Lowered Oxytocin in Schizophrenia

Researchers from Japan found, in a study of 27 persons with a schizophrenia diagnosis, 17 with major depressive disorder, and 27 controls, that negative symptoms of schizophrenia were associated with a lower level of oxytocin in cerebrospinal fluid. They also found lower levels of oxytocin were associated with use of second-generation antipsychotics. The article, published online today in Schizophrenia Research, discusses the role of oxytocin in social behavior and psychopathology.

Abstract → 

Sasayama, D., Hatton, K., et al; “Negative correlation between cerebrospinal fluid oxytocin levels and negative symptoms of male patients with schizophrenia,” Schizophrenia Research, online June 27, 2012

Related item:
Oxytocin levels linked to medication dose, symptoms in schizophrenia

From the introduction:

” … (Oxytocin’s) release is induced by a variety of stressful stimuli, including noxious stimuli, conditioned fear, and exposure to novel environments (Onaka, 2004). Accumulating evidence indicates that oxytocin plays an important role in social interactions ( [Lim and Young, 2006] and [Bartz et al., 2010]). Deficits in social functioning observed in psychiatric disorders including schizophrenia ( [Couture et al., 2006] and [Sparks et al., 2010]) and mood disorders ( [Inoue et al., 2004], [Montag et al., 2010] and [Wolkenstein et al., 2011]) imply the possible involvement of oxytocin in the pathophysiology of these disorders.

Many studies have investigated the possible link between oxytocin and psychiatric disorders. Some previous studies reported altered oxytocin function in patients with schizophrenia ( [Linkowski et al., 1984], [Beckmann et al., 1985] and [Mai et al., 1993]). Higher plasma oxytocin levels in schizophrenic patients were associated with lower symptom severity (Rubin et al., 2010). A clinical study showed that administration of this hormone ameliorated symptoms of schizophrenia (Feifel et al., 2010). In a preclinical study, systemically administered oxytocin reversed prepulse inhibition deficits induced by amphetamine and the phencyclidine analog in rats (Feifel and Reza, 1999). Oxytocin dysfunction has been implicated in the pathophysiology of depression as well. Two studies have shown that peripheral oxytocin levels and depressive symptoms were significantly correlated in patients with major depressive disorder (MDD) ( [Scantamburlo et al., 2007] and [Cyranowski et al., 2008]). Moreover, oxytocin knock-out mice have shown dysregulated stress responses to psychological stimuli (Mantella et al., 2005) and enhanced anxiety behaviors (Mantella et al., 2003).

From the conclusions:

Consistent with some previous studies ( [Glovinsky et al., 1994] and [Pitts et al., 1995]), CSF oxytocin levels did not significantly differ between healthy controls and patients with schizophrenia and MDD. However, the present results showed that higher levels of CSF oxytocin may be associated with less severe symptoms of schizophrenia.

The observed negative correlation between antipsychotic dose and CSF oxytocin levels points to the possibility that antipsychotic medication lowers oxytocin levels. A recent study suggests that an inhibitory feedback loop may exist between prolactin-secreting lactrophs and oxytocinergic paraventricular neurons (Sirzen-Zelenskaya et al., 2011). Therefore, the disinhibition of prolactin secretion due to the D2 receptor blockade by antipsychotics may have resulted in the suppression of oxytocin secretion. This, however, does not explain the stronger correlation of SGA dose compared to FGA dose. Kiss et al (2010) showed that SGAs have a more potent influence than haloperidol on the activity of oxytocin magnocellular neurons. This also seems contradictory to the present finding that SGA is negatively correlated with oxytocin levels. An alternative explanation for this negative correlation is that patients with low oxytocin levels may respond poorly to antipsychotic medication, and thus, higher dose was prescribed to such patients. Nevertheless, despite the relatively strong correlation with the antipsychotic dose, the cross-sectional design of the present study hinders any causal inferences. One previous study (Glovinsky et al., 1994) demonstrated that CSF oxytocin levels were unchanged by antipsychotic medication. Thus, further investigation is necessary to elucidate the effects of antipsychotic medication on oxytocin levels.

The present results showed that the negative symptoms of schizophrenia were negatively correlated with CSF oxytocin levels. The correlation coefficient between CSF oxytocin levels and total PANSS score was also significant, controlling for SGA dose. Rubin et al. (2010) reported that higher peripheral oxytocin levels were associated with more prosocial behaviors in female patients with schizophrenia. Furthermore, previous studies have demonstrated improvement of social behaviors with administration of intranasal oxytocin ( [Macdonald and Macdonald, 2010] and [Pedersen et al., 2011]). Since strong relationships between negative symptoms and social difficulties have been demonstrated in schizophrenia (Weinberg et al., 2009), the present finding associating higher CSF oxytocin levels with lower negative subscale is in accord with what has previously been described for peripheral oxytocin. Whether the peripheral oxytocin levels reflect the CSF oxytocin levels, or whether a different mechanisms of action in the brain and the peripheral result in a similar effect, remains to be explored.

Previous studies examining CSF oxytocin levels in patients with schizophrenia ( [Beckmann et al., 1985] and [Glovinsky et al., 1994]) and depression (Pitts et al., 1995) showed mean oxytocin levels of less than 10 pg/ml, which is lower than that in the present study (> 20 pg/ml). Such outcome may have resulted from some of the methodological differences between previous studies and the present one. Previous three studies measured oxytocin levels using radioimmunoassay (RIA), while the present study used a commercially available ELISA kit. A recent study that used the same ELISA kit to measure CSF oxytocin levels (Heim et al., 2009) also demonstrated higher levels of oxytocin (mean oxytocin levels of 17 pg/ml in women without a history of emotional abuse) compared to the previous studies using RIA. Thus, the different measurement techniques may have influenced the values.