconnection’ hypothesis of SCZ (115)
Kiss et al. (103)APD effect on OT-producing cellsClozapine and olanzapine, but not risperidone or haloperidol, activated OT and AVP cells, as measured by early gene activation (c-Fos) in the PVN and SON of hypothalamusAlong with (102,104), supports unique relationship between OT and clozapine
Feifel et al. (116)PPI modelOT, but not carbetocin (a long-acting structural analogue of OT), increased PPI and decreased acoustic startle in Brown Norway rats, a strain with natural PPI deficitsThese same Brown Norway rats show facilitation of PPI to clozapine but not haloperidol (117), another tie between oxytocin and clozapine

A first model, building on the dopaminergic theory of schizophrenia (118,119), uses stimulants (amphetamine, cocaine) to model the hyperactivity and hyperdopaminergic state presumed to be associated with psychosis. Established antipsychotics consistently reverse stimulant-induced hyperactivity, and thus this model serves as a predictive screen for potential antipsychotic drugs with antidopamine mechanisms. Using such a model, in 1990 Sarnyai et al. showed that subcutaneous OT decreased cocaine-induced hyperactivity in a ‘U-shaped’ dose-response manner, similar to the antipsychotic pimozide (96). Histological analysis validated that these findings were related to dopaminergic neurotransmission in the nucleus accumbens, part of the mesolimbic dopamine system implicated in schizophrenia (115,120). In a similar set of experiments using methamphetamine (MAP), Qi et al. showed that intracerebral OT inhibited MAP-induced hyperactivity in a dose-dependent manner; atosiban (an OTR antagonist) attenuated these effects (101). As in the study by Sarnyai above, these dopaminergic effects were localised to the striatum and accumbens. In a later experiment, this same group showed that the acquisition of MAP-induced conditioned place preference (CPP) – an animal model of addiction – was inhibited by OT, which also facilitated the extinction of this preference and blocked its stress-induced reinstatement (113). In this experiment, microdialysis in the prefrontal cortex showed that OT inhibited restraint-stress induced extracellular glutamate levels. This finding is of interest given the interaction proposed between prefrontal cortical dysfunction and aberrant dopaminergic transmission in schizophrenia (114), and given that the abovementioned stimulant models implicate a dopaminergic mechanism of action for OT. As discussed earlier, and in a variety of other experiments [(91,92,97–101), and see (61) for recent review], there are extensive interactions between OT and central dopaminergic systems. As such, and given that the excessive dopamine transmission in the mesolimbic system is strongly implicated in the positive psychotic symptoms of schizophrenia, the above series of experiments support that OT's inhibitory regulation of mesolimbic dopamine may be a part of its mechanism of antipsychotic action.

A second pharmacological animal model of schizophrenia utilises antagonists for the excitatory glutamate/N-methyl-d-aspartate (NMDA) receptor such as phencyclidine (PCP) or ketamine to induce behavioural syndromes that mimic negative symptoms of schizophrenia. For example, chronic PCP administration in rodents causes them to display social withdrawal, a clinical hallmark of schizophrenia (108,121). Importantly, clozapine – considered the most efficacious antipsychotic, especially for negative symptoms (122–124)– reverses PCP-induced social withdrawal more effectively than other antipsychotics (121) lending validity to this animal model. As noted earlier, OT has been linked with clozapine treatment in several pharmacological studies (102,103) and a genetic study (125).

Using a PCP model in rats, Lee et al. showed that chronic PCP treatment decreased hypothalamic OT mRNA expression and increased OTR binding in the CeA (107). Notably, direct OT infusion into the CeA selectively restored the normal quality and quantity of social behaviour (107). This latter finding – reversal of experimentally induced social deficits with direct injection of OT into the CeA – has been replicated in a prenatal stress model of schizophrenia (110). As background, rats from mothers exposed to unpredictable prenatal stress show neuroendocrine imbalances, behavioural deficits (reduced social drive), as well as decreased prepulse inhibition (PPI), indicating a resemblance to aspects of schizophrenia (110,126). Examining a group of these rats, Lee et al. found they had less OT mRNA in the PVN, increased OTR binding in the CeA, as well as the aforementioned reversal of social incompetence by direct administration of OT to the CeA (110). This group of findings are noteworthy given the presence of OT-responsive neuronal populations in the CeA (127,128), the role of the amygdala in social cognition (129), the stress-diathesis models of schizophrenia (111,112), as well as broad-scope theories tying OT's activity in the amygdala to its antipsychotic properties (59).

A third animal model used in schizophrenia research utilises a neurophysiological measure of sensorimotor gating called PPI of the startle reflex (130,131). Anatomically, PPI is mediated by a cortico-striato-pallido-pontine circuitry, which includes the nucleus accumbens, the hippocampus and the basolateral amygdala (132,133), all areas implicated in the pathophysiology of schizophrenia. Moreover, the PPI disruptions found in patients with schizophrenia can be restored with established antipsychotics, particularly second-generation antipsychotics (130), and schizophrenia-like deficits in PPI can be induced in animals using psychomimetic drugs acting on different neurotransmitter systems of relevance to schizophrenia, including dopamine enhancers (amphetamine), and NMDA antagonists such as PCP, ketamine and dizocilpine (MK801) (106,131,134). Finally, and pertaining to the experiments discussed below, PPI deficits can also be used to distinguish between first- and second-generation antipsychotics: while both families of antipsychotics are effective at reversing PPI deficits induced by dopamine enhancers, only second-generation antipsychotics are effective at reversing PPI deficits induced by NMDA antagonists (131).

Using a PPI model, Feifel and Reza showed that subcutaneous OT restored PPI that had been disrupted by both a dopamine enhancer (amphetamine) and an NMDA antagonist (diziclopine) suggesting a second-generation antipsychotic-like profile. Interestingly, though, OT did not reverse PPI deficits induced by the direct dopamine agonist apomorphine (105). More recently, Feifel et al. extended these findings by investigating the effects of OT in a non-pharmacological model of PPI deficits using the Brown Norway rat. This strain of rat has naturally low PPI compared to other strains, and thus may represent a more appropriate model of the inherent PPI deficits in schizophrenia (135). Moreover, the antipsychotics clozapine, but not haloperidol, restored PPI in Brown Norway rats to normal levels, indicating that PPI deficits in these rats may serve as a valid predictive screen for second-generation antipsychotics (117). Most recently, when Feifel et al. tested the activity of a long-acting OT analogue (carbetocin) and OT in this Brown Norway strain, they found that subcutaneous administration of OT (but not carbetocin) significantly enhanced PPI, similar to the effects of clozapine (116).

Another group to use the PPI model in a unique strain of mice did so with animals that were genetically engineered without the gene for OT [oxytocin knockout (OTKO) mice] (106). OTKO mice, it has been shown, have impaired social memory (136), show more anxiety-like behaviours than normal mice (137) and exhibit inflexibility of change in learned behaviour (20). In this particular experiment, Caldwell et al. showed that homogeneous (OTKO) mice (OT −/−) were significantly more susceptible to PCP-induced PPI deficits than mice expressing the normal OT gene (OT +/+), suggesting that endogenous OT may play an antipsychotic role by protecting against the disruption of glutaminergic circuits. Notably, and similar in some respects to the abovementioned findings from Feifel et al. (105), this group did not find a similar genotype-by-treatment effect when the dopaminergic compounds amphetamine and apomorphine were used to disrupt PPI, again suggesting that endogenous OT's antipsychotic-like effects may be specific for glutaminergic, but not dopaminergic, perturbations.

Besides these animal models, another line of evidence supporting OT's antipsychotic activity comes from experiments suggesting that the stimulation of endogenous OT may contribute to the therapeutic effects of certain antipsychotics. For example, Uvnas-Moberg showed that both clozaril and amperozide (a clozaril-like compound) produced elevations of plasma OT levels, whereas haloperidol did not (102). More recently, Kiss et al. showed that that several antipsychotic drugs induced c-Fos activity in hypothalamic magnocellular OT neurons, with clozaril and olanzapine showing more robust effects than risperidone and haloperidol (103). Additional evidence that the endogenous OT system mediates at least some of clozapine's therapeutic effects comes from a human study that found that a variant of the OT gene (rs2740204) was significantly associated with clozaril treatment response, and was nominally associated with negative symptoms (125). On the topic of potential genetic links between OT and schizophrenia, a just-published report from a unique Arab-Israeli schizophrenia cohort suggested involvement of four candidate genes including genes for both OT and AVP (138).

Notwithstanding challenges in translating from animal models to the complex, heterogeneous disease that is schizophrenia (139), multiple converging lines of evidence from animal research support that OT may have central actions highly relevant to the phenomenology and treatment of schizophrenia, and point to potential mechanisms, brain regions and circuits that may mediate these effects. Furthermore, these experiments implicate that certain antipsychotics, clozaril in particular, may have a unique relationship with the central OT system.

Human studies of the oxytocin system in schizophrenia

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References

A variety of studies, dating back several decades, have examined different aspects of the OT system in patients with schizophrenia (Table 2). Aspects of the system that have been studied include (a) levels of OT and OT-related molecules (i.e. the OT carrier protein neurophysin) in the CSF and blood, (b) levels of cellular activity in the brain areas (PVN, SON) where OT is synthesised and (c) the relationship of OT levels to clinical symptoms or abilities. Each of these experiments should be seen in the light of abovementioned controversies regarding the relationship and function of the central and peripheral OT systems (vide supra section on Oxytocin fundamentals), as well as the heterogeny of symptoms in patients with the illness. Although each of the parameters these researchers have studied is an indirect measure of central OT activity, it should be remembered that until the widespread use of functional imaging, there was no way to measure the central activity of OT in humans.

Table 2.  Studies of the OT system in patients with schizophrenia
AuthorsNOT parameterMain findingsNotes
  1. APD, antipsychotic drug; BPRS, brief psychotic rating scale; cOT, cerebrospinal fluid oxytocin level; DA, dopamine; NNS, normonatremic nonpolydipsic schizophrenia; PHS, polydipsic hyponatremic schizophrenia; PNS, polydipsic normonatremic schizophrenia; pOT, plasma oxytocin level; SCZ, schizophrenia.

Linkowski et al. (140)12 SCZ (9 M, 3 F); 12 controlsCSF OT-neurophysin (hNpII) levelsApomorphine-stimulated CSF hNpII levels were significantly lower in SCZ patients than controlsNeurophysin II is a carrier protein for OT. See also notes for Legros (141)
Beckmann et al. (142)28 M SCZ; 15 controlscOTcOT increased in patients with SCZ and were higher in patients on APDs (butyrophenones and phenothiazines, not clozaril)Relevance of cOT levels to central function debated [see text and (41)]
   cOT increased after 3 weeks of treatment with APDs. 
Legros et al. (141)9 MSCZ; 14 M controlsPlasma OT-neurophysin (hNpII) levelsBasal hNpII levels were increased in SCZ patients compared to controls and were significantly higher in the paranoid than in the non-paranoid SCZ groupApomorphine, a DA agonist, stimulates OT release in humans (141,143), consistent with bidirectional DA-OT interactions (144,145)
   Apomorphine caused elevation in plasma nNpII levels in normals; this response was blunted in SCZ patients 
Mai et al. (146)11 SCZ (sex not reported); 10 controlsNeurophysin staining in post-mortem brain samplesAbnormal neurophysin staining in PVN, globus pallidus, substantia nigra in brains of patients with SCZPatients were essentially untreated, making effects of medication unlikely
Glovinsky et al. (147)40 SCZ (31 M, 9 F); 15 controlscOTcOT levels did not differ within subject based on APD status (treated or withdrawn) nor between SCZ patients and controls 
Goldman et al. (42)15 SCZ (6 PHS, 4 PNS, 5 NNS); 7 controlspOTpOT levels increased in PHS patients compared to PNS or NNS or controls, and higher pOT associated with greater accuracy of rating facial emotionsAlong with (148), indicates potential of differential role of OT in various SCZ subtypes, especially PHS patients, who also show impaired hippocampal function (149), and structural pathology in the amygdala and anterior lateral hippocampus (150)
   pOT levels were inversely correlated with anterior hippocampal volume 
Keri et al. (151)50 SCZ (16 M, 34 F); 50 controlspOTControls showed elevated pOT levels after trust-related interactions, whereas patients with SCZ did not. Low pOT levels after trust-related interactions were associated with negative symptoms. No relationship found between pOT and APDNotable, given social sensitivity of OT effects (152), role of interpersonal stressors in SCZ (153) and oxytocin's augmentation of facial affect recognition in SCZ (154)
Rubin et al. (44)50 SCZ (27 M, 23 F); 58 controlspOTFemale patients with higher pOT had less severe positive symptoms and overall psychopathologySex differences noted in clinical course of SCZ (155,156). Oestrogen and prolactin regulate OT and OTR expression (74,89,157,158)
   In both sexes, patients with higher pOT levels showed more prosocial behaviours (a subset of the PANSS). Clinical symptoms improved during menstrual phases characterised by high levels of oestrogen and progesterone 
Souza et al. (125)140 M and F SCZ patientsOT and OTR genesThe OT gene was significantly associated with clozaril treatment response and nominally associated with negative symptomsClozaril and OT also associated in (102,103)
   Variants in the OTR (rs237887) were nominally associated with BPRS severity and improvement in positive symptoms 
Rubin et al. (43)48 SCZ (26 M, 22 F); 57 controlspOTHigher pOT levels related to perceiving faces as happier in both female patients and controls, but not in menSex differences noted in other studies of pOT (159,160), and in some (52) but not other studies of IN OT [for review, see (152)]
   Women showed menstrual cycle-dependent fluctuations in emotional cue responses 

Most early studies of central OT levels and their relation to schizophrenia found evidence for a perturbation of the OT system in this disorder, although the specific direction of change has not always been consistent. For example, though Beckman et al. (142) found increased baseline levels of CSF OT in patients with schizophrenia (levels were further increased with haloperidol treatment) (142), and Linkowski et al. found higher CSF levels of the OT carrier protein neurophysin in schizophrenia patients (140), a later study showed no change in CSF OT based on illness or treatment (147). Post-mortem studies of OT-rich areas in the brains of unmedicated schizophrenia patients have shown morphometric differences in the PVN, internal palladium and substantia nigra (146), and studies of hypothalamic regions associated with OT release (PVN) have shown reduced cell density in patients with schizophrenia (161). Most recently, as part of a multifaceted set of experiments in patients with schizophrenia and polydipsia, Goldman et al. found deformations in brain areas involved with the modulation of neuroendocrine responses (anterior lateral hippocampus, amygdala) in certain subsets of such patients (148,150).

Aside from these assays of the central OT system, early researchers have also examined peripheral OT levels in patients with schizophrenia, finding lower baseline levels of OT carrier proteins (neurophysins) compared to normal controls, with levels in the schizophrenia group inversely associated with the level of paranoia (141). A group of subsequent studies by Goldman et al. have shown lower levels of plasma OT in patients with polydipsia and schizophrenia (42), and found these levels to be inversely correlated with anterior hippocampal volume (162), positively correlated with hippocampal-mediated hypothalamic-pituitary-adrenal axis (HPA) feedback (149) and predictive of patients' ability to correctly identify facial emotions (42). This latter finding of a correlation between social cognition and plasma OT in patients with schizophrenia has since been replicated (43), and extended in treatment trials showing OT enhancement of social cognition (154,163, vide infra). In addition, the aforementioned findings around the role of OT and the HPA axis in schizophrenia again point to the role of OT in the stress-diathesis aspect of the illness (112), and raise the possibility that OT function may distinguish between some of the clinical subtypes (i.e. polydipsia) within the broad schizophrenia heading.

Further studies have also found correlations between pOT and schizophrenia. Following seminal studies in normal subjects indicating OT's role in trust (164), and a correlation of pOT levels with trustworthiness (165), Keri et al. examined whether OT played a role in trust in patients with schizophrenia. In this study, patients with schizophrenia had lower pOT levels following a trust-related social interaction than normal controls, who showed increased levels following these interactions (151). Non-trust-related OT levels were also lower in patients (although not significantly so) and low trust-related pOT levels predicted the negative symptoms of schizophrenia (151). These findings relating to trust are of interest with regard to the schizophrenia symptom of paranoia, and highlight the role of OT in the amygdala, a brain structure shown in normals to be important in interpersonal trust assessments (166,167), and responsive to OT in trust-related situations (50).

Biological sex (chromosomal maleness or femaleness) is a critical variable influencing OT's function, and an awareness of the sex-specificity of many of its actions informs a review of the OT literature. We note that although the term ‘gender’ is still often used in the OT literature to refer to this important factor, following the National Academy of Sciences recommendation (168), we use the term ‘sex’ throughout to refer to biological maleness or femaleness. Shedding light on a potential sex-specific role of OT in schizophrenia, Rubin et al. described that female patients with higher pOT levels had attenuated positive symptoms and psychopathology, and that in both males and females, higher OT levels were associated with more prosocial behaviours (44). In a follow-up study, this group also reported that although OT levels did not fluctuate across the menstrual phase, higher pOT levels in women were associated with increased sensitivity to happy facial emotion, less severe positive symptoms and less overall psychopathology (43). On the topic of sex and OT, it is worth noting that several studies have shown that OT levels can fluctuate throughout the menstrual cycle [(169,170), but see (171,172)], and that oral contraceptive use [which was exclusionary in (43,44)] may increase OT levels in healthy women [(173,174), but see (170)]. Furthermore, the issues around OT and sex raised by these experiments are especially salient given that (a) oestrogen upregulates OTRs (89), plays a role in OT's activity in the amygdala (88) and appears to influence the course of psychotic symptoms in women (175) (vide supra section on Introduction); (b) other sex-specific hormones (i.e. testosterone) may moderate OT's effects (176); (c) sex is an important factor in the natural history of schizophrenia (177) and (d) studies indicate that sex moderates OT levels (160,170), stress-based (178,179) and behavioural aspects of OT (159), the effect of OT on the brain in face processing tasks (51,52), as well as some of the effects of treatment with exogenous OT (152). To whit, the role of sex in OT's baseline and dynamic activity – as well as the impact of sex and gonadal hormones on OT treatment of patients with schizophrenia – requires much further study (Box 1).

Clinical trials using oxytocin in patients with schizophrenia

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References

Surprisingly, perhaps, the first documented report of the use of OT in schizophrenia predates the animal research discussed earlier by more than a decade (9) (Table 3). In several early reports, investigators in the Soviet Union reported that 6–10 treatments of between 10 and 25 IU OT given IV or IM induced rapid therapeutic effects and prevented hospitalization in patients with schizophrenia (9), potentially by acting as a ‘psychic energiser’ reversing energy, apathy and depression (180). In spite of their prescience, these early reports describe case series (9) or did not use standardised diagnostic or outcome scales (180). Only recently, more than 30 years later, have rigorously designed and executed clinical trials of exogenous OT been conducted in patients with schizophrenia.

Table 3.  OT treatment of patients with schizophrenia
AuthorsNParameter studiedMain findingsNotes
  1. APD, antipsychotic drug; F, female; M, male; SCZ, schizophrenia.

Bunjanow (9)Not mentionedGeneral psychopathology (underspecified)OT induced ‘rapid therapeutic effects' and ‘hospitalizations were prevented’Case reports in a letter to the editor
Bakharev (180)46 inpatientsSubsets of SCZ symptoms (not standardised)Improvements in self- and clinician-rated ‘asthenodepressive, apathodepressive, hypochondriac symptoms' compared with conventional APDsDouble-blind, placebo-controlled, between-subjects design
 27 M (OT), 19 M (conventional APDs)   
Feifel et al. (12)15 outpatients (12 M, 3 F)PANSS, CGI, side effectsOT improved PANSS and CGI at 3-week time pointDouble-blind, placebo-controlled, within-subjects design of adjunctive OT
   OT was well tolerated based on patient reports and labs 
Averbeck et al. (154)Experiment 1: 30 patients (24 M, 6 F), 29 controls Experiment 2: 21 patients (21 M)Emotion recognition [hexagon emotion discrimination test (181)]Patients had deficit in emotion recognition compared to controlsExperiment 1: between-subjects, experiment 2: within-subjects, cross-over
   OT improved ability of patients to recognise most emotions 
Goldman et al. (148)13 patientsPresence and intensity of facial emotions10 IU dose caused decreased emotion recognition in patients due to emotion overidentificationWithin-subjects, one-time treatment with multiple doses
 5 polydipsic (PS: 3 M, 2 F), 8 non-polydipsic (NPS: 4 M, 4 F) 11 controls   
   20 IU dose improved emotion recognition in PS vs. NPS, specifically around fear recognition 
Pederson et al. (13)20 inpatients and outpatients (17 M, 3 F)PANSS, social cognitionOT improved both PANSS scores and several measures of social cognition after 2 weeks of treatmentDouble-blind, placebo-controlled, between-subjects design of adjunctive OT

In the first of these, Feifel et al. treated 15 outpatients with residual symptoms of schizophrenia with 3 weeks of adjunctive intranasal OT (40 IU twice daily) in a randomised, double-blind cross-over study (12). In this experiment, OT produced significantly greater therapeutic effects across a broad spectrum of symptoms including both positive and negative symptom clusters based on changes in the Positive and Negative Syndrome Scale (PANSS), though improvement in positive symptoms appeared more robust. Supporting the clinical salience of these effects, Clinical Global Impression (CGI) scores also improved significantly with OT. Importantly, given the paucity of chronic treatment trials, is that OT was well tolerated from the perspective of reported side effects, vital signs and blood chemistry studies. Finally, it was found that in contrast to single administration studies of OT in normal subjects, which tended to produce amnestic effects on verbal memory (182,183), schizophrenia patients exhibited improved verbal memory after 3 weeks of daily intranasal OT (184).

Replicating and extending these findings, Pedersen et al. recently conducted a randomised, placebo-controlled, 2-week trial in which outpatients and inpatients with schizophrenia received either intranasal placebo or 24 IU twice daily. Similar to Feifel et al. (12), this study reported significant, global decreases in PANSS scores with OT compared to placebo. In addition, this group found significant improvements in several social cognition measures (theory of mind, facial trustworthiness) in the OT group compared to the placebo group, extending OT's well-documented prosocial effects in normal subjects (185) into a clinical population with impairments in this arena (154,186), and providing support for OT's ability to ameliorate some of the social cognitive deficits in schizophrenia. These social deficits, which have more association with the community function of schizophrenia patients than neurocognition (187), are poorly treated with current medications (188). Interestingly, Pedersen et al. found significant separation between OT and placebo in PANSS scores after the second week of treatment, whereas the study by Feifel et al. (12) did not observe an OT advantage until the third week of treatment. In considering this difference, it is notable that though magnitude of symptoms was similar between these studies, there were differences in dosing, setting (inpatient vs. outpatient) and patient characteristics (average age, years of illness).

Besides these chronic treatment trials, several recent, single-dose studies of interest have extended OT's well-documented ability to alter responses to socially salient stimuli in normals (56,185) to patients with schizophrenia, replicating the abovementioned prosocial findings by Pedersen et al. (13). In one such study, Averbeck et al. first showed that patients with schizophrenia performed worse than normals on a specific emotion recognition task, and subsequently showed – using the same task – that double-blind OT treatment improved patient's recognition of emotions (154). A second, similar study by Goldman et al. examined the effect of two doses of IN OT (10 and 20 IU) and placebo on emotion recognition in three groups: schizophrenia patients with (PS) and without polydipsia (NPS) and normals (148). Besides showing a differential effect of these two doses in patients (10 IU worsened performance, 20 IU improved performance), this experiment showed a differential benefit of the 20 IU dose in PS versus NPS. In addition to demonstrating a dose effect of OT, these findings raise the potential of OT to have differential effects in subsets of patients with schizophrenia. Together, these single-application experiments highlight the unique potential of OT to target the social cognitive and emotion-processing impairments that are such a disabling component of schizophrenia (187,189).

In reviewing the extant clinical research using IN OT in patients with schizophrenia, several practical issues deserve special mention. On the positive side, the extant research around the safety and tolerability of OT indicates that both short term [see (190) for recent review] and chronic use are both safe and tolerable in the populations and doses studied to date. Chronic trials supporting OT's safety and tolerability include the 2- and 3-week schizophrenia trials cited above (12,13), as well as a 13-week study of 40 IU BID in women with constipation (191). These findings are encouraging, given the often morbid side effects of current pharmacologic treatments for schizophrenia (192). Until more research accrues in vulnerable populations (i.e. patients with polydipsia) and with different dosing, however, we recommend ongoing vigalence, given OT's potential cross-reactivity with vasopressin (24), and the subsequent possibility of hyponatraemia and water intoxication [(22,23,25), but see (193)].

Although intranasal OT appears quite safe and tolerable, there are several practical barriers to its therapeutic drug development in humans. These include the lack of intellectual property ownership of the actual hormone, lack of US Food and Drug Administration (US FDA) approval for any psychiatric indication and challenges around the actual availability of the drug (194). These practical challenges to the use of OT exist in addition to the many outstanding scientific questions around its therapeutic profile (Box 1), and require novel solutions (i.e. OT analogues, new delivery systems).

Conclusions, questions and future directions

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References

En toto, the above set of convergent findings – from preclinical work with OT, from studies of the OT system in patients with schizophrenia and from several randomised, placebo-controlled trials – strongly support that OT holds promise as a novel treatment for schizophrenia. That said, our knowledge around the clinical use of OT is limited, and considerable work needs to be done to address a host of outstanding questions regarding the use of OT in psychotic illness (Box 1). Fortunately for the field – and for the patients who may benefit from OT therapy – ongoing study of the therapeutic potential of this ancient system will likely continue at its current feverish pace, and several large trials studying OT in schizophrenia are in process. We anticipate these trials will furnish critical data to address some of these important questions.

Box 1. Pending Questions Around the Use of OT in Schizophrenia

  • 1
    Dosing and delivery: What are the optimal dose and frequency of treatment, in the context of several studies indicating a dose effect of OT (102,148), as well as the finding of sustained levels after a single treatment (36). Is the intranasal route the optimal one or might less onerous routes (i.e. patch) be more practical or effective?
  • 2
    Adjunctive or primary: Does OT have a clinical impact as monotherapy? How does adjunctive OT impact the effect of currently prescribed antipsychotics? In women, do oral contraceptives or hormonal status impact these effects? Would co-administration of oestrogen with OT augment its effects?
  • 3
    Subpopulations and symptom clusters: Given the clinical heterogeny of schizophrenia, are there subpopulations (i.e. females, patients with negative symptoms) that are more prone to benefit from OT? Might some patient groups experience additional side effects from OT (i.e. patients with polydipsia)? Are there symptom clusters (positive, negative, social cognition) that show particular benefit?
  • 4
    Biomarkers: Noting that several studies show single-dose effects of OT (148,154), are there clinical biomarkers which may be early predictors of a therapeutic response (i.e. social cognition measures, EEG, eye tracking)?
  • 5
    Receptors: What roles do the known, consequential OTR polymorphisms (66–70) or variations in regional OTR density have in OT's therapeutic effects or in syndromic variations of schizophrenia?
  • 6
    Levels: Does an individual's OT level (salivary, plasma, urinary, cerebrospinal fluid) have any predictive value in terms of a patient's therapeutic response to OT? Which is more important, baseline or dynamic levels (i.e. in response to stressors, social stimuli or treatment)?
  • 7
    Context: Given the context-dependent effects of OT (152), and the suggestion of OT augmentation of aspects of a helping relationship (195), are there particular treatment settings or psychosocial interventions [social skills training (196)] that may work synergistically with OT?
  • 8
    Neurodevelopment/plasticity: Noting the neurodevelopmental and stress-diathesis aspects of schizophrenia (112), and given the suggestion that OT may serve a plasticity-enhancing or neuroprotective function (197–201), might OT have a particular role in ‘psychosis-prone’ individuals?

References

  1. Top of page
  2. Abstract
  3. Summations
  4. Considerations
  5. Introduction
  6. Oxytocin fundamentals
  7. Preclinical models of schizophrenia and oxytocin
  8. Human studies of the oxytocin system in schizophrenia
  9. Clinical trials using oxytocin in patients with schizophrenia
  10. Conclusions, questions and future directions
  11. Acknowledgement
  12. References