Download Sue 1 Running Head: SCHIZOPHRENIA AND OXYTOCIN

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Running Head: SCHIZOPHRENIA AND OXYTOCIN
Adjunctive Effects of Acute and Chronic Administration of Intranasal Oxytocin on Cognitive
Deficits in Schizophrenia
Irene J. Sue
University of Vermont
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Adjunctive Effects of Acute and Chronic Administration of Intranasal Oxytocin on Cognitive
Deficits in Schizophrenia
John Forbes Nash, Jr., one of the winners of the 1994 Nobel Memorial Prize in Economic
Sciences, once wrote cautionary letters to embassies in Washington, D.C. with regards to his
being pursued and conspired against by red-tied Communists. This conspiracy, entirely
unfounded and untrue, was a result of paranoia: Nash suffers from schizophrenia — a chronic,
severe, and significantly disabling neuropsychological disorder which affects approximately 1%
of the general American population. While Nash was diagnosed at 33 years old, the average
onset age of clinical symptoms of schizophrenia is approximately between the ages of 16 and 30.
Such symptoms are generally categorized into positive, negative, and cognitive symptoms. The
current discussion provides a brief overview of the psychopathology of schizophrenia, common
pharmacological treatments for cognitive function deficits in the disorder, and emerging evidence
for oxytocin’s potential role as an adjunctive pharmacological treatment for said deficits.
Psychopathology of Schizophrenia
The latest edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5)
exercises a dynamic approach which eliminates further differentiation of schizophrenia into
subtypes (paranoid, disorganized, catatonic, undifferentiated, and residual) listed in DSM-IV,
thereby accounting for the heterogeneity of symptom type and severity prominent in the disorder.
According to DSM-5, clinical diagnosis of schizophrenia requires presentation of two or more of
the following key symptoms: delusions, hallucinations, disorganized speech, disorganized or
catatonic behavior, and negative symptoms (anhedonia, lack of motivation, social withdrawal,
etc.). It is required that these symptoms to be continuously present for at least six months, during
which one’s social and occupational functioning is severely compromised in comparison to that
prior to the onset of the disorder. Additionally, the diagnosis is excluded if an individual presents
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symptoms associated with schizoaffective and mood disorders, unless prominent delusions
and/or hallucinations are present, or if such symptoms are a direct physiological consequence of
recreational or clinical drug use.
Pharmacological Treatments
Traditionally, pharmacological treatments of schizophrenia have targeted general clinical
symptoms and focused upon the central mechanisms of dopaminergic pathways. First-generation
antipsychotics, commonly referred to as neuroleptics, were introduced in the early 1950’s. They
included chlorpromazine (Thorazine) and haloperidol (Haldol), the former of which is no longer
available in the United States. While both are dopamine (DA) D2 receptor-specific antagonists,
these neuroleptics led to a wide range of central and peripheral side effects, such as dystonic
reactions, Parkinsonian symptoms, and akathisia (citation removed). Second-generation
antipsychotics, on the other hand, possess less D2 affinity, and therefore no longer solely utilize
D2-receptor antagonism. Their usage has been found to demonstrate, relative to neuroleptics
[section removed here] . . . .
The efficacy of these pharmacological treatments on negative symptoms of schizophrenia
is similar to or exceeds that of neuroleptics; and the rate of relapse is likewise significantly
decreased in comparison. In addition, while neuroleptics have been found to improve attention
and short-term memory in 30% of patients with schizophrenia, second-generation antipsychotics
have demonstrated significant enhancement in the same cognitive domains in 30% to 70% of
patients with the disorder (Citations removed). It is this increased scope of pharmacological
actions and effects that has encouraged researchers to explore and target other neurotransmitters
and their actions; for example, oxytocin.
Oxytocin
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Oxytocin (OXT) is a 9-amino acid peptide hormone which regulates lactation and uterine
contraction in the periphery, and functions centrally as a neurotransmitter involved in multiple
aspects of social behavior (Citations removed). It has been found that patients with schizophrenia
demonstrate decreased baseline levels of OXT, which were then strongly associated with
predictions of negative symptoms (Citations removed) and decreased ability in facial emotion
identification ( Citations removed). In addition, it has also been suggested that there exists a
negative correlation between OXT levels in the cerebrospinal fluid and negative symptoms of
male patients with schizophrenia ( Citations removed)).
OXT is therefore a potential candidate for treating clinical symptoms of schizophrenia. In
a randomized, double-blind, and placebo-controlled study, clinically diagnosed schizophrenia
patients were randomly assigned to receive intranasal OXT or matched placebo for 8 weeks (
(Citations removed)). The treatment intervention consisted of 20 international units (IU) of the
drug administered twice a day for the first week followed by 40 IU administered twice a day for
the following 7 weeks. Additionally, the patients were also maintained on a stable dose of 5 or 6
mg/day of risperidone. During the 8-week treatment, the patients were assessed using the
Positive and Negative Syndrome Scale (PANSS) at weeks 0. 2. 4. 6. And 8. Adverse side effects
of the drug treatment were examined using the Extrapyramidal Symptom Rating Scale (ESRS) at
baseline and at weeks 1, 2, 4, 6, and 8. It was found that [section removed here] . . . .The authors
concluded that [section removed here] . . . .
Other studies with shorter treatment durations have also reported similar beneficial results
on clinical symptoms and cognitive function deficits in schizophrenia. In a randomized, doubleblind, crossover study, 15 patients with schizophrenia, in addition to their stable dose of at least
one antipsychotic prescribed prior to the study, received 3 weeks of daily intranasal OXT at 20 IU
and another 3 weeks of daily intranasal placebo at the same dose (Feifel et al., 2010). These two
treatments were separated by a 1-week washout period, and their order (OXT-placebo vs.
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placebo-OXT) was randomly assigned to each subject. During the 7-week total study duration,
subjects were evaluated 7 times: They were assessed using the PANSS, Clinical Global
Impressions-Severity (CGS-S), and Clinical Global Impressions-Improvement (CGS-I). It was
found that the OXT treatment, compared to the placebo, led to significantly reduced scores on
the CGI-I and positive and negative subscales of PANSS.
Extension of the above study further demonstrated that adjunctive intranasal OXT might
improve verbal memory in patients with schizophrenia (Feifel, Macdonald, Cobb, & Minassian,
2012). In addition to PANSS, CGI-S, and CGI-I, two memory tasks, the California Verbal Learning
Test (CVLT II) and Letter Number Sequencing (LNS) task, were used to measure subjects’
cognitive function. The results showed that the 3-week intranasal OXT treatment did not lead to
significant effect of drug on LNS scores; however, it did lead to significantly improved performance
on total recall trials, short delay free recall, and total recall discrimination on the CVLT II. These
findings thus add to the evidence supporting [section removed here] . . . .
Social Cognition Deficit in Schizophrenia
In addition to general cognition deficits, patients with schizophrenia also exhibit social
cognition deficits, which can manifest as impairments in functional outcomes such as social skill,
social behavior in the milieu, community function, and social problem-solving (Citations
removed)). These impairments are further significantly associated with neurocognitive functions
including verbal fluency and processing speed, verbal/visual learning and memory, and reasoning
and problem-solving (Citations removed).
More specifically, growing literature on social cognition deficits in schizophrenia has
suggested emotional-processing impairments as an endophenotype of the disorder, especially
with regards to facial emotion recognition, which is generally assessed by presenting Ekman and
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Freisen’s pictures ( Citations removed) and administering the Facial Emotion Identification Test
(FEIT) and Facial Emotion Discrimination Test (FEDT). In the FEIT, subjects are instructed to
recognize, or label, a presented facial expression; in the FEDT, they are instructed to discriminate,
or differentiate between, two presented facial expressions. Patients with schizophrenia have been
found to perform poorly on these and other tasks of similar nature. For example, in a study
conducted by (citations removed), facial emotion recognition was examined in 50 patients with
early-stage schizophrenia, 50 patients with chronic schizophrenia, and 50 healthy control
subjects. All participants completed the Facial Emotion Recognition Test (FERT), which consisted
of 36 still photographs of human faces displaying 9 fundamental emotions: excitement, joy,
surprise, distress, disgust, contempt, anger, shame, and fear. It was found that patients with
chronic schizophrenia, relative to other subject groups, demonstrated significantly greater
difficulty in recognizing facial emotions, especially those representing negative affects.
This finding is furthered and somewhat contradicted by that found in a study conducted
by (Citations removed). The study involved 79 ultra-high risk patients, 30 first-episode
schizophrenia patients, and 30 healthy control subjects, all of whom completed a facial emotion
recognition task which consisted of 21 posed photographs of faces representing 7 fundamental
emotions: sadness, anger, happiness, disgust, surprise, fear, and neutrality. The authors found
that both ultra-high risk and first-episode schizophrenia patient groups exhibited significantly
greater facial emotion recognition deficit than did the healthy control group. Results from such
studies thus lend support to the notion that facial emotion recognition deficit may be an
endophenotype of schizophrenia; however, its independence from the stages of illness requires
further investigation.
While facial emotion recognition and discrimination are primarily involved in bottom-up
processing, there is also evidence which supports that top-down cognitive processing of emotions
may also be impaired in schizophrenia. Theory of Mind (ToM), in context of the current disorder,
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refers to impairment of one’s ability to relate his/her and others’ intentions with execution of
behaviors (Citations removed) . Deficits in ToM, therefore, may potentially lead to aforementioned
psychopathology in schizophrenia (Citations removed)). In a study which assessed ToM and
emotion recognition, 23 patients with schizophrenia and 18 healthy control subjects completed
several social cognition tasks and behavioral measures (Citations removed) . The former
assessed subjects’ performance on tasks related to ToM and facial emotion recognition. ToM was
assessed by a series of 6 cartoon picture stories, and facial emotion recognition by 6 still
photographs displaying 6 fundamental emotions: happiness, sadness, fear, surprise, anger, and
disgust. The behavioral measures included the PANSS and Social Behavior Scale (SBS). It was
found that patients with schizophrenia demonstrated significant impairment on all tasks related to
social perception and cognition, and had much greater difficulty in recognizing deception and
cheating detection and providing cogent answers to second- and third-order false belief questions.
Such results contribute to the existing literature regarding social cognition deficits in
schizophrenia.
Oxytocin and Social Cognition Deficits
In addition to alleviating symptoms of general cognitive deficits in schizophrenia, OXT has
also been observed to provide beneficial effects on social cognition deficits in the disorder. In a
randomized, double-blind, placebo-controlled trial conducted by (Citations removed), patients
with schizophrenia self-administered 24 IU intranasal OXT or placebo twice daily for 14 days,
during which they remained on their previously prescribed antipsychotic regimens. On the final
treatment day, social cognition measures (the Brüne ToM Picture Stories Task and the
Trustworthiness Task) and psychiatric measures (the PANSS and Paranoia Scale) were
administered. It was found that the OXT group, consistent with previous findings reported
previously, presented significantly reduced scores on PANSS. In addition, the results also
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demonstrated that the OXT group performed significantly better in accurately identifying secondorder false belief in the Brüne task.
Furthermore, it has also been shown that an acute, single dose of intranasal OXT may
improve social cognition deficit in schizophrenia (Citations removed). In this randomized, doubleblind, placebo-controlled, and crossover study, 48 healthy control subjects and 35 patients with
schizophrenia, in addition to their prescribed antipsychotic regiments prior and unrelated to the
study, received a single intranasal dose of OXT or placebo at 24 IU upon first administration, and
the other treatment at the same dose upon second administration. 7 days later. The order of such
treatments (OXT-placebo vs. placebo-OXT) was randomly assigned. Forty minutes proceeding
the drug administration, the subjects were assessed using the Interpersonal Perception Task
(IPT), which is a measure that assesses perception of nonverbal aspects of social exchange,
such as facial expression, body language, and social meanings of statements. During the task,
the subjects were presented with real-life scenes and situations, and instructed to make
judgments about the relationship between individuals involved in 2 types of social interactions:
kinship (familial relationships) and intimacy (romantic partnership). Subjects’ answers to
questions posed after each scene constituted as measures of how accurately interpersonal
judgments were made based on interpretation of verbal dialogues and nonverbal cues. The
overall results showed that there was a significant effect of drug on recognition and judgment of
both kinship and intimacy. However, when patients and control subjects were compared, such
effect was only significant for the recognition of kinship in the patient group. The investigators
thus concluded that an acute, single-dose administration of intranasal OXT might be instrumental
in improving social cognition in schizophrenia.
A study conducted by (Citations removed) further investigated the effects of acute, singledose administration of intranasal OXT. In this randomized, double-blind, placebo-controlled trial,
23 subjects on previously prescribed antipsychotic regiment received a dose of 40 IU intranasal
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OXT or placebo, and were administered clinical and social cognition assessments. The clinical
assessments included the PANSS, CGI-S, CGI-I, and MIRECC Global Assessment of
Functioning (MIRECC GAF), the latter of which was used to specifically measure occupational
and social functioning. Social cognition, in this particular study, was classified into lower- and
higher-level processes, and assessed by 4 tests which represented 4 different social cognitive
domains: ToM was measured by Part III of the Awareness of Social Inference Test (TASIT Part
III: Social Inference-Enriched); empathy by the Emotional Perspective Taking Task (EPTT); social
perception by the Half Profile of Nonverbal Sensitivity (Half-PONS); and facial affect recognition
by FEIT. Lower-level social cognition included facial affect perception, social perception, and
detection of lies; and higher-level social cognition involved empathy and detection of sarcasm and
deception. The results showed that while this acute, single dose of intranasal OXT did not lead to
improved performance on overall social cognitive function or clinical symptoms, there was a
significant drug effect, relative to placebo, on higher-level social cognition. The authors therefore
concluded that the effect of acute, single-dose administration of intranasal OXT might be specific
to more complex social cognition.
While studies reviewed in the current paper have demonstrated beneficial effects of
intranasal OXT on general and social cognitive functioning, it is crucial to remind oneself that
specific mechanisms of drug interactions between OXT and typical antipsychotic drugs remain
largely unknown. Long-term effects of adjunctive use likewise beg for further investigation.
Additionally, while these studies have utilized PANSS as a standardized and reliable assessment
of clinical symptoms of schizophrenia, there exists no similar behavioral measure in defining and
identifying specific aspects of social cognition deficits in the disorder. Future studies should focus
upon determining the potential drug interactions between OXT and currently available
antipsychotics, and developing a standardized measure which can be utilized in evaluating social
cognition deficits in patients with schizophrenia.
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