WO2014110234A1

WO2014110234A1 - Methods of treating developmental and personality disorders

Info

Publication number: WO2014110234A1
Application number: PCT/US2014/010837
Authority: WO
Inventors: Paul Shughrue
Original assignee: Elan Pharmaceuticals, Llc
Priority date: 2013-01-09
Filing date: 2014-01-09
Publication date: 2014-07-17
Also published as: WO2014110277A1

Abstract

The invention relates to the use of scyllo-inositol in treating personality disorders, in particular social withdrawal, as well as pharmaceutical compositions comprising effective amounts of scyllo-inositol for treating such disorders.

Description

METHODS OF TREATING DEVELOPMENTAL AMD PERSONALITY DISORDERS

FIELD OF THE INVENTION

The invention relates to methods for treating developmental and personality disorders.

BACKGROUND OF THE INVENTION

[001] Various diseases manifest with behavioral and psychiatric disturbances, such as social withdrawal, including major depressive disorder, postpartum depressive disorder, seasonal affective disorder, bipolar disorder, schizophrenia, dementias, Autism spectrum disorders, multiple sclerosis, and traumatic brain injury,

[002] For example, the Autism spectrum or autistic spectrum describes a range of conditions classified as pervasive developmental disorders in the Diagnostic and Statistical Manual of Mental Disorders (DS ). Pervasive developmental disorders include autism, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, and Rett syndrome. These disorders are typically characterized by social deficits, communication difficulties, stereotyped or repetitive behaviors and interests, and in some cases, cognitive delays.

[003] Fragile X syndrome (FXS), Martin-Bell syndrome, or Escalante's syndrome, is a genetic syndrome that is the most widespread single-gene cause of autism and inherited cause of mental retardation among boys. Fragile X syndrome is associated with the expansion of the CGG trinucleotide repeat affecting the Fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in a failure to express the fragile X mental retardation protein (FMRP), which is required for normal neural development. Depending on the length of the CGG repeat, an allele may be classified as normal (unaffected by the syndrome), a premutation (at risk of fragile X associated disorders), or full mutation (usually affected by the syndrome). A definitive diagnosis of fragile X syndrome is made through genetic testing to determine the number of CGG repeats. There is currently no drug treatment that has shown benefit specifically for fragile X syndrome. However, medications are commonly used to treat symptoms of attention deficit and hyperactivity, anxiety, and aggression.

[004] It is to be understood that both the foregoing genera! description and the following detail description are exemplary only and are not restrictive of the disclosure, as claimed. [005] It has been unexpectedly discovered, that scyllo-inositol ameliorates, prevents or delays onset or emergence of social withdrawal in animals. Accordingly, in an aspect of the invention, there is provided a method of treating social withdrawal in a subject, in particular an animal, comprising administering an effective amount of scyllo-inositol to the subject. In an aspect, the invention provides a method of treating a personality disorder in a subject, in particular an animal, comprising administering an effective amount of scyllo-inositol to the subject.

[008] In another aspect of the invention, there is provided a method for preventing the onset of social withdrawal behavior in a subject, in particular an animal, comprising administering an effective amount of scyllo-inositol to the animal to prevent onset of social withdrawal behavior in the subject. In an aspect, the invention provides a method for preventing the onset of a personality disorder behavior in a subject, in particular an animal, comprising administering an effective amount of scyllo-inositol to the animal to prevent onset of the personality disorder behavior in the subject.

[007] in another aspect of the invention, there is provided a method for delaying the onset of social withdrawal behavior in a subject, in particular an animal, comprising administering an effective amount of scyllo-inositol to the subject to delay onset of the social withdrawal behavior in the subject. In an aspect of the invention, there is provided a method for delaying the onset of a personality disorder behavior in a subject, in particular an animal, comprising administering an effective amount of scyllo- inositol to the subject to delay onset of the personality disorder behavior in the subject.

[008] In another aspect, the invention provides scyllo-inositol or a pharmaceutical composition comprising scyllo-inositol for use in treating social withdrawal or in the preparation of a medicament for treating social withdrawal in a subject, in particular an animal. In an aspect, the invention provides scyllo-inositol or a pharmaceutical composition comprising scyllo-inositol for use in treating a personality disorder or in the preparation of a medicament for treating a personality disorder in a subject, in particular an animal.

BRIEF DESCRIPTION

[009] Figure 1 illustrates the effect of scyllo-inositol (EL D005) on body weight. Data are presented as mean ± SE . [010] Figure 2 demonstrates the effect of scyllo-inositoi (ELNDGG5) on PCP- induced disruption of social interaction. Data are presented as mean ± 5EIVL Pound signs (#p<0.001) indicate a significant difference from vehicle-vehicle, Asterisks (*p<0.05, ***p<0,QG1 ) indicate significant differencefrom PCP-vehicle.

[01 1] Figures 3a - 3c show the social interaction data for rat pairs in each of the treatment groups. Outliers are highlighted.

DETAILED DESCRIPTION OF THE INVENTION!

[012] Particular aspects of the disclosure are described in greater detailed below, The terms, definitions and abbreviations as used in the present application and as clarified or designated herein are intended to represent the meaning within the present disclosure. The patent and scientific literature referred herein is hereby incorporated by reference. The terms and definitions provided herein control, if in conflict with the terms and/or definitions incorporated by reference.

[013] The singular forms "a," "an," and "the" include plural reference unless the context dictates otherwise.

[014] The terms "approximately" and "about" mean to be nearly the same as a referenced number or value. As used herein, the terms "approximately" and "about" should be generally understood to encompass ±10% of a specified amount, frequency or value, With regard to specific values, it should be understood that specific values described herein for subject populations (e.g., the subject of the described clinical trial) represent mean values, unless otherwise indicated. Accordingly, aspects of the present disclosure requiring a particular value in a subject are substantially supported herein by population data in which the relevant value is assessed to be a meaningful delimitation of the subject population.

[015] "BID" or "bid" means twice daily administration, when preceded by a quantity, it means that quantity is administered twice at different times in one day.

[016] "Baseline" refers to a patient's physical and/or mental condition and measurements related thereto taken before administration of a study drug is begun.

[017] "LTP" means long term potentiation and is used as an experimental model of memory formation. Bliss TV, et aL, (1993). "A synaptic model of memory: long-term potentiation in the hippocampus". Nature 381 (6407): 31-39,

[018] "MRS" is magnetic resonance spectroscopy as applied in scanning images of the brain and measuring compounds in the brain. [019] Scyllo-inositol is one of several endogenous stereoisomers of inositol. Myo-inosito! (Ml), which is the major endogenous inositol, plays an important role in osmoregulation and in phosphatidyl-inositol (PI) second messenger signaling, Ml is found at -4-5 mM intracellular concentrations in adult brain, while scyl!o-inositol concentrations are usually <1mM. Scyllo-inositol, unlike Ml, is not thought to be phosphorylated or directly involved in PI signaling. Scyllo-inositol is alternatively referred to as "ELfMDQGS" herein.

[020] "Personality disorder" includes without limitation paranoid personality disorder, schizoid personality disorder, schizotypical personality disorder, antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, social phobia, obsessive-compulsive personality disorder and personality disorder not otherwise specified.

[021] Criteria, including behaviors, for classifying the conditions disclosed herein may be found in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association in May 2013, DSM-IV-TR (American Psychiatric Association 2000), and the International Statistical Classification of Diseases and Related Health Problems 10^th Revision (ICD- 10), published by the World Health Organization (WHO) (http://apps.who.int/classifications/icd10/ browse/2010 /en# V).

[022] In aspects of the invention, the personality disorder is a Cluster C personality disorder including avoidant personality disorder or social withdrawal, obsessive-compulsive personality disorder (OCPD), and dependent personality disorder (DPD) in DSM-IV-TR (American Psychiatric Association 2000).

[023] "Social withdrawal" refers to an abnormal lack of contact with society for members of social species and is usually involuntary, making it distinct from isolating tendencies or actions consciously undertaken by a person. Social withdrawal is sometimes referred to "social isolation" or "avoidant personality disorder". Social withdrawal can be a negative symptom of schizophrenia and autism spectrum disorders such as Rett syndrome, Fragile X syndrome and Asperger's syndrome. Social withdrawal may be characterized by one or more of the following behaviors: a pervasive pattern of social inhibition, feelings of inadequacy, inferiority or insecurity, feelings of tension and apprehension, extreme sensitivity to negative evaluation, and avoidance of social interaction. [024] An avoidant personality disorder may be selected from one of the following subtypes: phobic, conflicted, hypersensitive or self-deserting. (See, Milton, Theadore. "Personality Subtypes Summary", http://www.millon.net Institute for Advanced Studies in Personology and Psychopathology.)

[025] Social withdrawal may occur along with other menial health disorders, in particular other personality disorders, including without limitation social phobia, dependent personality disorder or borderline personality disorder.

[026] The terms "subject" and "patient" are used interchangeably herein, and refer to an animal including a warm-blooded animal such as a mammal, which is afflicted with or suspected of having, at risk of, or being pre-disposed to a disorder or condition disclosed herein, ammal includes without limitation any members of the Mammalia. In general, the terms refer to a human. The methods herein for use on subjects/patients contemplate prophylactic as well as curative use. Typical subjects for treatment include persons susceptible to, suffering from or that have suffered a personality disorder, in particular social withdrawal or an avoidant personality disorder.

[027] Scyllo inositol has completed phase II clinical studies for the treatment of cognitive symptoms of Alzheimer's Disease. The study included neuropsychological assessments using the P! -12 item scale (Cummings et al. 1994, Neurology. 1994;44:2308-14), as well as assessments of scyllo-inositol and Mi brain levels using magnetic resonance spectroscopy (MRS). MRS data showed a dose-dependent increase of scyllo-inositol, and unexpectedly a corresponding dose-dependent decrease of Ml levels; these changes are significant but sub-maximal at week 24, and reach maximal levels at about 48 to about 78 weeks. The maximal I reduction measured at the 3 studied doses was 44%, 88% and 60% at the 250mg, i OOOmg, and 20Q0mg bid doses, respectively. While not being bound by any particular theory, scyllo- inositol is thought to competitively inhibit the active M! uptake by its transporter (Sodium-Sensitive Ml transporter. Wiesinger, 1991 , J Neurochem, 58(5): 1698-704). The beneficial effects of scyllo-inositol on neuropsychiatric index outcomes seem to be based, at least in part, on the down-regulation of Ml brain levels.

[028] The potential role of increased brain Ml in brain dysfunction is further supported by MRS measurements in normally aged, MCI and AD. Elevated Ml levels showed the strongest correlations with disease stage as measured by cognitive decline (Ml levels were significantly higher in AD than MCI, and in MCI than in normal aged subjects). Thus the methods of lowering brain levels of Ml by use of scyllo-inositol are useful for down-regulating and maintaining more normal (i.e., clinically observed range in non-dementia, non-MCI or non-mild Alzherimer's controls) brain levels of Ml in patients, such as dementia patients or Down's syndrome patients, where Ml is elevated and in bipolar disorder where Ml reduction has been demonstrated to have mood stabilizing therapeutic effects.

[029] To investigate changes in Ml levels and behavioral outcomes, a series of rodent studies were conducted, Adult male rats were pretreated with scyllo-inositol (1 or 10 mg/mL) or vehicle (drinking water) for 8 weeks prior to the administration of phencydidine (PCP) (2 mg/kg twice daily, 5 days) and tested in a model of social interaction. Unfamiliar rats were placed in an open field arena and their interactions (e.g. sniffing, grooming, ano-gen tal exploration) recorded over time. Subsequently, brain concentrations of scyllo-inositol and Ml were evaluated using a GC/MS/ S method. Analysis of behavior revealed a significant decrease in social interaction time when rats were pretreated with water for 8 weeks and then treated with PCP (p<.01 vs. water/vehicle). In contrast, rats pretreated with scyllo-inositol (1 or 10 mg/mL) before PCP, showed a significant improvement in social interaction times (p<.001 vs. water/PCP). The treatment of rats with scyllo-inositol also resulted in a significant reduction in brain Ml levels (~ 75%). when compared with controls.

[030] The optimal range of Ml reduction for treating social withdrawal seems to be from about 20 to about 90%, or from about 40% to about 85%, or about 50% to about 80% from baseline. In a particular embodiment, the amount of scyllo-inositol administered is the amount which reduces Ml to about 75% from baseline.

[031] The present results indicate that treatment with scyllo-inositol can reduce deficits in social interaction. Accordingly, in an aspect of the invention, there is provided a method of treating a personality disorder in an animal comprising administering an effective amount of scyllo-inositol to the subject. In another aspect of the invention, there is provided a method for preventing the onset of a personality disorder behavior in an animal, comprising administering an effective amount of scyllo- inositol to the animal to prevent onset of the personality disorder behavior in the animal. In another aspect of the invention, there is provided a method for delaying the onset of a personality disorder behavior in an animal, comprising administering an effective amount of scylio-inositol to the animal to delay onset of the personality disorder behavior in said animal. In an aspect, the personality disorder is a Cluster C personality disorder selected from the group consisting of avoidant personality disorder or social withdrawal, obsessive-compulsive personality disorder (OCPD), and dependent personality disorder (DPD).

[032] In an aspect of the invention, there is provided a method of treating social withdrawal in an animal comprising administering an effective amount of scylio-inositol to the subject. In another aspect of the invention, there is provided a method for preventing the onset of social withdrawal behavior in an animal, comprising administering an effective amount of scy!io-inositol to the animal to prevent onset of social withdrawal behavior in the animal. In another aspect of the invention, there is provided a method for delaying the onset of social withdrawal behavior in an animal, comprising administering an effective amount of scylio-inositol to the animal to delay onset of social withdrawal behavior in said animal. In an embodiment, the subject has a pervasive developmental disorder.

[033] In an embodiment, the subject is an animal, in particular a mammal. In a particular embodiment, the mammal is a human. In an embodiment, the human is a child (ages 4-8). In an embodiment, the human is a preadolescent (ages 9-12). In an embodiment, the human is an adolescent (ages 13-19). In an embodiment, the human is a young adult (ages 20-34).

[034] In a particular embodiment, social withdrawal is a symptom of schizophrenia. In another embodiment, the animal does not have the neuropsychiatric disorder of schizophrenia. In another embodiment, social withdrawal is a symptom of an autism spectrum disorder. In an embodiment, the autism spectrum disorder is Rett syndrome. In another embodiment the autism spectrum disorder is Fragile X syndrome. In another embodiment, the autism spectrum disorder is Asperger's syndrome. In a particular embodiment, the animal does not have an autism spectrum disorder.

[035] In another aspect of the invention, there is provided a method for treating an autism spectrum disorder in a subject comprising administering an effective amount of scylio-inositol to the subject. In a particular embodiment, the autism spectrum disorder is Rett syndrome. In a particular embodiment, the autism spectrum disorder is Fragile X syndrome. In another embodiment, the autism spectrum disorder is Asperger's syndrome.

[038] In another aspect of the invention, there is provided a method for treating multiple sclerosis in a subject comprising administering an effective amount of scylio- inositol to the subject. In another aspect of the invention, there is provided a method for treating cognitive disorders in a subject resulting from multiple sclerosis comprising administering an effective amount of scyl!o-inosito! to the subject. In another aspect of the invention, there is provided a method for treating behavioral disorders in a subject resulting from multiple sclerosis comprising administering an effective amount of scyilo- inositol to the subject,

[037] In another aspect of the invention, there is provided a method for treating traumatic brain injury in a subject comprising administering an effective amount of scyllo-inositol to the subject. In another aspect of the invention, there s provided a method for treating cognitive disorders in a subject resulting from traumatic brain injury comprising administering an effective amount of scyl!o-inositol to the subject. In another aspect of the invention, there is provided a method for treating behavioral disorders in a subject resulting from traumatic brain injury comprising administering an effective amount of scyllo-inositol to the subject.

[038] In embodiments of the invention, the treatment period is at least about 12 weeks, at least about 1 week, at least about 2 weeks or at least about 3 weeks, In an embodiment of the invention the treatment period is about 4 weeks. In an embodiment of the invention the treatment period is about 8 weeks. In embodiments of the invention, the treatment period is at least about 12 weeks, at least about 24 weeks, at least about 48 weeks or at least about 78 weeks. In another embodiment of the invention the treatment period is at least about 78 weeks.

[039] An "effective amount" or "therapeutically effective amount" of scyllo- inositol means the amount or dose of scyllo-inositol that provides the desired treatment or prophylactic effects in a patient, for example, reducing the severity or frequency of occurrence of the diseases and disorders herein. An effective amount scyllo-inositol can vary according to factors such as the particular disease or disorder, the age, sex, and weight of the patient. A dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. In a particular embodiment, an effective amount of scyllo-inositGl is about 1 mg to about 5000mg. In a particular embodiment, an effective amount of scyllo-inositol is about 10mg to about 20G0mg. In a particular embodiment, an effective amount of scyllo-inositol is about 100mg to about 1500mg per day. In a particular embodiment, an effective amount of scyllo-inositol is about 150mg to about 1300mg per day. In a particular embodiment, an effective amount of scyllo-inositol is about 2Q0mg to about 1200mg per day. In a particular embodiment, an effective amount of scyllo-inosito! is about 250mg to about 1100mg per day. In a particular embodiment, an effective amount of scy!lo-inositol is about 300mg to about 1000mg per day. In a particular embodiment, an effective amount of scyllo-inositol is about 500mg to about 1500mg per day. In a particular embodiment, an effective amount of scyllo-inositol is about 600mg to about 1300mg per day. In a particular embodiment, an effective amount of scyllo-inositol is about 700mg to about 1200mg per day. In a particular embodiment, an effective amount of scyllo-inositol is about 800mg to about 1100mg per day. In a particular embodiment, an effective amount of scyllo-inositol is about 900mg to about 1100mg per day. In a particular embodiment, an effective amount of scyllo-inositol is about 1000mg per day. In a particular embodiment, an effective amount of scyllo-inositol is 1000mg per day. In a particular embodiment, an effective amount of scyllo-inositol is 1000mg per day. In a particular embodiment, an effective amount of scyllo-inositol is about 500mg per day. In a particular embodiment, an effective amount of scyllo-inositol is 500mg per day. In a particular embodiment, the foregoing amounts of scyllo-inositol are administered once daily. In a particular embodiment, the foregoing amounts of scyllo-inositol are administered twice daily. In a particular embodiment, an effective amount of scyllo-inositol is about 250mg twice daily. In a particular embodiment, an effective amount of scyllo-inositol is 250mg twice daily. In a particular embodiment, an effective amount of scyllo-inositol is about 500mg twice daily. In a particular embodiment, an effective amount of scyllo-inositol is SQOrng twice daily. In another particular embodiment, the foregoing amounts of scyllo-inositol are administered three times daily.

[040] The methods of the invention also include co-administering other pharmaceutically active compounds prior to, following and contemporaneously with administration of scyllo-inositol. in a particular embodiment, scyllo-inositol is coadministered with therapeutic agents for treating neuropsychiatric disorders. In a particular embodiment, scyllo-inositol may be co-administered with or more additional therapeutic agents including without limitation anti-depressants. An anti-depressant may comprise a monoamine oxidase inhibitor, a Reversible inhibitor of monoamine oxidase A (RIMA), a Dopamine reuptake inhibitor (DART), a Norepinephrine-dopamine reuptake inhibitor, a Norepinephrine reuptake inhibitor (NRI), a Serofonin- norepinephrine reuptake inhibitor (SNRT), a Selective serotonin reuptake enhancer (SSRE), a Tricyclic antidepressant (TCA), a Tetracyclic anti-depressant, an NK1 receptor antagonist, or a Noradrenergic and specific serotonergic antidepressant (NaSSA), Examples of anti-depressants include, but are not limited to, amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyiine; citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; aprepitant; bupropion, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof,

[041] In an embodiment, scyllo-inositol is administered as a composition comprising the foregoing therapeutic agents. In an embodiment, the invention provides a pharmaceutical composition for use in treating a personality disorder, in particular social withdrawal, comprising scyllo-inositol and one or more second therapeutic agent. In some embodiments, the compositions comprise one or both active agents in subtherapeutic doses (e.g., amounts that are about 25%, 20%, 15%, 10%, 5%, 2%, 1 % or less than a full dose), A composition may be in a form for consumption by a subject such as a pill, tablet, caplet, soft and hard gelatin capsule, lozenge, sachet, cachet, vegicap, liquid drop, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium) suppository, sterile injectable solution, and/or sterile packaged powder.

[042] A pharmaceutical composition comprising scyllo-inositol may also comprise a pharmaceutically acceptable carrier, excipient, or vehicle. A pharmaceutically acceptable carrier, excipient. or vehicle generally refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered, A carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular composition. Examples of carriers etc. include but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for an active substance is well known in the art. Compositions and formulations for use in the present invention may be found in, for example, in Remington: The Science and Practice of Pharmacy, 21^st Ed., 2005; Martindale: The Complete Drug Reference, Sweetman, 2005, London: Pharmaceutical Press; Niazi, Handbook of Pharmaceutical Manufacturing Formulations, 2004, CRC Press; and Gibson, Pharmaceutical Preformuiation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, 2001 , Interpharm Press, which are hereby incorporated by reference herein.

[043] Scyllo-inositol may be prepared according to various conventional synthetic or semi-synthetic techniques or isolated as a natural product from coconut palm, in a particular embodiment, scyllo-inositol is prepared according to the processes described in WO2005035774 and WO2011100670 the entirety of which are incorporated herein by reference.

Animais

Male Sprague Dawley rats (~15Qg) from Harlan (indiana) were group housed in standard rat cages, 23/cage for the study. During the period of acclimation, rats were examined on a regular basis, handled, and weighed to assure adequate health and suitability. Rats were maintained on a 12/12 light/dark cycle with lights on at 7:00 a.m. The room temperature was maintained between 20 and 23°C with a relative humidity maintained between 30% and 70%. Chow and water were provided ad libitum for the duration of the study. Animals were randomly assigned across treatment groups and balanced by body-weight. Animais were not disturbed between test days. Testing was conducted during the light cycle of the animals.

Test Compounds

Challenge compound: Phencyclidine (Sigma; Lot # 081 4120V; 2 mg/kg) was dissolved in saline and administered subcutaneously (s.c.) twice daily for 5 days prior to test day.

Reference compound: (Sigma; Lot # 010K1206; Clozapine (2.5 mg/kg) was dissolved in 5% PEG:5% Tween 80 in saline and administered intraperitoneally (i.p.) 30 min prior to test at a dose volume of 1 mL/kg.

Test compound: ELND005 (1 and 10 mg/mL) was dissolved in drinking water. Test compound was prepared fresh weekly and administered for 8 weeks prior to testing. Method

Body weight measurements were taken prior to the ELND0Q5 treatment commencement and once a week through the duration of the study. Body weights were taken prior to the test as well. For five days prior to test, rats were injected twice daily with either PCP (2 mg/kg; s.c) or saline (s.c). On day 6 and following a 30 min pre- treatment time, a pair of unfamiliar rats, receiving the same treatment were placed in a white Plexiglas open field arena (24" x 17" x 8") and allowed to interact with each other for 6 minutes. Social interactions (^!S1') included: sniffing the other rat; grooming the other rat; climbing over or under or around the other rat; following the other rat; or exploring the ano-genital area of the other rat. Passive contact and aggressive contact were not considered a measure of social interaction, The time the rats spent interacting with each other during the 8 min test was recorded by a trained observer. The social interaction chambers were thoroughly cleaned after each 8-minute test session.

Statistical Analysis

Data were analyzed by analysis of variance (ANOVA) followed by Fisher's post-hoc tests when appropriate. An effect was considered significant if was p<0.05. Outliers defined as two standard deviations above or below the mean in each treatment group were noted in the raw data and excluded in the social interaction analysis. No outliers were excluded for body weights.

Results

The effect of compound ELND005 on body weight is shown in Figure 1 , Two-way ANOVA revealed a significant effect of time and interaction of time x treatment. No overall treatment effect was noted. The effect of compound ELND005 on interaction time is shown in Figure 2. Based on the NPi-12 item assessment, the mean total NPI scores were between 8 and 10 at baseline. This baseline severity is slightly lower than the range reported in many Mild to Moderate AD trials reported in the literature. Oneway ANOVA revealed a significant treatment effect. Post-hoc tests indicated that sub- chronic treatment with PCP significantly decreased social interaction time in rats. The PCP-induced deficit was attenuated by pretreatment with the atypical antipsychotic clozapine and ELND005 at both concentrations (1 and 10 mg/mL). t!eans Table for interaction Time (sec) Effect Treatment Count I fVfean Std. D©¥. Std, Err.

Water - Vehicle 12 I 90.250 7.008 § 2.023

Water - PCP 12 I 81.187 8.991 I 2.018

Clozapine 2,5 mg/kg - PCP 12 j 79.250 9.507 j 2.744 _s EL DQGS 1 mg/ml - PCP 12 1 78.333 8.907 I 2.571

EL D005 10 mg/ml - PCP 12 88.182 8.882 2.075

Fisher's PLSD Interaction Time (sec) Effect Significance Level; 5%

Claims

1. A method of treating social withdrawal in a subject comprising administering an effective amount of scyllo-inositol to the subject.

2. A method of treating a personality disorder in a subject comprising administering an effective amount of scyllo-inositol to the subject.

3. The method of claim 1 or 2, wherein the subject is a human.

4. The meihod of claim 1 , 2 or 3, wherein the effective amount of scy!io-inositoi is from about 1 mg to about 1 ,000mg per day,

5. The method of any one of claims 1 to 4, wherein the scyllo-inositol is administered twice a day.

8. The method of any one of claims 1 to 5, wherein the subject suffers from schizophrenia.

7. The method of any one of claims 1 to 5, wherein the subject suffers from an autism spectrum disorder.

8. The method of claim 7, wherein the autism spectrum disorder is Rett syndrome.

9. The method of claim 7, wherein the autism spectrum disorder is Fragile X syndrome.

10. The method of claim 7, wherein the autism spectrum disorder is Asperger's syndrome.

11. The method of any one of claims 1 to 10, wherein the amount of scyllo- inositol administered is about 250 mg.

12. The method of any one of claims 1 to 11 , wherein the scyllo-inositol is administered twice a day.

13. A method for preventing the onset of social withdrawal behavior in a subject comprising administering an effective amount of scyllo-inositol to the subject to prevent onset of social withdrawal behavior in the subject.

14. A method for delaying the onset of social withdrawal behavior in an animal, comprising administering an effective amount of scyllo-inositol to the subject to delay onset of social withdrawal behavior in the subject.

15. Scyllo-inositol or a pharmaceutical composition comprising scyllo-inositol for use in treating social withdrawal or in the preparation of a medicament for treating social withdrawal in a subject. 16, Scyiio-inositol or a pharmaceutical compositson of claim 15, wherein scyl inositol is present in an amount of about 250 mg.