WO2020018779A1

WO2020018779A1 - Use of phenylethylidenehydrazine to treat seizure disorders, developmental disorders, neurological disorders, behavioral disorders and addiction

Info

Publication number: WO2020018779A1
Application number: PCT/US2019/042383
Authority: WO
Inventors: Matthew During
Original assignee: Ovid Therapeutics Inc.
Priority date: 2018-07-18
Filing date: 2019-07-18
Publication date: 2020-01-23

Abstract

Methods and compositions are provided for treatment of seizure disorders, developmental disorders, neurological disorders, behavioral disorders and addiction with phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

Description

USE OF PHENYLETHYLIDENEHYDRAZINE TO TREAT

SEIZURE DISORDERS, DEVELOPMENTAL DISORDERS, NEUROLOGICAL DISORDERS, BEHAVIORAL DISORDERS AND ADDICTION

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of and priority to ET.S. Provisional Patent Application No. 62/699,835, filed on July 18, 2018, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

Treatment of seizure disorders, developmental disorders, neurological disorders, behavioral disorders and addiction using phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

BACKGROUND

Seizure disorders typically involve abnormal nerve cell activity in the brain, causing seizures which may be manifested by periods of unusual behavior, sensations, convulsions, diminished consciousness and sometimes loss of consciousness. Seizures can be a symptom of many different disorders that can affect the brain. Epilepsy is a seizure disorder characterized by recurrent seizures. See, e.g., Blume et al., Epilepsia. 2001; 42: 1212-1218. Epileptic seizures are usually marked by abnormal electrical discharges in the brain and typically manifested by sudden brief episodes of altered or diminished consciousness, involuntary movements, or convulsions.

Seizures can be categorized as focal seizures (also referred to as focal onset seizures or partial seizures) and generalized seizures. Focal seizures affect only one side of the brain, while generalized seizures affect both sides of the brain. Specific types of focal seizures include simple focal seizures, complex focal seizures, and secondarily generalized seizures. Simple focal seizures can be restricted or focused on a particular lobe (e.g., temporal lobe, frontal lobe, parietal lobe, or occipital lobe). Complex focal seizures generally affect a larger part of one hemisphere than simple focal seizures, but commonly originate in the temporal lobe or the frontal lobe. When a focal seizure spreads from one side (hemisphere) to both sides of the brain, the seizure is referred to as a secondarily generalized seizure. Specific types of generalized seizures include absences (also referred to as petit mal seizures), tonic seizures, atonic seizures, myoclonic seizures, tonic clonic seizures (also referred to as grand mal seizures), and clonic seizures.

Examples of seizure disorders include epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner Syndrome, Rasmussen’s syndrome, Dravet syndrome, Doose syndrome,

CDKL5 disorder, infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-related encephalopathy, intractable childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, increased seizure activity or breakthrough seizures (also called serial or cluster seizures). Seizure disorders can be associated with a sodium channel protein type 1 subunit alpha (Scnla)-related disorder.

Medications used to treat seizure disorders can be referred to as anti-epileptic drugs (“AED”). The treatment of recurrent seizures predominantly centers on the utilization of at least one AED, with possible adjunctive use of a second or even third agent in the case of

monotherapeutic failure. See, Tolman and Faulkner, Ther Clin Risk Manag. 2011; 7: 367-375. However, approximately 30%-40% of epileptic patients have inadequate seizure control with just one AED, and require the use of adjunctive agents. Id. A subset of this group will have regular and persistent seizure activity despite reasonable doses of multiple AEDs. These seizures are considered refractory to treatment. Id. Accordingly, there remains a need for improved and/or additional therapies for treating seizure disorders.

Developmental disorders are a group of disorders typically characterized by delays in the development of socialization and communication skills. Parents may note symptoms as early as infancy, although the typical age of onset is before 3 years of age. Symptoms may include problems with using and understanding language; difficulty relating to people, objects, and events; unusual play with toys and other objects; difficulty with changes in routine or familiar surroundings, and repetitive body movements or behavior patterns. In certain instances, symptoms of developmental disorders may occur later in life. Certain developmental disorders are seizure disorders or may involve seizures. Treatments for developmental disorders are limited. As used herein, developmental disorders include neurodevelopmental disorders. Developmental disorders include Angelman syndrome, Fragile X syndrome, Fragile X- associated tremor/ataxia syndrome (FXTAS), Rett syndrome, autism, Asperger’s syndrome, Childhood Disintegrative Disorder, Attention-deficit/hyperactivity disorder (ADHD), Prader- Willi Syndrome, Landau-Kleffner Syndrome, Rasmussen’s syndrome, Dravet syndrome, and Williams Syndrome.

Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the UBE3A gene encoding a ubiquitin E3 ligase. Characteristic symptoms include delayed development, intellectual disability, severe speech impairment, and motor dysfunction such as problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy) and a small head size. Effective therapeutic strategies have not yet been elucidated.

Fragile X syndrome may be the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The main efforts have focused on metabotropic glutamate receptor (mGluR) targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmrl -knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. These characteristics are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for Fragile X syndrome are leading the way in the treatment of other

neurodevelopmental syndromes and autism. Potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin have been discussed. However, further studies are needed to determine the safety and efficacy of GABAergic treatments for Fragile X syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset disorder, usually occurring after age 50. Mutations in the FMR1 gene increase the risk of developing FXTAS. The mutation relates to a DNA segment known as a CGG triplet repeat which is expanded within the FMR1 gene. Normally, this DNA segment is repeated from 5 to about 40 times. In people with FXTAS the CGG segment may be repeated 55 to 200 times. This mutation is known as an FMR1 gene premutation. An expansion of more than 200 repeats, a full mutation, causes Fragile X syndrome discussed above. FXTAS is typically characterized by problems with movement and thinking ability (cognition). FXTAS signs and symptoms usually worsen with age. Affected individuals have areas of damage in the cerebellum, the area of the brain that controls movement. Characteristic features of FXTAS are intention tremor, which is trembling or shaking of a limb when trying to perform a voluntary movement such as reaching for an object, and problems with coordination and balance (ataxia). Many affected individuals develop other movement problems, such as parkinsonism, which includes tremors when not moving (resting tremor), rigidity, and unusually slow movement (bradykinesia). In addition, affected individuals may have reduced sensation, numbness or tingling, pain, or muscle weakness in the lower limbs, and inability to control the bladder or bowel. Other symptoms may include chronic pain syndromes, such as fibromyalgia and chronic migraine, hypothyroidism, hypertension, insomnia, sleep apnea, vertigo, olfactory dysfunction, and hearing loss. People with FXTAS commonly have cognitive disabilities such as short-term memory loss and loss of executive function, which is the ability to plan and implement actions and develop problem-solving strategies. Loss of this function impairs skills such as impulse control, self-monitoring, focusing attention appropriately, and cognitive flexibility. Many people with FXTAS experience psychiatric symptoms such as anxiety, depression, moodiness, or irritability.

There is currently no targeted therapeutic intervention that can arrest or reverse the pathogenesis of FXTAS. However a number of treatment approaches of potential symptomatic benefit have been suggested. Primidone, beta-blockers such as propanolol, topiramate, carbidopa/levodopa, and benzodiazepines have been suggested to control tremors associated with FXTAS; botulinum toxin for involuntary muscle activities, such as dystonia and spasticity;

carbidopa/levodopa, amantadine and buspirone for ataxia; cholinesterase inhibitors such as donepezil, and memantine (an NMDA antagonist) for cognitive deficits and dementia; and antidepressants and antipsychotics for psychiatric symptoms. See, e.g., Hagerman, et al ., Clin Interv Aging. 2008 Jun; 3(2): 251-262.

Rett syndrome is a developmental disorder that typically affects girls. It is characterized by normal early growth and development followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability. Nearly all cases of Rett syndrome are caused by a mutation in the methyl CpG binding protein 2, or MECP2 gene. The A///(7^J2 gene contains instructions for the synthesis of methyl cytosine binding protein 2 (MeCP2), which is utilized in brain development and acts as one of the many biochemical switches that can either increase or decrease gene expression. The main diagnostic criteria or symptoms include partial or complete loss of acquired purposeful hand skills, partial or complete loss of acquired spoken language, repetitive hand movements (such has hand wringing or squeezing, clapping or rubbing), and gait abnormalities, including toe-walking or an unsteady, wide-based, stiff-legged walk. Supportive criteria are not required for a diagnosis of Rett syndrome but may occur in some individuals. In addition, these symptoms, which vary in severity from child to child, may not be observed in very young children but may develop with age. A child with supportive criteria but none of the essential criteria does not have Rett syndrome. Supportive criteria include scoliosis, teeth-grinding, small cold hands and feet in relation to height, abnormal sleep patterns, abnormal muscle tone, heart abnormalities, inappropriate laughing or screaming, intense eye

communication, and diminished response to pain. There is no cure for Rett syndrome. Treatment for the disorder is symptomatic, focusing on the management of symptoms, and supportive, requiring a multidisciplinary approach. Medication may be needed for breathing irregularities and motor difficulties, and anticonvulsant drugs may be used to control seizures.

Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI) is a developmental disorder which manifests a severe form of intractable epilepsy that begins in infancy with febrile seizures. Later, patients also manifest other seizure types, including absence, myoclonic, and partial seizures. The EEG is often normal at first, but later characteristically shows generalized spike-wave activity. Psychomotor development stagnates around the second year of life, and affected individuals show subsequent mental decline and other neurologic manifestations. Dravet syndrome is associated with ataxia, slowed psychomotor development, and mental decline, and is often refractory to medication. Dravet syndrome has been associated with mutation of the SCN1A gene on chromosome 2q24.

Autism spectrum disorder (ASD) (also referred to herein as autism) is a developmental disorder that affects communication and behavior. Symptoms generally appear in the first two years of life. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), people with ASD may have: difficulty with communication and interaction with other people, restricted interests and repetitive behaviors, symptoms that hurt the person’s ability to function properly in school, work, and other areas of life. Autism is known as a“spectrum” disorder because there is wide variation in the type and severity of symptoms people experience. Social communication/interaction behaviors may include: making little or inconsistent eye contact, tending not to look at or listen to people, rarely sharing enjoyment of objects or activities by pointing or showing things to others, failing to, or being slow to, respond to someone calling their name or to other verbal attempts to gain attention, having difficulties with the back and forth of conversation, often talking at length about a favorite subject without noticing that others are not interested or without giving others a chance to respond, having facial expressions, movements, and gestures that do not match what is being said, having an unusual tone of voice that may sound sing-song or flat and robot-like, having trouble understanding another person’s point of view or being unable to predict or understand other people’s actions.

Restrictive/repetitive behaviors may include: repeating certain behaviors or having unusual behaviors, e.g., repeating words or phrases, a behavior called echolalia, having a lasting intense interest in certain topics, such as numbers, details, or facts, having overly focused interests, such as with moving objects or parts of objects, getting upset by slight changes in a routine, being more or less sensitive than other people to sensory input, such as light, noise, clothing, or temperature, people with ASD may also experience sleep problems and irritability. Although ASD can be a lifelong disorder, treatments and services can improve a person’s symptoms and ability to function.

Asperger’s syndrome (AS) is a developmental disorder classified within ASD, but characterized by a relatively high level of functioning. Individuals with Asperger syndrome exhibit impairment in social interaction and a repetitive, stereotyped pattern of behavior. The individual, however, displays no delay in language or cognitive development, which

differentiates Asperger Syndrome from other aspects of autism. A distinguishing symptom of AS is a child's obsessive interest in a single object or topic to the exclusion of any other. Children with AS want to know everything about their topic of interest and their conversations with others will be about little else. Other characteristics of AS include repetitive routines or rituals;

peculiarities in speech and language; socially and emotionally inappropriate behavior and the inability to interact successfully with peers; problems with non-verbal communication; and clumsy and uncoordinated motor movements.

Pervasive developmental disorder not otherwise specified (PDD-NOS) is a

developmental disorder classified within ASD in which symptoms can vary widely from one child to the next. Overall, children with PDD-NOS can be characterized as having impaired social interaction, better language skills than children with autism but not as good as those with Asperger's syndrome, fewer repetitive behaviors than children with Asperger's syndrome or autism, and a possible later age of onset. Symptoms of PDD-NOS may include behavioral and communication problems such as difficulty using and understanding language, difficulty relating to people, objects, and events, e.g., lack of eye contact, pointing behavior, and lack of facial responses, unusual play with toys and other objects, difficulty with changes in routine or familiar surroundings, repetitive body movements or behavior patterns, such as hand flapping, hair twirling, foot tapping, or more complex movements, inability to cuddle or be comforted, difficulty regulating behaviors and emotions, which may result in temper tantrums, anxiety, and aggression, and emotional breakdowns.

Childhood disintegrative disorder (CDD) is a developmental disorder in which children develop normally through age 3 or 4. Then, over a few months, they lose language, motor, social, and other skills that they already learned. CDD has some similarity to autism, and may sometimes be considered a low-functioning form of autism. Typically, between the ages of 2 and 10, skills previously acquired are lost almost completely in at least two of the following six functional areas: 1. Expressive language skills, 2. receptive language skills, i.e., comprehension of language, 3. social skills and self-care skills, 4. bowel and bladder control, 5. play skills, and 6. motor skills. Lack of normal function or impairment also occurs in at least two of the following three areas: 1. social interaction, 2. communication, and 3. repetitive behavior and interest patterns.

Williams syndrome is a developmental disorder that affects many parts of the body. This condition is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel

(cardiovascular) problems. People with Williams syndrome typically have difficulty with visual- spatial tasks such as drawing and assembling puzzles, but they tend to do well on tasks that involve spoken language, music, and learning by repetition (rote memorization). Affected individuals have outgoing, engaging personalities and tend to take an extreme interest in other people. Attention deficit disorder (ADD), problems with anxiety, and phobias are common among people with this disorder. Young children with Williams syndrome have distinctive facial features including a broad forehead, a short nose with a broad tip, full cheeks, and a wide mouth with full lips. Many affected people have dental problems such as teeth that are small, widely spaced, crooked, or missing. In older children and adults, the face appears longer and more gaunt. Supravalvular aortic stenosis occurs frequently in people with Williams syndrome. Additional signs and symptoms of Williams syndrome include abnormalities of connective tissue such as joint problems and soft, loose skin. Affected people may also have increased calcium levels in the blood in infancy, developmental delays, problems with coordination, and short stature.

Jacobsen syndrome is a developmental disorder caused by a loss of genetic material from chromosome 11. Because this deletion occurs at the end (terminus) of the long (q) arm of chromosome 11, Jacobsen syndrome is also known as 1 lq terminal deletion disorder.

The signs and symptoms of Jacobsen syndrome vary considerably. Most affected individuals have delayed development, including delays in the development of speech and motor skills (such as sitting, standing, and walking). Most also have cognitive impairment and learning difficulties. Behavioral problems have been reported, including compulsive behavior (such as shredding paper), a short attention span, and easy distractibility. Many people with Jacobsen syndrome have been diagnosed with attention deficit-hyperactivity disorder (ADHD). Jacobsen

syndrome is also associated with an increased likelihood of autism spectrum disorders. Jacobsen syndrome is also characterized by distinctive facial features. These include small and low-set ears, widely set eyes (hypertelorism) with droopy eyelids (ptosis), skin folds covering the inner corner of the eyes (epicanthalfolds), a broad nasal bridge, downtumed corners of the mouth, a thin upper lip, and a small lower jaw. Affected individuals often have a large head size

(macrocephaly) and a skull abnormality called trigonocephaly, which gives the forehead a pointed appearance. Many people with Jacobsen syndrome have a bleeding disorder called Paris- Trousseau syndrome. This condition causes a lifelong risk of abnormal bleeding and easy bruising. Other features of Jacobsen syndrome can include heart defects, feeding difficulties in infancy, short stature, frequent ear and sinus infections, and skeletal abnormalities. The disorder can also affect the digestive system, kidneys, and genitalia.

Prader-Willi syndrome (PWS) is a developmental disorder caused by lack of expression of genes from an imprinted region of the paternally inherited chromosome 15ql l-ql3, near the centromere (Aycan and Bas, J Clin Res Pediatr Endocrinol, 6(2):62-67 (2014)). The frequency of the disease is between about 1/10,000 and 1/30,000 with approximately 400,000 PWS patients living worldwide. PWS is a spectrum disorder which affects many systems in the body. Subjects with PWS typically suffer from a host of symptoms including neurologic, cognitive, endocrine, and behavioral abnormalities. Initially, infants exhibit hypotonia (floppy baby syndrome) and experience difficulty in sucking and feeding which can lead to growth delay. Subjects with PWS frequently have poor muscle tone, growth hormone deficiency, low levels of sex hormones, a constant feeling of hunger and excessive appetite (hyperphagia). They overeat, leading to weight gain, obesity and a high incidence of diabetes. Other signs appear including short stature, poor motor skills, underdeveloped sex organs, and mild intellectual and learning disabilities. PWS subjects may experience delayed speech and language development, and infertility. Behavioral symptoms may include cognitive impairment, cognitive rigidity, emotional lability and obsessive-compulsive behavior, with autistic symptomology, psychotic episodes, and biopolar disorder with psychosis. Additional clinical manifestations may include excessive daytime sleepiness, scoliosis, osteopenia/osteoporosis, decreased gastrointestinal motility, sleep disturbances, and reduced pain sensitivity.

Landau-Kleffner syndrome is a developmental disorder characterized by the sudden or gradual development of aphasia (the inability to understand or express language) and

recurrent seizures (epilepsy). Children with Landau-Kleffner syndrome typically develop normally until signs and symptoms of the syndrome begin to develop between age 2 and 8 years. The seizures associated with LKS are known as complex partial, generalized clonic, and atypical absence seizures. Treatment for Landau-Kleffner syndrome usually consists of medications such as anticonvulsants and corticosteroids to help prevent seizures.

Rasmussen’s syndrome is a developmental disorder and a chronic inflammatory neurological disease that usually affects only one hemisphere of the brain. It usually occurs in children under the age of 10 (more rarely in adolescents and adults), and is characterized by frequent and severe seizures, loss of motor skills and speech, paralysis on one side of the body (hemiparesis), inflammation of the brain (encephalitis), and mental deterioration. Most individuals with Rasmussen’s syndrome will experience frequent seizures and progressive brain damage in the affected hemisphere of the brain over the course of the first 8 to 12 months, and then enter a phase of permanent, but stable, neurological deficits. Anti -epileptic drugs are usually not effective in controlling seizures. Recent studies have shown some success with treatments that suppress or modulate the immune system, in particular those that use corticosteroids, intravenous immunoglobulin, or tacrolimus.

Ohtahara syndrome is a developmental disorder characterized by seizures. The disorder affects newborns, usually within the first three months of life (most often within the first 10 days) in the form of epileptic seizures. Infants have primarily tonic seizures, but may also experience partial seizures, and rarely, myoclonic seizures. Ohtahara syndrome is most commonly caused by metabolic disorders or structural damage in the brain, although the cause or causes for many cases can’t be determined. The course of Ohtahara syndrome is severely progressive. Seizures become more frequent, accompanied by delays in physical and cognitive development. Antiepileptic drugs are used to control seizures, but are unfortunately not usually very effective for this disorder. Corticosteroids are occasionally helpful.

West syndrome is a developmental disorder characterized by infantile spasms seen in infancy and childhood. This syndrome leads to developmental regression and causes a specific pattern, known as hypsarrhythmia (chaotic brain waves), on electroencephalography

(EEG) testing. The infantile spasms usually begin in the first year of life, typically between 4-8 months. The seizures primarily consist of a sudden bending forward of the body with stiffening of the arms and legs; some children arch their backs as they extend their arms and legs. Spasms tend to occur upon awakening or after feeding, and often occur in clusters of up to 100 spasms at a time. Infants may have dozens of clusters and several hundred spasms per day. Infantile spasms usually stop by age five, but may be replaced by other types of seizures. Treatment with corticosteroids such as prednisone is standard, although serious side effects can occur. Several antiepileptic medications, such as topiramate may ease some symptoms. Vigabatrin has been approved by the ET.S. Food and Drug Administration to treat infantile spasms in children ages one month to two years.

Lennox-Gastaut syndrome is a developmental disorder and a severe form of epilepsy. Seizures usually begin before 4 years of age. Seizure types, which vary among patients, include tonic (stiffening of the body, upward deviation of the eyes, dilation of the pupils, and altered respiratory patterns), atonic (brief loss of muscle tone and consciousness, causing abrupt falls), atypical absence (staring spells), and myoclonic (sudden muscle jerks). There may be periods of frequent seizures mixed with brief, relatively seizure-free periods. Most children with Lennox- Gastaut syndrome experience some degree of impaired intellectual functioning or information processing, along with developmental delays, and behavioral disturbances. Treatments for Lennox-Gastaut syndrome include anti-epileptic medications such as cannabidiol, clobazam, valproate, lamotrigine, felbamate, or topiramate. There is usually no single antiepileptic medication that will control seizures.

Doose syndrome, otherwise known as myoclonic-astatic epilepsy (MAE) is a

epilepsy syndrome of childhood characterized by the occurrence of multiple different

seizure types including myoclonic-astatic, generalized tonic-clonic and absence seizures, usually in previously healthy children. In most cases, onset occurs during the first 5 years of life, most commonly between the ages of 3-4 years. Before onset, children usually have normal

psychomotor development, but primary developmental delay has been described in some cases. Characteristic of MAE are myoclonic-atonic or myoclonic-astatic seizures, which consist of quick jerking movements (occuring axially or truncally), followed by a drop attack (loss of muscle tone), which can result in falls and injuries. Astatic seizures can also be observed without the myoclonic component. Generalized tonic-clonic seizures are also among the most frequently observed seizures. Absence seizures may occur. Cognitive impairment is variable and both normal cognition and moderate to severe cognitive impairment have been described. Impulsivity, aggression and autistic-like behavior have also been noted in certain cases.

Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder marked by an ongoing pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development. According to the DSM-5 (2013) criteria for ADHD include six or more symptoms of inattention and six or more symptoms of hyperactivity and impulsivity for children up to age 16, or 5 or more such symptoms for adolescents 17 or older and adults. Inattention symptoms include: 1. often failure to give close attention to details or make careless mistakes in

schoolwork, at work, or with other activities, 2. often has trouble holding attention on tasks or play activities, 3. often does not seem to listen when spoken to directly, 4. often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (e.g., loses focus, side-tracked), 5. often has trouble organizing tasks and activities, 6. often easily distracted, and 7. often forgetful in daily activities. Hyperactivity and impulsivity symptoms include: 1. often fidgets with or taps hands or feet, or squirms in seat, 2, often leaves seat in situations when remaining seated is expected, 3. often runs about or climbs in situations where it is not appropriate (adolescents or adults may be limited to feeling restless), 4. often unable to play or take part in leisure activities quietly, 5. Is often“on the go” acting as if‘‘driven by a motor”, 6. often talks excessively, 7. often interrupts or intaides on others (e.g., butts into conversations or games), 8. often blurts out an answer before a question has been completed.

Medications may be administered to control some symptoms of ADHD. Stimulants such as methylphenidate, methamphetamine, dextroamphetamine, may be prescribed but can have adverse effects such as diminished appetite and headaches non-stimulant medications, such as atomoxetine, bupropion, guanfacine, and clonidine that may be used as alternatives, or added to stimulant therapy.

There remains a need for effective treatments of patients with developmental disorders, such as pervasive developmental disorder, autism, Asperger’s syndrome, Angelman syndrome, Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), Rett syndrome, Childhood Disintegrative Disorder, Attention-deficit/hyperactivity disorder (ADHD), Prader- Willi Syndrome, Landau-Kleffner Syndrome, Rasmussen’s syndrome, Dravet syndrome, Tardive Dyskinesia, Williams Syndrome, Jacobsen syndrome and/or seizure disorders per se, and/or seizure disorders associated with any of the foregoing developmental disorders.

Tuberous sclerosis complex (TSC) is a genetic developmental disorder characterized by the growth of numerous noncancerous (benign) tumors (hamartomas) in many parts of the body. These tumors can occur in the skin, brain, kidneys, and other organs, in some cases leading to significant health problems. Tuberous sclerosis complex also causes developmental problems, and the signs and symptoms of the condition vary from person to person. Virtually all affected people have skin abnormalities, including patches of unusually light-colored skin, areas of raised and thickened skin, and growths under the nails. Tumors on the face called facial angiofibromas are also common beginning in childhood. Tuberous sclerosis complex often affects the brain, causing seizures, behavioral problems such as hyperactivity and aggression, and intellectual disability or learning problems. Some affected children have the characteristic features of autism, a developmental disorder that affects communication and social interaction. Benign brain tumors can also develop in people with tuberous sclerosis complex; these tumors can cause serious or life-threatening complications. Patients who have this disorder can exhibit a high rate of epilepsy and cognitive problems resulting from multiple lesions in the brain. TSC lesions (corticol tubers) typically contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations. Seizures associated with TSC can be intractable. Tuber cinereum hamartoma (also known as hypothalamic hamartoma) is a benign tumor in which a disorganized collection of neurons and glia accumulate at the tuber cinereum of the hypothalamus. Symptoms include gelastic seizures, a disorder characterized by spells of involuntary laughter with interval irritability and depressed mood.

Tourette syndrome (TS) is a neurological disorder characterized by repetitive, stereotyped, involuntary movements and vocalizations called tics. The first symptoms of TS are almost always noticed in childhood, usually appearing between the ages of 3 and 12. Some of the more common tics include eye blinking and other vision irregularities, throat clearing, grunting, facial grimacing, shoulder shrugging, and head or shoulder jerking. Perhaps the most dramatic and disabling tics are those that result in self-harm such as punching oneself, or vocal tics including coprolalia (uttering swear words) or echolalia (repeating the words or phrases of others). Medications may be administered to control some symptoms of TS. For example, typical and atypical neuroleptics including risperidone, ziprasidone, haloperidol, pimozide and fluphenazine may be utilized but can have long-term and short-term adverse effects.

Antihypertensive agents such as clonidine and guanfacine are also used to treat tics.

Addiction is a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences. The disorder of the brain's reward system arises through transcriptional and epigenetic mechanisms and occurs over time from chronically high levels of exposure to an addictive stimulus (e.g., eating food, the use of drugs, engagement in sexual intercourse, participation in high-thrill cultural activities such as gambling, etc.). Classic symptoms of addiction include impaired control over substances or behavior, preoccupation with substance or behavior, and continued use despite consequences. Habits and patterns associated with addiction are typically characterized by immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs). Examples of drug and behavioral addictions include: alcoholism, amphetamine addiction, cocaine addiction, nicotine addiction, opiate addiction, benzodiazepine addiction, food addiction, gambling addiction, and sexual addiction. Pharmacological treatments for alcohol addiction include drugs like naltrexone, disulfiram, acamprosate, and topiramate. Opiate addiction may be treated with narcotic antagonists or replacement drugs such as buprenorphine and methadone. Currently, there are no medications approved for treatment of behavioral addictions in general, but some medications used for treatment of drug addiction may also be beneficial with specific behavioral addictions. Gabapentin and pregabalin may be used in connection with treatment for addiction. Binge eating disorder (BED) is behavioral disorder characterized by frequent and recurrent binge eating episodes with associated negative psychological and social problems, but without subsequent purging episodes (e.g. vomiting). People with binge-eating disorder lose control over their eating. According to the National Institutes of Health, binge-eating disorder is the most common eating disorder in the U.S. Symptoms include, eating unusually large amounts of food in a specific amount of time, eating even when the subject is full or not hungry, eating quickly during binge episodes, eating until the subject uncomfortably full, eating alone or in secret to avoid embarrassment, feeling distressed, ashamed, or guilty about eating, and frequently dieting, possibly without weight loss.

Obsessive-Compulsive Disorder (OCD) is a common, chronic and long-lasting behavioral disorder in which a person has uncontrollable, reoccurring thoughts (obsessions) and behaviors (compulsions) that he or she feels the urge to repeat over and over. OCD is typically treated with medication, psychotherapy or a combination of the two. Serotonin reuptake inhibitors (SRIs) and selective serotonin reuptake inhibitors (SSRIs) may be used to help reduce OCD symptoms.

There is a continuing need for medications that can be used to treat the above-described disorders and provide relief to those suffering from those disorders.

SUMMARY

Methods of treating a seizure disorder described herein include administering

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the disorder. Pharmaceutical compositions including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof are provided for use in treating a seizure disorder described herein. Methods of treating a seizure disorder described herein include administering a pharmaceutical composition including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating a seizure disorder described herein include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in symptoms of the seizure disorder in the patient a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the seizure disorder is epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, focal onset seizures, Landau-Kleffner Syndrome, Ohtahara syndrome, Rasmussen’s syndrome, West’s syndrome, Lennox-Gastaut syndrome, Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status, epilepticus, super-refractory status epilepticus, PCDH19 pediatric epilepsy, increased seizure activity or breakthrough seizures, or sodium channel protein type 1 subunit alpha (Scnla)-related disorders.

Methods of treating a developmental disorder described herein include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the disorder. Pharmaceutical compositions including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof are provided for use in treating a developmental disorder described herein. Methods of treating a developmental disorder described herein include administering a pharmaceutical composition including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating a developmental disorder described herein include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in symptoms of the developmental disorder in the patient a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

In embodiments, the developmental disorder is Angelman syndrome, Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), Rett syndrome, pervasive developmental disorder not otherwise specified, autism, Asperger’s syndrome, Childhood Disintegrative Disorder, Attention-deficit/hyperactivity disorder (ADHD), Prader-Willi

Syndrome, Landau-Kleffner Syndrome, Rasmussen’s syndrome, Dravet syndrome, Tardive Dyskinesia, Williams Syndrome, Jacobsen syndrome, or seizure disorders associated with any of the foregoing developmental disorders.

Methods of treating tuberous sclerosis complex include administering

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the tuberous sclerosis complex. Pharmaceutical compositions including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof are provided for use in treating tuberous sclerosis complex. Methods of treating tuberous sclerosis complex include administering a pharmaceutical composition including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating tuberous sclerosis complex include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in symptoms of the tuberous sclerosis complex in the patient a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

Methods of treating Tourette syndrome include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the Tourette syndrome. Pharmaceutical compositions including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof are provided for use in treating Tourette syndrome. Methods of treating Tourette syndrome include administering a pharmaceutical composition including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating Tourette syndrome include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in symptoms of the Tourette syndrome in the patient a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

Methods of treating addiction include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the addiction. Pharmaceutical compositions including

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof are provided for use in treating addiction. Methods of treating addiction include administering a pharmaceutical composition including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating addiction include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in symptoms of the addiction in the patient a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

Methods of treating a binge eating disorder include administering

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the binge eating disorder.

Pharmaceutical compositions including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof are provided for use in treating a binge eating disorder. Methods of treating a binge eating disorder include administering a pharmaceutical composition including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating a binge eating disorder include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in symptoms of the binge eating disorder in the patient a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

Methods of treating obsessive-compulsive disorder include administering

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the obsessive-compulsive disorder. Pharmaceutical compositions including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof are provided for use in treating obsessive-compulsive disorder. Methods of treating obsessive-compulsive disorder include administering a pharmaceutical composition including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating obsessive-compulsive disorder include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in symptoms of the obsessive-compulsive disorder in the patient a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Described herein are methods and compositions for treating of seizure disorders, developmental disorders, neurological disorders, behavioral disorders and addiction disorder using phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

Phenylethylidenehydrazine (PEH) is also known as 2-phenylethylhydrazone or b- phenylethylidenehydrazine. Phenylethylidenehydrazine is a metabolite of phenelzine and is an inhibitor of GABA-transaminase (GABA-T). Phenylethylidenehydrazine can exist in two isomeric forms (E) and (Z):

(E)-PEH (Z)-PEH

In embodiments, compositions of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof may include a racemic mixture. In embodiments, compositions of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof may include each isomer individually. ETnless otherwise specified,” phenylethylidenehydrazine” as used herein refers to both racemic and isomerically enriched forms. In embodiments, the compositions and methods described herein may provide reduced dosing frequency, reduced adverse events and/or increased efficacy compared to a racemic mixture of phenylethylidenehydrazine isomers. In embodiments, compositions and methods that include each isomer individually may provide reduced dosing frequency, reduced adverse events and/or increased efficacy compared to the minor isomer. Thus, in embodiments, contemplated herein are compositions and methods of treatment that provide the Z isomer of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof that is substantially free of the E isomer of phenylethylidenehydrazine. In embodiments, the methods and compositions described herein include the E isomer of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof substantially free of the Z isomer of phenylethylidenehydrazine. By“substantially free” it is meant that the composition includes less than 50% of the minor isomer of phenylethylidenehydrazine. For example, in embodiments, the compositions and methods described herein may include less than about, e.g .,

45%, 40%, 35%, 30 %, 25%, 20% 15%, 10%, 8%, 5%, 3%, 2%, or less than 1% of the minor E isomer of phenylethylidenehydrazine. In embodiments, the compositions and methods described herein may include less than about, e.g, 45%, 40%, 35%, 30 %, 25%, 20% 15%, 10%, 8%, 5%, 3%, 2%, or less than 1% of the minor Z isomer of phenylethylidenehydrazine. In embodiments, the methods and compositions described herein include the Z isomer of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the compositions include more than, e.g, about 75%, about 85%, about 90%, about 95% or about 98% Z isomer of phenylethylidenehydrazine. In embodiments, the compositions include between, e.g, about 50% to about 75%, about 75% to about 100%, about 85% to about 100%, about 90% to about 100%, or about 95% to about 100% Z isomer of phenylethylidenehydrazine. In embodiments, the methods and compositions described herein include the E isomer of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the compositions include more than, e.g, about 75%, about 85%, about 90%, about 95% or about 98% E isomer of phenylethylidenehydrazine. In embodiments, the compositions include between, e.g, about 50% to about 75%, about 75% to about 100%, about 85% to about 100%, about 90% to about 100%, or about 95% to about 100% E isomer of phenylethylidenehydrazine.

In embodiments, phenylethylidenehydrazine may be provided as an acid addition salt, a zwitter ion hydrate, zwitter ion anhydrate, hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate. Acid addition salts, include but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethane-disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, pantothenic, p-amino-benzoic, glutamic, benzene sulfonic or theophylline acetic acid addition salts, as well as the 8-halotheophyllines, for example 8-bromo-theophylline. In embodiments, inorganic acid addition salts, including but not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric or nitric acid addition salts may be used.

In embodiments, methods of treating a seizure disorder, developmental disorder, neurological disorder, behavioral disorder, or addiction include administering

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating a seizure disorder, developmental disorder, neurological disorder, behavioral disorder, or addiction include administering an effective amount of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating a seizure disorder, developmental disorder, neurological disorder, behavioral disorder or addiction include administering a pharmaceutical composition including an effective amount of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof. In embodiments, methods of treating a seizure disorder, developmental disorder, neurological disorder, behavioral disorder, or addiction include administering phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the seizure disorder, developmental disorder, neurological disorder, behavioral disorder, or addiction. In

embodiments, methods of treating a seizure disorder, developmental disorder, neurological disorder, behavioral disorder, or addiction include administering a pharmaceutical composition including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the seizure disorder, developmental disorder, neurological disorder, behavioral disorder, or addiction. In

embodiments, methods of treating a seizure disorder, developmental disorder, neurological disorder, behavioral disorder, or addiction include administering a pharmaceutical composition including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof to a patient in need thereof to provide improvement in one or more symptoms of the seizure disorder, developmental disorder, neurological disorder, behavioral disorder, or addiction a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

In embodiments, seizure disorders include epilepsy, epilepsy with generalized tonic- clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, focal onset seizures, Landau-Kleffner Syndrome, Rasmussen’s syndrome, Dravet syndrome, Doose syndrome, CDKL5 disorder, infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-related encephalopathy, intractable childhood epilepsy (ICE), Lennox- Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome, childhood absence epilepsy, essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, or increased seizure activity or breakthrough seizures (also called serial or cluster seizures). In embodiments, the seizure disorder is associated with a sodium channel protein type 1 subunit alpha (Scnla)-related disorder.

Symptoms of a seizure disorder may include, but are not limited to, episodes involving ataxia, gait impairment, speech impairment, vocalization, involuntary laughter, impaired cognition, abnormal motor activity, clinical seizure, subclinical seizure, hypotonia, hypertonia, drooling, mouthing behavior, aura, repetitive movements, and unusual sensations. Tonic seizures can cause the muscles to stiffen (contract) uncontrollably. Atypical absence seizures cause a partial or complete loss of consciousness. Additionally, some affected individuals have drop attacks, which are sudden episodes of weak muscle tone. In embodiments, the methods and compositions provided may reduce or prevent one or more different types of seizures and symptoms of seizures. Methods of treatment herein can include providing improvement in one or more of the foregoing symptoms.

In embodiments, the developmental disorder may be Angelman syndrome, Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), Rett syndrome, pervasive developmental disorder not otherwise specified, autism, Asperger’s syndrome, Childhood Disintegrative Disorder, Attention-deficit/hyperactivity disorder (ADHD), Prader-Willi

In embodiments, symptoms of Angelman syndrome include delayed development, intellectual disability, cognitive impairment, uncontrolled laughter, excitability, severe speech impairment, hand flapping, and/or motor dysfunction, e.g., problems with movement and balance (ataxia).

In embodiments, symptoms of Fragile X syndrome include intellectual disability, cognitive impairment, attention disorders, hyperactivity, anxiety, language-processing problems, lack of eye contact, trouble speaking clearly, stuttering, and/or sensitivity to sensory input such as bright light or loud noises.

In embodiments, symptoms of Fragile X-associated tremor/ataxia syndrome include intention tremor, problems with coordination and balance (ataxia), parkinsonism, reduced sensation, numbness or tingling, pain, or muscle weakness in the lower limbs, inability to control the bladder or bowel, chronic pain syndromes, fibromyalgia, chronic migraine, hypothyroidism, hypertension, insomnia, sleep apnea, vertigo, olfactory dysfunction, hearing loss, cognitive impairment, short-term memory loss, loss of executive function, impulse control, self monitoring, focusing attention appropriately, cognitive impairment, cognitive flexibility, and/or psychiatric symptoms such as anxiety, depression, moodiness, or irritability.

In embodiments, symptoms of Rett syndrome include partial or complete loss of acquired purposeful hand skills, partial or complete loss of acquired spoken language, repetitive hand movements (such has hand wringing or squeezing, clapping or rubbing), and gait abnormalities, including toe-walking or an unsteady, wide-based, stiff-legged walk, abnormal sleep patterns, abnormal muscle tone, heart abnormalities, inappropriate laughing or screaming, intense eye communication, and diminished response to pain.

In embodiments, symptoms of autism include difficulty with communication and interaction with other people, restricted interests and repetitive behaviors,

making little or inconsistent eye contact, tending not to look at or listen to people, rarely sharing enjoyment of objects or activities by pointing or showing things to others, failing to, or being slow to, respond to someone calling their name or to other verbal attempts to gain attention, having difficulties with the back and forth of conversation, often talking at length about a favorite subject without noticing that others are not interested or without giving others a chance to respond, having facial expressions, movements, and gestures that do not match what is being said, having an unusual tone of voice that may sound sing-song or flat and robot-like, having trouble understanding another person’s point of view or being unable to predict or understand other people’s actions, repeating certain behaviors or having unusual behaviors, e.g., echolalia, having a lasting intense interest in certain topics, such as numbers, details, or facts, having overly focused interests, such as with moving objects or parts of objects, getting upset by slight changes in a routine, being more or less sensitive than other people to sensory input, such as light, noise, clothing, or temperature, sleep problems cognitive impairment and/or irritability.

In embodiments, symptoms of Asperger’s syndrome include impairment in social interaction, obsessive interest in a single object or topic, repetitive routines or rituals, peculiarities in speech and language, socially and emotionally inappropriate behavior and the inability to interact successfully with peers, problems with non-verbal communication, and clumsy and uncoordinated motor movements.

In embodiments, symptoms of PDD-NOS include behavioral and communication problems such as difficulty using and understanding language, difficulty relating to people, objects, and events, e.g., lack of eye contact, pointing behavior, and lack of facial responses, unusual play with toys and other objects, difficulty with changes in routine or familiar surroundings, cognitive impairment, repetitive body movements or behavior patterns, such as hand flapping, hair twirling, foot tapping, or more complex movements, inability to cuddle or be comforted, difficulty regulating behaviors and emotions, temper tantrums, anxiety, aggression, and/or emotional breakdowns.

In embodiments, symptoms of childhood disintegrative disorder include, loss of language, motor, social, and other skills previously learned including loss of one or more of: 1. expressive language skills, 2. receptive language skills, i.e., comprehension of language, 3. social skills and self-care skills, 4. bowel and bladder control, 5. play skills, and 6. motor skills, 7. social interaction, and 8. communication. CDD subjects may demonstrate autistic symptoms, e.g., cognitive impairment, repetitive behavior and interest patterns, etc.

In embodiments, symptoms of Prader-Willi syndrome include poor muscle tone, growth hormone deficiency, low levels of sex hormones, a constant feeling of hunger and excessive appetite (hyperphagia), poor motor skills, underdeveloped sex organs, and mild intellectual and learning disabilities, delayed speech and language development, cognitive impairment, cognitive rigidity, emotional lability and obsessive-compulsive behavior, with autistic symptomology, psychotic episodes, biopolar disorder with psychosis, excessive daytime sleepiness, decreased gastrointestinal motility, sleep disturbances, and reduced pain sensitivity.

In embodiments, symptoms of ADHD include inattention, hyperactivity and impulsivity.

In embodiments, symptoms of Williams syndrome include mild to moderate intellectual disability or learning problems, cognitive impairment, unique personality characteristics, distinctive facial features, heart and blood vessel (cardiovascular) problems, difficulty with visual-spatial tasks such as drawing and assembling puzzles, attention deficit disorder (ADD), problems with anxiety and phobias, developmental delays, problems with coordination, and/or short stature.

In embodiments, symptoms of Jacobsen syndrome include delayed development, including delays in the development of speech and motor skills (such as sitting, standing, and walking), cognitive impairment, learning difficulties, compulsive behavior, short attention span, easy di stracti b i 1 ity , attention deficit-hyperactivity disorder (ADHD, autism, and/or feeding difficulties in infancy.

In embodiments, symptoms of tuberous sclerosis complex include autism, epilepsy and cognitive problems resulting from multiple lesions in the brain. Symptoms also include gelastic seizures, a disorder characterized by spells of involuntary laughter with interval irritability and depressed mood. In embodiments, symptoms of Tourette’s syndrome include eye blinking and other vision irregularities, throat clearing, grunting, facial grimacing, shoulder shrugging, and head or shoulder jerking, self-punching, and vocal tics including coprolalia (uttering swear words) or echolalia (repeating the words or phrases of others).

In embodiments, symptoms of addiction include compulsive engagement in rewarding stimuli despite adverse consequences, impaired control over substances or behavior,

preoccupation with substance or behavior, continued use despite consequences, cravings, immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs). Examples of drug and behavioral addictions include alcoholism, amphetamine addiction, cocaine addiction, nicotine addiction, opiate addiction, benzodiazepine addiction, food addiction, gambling addiction, and sexual addiction.

In embodiments, symptoms of binge eating disorder include eating unusually large amounts of food in a specific amount of time, eating even when the subject is full or not hungry', eating quickly during binge episodes, eating until the subject uncomfortably full, eating alone or in secret to avoid embarrassment, feeling distressed, ashamed, or guilty about eating, and frequently dieting, possibly without weight loss.

In embodiments, symptoms of obsessive compulsive disorder include uncontrollable, reoccurring thoughts (obsessions) and repetitive behaviors (compulsions) that a patient feels the urge to repeat over and over.

Cognitive impairment, if present in the disorders herein, may be measured against normal cognitive function, which refers to the normal physiologic activity of the brain, including, but not limited to, one or more of the following: mental stability, memory/recall abilities, problem solving abilities, reasoning abilities, thinking abilities, judging abilities, ability to discriminate or make choices, capacity for learning, ease of learning, perception, intuition, attention, and awareness, as measured by any criteria suitable in the art.

Cognitive impairment may also include deficits in mental activities that are mild or that otherwise do not significantly interfere with daily life. Mild cognitive impairment (MCI) is an example of such a condition. A subject with mild cognitive impairment may display symptoms of dementia (eg., difficulties with language or memory) but the severity of these symptoms is such that a diagnosis of dementia may not be appropriate. One skilled in the art will appreciate that there are numerous human and animal models that may be used to evaluate and compare the relative safety and efficacy of

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof in connection with the treatment of the disorders discussed above. In humans, cognitive function may be measured, for example and without limitation, by the clinical global impression of change scale (CGI); the Mini Mental State Exam (MMSE) (aka the Folstein Test); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Sandoz Clinical Assessment-Geriatric (SCAG) scale, the Benton Visual Retention Test (BVRT), Montreal Cognitive Assessment (MoCA) or Digit Symbol Substitution Test (DSST).

In animal model systems, cognitive function may be measured in various conventional ways known in the art, including using a Morris Water Navigation Task, Barnes maze, radial arm maze task, T maze and the like. Other tests known in the art may also be used to assess cognitive function, such as novel object recognition and odor recognition tasks.

Cognitive function may also be measured using imaging techniques such as Positron Emission Tomography (PET), functional magnetic resonance imaging (fMRI), Single Photon Emission Computed Tomography (SPECT), or any other imaging technique that allows one to measure brain function. In animals, cognitive function may also be measured with

electrophysiological techniques.

As used herein,“patient” and“subject” are used interchangeably. The patient may be an animal, e.g., mammal, e.g., rodents, humans, etc. As used herein, the terms“treat”,“treatment" or“treating” encompass any manner in which symptoms or pathology of a condition, disorder or disease described herein are ameliorated or otherwise beneficially altered. In embodiments, “treat”,“treatment" or“treating” can refer to inhibiting a disorder, disease or condition, e.g., arresting or reducing its development or at least one clinical or subclinical symptom thereof. In embodiments,“treat”,“treatment" or“treating” can refer to relieving the disorder, disease or condition, e.g., causing regression of the disorder, disease or condition or at least one of its clinical or subclinical symptoms. Prophylactic (preventive) and therapeutic (curative) treatment are separate embodiments of the disclosure herein.

In embodiments, "treating cognitive impairment" means ameliorating, beneficially altering and/or providing relief from one or more of the symptoms of cognitive impairment. In embodiments, treating a seizure disorder, a developmental disorder, a neurological disorder, a behavioral disorder or addiction means ameliorating, beneficially altering and/or providing relief from one or more of the symptoms of the seizure disorder, the developmental disorder, the neurological disorder, the behavioral disorder or addiction The benefit to a subject being treated may be statistically significant, mathematically significant, or at least perceptible to the subject and/or the physician.

In embodiments, the terms "effective amount" or“therapeutically effective amount” refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and/or physiologic effect in connection with symptoms of a seizure disorder, a developmental disorder, a neurological disorder, a behavioral disorder or addiction as described above. For example, administration of an effective amount of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is intended to accomplish one or more of the following: reduce, prevent or eliminate episodes involving ataxia, gait impairment, speech impairment, vocalization, involuntary laughter, impaired cognition, abnormal motor activity, clinical seizure, subclinical seizure, hypotonia, hypertonia, drooling, mouthing behavior, aura, repetitive movements, or unusual sensations, reduce, prevent or eliminate tonic seizures, reduce, prevent or eliminate absence seizures, reduce, prevent or eliminate drop attacks, reduce, prevent or prevent one or more different types of seizures and symptoms of seizures, reduce, prevent or eliminate difficulty in sucking, reduce, prevent or eliminate difficulty in feeding, reduce, prevent or eliminate motor dysfunction, reduce, prevent or eliminate poor muscle tone, reduce, prevent or eliminate hand flapping, increase motor skills, increase coordination, increase bladder control, reduce, prevent or eliminate parkinsonism, reduce, prevent or eliminate repetitive body movements, reduce, prevent or eliminate intellectual disability, reduce, prevent or eliminate learning disability, reduce, prevent or eliminate delayed speech development, reduce, prevent or eliminate delayed language development, reduce, prevent or eliminate language processing problems, reduce, prevent or eliminate stuttering, reduce, prevent or eliminate loss of executive function, reduce, prevent or eliminate cognitive rigidity, reduce, prevent or eliminate emotional lability, enhance impulse control, reduce, prevent or eliminate anxiety, reduce, prevent or eliminate hyperactivity, reduce, prevent or eliminate aggressive behavior, reduce, prevent or eliminate temper tantrums, reduce, prevent or eliminate uncontrolled laughter, reduce, prevent or eliminate obsessive-compulsive behavior, reduce, prevent or eliminate autistic symptomology, reduce, prevent or eliminate psychotic episodes, reduce, prevent or eliminate sleep disturbances, reduce, prevent or eliminate reduced pain sensitivity, reduce, prevent or eliminate reduced sensation, reduce, prevent or eliminate pain, reduce, prevent or eliminate fibromyalgia, reduce, prevent or eliminate chronic migraine, reduce, prevent or eliminate insomnia, reduce, prevent or eliminate vertigo, reduce, prevent or eliminate sensitivity to sensory input, reduce, prevent or eliminate cognitive impairment, enhance cognitive function, increase daytime activity, improve learning (either the rate or ease of learning), improve attention, improve social behavior, reduce or eliminate lack of eye contact, and/or improving cerebrovascular function. In embodiments, effective amount refers to an amount which may be suitable to prevent a decline in any one or more of the above qualities, or, in embodiments, to improve any one or more of the above qualities, for example, cognitive function or performance, learning rate or ability, problem solving ability, attention span and ability to focus on a task or problem, social behavior, and the like. Such effectiveness may be achieved, for example, by administering compositions described herein to an individual or to a population. In embodiments, the reduction, or delay of such a decline, or the improvement in an individual or population can be relative to a cohort, e.g., a control subject or a cohort population that has not received the treatment, or been administered the composition or medicament.

The dosage amount can vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system, health, etc.), the disease or disorder being treated, as well as the route of administration and the pharmacokinetics of the agent being administered.

Many pharmaceutical products are administered as a fixed dose, at regular intervals, to achieve therapeutic efficacy. The duration of action is reflected by the product’s plasma half-life. Since efficacy is often dependent on sufficient exposure within the central nervous system administration of CNS drugs with a short half-life may require frequent maintenance dosing. The elimination half-life of phenylethylidenehydrazine is about 12 hours. Advantageously disclosed herein are methods of treating the disorders described herein by administration of

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

In embodiments, methods of treating a seizure disorder are provided which include administering to a patient in need thereof a pharmaceutical composition including about 0.1 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 1 mg to about 75 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 10 mg to about 25 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 15 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the composition provides improvement for more than 12 hours after administration to the patient. In embodiments, the patient experiences improvement a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

In embodiments, the seizure disorder is epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, focal onset seizures, Landau-Kleffner Syndrome, Ohtahara syndrome, Rasmussen’s syndrome, West’s syndrome, Lennox-Gastaut syndrome, Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status, epilepticus, super-refractory status epilepticus, PCDH19 pediatric epilepsy, increased seizure activity or breakthrough seizures, or sodium channel protein type 1 subunit alpha (Scnla)-related disorders.

In embodiments, methods of treating a developmental disorder herein are provided which include administering to a patient in need thereof a pharmaceutical composition including about 0.1 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 1 mg to about 75 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 10 mg to about 25 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 15 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the composition provides improvement for more than 12 hours after administration to the patient. In embodiments, the patient experiences improvement a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the developmental disorder is Angelman syndrome, Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), Rett syndrome, pervasive developmental disorder not otherwise specified, autism, Asperger’s syndrome, Childhood Disintegrative Disorder, Attention-deficit/hyperactivity disorder (ADHD), Prader-Willi

In embodiments, methods of treating tuberous sclerosis complex are provided which include administering to a patient in need thereof a pharmaceutical composition including about 0.1 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 1 mg to about 75 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 10 mg to about 25 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 15 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the composition provides improvement for more than 12 hours after administration to the patient. In embodiments, the patient experiences improvement a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

In embodiments, methods of treating Tourette syndrome are provided which include administering to a patient in need thereof a pharmaceutical composition including about 0.1 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 1 mg to about 75 mg of

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 10 mg to about 25 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 15 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the composition provides improvement for more than 12 hours after administration to the patient. In embodiments, the patient experiences improvement a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

In embodiments, methods of treating addiction are provided which include administering to a patient in need thereof a pharmaceutical composition including about 0.1 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 1 mg to about 75 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 10 mg to about 25 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 15 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the composition provides improvement for more than 12 hours after administration to the patient. In embodiments, the patient experiences improvement a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

In embodiments, methods of treating binge eating disorder are provided which include administering to a patient in need thereof a pharmaceutical composition including about 0.1 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 1 mg to about 75 mg of

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 10 mg to about 25 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 15 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the composition provides improvement for more than 12 hours after administration to the patient. In embodiments, the patient experiences improvement a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

In embodiments, methods of treating obsessive-compulsive disorder are provided which include administering to a patient in need thereof a pharmaceutical composition including about 0.1 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 1 mg to about 75 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 10 mg to about 25 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition includes about 15 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof. In embodiments, the composition provides improvement for more than 12 hours after administration to the patient. In embodiments, the patient experiences improvement a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

In embodiments, in treatment of a seizure disorder, a developmental disorder, a neurological disorder, a behavioral disorder or addiction, phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is administered at dosages ranging from about 0.01 mg/kg and about 10 mg/kg of body weight of a patient in need thereof, e.g., from about 0.1 mg/kg to 5.0 mg/kg, about 0.2 mg/kg to about 3 mg/kg, at least once a day. For example, dosages may include amounts of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof in the range of about, e.g., 1 mg to 500 mg, 1 mg to 250 mg, 1 mg to 100 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 15 mg, 0.1 mg to 20 mg, 0.1 mg to 30 mg, 0.1 mg to 40 mg, 0.1 mg to 50 mg, 0.1 mg to 60 mg, 0.1 mg to 70 mg, 0.1 mg to 80 mg, 0.1 mg to 90 mg, 0.1 mg to 100 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, with doses of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, and 500 mg being specific examples of doses.

Typically, dosages of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof are administered once, twice, thrice or four times daily to a patient in need thereof. The methods and compositions described herein may provide reduced dosing frequency and reduced adverse events and/or increased efficacy. In embodiments, phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof may be administered once weekly or twice weekly. In embodiments, the dosage may be about, e.g ., 0.1-20 mg/day, or 0.2-15 mg/day, or 0.5-10 mg/day, or 0.75-5 mg/day, l-300mg/day, 1-200 mg/day, 5-100 mg/day, 10-100 mg/day for example 0.2 mg/day, 0.5 mg/day, 0.75 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, 8 mg/day, 9 mg/day, 10 mg/day, 11 mg/day, 12 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, 200 mg/day, 210 mg/day, 220 mg/day, 230 m/day, 240 mg/day, 250 mg/day, 260 mg/day, 270 mg/day, 280 mg/day, 290 m/day, 300 mg/day, 310 mg/day, 320 mg/day, 330 m/day, 340 mg/day, 350 mg/day, 360 mg/day, 370 mg/day, 380 mg/day, 390 m/day, or 400 mg/day. In embodiments, phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is administered at doses of e.g., 0.2 mg to 1 mg in infants, 0.5 mg to 50 mg in children, or lmg to 300 mg in adults, once, twice, thrice or four times daily. It should be understood that these doses are exemplary and that those skilled in the art can adjust the doses upwardly or downwardly based on specific requirements of particular situations. In embodiments, a pharmaceutical composition described herein is provided to the patient in the morning. In embodiments, a pharmaceutical composition described herein is provided to the patient in the evening. In embodiments, a pharmaceutical composition described herein is provided to the patient once in the evening and once in the morning. In embodiments, a pharmaceutical composition described herein is provided to the patient once in the morning, once in the afternoon and once in the evening or at night. Any suitable route of administration may be utilized, e.g., oral, rectal, nasal, pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial, intramuscular, intraperitoneal and subcutaneous routes.

In embodiments, the methods and compositions described herein may be particularly useful for treating children and infants, and for treating seizure disorders, developmental disorders, neurological disorders, behavioral disorders or addiction disorder that onset during infancy or childhood. In embodiments, the subject of the disclosed method is a newborn, a baby, a toddler, a preschooler, a school-age child, a tween, or a teenager. In embodiments, the subject is 18 years old or younger, 12 years old or younger, 10 years old or younger, 8 years old or younger, 6 years old or younger, 4 years old or younger, 2 years old or younger, 1 year old or younger. In embodiments, the subject is an adult that is over eighteen years old.

Pharmaceutical compositions herein may be provided with conventional release or modified release profiles. In embodiments, pharmaceutical compositions with different drug release profiles may be combined to create a two phase or three-phase release profile. For example, pharmaceutical compositions may be provided with an immediate release and an extended release profile. In embodiments, pharmaceutical compositions may be provided with an extended release and delayed release profile. Such compositions may be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.

Compositions may be prepared using a pharmaceutically acceptable“carrier” composed of materials that are considered safe and effective. The“carrier” includes all components present in the pharmaceutical formulation other than the active ingredient or ingredients. The term “carrier” includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions.

Modified release profiles include immediate release, delayed release, or extended release profiles. Conventional (or unmodified) release oral dosage forms such as tablets or capsules typically release medications into the stomach or intestines as the tablet or capsule shell dissolves. The pattern of drug release from modified release (MR) dosage forms is deliberately changed from that of a conventional dosage form to achieve a desired therapeutic objective and/or better patient compliance. Types of MR drug products include orally disintegrating dosage forms (ODDFs) which provide immediate release, extended release dosage forms, delayed release dosage forms (e.g., enteric coated), and pulsatile release dosage forms.

An ODDF is a solid dosage form containing a medicinal substance or active ingredient which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue.

The disintegration time for ODDFs generally range from one or two seconds to about a minute. ODDFs are designed to disintegrate or dissolve rapidly on contact with saliva. This mode of administration can be beneficial to people who may have problems swallowing tablets whether it be from physical infirmity or psychiatric in nature. For example, patients with Angelman syndrome, Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome or Rett syndrome may exhibit such behavior. Examples of ODDFs include orally disintegrating tablets, capsules and rapidly dissolving films and wafers.

Extended release dosage forms (ERDFs) have extended release profiles and are those that allow a reduction in dosing frequency as compared to that presented by a conventional dosage form, e.g., a solution or unmodified release dosage form. ERDFs provide a sustained duration of action of a drug. Suitable formulations which provide extended release profiles are well-known in the art. For example, coated slow release beads or granules (“beads” and“granules” are used interchangeably herein) in which phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is applied to beads, e.g., confectioners nonpareil beads, and then coated with conventional release retarding materials such as waxes, enteric coatings and the like. In embodiments, beads can be formed in which phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is mixed with a material to provide a mass from which the drug leaches out. In embodiments, the beads may be engineered to provide different rates of release by varying characteristics of the coating or mass, e.g., thickness, porosity, using different materials, etc. Beads having different rates of release may be combined into a single dosage form to provide variable or continuous release. The beads can be contained in capsules or compressed into tablets. In embodiments, extended release phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof dosage forms may contain, e.g., 500 mg, 250 mg, 200 mg, 150 mg, 100 mg or 50 mg phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof as the active ingredient. In embodiments, phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof are contained in extended release dosage forms that incorporate a dual hydrophilic polymer matrix system. In embodiments, phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is combined with a drug release controlling polymer to form an“inner” phase, which is then incorporated as discrete particles into an“external” phase of a second polymer. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH.

In embodiments, modified dosage forms herein incorporate delayed release dosage forms having delayed release profiles. Delayed release dosage forms can include delayed release tablets or delayed release capsules. A delayed release tablet is a solid dosage form which releases a drug (or drugs) such as phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof at a time other than promptly after administration. A delayed release capsule is a solid dosage form in which the drug is enclosed within either a hard or soft soluble container made from a suitable form of gelatin, and which releases a drug (or drugs) at a time other than promptly after administration. For example, enteric-coated tablets, capsules, particles and beads are well-known examples of delayed release dosage forms. Enteric coated tablets, capsules and particles and beads pass through the stomach and release the drug in the intestine. In embodiments, a delayed release tablet is a solid dosage form containing a conglomerate of medicinal particles that releases a drug (or drugs) at a time other than promptly after administration. In embodiments, the conglomerate of medicinal particles are covered with a coating which delays release of the drug. In embodiments, a delayed release capsule is a solid dosage form containing a conglomerate of medicinal particles that releases a drug (or drugs) at a time other than promptly after

administration. In embodiments, the conglomerate of medicinal particles are covered with a coating which delays release of the drug.

Delayed release dosage forms are known to those skilled in the art. For example, coated delayed release beads or granules in which, e.g., phenylethylidenehydrazine or a

pharmaceutically acceptable salt thereof is applied to beads, e.g., confectioners nonpareil beads, and then coated with conventional release delaying materials such as waxes, enteric coatings and the like. In embodiments, beads can be formed in which phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is mixed with a material to provide a mass from which the drug leaches out. In embodiments, the beads may be engineered to provide different rates of release by varying characteristics of the coating or mass, e.g., thickness, porosity, using different materials, etc. In embodiments, enteric coated granules of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof can be contained in an enterically coated capsule or tablet which releases the granules in the small intestine. In embodiments, the granules have a coating which remains intact until the coated granules reach at least the ileum and thereafter provide a delayed release of the drug in the colon. Suitable enteric coating materials are well known in the art, e.g., Eudragit® coatings such methacrylic acid and methyl methacrylate polymers and others. The granules can be contained in capsules or compressed into tablets.

In embodiments, phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof can be incorporated into porous inert carriers that provide delayed release profiles. In

embodiments, the porous inert carriers incorporate channels or passages from which the drug diffuses into surrounding fluids. In embodiments, phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof can be incorporated into an ion-exchange resin to provide a delayed release profile. Delayed action may result from a predetermined rate of release of the drug from the resin when the drug-resin complex contacts gastrointestinal fluids and the ionic constituents dissolved therein. In embodiments, membranes are utilized to control rate of release from drug containing reservoirs. In embodiments, liquid preparations may also be utilized to provide a delayed release profile. For example, a liquid preparation consisting of solid particles dispersed throughout a liquid phase in which the particles are not soluble. The suspension is formulated to allow at least a reduction in dosing frequency as compared to that drug presented as a conventional dosage form (e.g., as a solution or a prompt drug-releasing, conventional solid dosage form). For example, a suspension of ion-exchange resin constituents or microbeads.

In embodiments, pharmaceutical compositions described herein are suitable for parenteral administration, including, e.g., intramuscular (i.m.), intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), or intrathecal (i.t). Parenteral compositions must be sterile for administration by injection, infusion or implantation into the body and may be packaged in either single-dose or multi-dose containers. In embodiments, liquid pharmaceutical compositions for parenteral administration to a subject include phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof in any of the amounts described above. In embodiments, the pharmaceutical compositions for parenteral administration are formulated as a total volume of about, e.g., 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In embodiments, the compositions are contained in a bag, a glass vial, a plastic vial, or a bottle.

In embodiments, the solubility of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition for parenteral administration is greater than, e.g, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 75 mg/mL, about 100 mg/mL, about 150 mg/mL, when measured, for example, in water at 25°C. In embodiments, a pharmaceutical composition for parenteral administration is provided wherein the pharmaceutical composition is stable for at least six months. In embodiments, the pharmaceutical compositions for parenteral administration exhibit no more than about 5% decrease in active substance. In embodiments, the amount of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof degrades at no more than about, e.g, 2.5%, 1%, 0.5% or 0.1%. In embodiments, the degradation is less than about, e.g. , 5%, 2.5%, 1%, 0.5%, 0.25%, 0.1%, for at least six months.

In embodiments, pharmaceutical compositions for parenteral administration are provided wherein the pharmaceutical composition remains soluble. In embodiments, pharmaceutical compositions for parenteral administration are provided that are stable, soluble, local site compatible and/or ready-to-use. In embodiments, the pharmaceutical compositions herein are ready-to-use for direct administration to a patient in need thereof. In embodiments, parenteral compositions containing phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof herein may include solubility enhancers such as a cyclodextrin. Examples of a cyclodextrin include, but are not limited to, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta- cyclodextrin sodium salt, or a mixture thereof.

The parenteral compositions provided herein may include one or more excipients, e.g, solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, stabilizers or antimicrobial preservatives. When used, the excipients of the parenteral compositions will not adversely affect the stability, bioavailability, safety, and/or efficacy of

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof used in the composition. Thus, parenteral compositions are provided wherein there is no incompatibility between any of the components of the dosage form.

In embodiments, parenteral compositions including phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof include a stabilizing amount of at least one excipient.

For example, excipients may be selected from the group consisting of buffering agents, solubilizing agents, tonicity agents, antioxidants, chelating agents, antimicrobial agents, and preservative. One skilled in the art will appreciate that an excipient may have more than one function and be classified in one or more defined group.

In embodiments, parenteral compositions of phenylethylidenehydrazine or a

pharmaceutically acceptable salt thereof are provided, wherein the pH of the composition is between about 4.0 to about 8.0. In embodiments, the pH of the compositions is between, e.g, about 5.0 to about 8.0, about 6.0 to about 8.0, about 6.5 to about 8.0. In embodiments, the pH of the compositions is between, e.g, about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In embodiments, the pH of the aqueous solution is, e.g, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosure herein belongs.

The term "about" or "approximately" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, and/or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.

“Improvement” refers to the treatment of a seizure disorder, developmental disorder, neurological disorder, behavioral disorder or addiction disorder herein measured relative to at least one symptom.

"PK" refers to the pharmacokinetic profile. Cmax is defined as the highest plasma drug concentration estimated during an experiment (ng/ml). Tmax is defined as the time when Cmax is estimated (min). AUCo- is the total area under the plasma drug concentration-time curve, from drug administration until the drug is eliminated (ng.hr/ml). The area under the curve is governed by clearance. Clearance is defined as the volume of blood or plasma that is totally cleared of its content of drug per unit time (ml/min).

"Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe", e.g ., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human. In embodiments, this term refers to molecular entities and compositions approved by a regulatory agency of the federal or a state government, as the GRAS list under section 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, that is subject to premarket review and approval by the FDA or similar lists, the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans. “Patient in need thereof’ includes individuals that have been diagnosed with a seizure disorder, a developmental disorder, a neurological disorder, a behavioral disorder or addiction as described herein.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the claims.

Claims

What is claimed is:

1. A method of treating a developmental disorder comprising administering to a patient in need thereof a therapeutically effective amount of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof wherein the method provides improvement in one or more symptoms of the disorder.

2. The method of claim 1, wherein the developmental disorder is selected from the group consisting of autism, pervasive developmental disorder not otherwise specified, Angelman syndrome,

Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), Rett syndrome, Asperger’s syndrome, Childhood Disintegrative Disorder, Attention-deficit/hyperactivity disorder (ADHD), Prader-Willi Syndrome, Landau-Kleffner Syndrome, Rasmussen’s syndrome, Dravet syndrome, Tardive Dyskinesia, Williams Syndrome, and seizure disorders associated with any of the foregoing developmental disorders.

3. The method of claim 1, wherein the patient is administered from about 0.01 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the patient is administered from about 15 mg to about 200 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

5. The method of claim 1, wherein the phenylethylidenehydrazine or a pharmaceutically

acceptable salt thereof is administered in a pharmaceutical composition.

6. The method of claim 1, wherein the phenylethylidenehydrazine is (E)

phenylethylidenehydrazine.

7. The method of claim 1, wherein the phenylethylidenehydrazine is (Z)

phenylethylidenehydrazine.

8. The method of claim 1, wherein the phenylethylidenehydrazine is racemic

phenylethylidenehydrazine.

9. The method of claim 1, wherein the in vivo plasma profile of the patient 12 hours after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is reduced by more than 50% and the method provides improvement in symptoms of the developmental disorder in the patient a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

10. The method of claim 1, wherein the method provides improvement in at least one symptom

selected from the group consisting of ataxia, gait, speech impairment, vocalization, cognition, motor activity, clinical seizure, subclinical seizure, hypotonia, hypertonia, feeding difficulty, drooling, mouthing behavior, sleep difficulties, repetitive hand movements, hand flapping, hand ringing, shakiness of the torso, apnea, hyperventilation and air swallowing, muscle rigidity, spasticity, teeth grinding, poor circulation of the lower extremities, easily provoked laughter, short attention span, a constant feeling of hunger and excessive appetite, cognitive rigidity, emotional lability, obsessive-compulsive behavior, sleep disturbances, reduced pain sensitivity, difficulty regulating behaviors and emotions, temper tantrums, aggression, emotional breakdowns, and impulse control.

11. The method of claim 1, wherein a pharmaceutical composition containing from about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is administered to the patient.

12. A method of treating a seizure disorder comprising administering to a patient in need thereof a therapeutically effective amount of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof wherein the method provides improvement in one or more symptoms of the disorder.

13. The method of claim 12, wherein the seizure disorder is selected from the group consisting of is epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, focal onset seizures, Landau-Kleffner Syndrome, Ohtahara syndrome, Rasmussen’s syndrome, West’s syndrome, Lennox-Gastaut syndrome, Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status, epilepticus, super-refractory status epilepticus, PCDH19 pediatric epilepsy, increased seizure activity or breakthrough seizures, and sodium channel protein type 1 subunit alpha (Scnla)-related disorders.

14. The method of claim 12, wherein the patient is administered from about 0.01 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

15. The method of claim 12, wherein the patient is administered from about 15 mg to about 200 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

16. The method of claim 12, wherein the phenylethylidenehydrazine or a pharmaceutically

acceptable salt thereof is administered in a pharmaceutical composition.

17. The method of claim 12, wherein the phenylethylidenehydrazine is (E)

phenylethylidenehydrazine.

18. The method of claim 12, wherein the phenylethylidenehydrazine is (Z)

phenylethylidenehydrazine.

19. The method of claim 12, wherein the phenylethylidenehydrazine is racemic

phenylethylidenehydrazine.

20. The method of claim 12, wherein the in vivo plasma profile of the patient 12 hours after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is reduced by more than 50% and the method provides improvement in symptoms of the developmental disorder in the patient a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

21. The method of claim 12, wherein the method provides improvement in at least one symptom selected from the group consisting of aura, convulsions, repetitive movements, unusual sensations, involuntary laughter, drop attacks, muscle rigidity, weak muscle tone, abnormal motor activity, clinical seizure, subclinical seizure, absence seizure, frequency of seizures and severity of seizures.

22. The method of claim 12, wherein a pharmaceutical composition containing from about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is administered to the patient.

23. A method of treating tuberous sclerosis complex comprising administering to a patient in need thereof a therapeutically effective amount of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof wherein the method provides improvement in one or more symptoms of the tuberous sclerosis complex.

24. The method of claim 23, wherein the patient is administered from about 0.01 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

25. The method of claim 23, wherein the patient is administered from about 15 mg to about 200 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

26. The method of claim 23, wherein the phenylethylidenehydrazine or a pharmaceutically

acceptable salt thereof is administered in a pharmaceutical composition.

27. The method of claim 23, wherein the in vivo plasma profile of the patient 12 hours after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is reduced by more than 50% and the method provides improvement in symptoms of tuberous sclerosis complex in the patient a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

28. The method of claim 23, wherein the method provides improvement in at least one symptom selected from the group consisting of autism, seizures, hyperactivity, cognitive problems impairment and gelastic seizures.

29. The method of claim 23, wherein a pharmaceutical composition containing from about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is administered to the patient.

30. The method of claim 23, wherein the phenylethylidenehydrazine is (E)

phenylethylidenehydrazine.

31. The method of claim 23, wherein the phenylethylidenehydrazine is (Z)

phenylethylidenehydrazine.

32. The method of claim 23, wherein the phenylethylidenehydrazine is racemic

phenylethylidenehydrazine.

33. A method of treating Tourette syndrome comprising administering to a patient in need

thereof a therapeutically effective amount of phenylethylidenehydrazine or a

pharmaceutically acceptable salt thereof wherein the method provides improvement in one or more symptoms of the Tourette syndrome.

34. The method of claim 33, wherein the patient is administered from about 0.01 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

35. The method of claim 33, wherein the patient is administered from about 15 mg to about 200 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

36. The method of claim 33, wherein the phenylethylidenehydrazine or a pharmaceutically

acceptable salt thereof is administered in a pharmaceutical composition.

37. The method of claim 33, wherein the in vivo plasma profile of the patient 12 hours after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is reduced by more than 50% and the method provides improvement in symptoms of Tourette syndrome in the patient a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

38. The method of claim 33, wherein the method provides improvement in at least one symptom selected from the group consisting of eye blinking, throat clearing, grunting, facial grimacing, shoulder shrugging, head or shoulder jerking, self-punching, and vocal tics.

39. The method of claim 33, wherein a pharmaceutical composition containing from about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is administered to the patient.

40. The method of claim 33, wherein the phenylethylidenehydrazine is (E)

phenylethylidenehydrazine.

41. The method of claim 33, wherein the phenylethylidenehydrazine is (Z)

phenylethylidenehydrazine.

42. The method of claim 33, wherein the phenylethylidenehydrazine is racemic

phenylethylidenehydrazine.

43. A method of treating binge eating disorder comprising administering to a patient in need thereof a therapeutically effective amount of phenylethylidenehydrazine or a

pharmaceutically acceptable salt thereof wherein the method provides improvement in one or more symptoms of the binge eating disorder.

44. The method of claim 43, wherein the patient is administered from about 0.01 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

45. The method of claim 43, wherein the patient is administered from about 15 mg to about 200 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

46. The method of claim 43, wherein the phenylethylidenehydrazine or a pharmaceutically

acceptable salt thereof is administered in a pharmaceutical composition.

47. The method of claim 43, wherein the in vivo plasma profile of the patient 12 hours after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is reduced by more than 50% and the method provides improvement in symptoms of binge eating disorder in the patient a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

48. The method of claim 43, wherein the method provides improvement in at least one symptom selected from the group consisting of eating unusually large amounts of food in a specific amount of time, eating even when full or not hungry, eating quickly during binge episodes, eating until uncomfortably full, eating alone or in secret, feeling distressed, ashamed, or guilty about eating, and frequently dieting.

49. The method of claim 43, wherein a pharmaceutical composition containing from about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is administered to the patient.

50. The method of claim 43, wherein the phenylethylidenehydrazine is (E)

phenylethylidenehydrazine.

51. The method of claim 43, wherein the phenylethylidenehydrazine is (Z)

phenylethylidenehydrazine.

52. The method of claim 43, wherein the phenylethylidenehydrazine is racemic

phenylethylidenehydrazine.

53. A method of treating addiction comprising administering to a patient in need thereof a therapeutically effective amount of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof wherein the method provides improvement in one or more symptoms of the addiction.

54. The method of claim 53, wherein the patient is administered from about 0.01 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

55. The method of claim 53, wherein the patient is administered from about 15 mg to about 200 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

56. The method of claim 53, wherein the phenylethylidenehydrazine or a pharmaceutically

acceptable salt thereof is administered in a pharmaceutical composition.

57. The method of claim 53, wherein the in vivo plasma profile of the patient 12 hours after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is reduced by more than 50% and the method provides improvement in symptoms of addiction in the patient a day after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

58. The method of claim 53, wherein the method provides improvement in at least one symptom selected from the group consisting of compulsive engagement in rewarding stimuli despite adverse consequences, impaired control over substances or behavior, preoccupation with substance or behavior, continued use despite consequences, cravings, and need for immediate gratification.

59. The method of claim 53, wherein the addiction is selected from the group consisting of

alcoholism, amphetamine addiction, cocaine addiction, nicotine addiction, opiate addiction, benzodiazepine addiction, food addiction, gambling addiction, and sexual addiction.

60. The method of claim 53, wherein a pharmaceutical composition containing from about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is administered to the patient.

61. The method of claim 53, wherein the phenylethylidenehydrazine is (E)

phenylethylidenehydrazine.

62. The method of claim 53, wherein the phenylethylidenehydrazine is (Z)

phenylethylidenehydrazine.

63. The method of claim 53, wherein the phenylethylidenehydrazine is racemic

phenylethylidenehydrazine.

64. A method of treating obsessive-compulsive disorder comprising administering to a patient in need thereof a therapeutically effective amount of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof wherein the method provides improvement in one or more symptoms of the obsessive-compulsive disorder.

65. The method of claim 64, wherein the patient is administered from about 0.01 mg to about 500 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

66. The method of claim 64, wherein the patient is administered from about 15 mg to about 200 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

67. The method of claim 64, wherein the phenylethylidenehydrazine or a pharmaceutically

acceptable salt thereof is administered in a pharmaceutical composition.

68. The method of claim 64, wherein the in vivo plasma profile of the patient 12 hours after administration of the phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is reduced by more than 50% and the method provides improvement in symptoms of obsessive-compulsive disorder in the patient a day after administration of the

phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof.

69. The method of claim 64, wherein the method provides improvement in at least one symptom selected from the group consisting of uncontrollable, reoccurring thoughts and repetitive behaviors.

70. The method of claim 64, wherein a pharmaceutical composition containing from about 5 mg to about 50 mg of phenylethylidenehydrazine or a pharmaceutically acceptable salt thereof is administered to the patient.

71. The method of claim 64, wherein the phenylethylidenehydrazine is (E)

phenylethylidenehydrazine.

72. The method of claim 64, wherein the phenylethylidenehydrazine is (Z)

phenylethylidenehydrazine.

73. The method of claim 64, wherein the phenylethylidenehydrazine is racemic

phenylethylidenehydrazine.