KR20160138365A - The Use of Oxytocin for Controlling Social Emotional-Related Behaviors - Google Patents

Abstract

The present invention relates to a novel use of oxytocin (OT) for controlling eating disorder and, more specifically, to a novel function and a use thereof for reducing visual attention bias with respect to negative body type stimulation in anorexia nervosa (AN) patients.

Description

The use of oxytocin as an agent for the treatment of eating disorders has been described in " The Use of Oxytocin for Controlling Social Emotional-Related Behaviors &

The present invention relates to a novel use of oxytocin (OT) for alleviating eating disorders, in which an attention deficit in which anorexia nervosa (AN) patients, particularly eating disorders, is sensitive to negative body stimuli And to its use.

The incidence and prevalence of eating disorder have been reported variously according to researchers and research subjects, but they are increasing gradually in recent years. (Fogel & Woods, 1995; Williamson, Cubic, & Gleaves, 1995), and that the incidence and prevalence of the disease are much higher than those reported in the studies, especially considering that women often do not accurately report their eating behavior 1993).

Eating disorder is one of the most common mental disorders among young women. It has a high likelihood of continuing chronic after recurrence even after recovery, and also has a high mortality rate with other mental disorders such as affective disorder. In addition, eating disorder is a serious disability in that it can cause serious physical damage to the patient such as amenorrhea and osteoporosis, and suicide and suicide attempts can be repeated due to continuous self-blame and depression (Stice, 2001a).

The causes of eating disorders include biological factors, genetic influences, childhood experiences, individual weight and family weight experiences, family history of psychopathology, social and cultural contexts, adolescent sexuality and self-identity development (physical maturity, development of intimate relationships , The development of self-awareness), dieting, individual personality characteristics, family factors, socio-cultural factors, and the role of the mass media (Kim, Jeong-hee, 2006).

In Korea, the eating behavior and weight control problems of adolescents and adult women for the ideal body shape are becoming more and more serious due to the recent social atmosphere that emphasizes appearance. Distorted eating habits that are obsessed with a thin body shape not only cause personal emotional, social, and professional problems, but also threaten physical health, so it is imperative to prepare countermeasures (Sung Mi Hye, 2005).

In particular, anorexia nervosa (AN) is a hereditary mental disorder in which social function is severely impaired, such as a high level of anxiety and recurrent repulsive behavior. The causes that make them vulnerable to anorexia nervosa include genes, developmental characteristics such as negative emotions (anxiety), absence of social competence, environmental factors such as postnatal and adolescent adversity, and genetic and environmental interactions have. From a neurobiological point of view, fasting in patients with anorexia nervosa will reduce brain neurite plasticity, which causes neurological anorexia to persist. In a recently proposed maintenance model of anorexia nervosa, the secondary effects of fasting are further exploited to cause disease persistence by further destroying social intelligence, emotional regulation, and cognitive flexibility (Schmidt and Treasure , 2006; Treasure and Schmidt, 2013).

Therefore, in order to understand and effectively treat the psychological mechanism of eating disorder, it is very important to study various characteristics of personality related to eating disorder and to develop effective therapeutic agents.

The present inventors confirmed that oxytocin affects the neurocognitive processes that are more sensitive to eating, body shape and weight stimulation in patients with eating disorders, The present invention has been completed.

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It is an object of the present invention to provide a composition for preventing or treating anorexia nervosa comprising oxytocin as an active ingredient, wherein said anorexia nervosa is characterized by an increase in attention deficit for negative shape stimuli, The present invention provides a composition for preventing or treating anorexia nervosa characterized by being administered intranasally.

In order to achieve the above object, the present invention provides a composition for preventing or treating anorexia nervosa comprising oxytocin as an active ingredient, wherein the anorexia nervosa is characterized by an increase in attention deficit for negative shape stimuli And the oxytocin is administered intranasally. The present invention also provides a composition for preventing or treating anorexia nervosa.

In one embodiment of the present invention, the oxytocin may be to attenuate attention deficits for negative shape stimuli in anorexia nervosa.

The present invention may be useful for the treatment of patients with eating disorders by providing a new function that oxytocin weakens attention deficits on stimulation of negative body image of patients with anorexia nervosa.

FIG. 1 is a graph showing the effect of oxytocin on attention deflection due to diet, body weight, and body stimulation in an anorexia nervosa (AN) patient group and a healthy human group (HC).

Representative terms used in the present invention are as follows.

"Eating disorders" refers to behavioral disturbances that repel food, repetitively eat, and vomit in order to lose weight due to dissatisfaction with their image (American Psychiatric Association, 1994).

"Eating behavior" is a biological function that is essential for maintaining life and running a life. It refers to food-related attitudes, feelings, and behaviors.

"Attentional bias" refers to a tendency to give more attention to a particular object or a particular attribute, and the phenomenon of immersion or attachment arises from bias of the state mechanism.

"Stimulus" refers to the transmission of a signal, stimulus, or shock to a nerve tissue to act on neuronal activity of the nerve tissue (a large amount of nerve tissue of the brain or nerve).

"Chemical entity" means a compound, drug or agent capable of stimulating neuronal activity in nerve or nervous tissue exposed to a substance described in an embodiment of the present invention. Examples of such substances include inhibitory neurotransmitter agonists, excitatory neurotransmitter antagonists, substances that increase the levels of inhibitory neurotransmitters, substances that decrease the levels of excitatory neurotransmitters, and local anesthetics.

A "subject" may include all mammals, including humans. An "object" may also include other animals (eg, cattle, sheep, pigs, goats) as well as pets (eg dogs, cats, horses). In the present invention, human beings are preferable.

By "inhibitor" is meant a substance that inhibits, blocks, or reduces the expression, specific physiological function or activity of a particular protein (gene).

"Treatment" is a method for obtaining beneficial or desired results, including clinical results. To " treating "or" alleviating " a disease, disorder or condition refers to alleviating the condition or disorder or degree of disease or unwanted clinical symptoms or both, It means to extend. Depending on the purpose of the methods described herein, useful or desirable clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, decrease in the degree of disorder, stabilized (i.e., not worsened) But are not limited to, state of the art, delay or slowing of the disorder progression, improvement or alleviation of the disorder and remission (partial or complete). Also, treatment does not necessarily occur by the administration of a single dose, but often occurs after administration of a series of doses. Thus, a therapeutically effective amount, an amount sufficient to alleviate, or an amount sufficient to treat a disease, disorder or condition, may be administered in one or more administrations. The present invention refers to the treatment of an eating disorder, preferably anorexia nervosa (AN).

Hereinafter, the present invention will be described in detail.

The present invention relates to a new function of oxytocin (OT).

It is known that oxytocin is a potent uterine contraction agent that is clinically used for induction of labor and enhances lactation initiation and maintenance (Gimpl, G. et al., Physiol. Rev. 81 (2001) 629-683 And Ruis H. et al., British Medical Journal 283 (1981) 340-342).

The "oxytocin" protein of the present invention includes all oxytocin proteins derived from an animal. Include variants of the oxytocin protein, including deletion, insertion, non-conservative or conservative substitutions, or combinations thereof, including wild type oxytocin proteins. For example, the "oxytocin" protein or oxytocin polypeptide of the present invention includes polypeptide fragments, chemically modified derivatives thereof, as well as nucleic acids and / or amino acid sequence variants thereof.

A variant of an oxytocin protein means a protein having a sequence having a different amino acid sequence from that of a wild-type amino acid sequence. Insertions typically consist of a contiguous sequence of about 1 to 20 amino acids, although larger insertions may be possible. Deletions usually consist of about 1 to 30 residues, but in some cases larger deletions may also be possible, such that one of the domains can be deleted. Such variants can be produced by chemical peptide synthesis methods known in the art or recombinant methods based on DNA sequences (Sambrook et al., Molecular Cloning, Cold Spring Harbor Laboratory Press, New York, USA, 2d Ed. , 1989). Amino acid exchanges in proteins and peptides that do not globally alter the activity of the molecule are known in the art (H. Neurath, R. L. Hill, The Proteins, Academic Press, New York, 1979). The most commonly occurring exchanges involve amino acid residues Ala / Ser, Val / Ile, Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Ser / Gly, Thy / Pro, Lys / Arg, Asp / Asn, Leu / Ile, Leu / Val, Ala / Glu and Asp / Gly.

Since the sequence of oxytocin is known, it can be obtained by chemical synthesis (Merrifleld, J. Amer. Chem. Soc. 85: 2149-2156, 1963) or by using genetic recombination technology.

When they are chemically synthesized, they can be obtained by using a polypeptide synthesis method well known in the art. When the recombinant technology is used, a nucleic acid encoding oxytocin is inserted into an appropriate expression vector, the vector is transformed into a host cell, the host cell is cultured to express oxytocin, and then neitin is recovered from the host cell can do. The gene sequence of neuritin is known and available to those skilled in the art. Thus, using conventional methods, known recombinant nucleic acid techniques (see, for example, Sambrook et al., Eds., "Molecular Cloning: A Laboratory Manual", Part 2, Cold Spring Harbor Laboratory Press, , 1989 and Current Protocols in Molecular Biology, John Wiley & Sons, NY 1989) can be used to obtain expression of oxytocin in selected cells.

The present invention relates to a novel function of the oxytocin on the eating disorder, more specifically the attention deficit of patients with anorexia nervosa (AN).

In particular, it relates to a new function that oxytocin weakens attention deficits on stimulation associated with eating and body shape in patients with anorexia nervosa.

The present inventors have found that oxytocin attenuates attention deficits on stimuli related to eating and body shape in patients with anorexia nervosa by confirming the effect of oxytocin on the diet, body shape and weight stimulation, (In the case of autistic symptoms, for example).

Subject to treatment

The eating disorder, which is the subject of treatment of the present invention, is a new psychiatric phenomenon that has recently begun to be noticed. The determination of the diagnostic characteristics has been clearly made since DSM-III in 1980, , 1993) and DSM-5 (American Psychiatric Association, 2013). These eating disorders are the main pathological eating behavior associated with psychological conditions and are largely due to anorexia nervosa, bulimia nervosa, binge eating disorder, avoidant / restrictive eating disorders, food intake disorder).

The subject of treatment of the present invention is an eating disorder, more preferably anorexia nervosa (AN).

The diagnostic criteria of DSM-5 for anorexia nervosa are as follows.

A. It causes severe lowering of weight by limiting intake than energy required in the context of age, gender, developmental trajectory and physical health. Severe underweight is defined as a lower than normal weight or a child or adolescent who does not meet the expected weight.

B. There is extreme fear of increased weight or obesity, or persistent behavior to prevent weight gain despite severe underweight.

C. Disability occurs in a way that either the individual's weight or body's way of experiencing, body weight or body shape over-influences self-assessment, or denies the present low-severity severity.

The diagnostic criteria of ICD-10 for anorexia nervosa are as follows.

(a) Body mass index (kg / m ² ) <17.5

(b) Voluntary weight loss (compensatory behavior such as food avoidance, vomiting, excessive exercise)

(c) "Distortion in the body": "Fear of fatigue persists as an invasive excess accident"

(d) Endocrine abnormalities (amenorrhea, sexual interest and reduction of ability if male)

(e) If it is before puberty,

Two important aspects of anorexia nervosa are feeding and body aspects (Kaye, 2008). Among them, abnormal perception of body image appears as a fear of weight gain and a distorted perception of body shape. Patients with anorexia nervosa feel themselves fat, fat, fearful of weight gain, and worried about their body. Such anomalous perception of body image is not only related to the severity of feeding problems (eg, eating restrictions), but also is a global symptom of feeding behavior problems such as dietary restrictions (Cash and Deagle, 1997). In the present study, we examined the effects of anxiety and depressive symptoms on anxiety and depression in anorexia nervosa.

The prevalence of anorexia nervosa is estimated to be approximately 0.5 to 1% in adolescents and young adults, with an average age of onset of 17 years. Because more than 90% of these disorders occur in women, they are thought to be due to the socio-cultural effects that make skinny aesthetically worthy. Anorexia nervosa is a terrible disease that leads to death due to underweight when the disorder is severe.

On the other hand, some of the patients with anorexia nervosa have autistic characteristics such as lack of communication ability, lack of social information processing ability, and neurocognitive abnormality. The deficit of social information processing ability and emotion regulation in patients with anorexia nervosa can be caused by problems in the oxytocin circuit, and this problem may be more apparent in patients with anorexia nervosa with high autistic characteristics.

The present invention is characterized in that oxytocin utilizes oxytocin for treating such an eating disorder, more preferably "anorexia nervosa ", based on the function of reducing attention deficit for negative body image stimulation in patients suffering from anorexia nervosa do.

Related mechanisms

In the present invention, oxytocin affects many neural circuits associated with anorexia nervosa (AN) such as social information processing, anxiety, stress, and appetite.

Studies have shown that oxytocin works abnormally in patients with anorexia nervosa (Maguire et al., 2013), decreases CSF concentrations in oxytocin during the fasting cycle of anorexia nervosa (Chiodera et al., 1991; Demitrack et It has been reported that nighttime serum oxytocin levels in patients with anorexia nervosa are also lower than those in the general population (Lawson et al., 2011a). It is also reported that postprandial oxytocin secretion increases in the acute phase of anorexia nervosa and decreases after recovery (Lawson et al., 2012).

These facts suggest that oxytocin may be abnormal and function abnormally in patients with anorexia nervosa, and abnormalities of oxytocin secretion may be related to the intensity of eating disorder psychopathology or the response to images related to the body .

Also, according to animal studies, oxytocin acts to reduce appetite and feeding behavior (Sabatier et al., 2007). However, considering that anorexia nervosa is a problem with fear of food and body shape, not with the absence of appetite, reducing the threat treatment of oxytocin may be effective in the treatment of anorexia nervosa.

In this respect, it is important whether oxytocin can mediate the psychopathology of anorexia nervosa. In clinical trials, nervous anorexia patients received nasal intakes of oxytocin for six weeks and nutritional rehabilitation combined resulted in reduced food concerns (Russell et al., 2012). This may be explained by the fact that oxytocin responds differently to the threat and reduces anxiety (Panksepp, 2011).

Attention reaction is one of the primary emotional processes. A meta-analysis of 172 students revealed that people with multiple anxiety disorders had a slight to moderate attention bias to the threat (effect size = 0.45) (Bar-Haim et al., 2007). Eating disorders have been reported in patients with attention deficits in relation to food-related psychological pathologies such as food, weight, and body shape (Dobson and Dozois, 2004; Faunce, 2002; Johansson et al., 2005). Most studies on attention deflection of eating disorders using the Stroop paradigm found an average bias of 0.38 (n = 13) in neurogenic anorexia nervosa and a slight bias in the effect size of 0.43 (n = 11) in neurogenic bulimia patients (Brooks et al., 2011). In addition, we found a bias in attention to food, weight, and body-related photo stimuli from women with eating disorders through a dot-probe task using pictures (Cardi et al., 2013; Lee and Shafran, 2008; Shafran et al., 2007, 2008). Some research has shown that patients with anorexia nervosa have an information processing bias that avoids positive stimuli toward negative stimuli for body shape and weight-related stimuli (Bentovim et al., 1989).

In addition, the inventors further identified that oxytocin can reduce abnormal attention reactions to visual stimuli associated with eating disorders in patients with anorexia nervosa.

In other words, the present inventor has revealed the mechanism underlying the effect of oxytocin, which mediates factors that sustain an eating disorder. More specifically, the effects of oxytocin on the attention-defying process of eating, body shape and weight-related visual stimuli in patients with anorexia nervosa were studied to examine the effect of oxytocin on eating, body-related visual stimuli in patients with anorexia nervosa, We found a decrease in the bias of the same week.

Through experiments according to an embodiment of the present invention, it has been shown that in the anorexia nervosa group,

(i) the selective attention to visual stimulation of food, body shape, and weight associated with eating disorder psychopathology is weakened;

(ii) the attentional bias to visual stimuli, particularly about meals,

(iii) the visual stimulus of the body shape shows a correlation of the following significant drug x valence,

- In the visual stimulation of negative body shape, attention deflection is weakened,

(iv) The effect of oxytocin on visual stimuli on negative body shape in the anorexia nervosa group was also related to the communication problem, and in particular, the stronger the autistic tendency of anorexia nervosa patients, the greater the effect of oxytocin Respectively.

In other words, oxytocin weakens attention deficits on diet-related stimuli and weakens attention deficits on negative body-related images. At this time, the weaker the communication level, the stronger the level of weakness.

A specific use

The present invention, based on the novel oxytocin function (mechanism) described above,

In one specific embodiment, there is provided a composition for treating eating disorders comprising oxytocin that reduces attention deficits on stimulation associated with eating and body shape, and a method of treating an eating disorder using the same. More preferably, it relates to the treatment of anorexia nervosa (AN).

The compositions of the present invention may be formulated into pharmaceutical compositions prepared according to conventional pharmaceutical synthesis techniques. See, for example, Remington ' s Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing, Inc., Easton, PA, U.S.A.). The composition may comprise a pharmaceutically acceptable salt of the active or active agent. The composition may be administered simultaneously or sequentially.

These compositions may contain, in addition to one active ingredient, pharmaceutically acceptable excipients, carriers, buffers, stabilizers or other materials well known in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The carrier may take a variety of forms depending on the form of preparation desired for administration, for example, localized, intravenous, oral, brain, neural, or parenteral. And may be prepared for oral or parenteral administration by admixture with diluents, excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like. For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, powders, suspensions or emulsions. Solid formulations for oral administration may include tablets, pills, dusting powders, granules, and capsules. Such solid formulations may be prepared by mixing with one or more suitable excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may be used. Liquid formulations for oral administration may include suspensions, solutions, emulsions and syrups, and the above-mentioned formulations may contain conventional diluents such as water and liquid paraffin, as well as wetting agents, sweeteners, fragrances and preservatives ). &Lt; / RTI &gt; Because of their ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are used. If desired, tablets may be sugar-coated or enteric-coated by standard methods. The active agent, besides the coating, is safe when passing through the gastrointestinal tract and at the same time allows it to pass through the blood-brain barrier.

For parenteral administration, the compound may be dissolved in a pharmaceutical carrier and administered as a suspension solution. Examples of suitable carriers are water, saline, dextrose solution, fructose solution, ethanol, liposomes or derivatives thereof, or animal, vegetable or synthetic oils. The carrier may also contain other ingredients, for example, preservatives, suspending agents, solubilizing agents, buffers, and the like. Formulations for parenteral administration include sterile aqueous solutions, water-insoluble excipients, suspensions, emulsions, suppositories, and the like. The water-insoluble excipients and suspensions may contain active compounds, including propylene, glycols, polyethylene glycols, vegetable oils such as olive oil, injectable esters such as ethyl laurate, and the like. Suppositories may include witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerinated gelatin, and the like

In particular, the compositions of the present invention are preferably administered nasally. It may therefore be desirable to be in the form of a spray, aerosol or dry powder, preferably comprising spray-dried or frozen-dried particles, microspheres or nanoparticles.

Transmission through the nasal passage is particularly convenient and the therapeutic agent can be transported directly to the brain through the cerebrovascular barrier avoiding the systemic circulation and thus avoiding degradation from gastric acid, bile acid, digestive enzymes and other primary transit effects. Thus, these delivery pathways provide for the initiation of improved action, capacity reduction and the possibility of a more accurate dose, thus enhancing the efficacy and safety profile of the therapeutic agent.

The active agent is preferably administered in a therapeutically effective amount. The actual amount administered and the time of administration will vary depending upon the nature and severity of the disease being treated. For example, the determination of the therapeutic regimen for dosage, time, etc. is within the capabilities of the ordinary person skilled in the art, and will normally take into account the disease to be treated, the condition of the individual patient, the site of delivery, the mode of administration and other factors known to those skilled in the art.

The compositions of the present invention may be administered in a therapeutically or prophylactically effective amount. The dose may vary depending on various factors such as the type and severity of the patient, age, sex, administration method, target cell, expression level, and the like, and can be easily determined by those skilled in the art.

As such, the present invention encompasses diverse uses of novel functions that reduce the visual attention bias to stimuli on the diet and stimuli on the negative body form in new uses of oxytocin (OT) in relation to eating disorders .

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.

Experiments were carried out in the following manner.

Participants

A total of 64 women, 31 with anorexia nervosa and 33 healthy college students, participated in double-blind, placebo, and control cross-over trials. The first experiment took place on August 16, 2012 and the last experiment took place on November 30, 2013. Patients with anorexia nervosa were recruited from inpatients and outpatients at the Seoul Paik Hospital Eating Disorders Clinic. The diagnosis of anorexia nervosa was made using the Structured Clinical Interview (SCID-1) of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (First et al., 2002 ). Patients with an ongoing drug use disorder, psychiatric illness (asthma, schizoaffective disorder, psychosis NOS), autism or Asperger's disorder were excluded from the patient population. Patients with other accompanying disorders were not excluded from the patient group.

Participants in the control group were undergraduate and graduate students who reported and supported the publicity materials posted at the psychology department of a female university in Seoul. Women 17 years of age or older, with no mental history, were included in the experimental group. All study participants were heterosexual to non-smokers, never had children, and had no medication, including the birth control pills. People with a self-reported history of major depressive disorder, bipolar disorder, panic disorder, mental disorders, drug-dependent disorders, epilepsy, eating disorders, autism, and traumatic brain injury were excluded from the participants.

Intelligence was measured using a Korean version of the Wechsler Intelligence Scale (K-WAIS). Normal group was visited during the menstrual period (about 4-12 days) and the experiment was conducted. The draft of this study was approved by the Korea Food and Drug Administration's Clinical Trials Committee (12061) and the Seoul Paik Hospital Clinical Trials Committee (IIT-2012-096). All participants submitted written consent of the guardian before the trial participation and the minor (under 17 years old). This study was registered in the Clinical Research Information Service (http://cris.nih.go.kr) (registration number: KCT0000716).

Preparation for experiment

1. Oxytocin preparation

Nasal oxytocin spray was prepared using powdered oxytocin (Hemmo Pharmaceuticals, Mumbai, India) by Choongwae Pharm (Seoul, Korea). The reagents were prepared by mixing 35.2 mg of oxytocin and 300 mL of (568 U) 0.9% saline and adjusting the pH to 4.01 with 10-fold diluted acetic acid. The placebo reagent (pH 4.01) was prepared using only 0.9% saline and acetic acid except for the peptide. The solution was filtered and sterilized and sealed in 1.5 mL vials and stored frozen. On the day of use, the vials were thawed and refrigerated at 4 ° C until just before use. The clinician moved oxytocin or placebo from the vial to the nasal spray and the prepared spray was administered directly by the subject under the observation of the clinician.

2. Oxytocin administration

Oxytocin and placebo were intranasally administered weekly. The order of placebo and oxytocin administration of each participant was wirelessly allocated by the researcher using the Microsoft Excel program. The method is as follows: (1) Wirelessly generate numbers between 0 and 1 with the RAND function (2) If the number generated for the participant is less than 0.5, the participant is first administered a placebo. (3) If the number of participants is greater than or equal to 0.5, the participant is first administered oxytocin. Participants were instructed to administer a spray containing oxytocin or a placebo by themselves on the first day of the experiment. Both the experimenter and the subject did not know what medication was prescribed on the day of the experiment. On the second day of the experiment, each participant administered the other drug, which was not assigned on the first day, by the cross-over method.

3. Stimulation

The photographic stimuli used in the Dot probe task were borrowed from a validated population used for eating disordered patients (Shafran et al., 2007).

The photographs consisted of meals, body shape, and weight-related images that could lead to an emotional response. The meal image depicted eating food under certain circumstances. The body image depicting body or part of the body, and the weight image depicting weight scales and body weight. The target stimulus consisted of 18 meal pictures, 18 body images (6 positives, 6 neutrals, 6 negatives), and 11 weights (all the same valence). Target stimuli were matched with non-target stimuli with the same attractiveness (animal phobias were pre-screened and filtered by participants). Targeted stimulation images associated with eating disorders and non-target stimulated animal images were determined by the paradigm developed by Shafran et al. (2007). Originally, according to the experimental method of Shafran et al. (2007), the food image was also tried to be classified according to the emotional attractiveness like the body image. However, the patients with anorexia nervosa tend to interpret all the meal images as negative, (Strober et al., 2011; Strober, 2004; Treasure, 2012). In this experiment, we incorporated all of the meal stimuli into one (negative attractor) stimulus.

4. Experimental Design and Procedure

The attention deflection was measured by a visual probe detection task that pairs emotional and neutral photographs (Posner et al., 1980; Macleod et al., 1986).

According to the paradigm of Mansell (1999), a pair of eye images (meal / body / weight) and a non-target image (animal) . As the two images disappeared from the screen, one of two types of probes (':' or '· ·') appeared at the center of one of the two pictures. At this time, the participant presses one of the two keyboard stickers made with white sticker and matches the corresponding probe (':' is a Q board, '...' is a Z board). According to Mogg and Bradley's paradigm, the position of the target image and the position of the probe associated with the eating disorder were adjusted to be the same at both frequencies (Mogg and Bradley, 1998). When the participant pressed the keyboard, the probe disappeared from the screen and the next run began immediately.

In this visual probe detection task, the distribution of attention was measured as the time taken to respond to the probe. The rationale was that if the attention was already centered on where the probe appeared, it would react faster to the probe. In non - cooperative trials in which probes appeared at the neutral stimulus location, a faster response to probes in a joint trial in which the probes appeared at the location of a more threatening stimulus was interpreted as a higher boundary for the threat.

This experiment was carried out with 112 experiments including rest in the middle after 8 exercises. In experimental trials, all possible targets and (non-target) animal pairs were used. A total of 112 trials consisted of 14 trials with the following eight conditions: three targeted stimuli (meals, body type, weight), three emotional attractors (positive, neutral, negative; , And two probe positions (target or non-target position). The experiment was conducted in random order for each participant.

5. Self report scale

The Eating Disorder Examination Questionnaire (EDE-Q) (Fairburn and Beglin, 1994) was used to test eating disorders.

Eating disorder screening questionnaire assesses the main behavioral characteristics of eating disorders during the last 28 days. The questionnaire consisted of 36 questions, 7 points for each question on the mandatory selection scale. This test measures body weight, body shape, and anxiety about eating and eating habits. This study used the standardized Korean version of the EDE-Q 12 version, which has high internal consistency and good reliability over two weeks (Heo et al., 2004).

6. Autism-Spectrum Quotient (AQ) (Baron-Cohen et al., 2001)

The Autism Index Test is a self-administered questionnaire composed of 50 questions. It is a self-administered questionnaire that measures the autistic index of five subscales of social skills, attention turning, attention to details, to be.

7. Other measurements

Depression and anxiety of each subject were measured using the Korean version of the Beck Depression Inventory Depression (BDI; Beck et al., 1961) and the Spielberger State and Trait Anxiety Inventory (STAI) (Spielberger et al., 1983).

8. Course

The experiment was conducted in the interview room of Seoul Paik Hospital. Participants were instructed to refrain from caffeine or alcohol consumption on the day and to refrain from ingesting food other than water 2 hours before the administration of the reagent. Participants arrived at the test site and were first examined for baseline levels of negative symptoms such as abdomen, nerves, skin, and heart. Subsequently, participants were given a dose of oxytocin or placebo (40 IU) each nasally. Doses of oxytocin and placebo were randomly assigned to double blind treatment using Microsoft Excel. Participants completed a self-report test to assess mental status for 45 minutes after administration of the reagent. After the experiment, each participant received a follow-up examination to check for negative symptoms.

9. Statistical analysis

Analysis included only the reaction time (RT) of the trial in which the probe was reacted correctly. The mean RT values of each participant were calculated and excluded from the analysis of respondents whose responses were slower than two standard deviations (Bradley et al., 1999).

The bias score for each type of trial pair (meal-animal, body-animal, body-animal) was calculated as PN-PE (PN: average RT when probe appears after non-target stimulus, PE: Mean RT after presentation), meaning that a positive score indicates more attention to eating disorder-related stimuli and a negative score indicates that attention is being avoided from the relevant stimulus, and a score of 0 is biased towards any stimulus It means that the boundary is not visible.

Attention reactions to body stimuli were analyzed by repeated measures ANOVA for 2 (groups: AN and HC) x 2 (reagents: oxytocin and placebo) x 3 (attractiveness: positive, neutral, negative). Attention to diet and weight stimuli was analyzed by repeated measures analysis of variance (group 2: AN and HC) x 2 (reagent: oxytocin and placebo). In the case of meal stimuli, there was no difference between the incentives of stimuli, so the RT of all incentives was included in the results to enhance the statistical validity. A post-hoc comparison analysis was conducted through a t-test of each group and a Greenhouse-Geisser correction formula was used when the equally divided assumption was violated. Data were expressed as means, standard deviations, and, where possible, effect sizes (Cohens d for t-test and partial eta square (Δη2) for ANOVA).

The effect sizes using Cohens d were evaluated as follows: trivial (= 0 and <0.15), small (≥ 0.15 and <0.40), moderate (≥ 0.40 and <0.75), large (≥ 0.75 and < Very large (≥ 1.10 and <1.45) enormous (> 1.45) (Cohen, 1992).

The effect sizes using the partial eta square (Δη2) were evaluated as follows: small (<0.01), moderate (<0.059), large (<0.138) (Cohen, 1988).

The relationship between attention bias and psychological variables and reagent effects was analyzed using Pearsons correlations. In addition, an independent t-test was conducted to determine the effect of reagents on the attention bias and juice intake of inpatients. All analyzes were performed using SPSS 19.0 (SPSS Inc., Chicago, IL, USA) and the paired-value was 0.05.

10. Hypothesis

To examine the effect of oxytocin on attention, weight, and body weight stimulation in patients with anorexia nervosa, the following hypothesis was developed:

(1) Oxytocin will weaken selective attention to stimuli associated with food or other anorexia nervosa psychopathology.

(2) The autistic tendency of patients with anorexia nervosa will increase the effect of oxytocin.

Example 1: Demographic characteristics

The demographic characteristics of the participants are shown in Table 1.

Chracteristics AN ( n = 31) Controls ( n = 33) t df p Age 23.10 (9.35) 22.18 (2.14) -0.536 32.87 .596 Intelligence 109.27 (14.01) 114.62 (9.05) 1.788 48.51 .080 BMI 15.15 (2.51) 20.91 (2.22) 9.819 ^*** 62 <.001 EDE-Q Restraint 2.50 (1.89) 0.79 (0.86) -4.558 ^*** 39.31 <.001 Eating Concern 2.10 (1.80) 0.55 (0.76) -4.388 ^*** 38.14 <.001 Weight Concern 2.63 (1.61) 1.46 (1.13) -3.330 ^** 51.06 .002 Shape Concern 3.01 (1.56) 2.14 (1.31) -2.435 ^* 62 .018 Global 2.56 (1.56) 1.23 (0.89) -4.120 ^*** 44.91 <.001 AQ Social Skill 3.94 (1.93) 2.67 (1.81) -2,710 ^** 62 .009 Attention Switching 4.52 (1.93) 4.21 (1.36) -0.724 53.67 .472 Attention to Detail 5.03 (2.23) 3.97 (2.08) -1.971 62 .053 Communication 2.73 (1.82) 1.58 (1.35) -2.848 ^** 53.17 .006 Imagination 2.29 (1.88) 2.12 (1.50) -0.399 62 .691 Total 18.60 (5.33) 14.55 (4.28) -3.344 ^** 62 .001 BDI 24.53 (14.01) 7.38 (6.89) -6.057 ^*** 41.64 <.001 STAI State 58.47 (13.13) 43.28 (11.25) -4.899 ^*** 62 <.001 Trait 57.53 (13.46) 43.75 (11.33) -4.371 ^*** 62 <.001 AN, anorexia nervosa; BMI, body mass index; EDE-Q, Eating Disorder Examination Questionnaire; AQ, autism-spectrum quotient; STAI-State, Spielberger State and the Trait Anxiety Inventory State score; STAI-Trait, Spielberger State and Trait Anxiety Inventory Trait score.
* p < 0.05, ** p < 0.01, *** p < 0.001

The mean age and intelligence of the anorexia nervosa group and the control group were similar. On the other hand, as expected, there was a significant difference in body mass index (kg / m ² ) and EDE-Q score. Nervous anorexia group showed higher scores in social skills and communication among BDI, STAI, and AQ. Neurogenic anorexia group and normal control group showed no difference in attention transitions, attention to detail, imagination subscale.

Example 2: Relationship with various stimuli

2-1: Meal stimulation

The difference between the two groups was significant (AN: 19.04 ± 72.26; HC: 7.26 ± 49.30), indicating that the difference between the two groups was significant ( t (62) = -0.765 , p = 0.062, d = 0.192).

The results are shown in Fig.

(AN vs. HC) × reagent (oxytocin vs. placebo) Binary repeatability analysis showed that the main effect of the reagent was on the bias of the meal stimulus ( F (1,62) = 8.09, p ^{= 0.006, Δη 2 = 0.115)} , the main effect (F (1,62) = 0.187, p = 0.667, interaction of Δη ² = 0.003) and group × reagent of group was not observed (F (1,62) = 0.506, p = 0.479, ?? ² = 0.008).

Table 2 and Figure 1 show the mean scores for different groups and conditions.

Post-test results showed that oxytocin significantly reduced attention deficit only in the anorexia nervosa group ( t (30) = 2.281, p = 0.030, d = 0.808). (AN vs. HC) × reagent (oxytocin vs. placebo) × attractant (positive: low calorie; neutral; negative: high calorie / binge) Were not verified.

AN ( n = 31) HC ( n = 33) Placebo Oxytocin t ( df = 30) p Cohen's
d Placebo Oxytocin t ( df = 32) p Cohen's
d Eating stimuli Overall 19.04 (72.26) -14.63 (57.52) 2.281 ^* .030 0.516 7.26 (49.40) -12.93 (59.36) 1.680 .103 0.292 Weight stimuli Overall -0.30 (92.14) 1.74 (75.69) -0.101 .920 -0.024 1.48 (96.36) -7.95 (65.53) 0.430 .670 0.075 Shape stimuli Positive 1.57 (126.33) -18.78 (104.90) 0.612 .545 0.175 6.94 (94.94) 19.68 (92.62) -0.576 .569 -0.100 Neutral 21.51 (105.77) 10.78 (106.52) 0.478 .636 0.101 43.87 (122.43) 14.77 (87.83) 1.094 .282 0.190 Negative 42.03 (104.69) -7.49 (93.84) 2.592 ^* .015 0.498 -1.19 (81.13) 12.21 (96.11) -0.666 .510 -0.116 Data are shown as mean (standard deviation).
AN, anorexia nervosa; HC, healthy control
Statistical values represented by paired t-test between the oxytocin and placebo conditions in each group.
* p < 0.05, ** p < 0.01, *** p < 0.001

2-2 Weight stimulation

Because there was only neutral image in the weight stimulus, repeated (AN vs. HC) x reagent (oxytocin vs. placebo) repeated measures analysis was used for the analysis method.

As a result of the main group to note deflection score for weight stimulating effect (F (1,62) = 0.062, p = 0.805, Δη 2 = 0.001) x group interaction with the reagent effect (F (1,62) = 0.148 , p = 0.702 , and? ² = 0.002) (Table 2 and Fig. 1).

2-3 body stimulation

The results of the body stimulation, anorexia nervosa group and the control group had positive body stimulation (t (62) = 0.192, p = 0.849, d = -0.048) and neutral body stimulation (t (62) = 0.764, p = 0.448, d = -0.195) did not show the baseline deviation of attention deflection.

However, the group with anorexia nervosa showed a tendency to be more alert to negative body stimuli than the control group ( t (62) = -1.507, p = 0.137, d = 0.380).

As a result of three-way repeated measures analysis of group (AN vs. HC) x reagent (oxytocin vs. placebo) × attractant (negative, neutral, positive), the reagent ( F (1,62) = 1.372 ^{, p = 0.246, Δη 2 =} 0.024) and yuinga (F (2,124) = 1.590, p = 0.209, Δη 2 = were the main effects of 0.027) to open, effect interaction of group × drug × yuinga (F (2,124) = 1.194, p = 0.307, and Δη ² = 0.021) (Table 2).

( F (1,30) = 1.852, p = 0.186, and Δη ² = 0.069) in the repeated measures analysis of variance and the influences of the attractiveness (oxytocin vs. placebo) F (2, 60) = 1.255 , p = 0.294, Δη 2 = There was no main effect of 0.048), the interaction of the drug × yuinga effect (F (2,60) = 0.947, p = 0.395, Δη 2 = 0.037 ) Did not appear. However, it has been verified that oxytocin administration to a group of anorexia nervosa in a negative body stimulation condition results in a decrease in attention bias ( t (30) = 2.592, p = 0.015, d = 0.498).

Example 3: Correlation between attention deflection and psychopathology in patients with anorexia nervosa

The effect of _oxytocin on the negative body stimulation in the anorexia nervosa group and the effect of oxytocin on the autistic spectrum (RT) were _evaluated when the reagent effect was defined as the difference in reaction time (RT) between the placebo and oxytocin conditions (reagent effect = RT _placebo - RT _oxytocin ) AQ) was verified (r = 0.49, p = 0.009). The correlation between the AQ total score (r = 0.032, p = 0.101) and the other four sub-factors of AQ and oxytocin effect was not statistically significant. There was also no correlation between the effects of commonly associated psychiatric disorders such as eating disorders, depression, and anxiety in the anorexia nervosa group.

Example 4: Intake of juice after administration of oxytocin

The average juice intake of the anorexia nervosa group was 89.16 ± 84.77 mL in the placebo condition and 97.84 ± 84.57 mL in the oxytocin condition. The average juice intake of the control group was 162.91 ± 50.20 in the placebo condition and 173.42 ± 43.41 mL in the oxytocin condition. Analysis of the population (AN vs. HC) × reagent (oxytocin vs. placebo) showed no significant effect of the reagent ( F (1,63) = 1.830, p = 0.181) ( F (1,63) = 0.001, p = 0.976). The Wilcoxon signed-rank test was performed for both the anorexia nervosa ( z = -0.213, p = 0.831) and the control group ( z = -1.244, p = 0.214). However, the decrease in oxytocin-induced juice intake was statistically significant I did not pay attention.

Thus, the present invention is directed to a mechanism whereby oxytocin weakens attention deflected in the diet and body stimulation of anorexic nerves by women, especially as the lack of communication power is less, and is useful for treating neurogenic anorexia dysfunctional bodily experience It can be utilized.

Claims (2)

A composition for preventing or treating anorexia nervosa comprising oxytocin as an active ingredient,
The anorexia nervosa is characterized by an increase in visual attention deficits to negative shape stimuli,
Wherein the oxytocin is administered intranasally. The composition for preventing or treating anorexia nervosa according to claim 1, wherein the oxytocin is administered intranasally. The method according to claim 1,
Wherein said oxytocin weakens visual attention bias to negative shape stimuli in anorexia nervosa.

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