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Traci L. Turner, PharmD
PGY2 Psychiatric Pharmacy Resident
Chillicothe VAMC

Speaker Heidi Wehring, PharmD, BCPP, provided information at CPNP 2014 in an effort to answer the question of Negative Symptoms in Schizophrenia: A Place for Oxytocin? Negative symptoms of schizophrenia are often the most functionally debilitating symptoms. They are present in two clusters: (1) deficits in emotion expression such as alogia and blunted affect, and (2) avolition, which can also been seen with asociality and anhedonia. Patients with severe negative symptoms often have a decreased response to interventions. They may also have a reduction in emotional responsivity, speech, movement, and motivation.

Studies have shown an inverse relationship between negative symptoms and functional outcomes. A study by Strauss et al. explored the differences between two groups of patients based on the two clusters above (deficits in emotion expression versus avolition). They concluded that patients with high scores for negative symptoms, no matter which cluster they were in, had worse scores in attitude, work, family role function, and independent living.

Currently, there are no FDA approved medications for the treatment of negative symptoms. Clozapine was originally thought to have superior efficacy when compared to other antipsychotics for the treatment of negative symptoms, but meta analyses and clinical trials have shown that this may not be true for patients with primarily negative symptoms. While adjunctive treatments and non-pharmacologic interventions are being explored, oxytocin is beginning to establish its role for treating negative symptoms.

Oxytocin, the “love hormone”, is currently used for induction/augmentation of labor, prevention/treatment of postpartum hemorrhage, stimulation of milk ejection, and prevention of mastitis. At first glance, it doesn’t appear to have much relation to the treatment of negative symptoms. However, it has been linked to having an effect on both social behaviors (such as social memory and sexual arousal) and non-social behaviors (i.e., learning, memory, and stress). Oxytocin has begun being explored for negative symptoms because of its interaction with serotonin, dopamine, and glutamate systems.

Early studies found that central levels of oxytocin often showed a disruption in oxytocin systems in patients with schizophrenia. Interestingly, these studies showed differing results on this abnormality, with some patients having increased levels, and others having decreased levels. Patients with higher oxytocin levels were noted to have more prosocial behavior. Low levels of plasma cortisol have also been noted in patients with greater negative symptoms severity.

Four recent studies have reported findings on the impact of oxytocin on negative symptoms. It should be noted though that these studies did not use negative symptoms as the primary outcome measure. The findings, however, can be used as a springboard for future studies.

  1. Feifel, et al., 2010: Participants receiving intranasal oxytocin 40 IU BID had significantly greater improvement in the PANSS negative subscale when compared to placebo after three week of treatment (p=0.023).
  2. Pederson, et al., 2011: Participants receiving intranasal oxytocin 24 IU BID for two weeks showed improvement on a social cognition measure.
  3. Modabbernia, et al., 2013: Participants receiving oxytocin 40 IU BID had a 7% reduction in negative symptoms on the PANSS scale, compared to a 2% reduction in participants receiving placebo, though the average reduction was only 1.5 points.
  4. Lee, et al., 2013: Inpatient participants receiving intranasal oxytocin 20 IU BID in addition to their current antipsychotic regimen showed a more pronounced decrease in SANS score when compared to inpatients receiving placebo.

Many questions still remain regarding the use of oxytocin. The optimal dose, frequency, route, and duration of administration still needs to be established. Additionally, whether or not oxytocin is more effective in different treatment settings could be explored. Finally, researchers can focus on the two different symptoms clusters described above and decide if these have an impact on therapy.

Take Home Messages

  • Negative symptoms, such as alogia, avolition, and anhedonia, are the most functionally debilitating in patients with schizophrenia
  • While there are currently no FDA approved agents for the treatment of negative symptoms, oxytocin is beginning to establish its role based on its interactions with multiple neurotransmitter systems
  • Preliminary data has shown that participants treated with oxytocin have an improvement in negative symptoms, though this was not the primary outcome being studied
  • Oxytocin is a new and promising treatment for improving negative symptoms and is likely to be explored more in the near future

References

  1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA:  American Psychiatric Publishing.
  2. Strauss GP, Horan WP, Kirkpatrick B, Fischer BA. “Deconstructing negative symptoms of schizophrenia: avolition-apathy and diminished expression clusters predict clinical presentation and functional outcome”. J Psychiatr Res. 2013 Jun;47(6):783-90.
  3. Rubin LH, Carter CS, Drogos L, Pournajafi-Nazarloo H, et al. “Peripheral oxytocin is associated with reduced symptom severity in schizophrenia”. Schizophr Res. Dec 2010;124(1-3):13–21.
  4. MacDonald K, Feifel D. “Oxytocin in schizophrenia: a review of evidence for its therapeutic effects”. Acta Neuropsychiatrica 2012;24:130–146.
  5. Kéri S, Kiss I, Kelemen O. “Sharing secrets: oxytocin and trust in schizophrenia”. Soc Neurosci. 2009;4(4):287-93
  6. Feifel D, Macdonald K, Nguyen A, Cobb P, et al. “Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients”. Biol Psychiatry. 2010 Oct 1;68(7):678-80
  7. Pedersen CA, Gibson CM, Rau SW, Salimi K, et al. “Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia”. Schizophr Res. 2011 Oct;132(1):50-3.
  8. Modabbernia A, Rezaej F, salehi M, Jafarinia M, et al. “Intranasal oxytocin as an adjunct to risperidone in patients with schizophrenia”. CNS drugs 27(1):57-65.
  9. Lee MR, Wehring HJ, McMahon RP, Linthicum J. “Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: results from a randomized double blind placebo controlled pilot study”. Schizophr Res. 2013 Apr;145(1-3):110-5
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